antimicrobial treatment guidelines for common …...antimicrobial treatment guidelines for common...

Antimicrobial Treatment

Guidelines for Common

Infections

March 2019

Published by: The NB Provincial Health Authorities Anti-infective Stewardship Committeeunder the direction of the Drugs and Therapeutics Committee

Introduction:

These clinical guidelines have been developed or endorsed by the NB Provincial Health Authorities Anti-infective Stewardship Committee and its Working Group, a sub-committee of the New Brunswick Drugs and Therapeutics Committee. Local antibiotic resistance patterns and input from local infectious disease specialists, medical microbiologists, pharmacists and other physician specialists were considered in their development. These guidelines provide general recommendations for appropriate antibiotic use in specific infectious diseases and are not a substitute for clinical judgment.

Website Links For Horizon Physicians and Staff:

http://skyline/patientcare/antimicrobial

For Vitalité Physicians and Staff:

http://boulevard/FR/patientcare/antimicrobial

To contact us: [email protected]

When prescribing antimicrobials:

Carefully consider if an antimicrobial is truly warranted in the given clinical situation Consult local antibiograms when selecting empiric therapyInclude a documented indication, appropriate dose, route and the planned duration of

therapy in all antimicrobial drug ordersObtain microbiological cultures before the administration of antibiotics (when possible)Reassess therapy after 24-72 hours to determine if antibiotic therapy is still warranted

or effective for the given organism or clinical situation. Reassess based on relevantclinical data, microbiologic and/or radiographic information

Assess for de-escalation as appropriate based on available microbiology culture andsusceptibility results

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Antimicrobial Treatment Guidelines For Common Infections

(Click arrow buttons to navigate)

Section 1: Anatomical Page Foot Diabetic Foot Infections 4

Gastrointestinal Clostridium difficile Infection 5 Intra-Abdominal Infections 7

Respiratory Acute Bacterial Rhinosinusitis 9 Acute Exacerbation of Chronic Obstructive Pulmonary Disease 10 Community Acquired Pneumonia 11 Hospital Acquired Pneumonia 13 Ventilator Acquired Pneumonia 15

Skin and Soft Tissue Cellulitis/Erysipelas 17

Genitourinary When to Send a Urine for Culture and Urinalysis 18

Positive Urine Culture Assessment Algorithm 19 Urinary Tract Infection Treatment Guideline 20

Drug Use Guidelines Aminoglycoside Dosing and Monitoring Guidelines 21 Antimicrobial Dosing Tool 37 Management of Penicillin and β-Lactam Allergy 49 Antimicrobial Allergy Evaluation Tool 58 IV-to-PO Conversion Criteria 64Surgical Prophylaxis Guidelines 65 Vancomycin Dosing and Monitoring Guidelines 84

Other Splenectomy Vaccination Kit 91

References 98

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EMPIRIC ANTIMICROBIAL THERAPY FOR DIABETIC FOOT INFECTION (Endorsed by NB Health Authorities Anti-Infective Stewardship Committee February 2016)

Infection Severity Preferred Empiric Regimens1 Alternative Regimens1 Comments Mild • Cellulitis less than 2 cm

and without involvement ofdeeper tissues

• Non-limb threatening• No signs of systemic toxicity

Wound less than 4 weeks duration • cephalexin 500 mg PO four times daily*Wound greater than 4 weeks duration • sulfamethoxazole/trimethoprim 800/160 mg PO twice daily* +

metroNIDAZOLE 500 mg PO twice daily

Wound less than 4 weeks duration • clindamycin 300 – 450 mg PO four times daily (only if

severe β-lactam allergy)Wound greater than 4 weeks duration • amoxicillin/clavulanate 875/125mg PO twice daily* OR• doxycycline 100 mg PO twice daily + metroNIDAZOLE

500 mg PO twice daily

• Outpatient management recommended

• Tailor regimen based on C&Sresults & patient response

Moderate • Cellulitis greater than 2

cm or involvement of deeper tissues

• Non-limb threatening• No signs of systemic toxicity

Wound less than 4 weeks duration • ceFAZolin 2 g IV q8h* OR• cefTRIAXone 2 g IV once daily (to facilitate outpatient management when

ambulatory administration of ceFAZolin not possible)Wound greater than 4 weeks duration • ceFAZolin 2 g IV q8h* + metroNIDAZOLE 500 mg PO twice daily OR• cefTRIAXone 2 g IV once daily + metroNIDAZOLE 500 mg PO twice daily

(to facilitate outpatient management when ambulatory administration of ceFAZolin not possible)

Wound less than 4 weeks duration • levofloxacin 750mg IV/PO once daily* (only if severe

β-lactam allergy)Wound greater than 4 weeks duration • levofloxacin 750mg IV/PO once daily* +

metroNIDAZOLE 500 mg PO twice daily (only if severe β-lactam allergy)

• Initial management with outpatient parenteral therapy with rapid step-down to oral therapy after 48 to 72 hours based on patient response recommended


Severe • Systemic signs of sepsis• Limb or foot threatening• Extensive soft tissue

involvement• Pulseless foot

• piperacillin-tazobactam 3.375 g IV q6h* • imipenem/cilastatin 500 mg IV q6h* OR• levofloxacin 750 mg IV once daily* + metroNIDAZOLE

500 mg PO/IV twice daily (only if severe β-lactam allergy)

• Inpatient management recommended

• Urgent vascular assessment if pulseless foot


Clinical Pearls: 1 If high risk for MRSA, should include sulfamethoxazole/

trimethoprim 800/160 mg PO twice daily * or doxycycline 100 mg PO twice daily for mild infections and vancomycin weight- based dosing to a target trough of 15 – 20 mg/L for moderate- severe infections

• Debridement, good glycemic control and proper wound care are important for the management of diabetic foot infections

• Cultures: prefer tissue specimens post-debridement and cleansing of wound; surface or wound drainage swabs not recommended

• In a clinically infected wound a positive probe-to-bone (PTB)test is highly suggestive of osteomyelitis

• Imaging: recommend plain radiography (radionuclide imaging unnecessary)

Duration of Therapy • Soft tissue only – 2 weeks• Bone involvement with complete surgical resection of all infected bone – 2 weeks• Bone involvement with incomplete surgical debridement of infected bone – 4-6 weeks IV• Bone involvement with no surgical debridement or residual dead bone postoperatively – 6 weeks IV, followed by 6 weeks PO

References: 1. Bowering K, Embil JM. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in

Canada: Foot Care. Can J Diabetes 37(2013) S145-S1492. Lipsky BA, Berendt AR, Cornia PB et al. 2012 Infectious Disease Society of America Clinical Practice Guidelines for the Diagnosis and Treatment

of Diabetic Foot Infections. CID 2012:54(12):132-1733. Lipsky BA, Armstrong DG, Citron DM et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective,

randomized, controlled, double-blinded, multicentre trial. Lancet 2005; 366:1695 – 17034. Blond-Hill E, Fryters S. Bugs & Drugs An Antimicrobial/Infectious Diseases Reference. 2012. Alberta Health Services

* Dose adjustment required in renal impairment

9782-10650-04-2016

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Patient with 3 or more unformed or watery stools in 24 hours(NOT clearly attributable to underlying conditions or laxative use)

Results pending but high clinical suspicion

Send stool for Clostridioides difficile testing

Colonoscopic or histopathologic findings of pseudomembranous colitis

Positive Clostridioidesdifficile testing results

Discontinue therapy with the inciting antimicrobial agent if possible

o If discontinuation of antimicrobials is not possible, de-escalate therapy to narrowest effective spectrum of activity Begin infection control precautions

o Accommodate patient in a private room (if possible)o Gowns and gloves (masks unnecessary)o Perform hand hygiene with soap and water at point of care; if not available, use alcohol hand sanitizer at point of care

followed immediately with soap and water at the nearest clean sink (alcohol hand sanitizer does NOT effectively removeClostridioides difficile spores)

Stop all anti-peristaltic and pro-motility agents1 unless clearly indicated

Treat according to severity of CDI (see below)

Mild-to-moderate CDICriteria: WBC lower than 15 x109/L AND serum creatinine less than 1.5 x baseline

level2

Severe CDICriteria: WBC greater than or equal to 15 x109/L OR serum creatinine greater than

1.5 x baseline level2

Fulminant CDICriteria: Hypotension/shock OR ileus OR

megacolon

Initial episodeVancomycin 125 mg PO q6h

x 10 days3

If the patient is otherwise healthy and ambulatory, OR cannot access oral vancomycin or fidaxomicin due to

prohibitive cost, may consider:

metroNIDAZOLE 500 mg PO q8hx 10 days3

If contraindication to, treatment failure

6 of or intolerance to oral

vancomycin:

Fidaxomicin 200 mg PO q12h x 10 days

Initial episodeVancomycin 125 mg PO q6h

x 10 days3



vancomycin:

Fidaxomicin 200 mg PO q12h x 10 days

ANY episodeVancomycin 500 mg PO/NG q6h x 10

days3 PLUS metroNIDAZOLE 500 mg IV q8h4



vancomycin:Fidaxomicin 200 mg PO q12h

PLUS metroNIDAZOLE 500 mg IV q8h4

If ileus or vomiting, ADD vancomycin 500 mg in 100 mL NS retention enema

q6h5

Antimicrobial Therapy for Clostridioides difficile Infection (CDI) (formerly Clostridium difficile)

NB Provincial Health Authorities Anti-Infective Stewardship Committee, March 2019

5

Recurrent CDIDefinition: Recurrence of CDI within 8 weeks following the onset of a successfully treated previous episode.

First recurrence: Vancomycin 125 mg PO q6h x 14 days OR May consider: Vancomycin Taper-Pulse regimen [Vancomycin 125 mg PO q6h x 14 days, then 125 mg PO q12h x 7 days, then 125 mg

PO q24h x 7 days, then 125 mg PO q48h x 21 days, then 125 mg PO q72h x 21 days, then STOP] OR If contraindication to, treatment failure6 of or intolerance to oral vancomycin: Fidaxomicin 200 mg PO q12h x 10 days

Second recurrence: Vancomycin Taper-Pulse Regimen [Vancomycin 125 mg PO q6h x 14 days, then 125 mg PO q12h x 7 days, then 125 mg PO q24h x 7

days, then 125 mg PO q48h x 21 days, then 125 mg PO q72h x 21 days, then STOP] OR Fidaxomicin 200 mg PO q12h x 10 days Consider fecal microbiota transplant (FMT) for patients who have recurred after receiving treatment with a vancomycin taper-pulse

regimen; consult ID specialist or medical-microbiologist

Third or more recurrence: Initiate vancomycin 125 mg PO q6h and consult an infectious diseases specialist or medical-microbiologist

Note: Re-treatment with fidaxomicin will only be considered for a relapse occurring within 8 weeks of the completion of the most recent

fidaxomicin course CDI occurring beyond 8 weeks after the completion of the most recent fidaxomicin course will require a trial with vancomycin, unless

there is a documented allergy, severe adverse reaction or intolerance to prior oral vancomycin use

Clinical Pearls

Consider urgent surgical consultation in patients with fulminant CDI who have rising WBC and lactate levels despiteappropriate therapy.

Avoid the use of metroNIDAZOLE in pregnant or breastfeeding women Vancomycin administered intravenously is ineffective for the treatment of CDI DO NOT test asymptomatic patients (i.e. test of cure); at least 60% of successfully treated patients will continue to test CDI

positive, but do not require therapy if they are asymptomatic Empiric treatment of suspected recurrent CDI without sending confirmatory testing is discouraged – while up to 30% of

patients will have a recurrent episode after first diagnosis of CDI, altered bowel habits with recurrent diarrhea is commonand up to 35% test negative for CDI

The best method to prevent CDI is to minimize the frequency and duration of exposure to high risk antibiotics (such asclindamycin, fluoroquinolones, 3rd and 4th generation cephalosporins, and carbapenems)

The use of proton pump inhibitors (PPIs) has been associated with CDI, and may increase the risk of recurrent CDI.Evaluate appropriateness of PPI therapy, and discontinue PPI if inappropriately used

1 Examples: loperamide, diphenoxylate, opioids, metoclopramide, domperidone, etc.2 In patients where the baseline creatinine level is unavailable, use an absolute serum creatinine level of 135 mmol/L as a breakpoint.3 Consider extending treatment duration to 14 days if clinically improving but without symptom resolution by 10 days of therapy.4 Continue add-on IV metroNIDAZOLE until the patient is no longer critically ill (usually 5-7 days)5 In normal circumstances, vancomycin is not absorbed via the GI tract; however, in fulminant CDI, intestinal epithelial integrity may be disrupted, and could lead to systemic drug absorption. Consider monitoring serum vancomycin levels in patients with fulminant CDI who are receiving high dose vancomycin (500 mg q6h) via the oral and rectal routes concomitantly to rule out drug accumulation.6 Vancomycin treatment failure: defined as 7 days of vancomycin therapy without acceptable clinical improvement and without other identified cause of persistent diarrhea

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Antimicrobial Therapy for Intra-Abdominal Infections (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2018 Origin/Severity of Intra-

Abdominal Infection Probable

Pathogens Preferred Empiric

Regimens Alternative Empiric

Regimens Comments Community Acquired Infection, Mild to Moderate severity: • i.e. gastroduodenalperforation, cholangitisa,cholecystitisa, appendicitis,diverticulitisb, primary(spontaneous) bacterialperitonitis• With no evidence of systemictoxicity (APACHE II score less than 15)

Core: Enterobacteriaceae (i.e. E.coli, Klebsiella spp, Proteus spp, Enterobacter spp.) Anaerobes (i.e. B. fragilis, Clostridium spp. etc…), Streptococcus spp, ± Enterococcus spp (see below if isolated)

cefuroxime 1.5 g IV q8h f,* + metroNIDAZOLE 500 mg IV/PO q12ha,b

Intravenous-to-Oral Conversionc: amoxicillin/clavulanate 875/125 mg po q12hg,*

OR cefuroxime axetil 500 mg PO q8hf,*

+ metroNIDAZOLE 500 mg POq12h

ciprofloxacin 400 mg IV OR 500 mg PO q12h* + metroNIDAZOLE 500 mg IV/PO q12h

OR aminoglycoside (tobramycin OR gentamicin) 5 – 7 mg/kg IV q24h* + metroNIDAZOLE 500 mg IV/PO q12h

OR

cefOXitin 2 g IV q6hg,*

Duration of Therapy: • 5 – 7 days if optimal source

control obtained• Day of source control intervention

(drainage, surgery, etc.) considered as day 1 of therapy

• If intra-abdominal abscess notresolved after optimal drainage,or if drainage not feasible:antimicrobial therapy may beprolonged, with durationdependant on radiologicalresolution (up to 4 to 6 weeks)

Stop antimicrobial within 24 hours if: • acute stomach, duodenum &/or

proximal jejunum perforation, if noacid-reducing therapy ormalignancy; and source controlachieved OR

• penetrating bowel trauma repairedwithin 12 hours OR

• intraoperative contamination of asurgical field from enteric contentsOR

• acute appendicitis withoutperforation, abscess or localperitonitis OR

• patients undergoingcholecystectomy for acutecholecystitis unless evidence ofinfection outside wall of thegallbladder (ex. perforation)

Community Acquired Infection, Severe: • As above with APACHE IIscore greater than or equal to15, signs of systemic toxicity,greater than 70 years old,immunocompromised,secondary peritonitis, cancer,poor nutritional status orincomplete or delayed sourcecontrol

Core (see above)

cefTRIAXone 2 g IV q24hf + metroNIDAZOLE 500 mg IV/PO q12h

Intravenous-to-Oral Conversionc: As for mild to moderate above

piperacillin/tazobactam 3.375 g IV q6hd,e,g,*

OR levoFLOXacin 750 mg IV q24h* + metroNIDAZOLE 500 mg IV q12h

OR

ampicillin 2 g IV q6hg,* + aminoglycoside (tobramycin OR gentamicin) 5 – 7 mg/kg IV q24h* + metroNIDAZOLE 500 mg IV q12h

Healthcare Associated • Hospitalized greater than 48hours at time of onset, recentprolonged hospitalization,post-operative infection, longterm care, rehab, dialysis,nursing home, recentantibiotics

Core Plus: Pseudomonas, Multidrug Resistant (MDR) Gram negative bacteria, S aureus

piperacillin/tazobactam 4.5 g IV q6hd,e,g,*

meropenem 500 mg IV q6he,f,*

(preferred if suspected MDR Gram-negative)

OR

ciprofloxacin 400 mg IV q8h* + metroNIDAZOLE 500 mg IV q12h + vancomycin 15 mg /kg IV q12hf,*

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Origin/Severity of Intra-Abdominal Infection

Probable Pathogens

Preferred Directed Regimens

Alternative Directed Regimens Comments

If MRSA suspected or isolated

(colonized or history of MRSA infection)

Add vancomycin 15 mg/kg IV q8-12h* (for target trough of 15 – 20 mg/L)

If Candida isolated Add fluconazole 800 mg IV/PO then 400 mg IV/PO q24h* micafungin 100 mg IV q24h

• micafungin preferred if Candida krusei orCandida glabrata isolated

If Enterococci isolated

If Enterococcus faecalis isolated: Add ampicillin 2 g IV q6hg,*(not required if on piperacillin/tazobactam or imipenem-cilastatin)

If Enterococcus faecium isolated: Add vancomycin 15 mg/kg IV q12h* (for target trough of 10 – 20 mg/L)

Immediate (IgE-mediated) penicillin allergy or penicillin resistant: vancomycin 15 mg/kg IV q12h* (for target trough of 10 – 20 mg/L)

• Enterococcal coverage only necessary if: isolated as predominant organism in

culture OR healthcare associated infection OR patient is immunocompromised OR Blood culture positive

• If vancomycin resistant Entrococcus (VRE)is isolated, treatment options include linezolidh or DAPTOmycinh.

Clinical Pearls: • Antimicrobial therapy does not preclude source control (ex. percutaneous drainage or surgery)• Patients with recent prolonged hospitalization (5 or more days) or recent antimicrobials (2 or more days) within the previous 3 months pose risk for resistance and

treatment failure, treat as healthcare associated• Empiric Enterococci coverage is not recommended for mild-moderate severity community-acquired intra-abdominal infections. It should be reserved for patients in

whom this pathogen is more frequently found (healthcare-associated infections, particularly those with postoperative infection, presence of severeimmunosuppression, recurrent infection, patients who receive long-term cephalosporin treatment, and those with valvular heart disease or prosthetic intravascularmaterials)

• CAUTION: Significant E.coli resistance (greater than 20%) to fluoroquinolones and amoxicillin exist in some areas of the province; check local antibiogram andconfirm C&S results when available

• Pathogen directed therapy should be used when culture and susceptibility results are availableWorkup:• Recommend blood, intraoperative and/or abscess fluid cultures in patients with post-operative or healthcare-associated infections; those with treatment failure and/or

requiring re-operation; or recently on antimicrobial therapy• Blood cultures recommended if patient has sepsis syndrome• Reassess initial empiric therapy based on clinical state & results of microbiological analysisa Anaerobic coverage not indicated for cholecystitis & cholangitis unless biliary-enteric anastomosis is present or aggravating factors (advanced age, immunosuppression

or metabolic instability) b Most cases of diverticulitis can be managed with oral antibiotic therapy c Intravenous-to-Oral conversion: consider if infection well controlled, afebrile x 24 hrs., hemodynamically stable, tolerating oral intake and no clinical, radiographic or

surgical sign of intra-abdominal collection from non-optimal drainage d For Pseudomonas aeruginosa infection, piperacillin/tazobactam dosage may be increased to 4.5 gm IV q6h e Anaerobic coverage adequate, addition of metroNIDAZOLE or clindamycin to piperacillin/tazobactam or meropenem not necessary f Appropriate therapy option for patients with an immediate Type-1 (IgE-mediated) hypersensitivity reaction to penicillin (i.e. anaphylaxis, angioedema, laryngeal edema, urticaria) g Avoid in patients with immediate Type-1 (IgE-mediated) hypsensitivity reaction to penicillin, significant risk of cross-reactivity exists. hDiscussion with an Infectious Disease or Microbiology specialist or Internal Medicine Specialist with expertise in infectious disease is required. *Dose adjustment required in renal impairment

8

Antimicrobial Therapy for Acute Uncomplicated Bacterial Rhinosinusitis (ABRS) (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2018) Treatment Criteria Cardinal features of acute rhinosinusitis: Purulent nasal drainage accompanied by nasal obstruction, facial pain-pressure-fullness, or both lasting less than 4 weeks Clinical diagnosis and differentiation of acute bacterial from viral rhinosinusitis is based on the characteristic patterns of clinical presentations taking into account duration

of symptoms, severity of illness, temporal progression and “double-sickening” in the clinical course The following clinical presentations (any of the 3) are recommended for identifying patients with acute bacterial vs. viral rhinosinusitis:

1. Onset with persistent symptoms or signs compatible with acute rhinosinusitis, lasting for greater than or equal to 10 days without any evidence of clinical improvement2. Onset with severe symptoms or signs of high fever (greater than or equal to 39 °C) and purulent nasal discharge or facial pain lasting for at least 3 to 4 consecutive days at the beginning of illness3. Onset with worsening symptoms or signs characterized by the new onset of fever, headache or increased in nasal discharge following a typical viral upper respiratory infection that lasted 5 – 6 days and

were initially improving (“double sickening”) Caution: These guideline recommendations are not intended for patients with complicating factors such as immune deficiency or uncontrolled diabetes; watchful

waiting should not be used for patients with complicating factors and they should be started promptly on appropriate antimicrobial therapy

Presentation Preferred Empiric Regimen Alternative Empiric Regimen Duration Comments

Mild – Moderate Symptoms less than 10 days

duration

Symptomatic therapy only Consider intranasal saline irrigation

• with or without intranasal corticosteroids and/oranalgesics (acetaminophen or ibuprofen)

Mild – Moderate Symptoms greater than 10 days OR worsening after 5 to 6 days OR Severe Symptoms for 3 to 4 consecutive days

doxycycline 100 mg po q12h OR

May offer watchful waiting along with agents for symptom relief if mild symptoms and follow-up can be completed such that antimicrobial therapy is started if condition fails to improve by day 7 after diagnosis of ABRS or worsens at any time.

amoxicillin 1000 mg po q8h* OR

amoxicillin/clavulanate 875/125 mg po q12h* OR

sulfamethoxazole/trimethoprim 800/160 mg po q12h*

5 – 7 days

• May recommend analgesics (acetaminophen oribuprofen), topical intranasal corticosteroids and/ornasal saline irrigation for symptomatic relief

• If a patient has been on antibiotic therapy in the pastmonth the antimicrobial therapy chosen should bebased on a different mechanism of action regardlessof the clinical success

Failure of Initial Therapy Symptoms worsening after 48 – 72 hrs. or failure to improve after 3 – 5 days of initial empiric antimicrobial therapy

amoxicillin/clavulanate 875/125 mg po q12h* + amoxicillin 1000 mg po q12h* (high-dose amoxicillin with clavulanate)

levoFLOXacin 750 mg po q24h* OR cefuroxime 500 mg po q8-12h*

• May recommend analgesics (acetaminophen oribuprofen), topical intranasal corticosteroids and/ornasal saline irrigation for symptomatic relief

• Patients who fail to respond should be assessed forpossible causes including infection with resistantorganism, inadequate dosing and noninfectiouscause

• Select an agent with broader spectrum of activityand from a different antimicrobial class

Clinical Pearls • Facial pain-pressure-fullness without purulent nasal discharge is not sufficient for a diagnosis of acute uncomplicated bacterial rhinosinusitis• Majority of cases of acute sinusitis are viral and resolve within 5 to 7 days without the need for antibiotics; only 0.5 – 2% of viral upper respiratory infections are complicated by bacterial

infection• Colour of nasal discharge or sputum is related to the presence of neutrophils, not bacteria, and should not be used alone to diagnose bacterial rhinosinusitis• Watchful waiting should be excluded in patients with immune deficiency or coexisting bacterial illness; prescribers should also consider the patient’s age, general health, cardiopulmonary

status and comorbid conditions when assessing suitability for watchful waiting• Macrolides are not recommended for empiric therapy due to growing resistance rates for Streptococcus pneumoniae and Haemophilus influenzae within the Province• Respiratory fluoroquinolones (e.g. levoFLOXacin, moxifloxacin) should be reserved for failure of first-line options due to the potential for increasing resistance, risk of Clostridium difficile

infection and their importance in the management of other infections• Respiratory fluoroquinolones (e.g. levoFLOXacin, moxifloxacin) have not been found to be superior to β-lactams in the management of ABRS• Antibiotics have not been shown to be beneficial in chronic rhinosinusitis without acute clinical deterioration• Consider ID consultation for refractory nosocomial rhinosinusitis or if immunocompromised • Decongestants (topical or oral) and/or antihistamines are not recommended as adjunctive therapy• Bacteriology of ABRS: S. pneumoniae, H. influenzae, Moraxella catarrhalis and S. aureus (less than 10%)

*Dose adjustment required in renal impairment9

Antimicrobial Therapy for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (NB Provincial Health Authorities Anti-Infective Stewardship Committee, November 2015) Treatment Criteria The use of antibiotics in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is controversial Antimicrobial therapy is only recommended when AECOPD are accompanied by all 3 cardinal symptoms or at least 2 of the 3 cardinal symptoms, if increased sputum purulence is one

of the 2 symptoms:1. Increased dyspnea2. Increased sputum volume3. Increased sputum purulence

Patients receiving invasive or non-invasive ventilation for AECOPD should be initiated on intravenous antimicrobial therapy Antibiotic selection should be based on patient symptoms and risk factors If infiltrate on chest x-ray or pneumonia suspected then treat as per pneumonia treatment guidelines

Risk Stratification Probable Organism

Preferred Empiric Regimen

Alternative Empiric Regimens Duration Comments

Acute Bronchitis • patients presenting with only 1 of

the 3 cardinal symptoms

Viral in most cases Antimicrobial therapy not recommended Symptomatic therapy only

Simple (Low-Risk Patients) • Less than 4 exacerbations per year

Streptococcus pneumoniae Haemophilus

influenzae Moraxella catarrhalis

doxycycline 100 mg po q12h amoxicillin/clavulanate 875/125 mg po q12h* OR sulfamethoxazole/trimethoprim 800/160 mg po q12h* OR cefuroxime 500 mg po q12h* OR clarithromycin 500 mg po q12h

5 days

• If a patient has received an antibioticin the last 3 months the therapychosen should be a regimen basedon a different mechanism of actionregardless of the clinical success

• Tailor antibiotic therapy for sputumculture results if available

Complicated (High Risk Patients) At least one of: • Forced expiratory volume in 1

second (FEV1) less than 50%predicted

• Greater than or equal to 4exacerbations per year

• Ischemic heart disease• Use of home oxygen• Chronic steroid use

As in simple plus: Klebsiella spp and other Gram-negatives, Increased probability of beta-lactam resistance

Oral Therapy: amoxicillin/clavulanate 875/125 mg po q12h*

Intravenous Therapy: cefTRIAXone 1-2 g IV q24h

Oral Therapy: cefuroxime 500 mg po q12h* OR clarithromycin 500 mg po q12h* OR levofloxacin 750 mg po q24h*

Intravenous Therapy: levofloxacin 750 mg IV q24h*

5 – 10 days

5 days (for levofloxacin)

• If a patient has received an antibioticin the last 3 months the therapychosen should be a regimen basedon a different mechanism of actionregardless of the clinical success

• Tailor antibiotic therapy for sputumculture results if available

Bronchiectasis/ End-stage Lung Disease

As in simple and complicated plus: Pseudomonas

aeruginosa, Staphylococcus

aureus, MRSA Other non-

fermenting Gram negative bacilli

Oral Therapy: amoxicillin/clavulanate 875/125 mg po q12h* ± ciprofloxacin 500 -750 mg po q12h* (if Pseudomonas aeruginosa is suspected) Intravenous Therapy: cefTRIAXone 1-2 g IV q24h OR piperacillin/tazobactam 4.5 g IV q6h* (if Pseudomonas aeruginosa is suspected)

Oral Therapy: levofloxacin 750 mg po q24h*

Intravenous Therapy: levofloxacin 750 mg IV q24h*

7 – 14 days

• Tailor antibiotic therapy forsputum culture results (past orcurrent)

Clinical Pearls • Macrolides are not recommended as first line empiric therapy due to growing resistance rates for Streptococcus pneumoniae and Haemophilus influenzae• Fluoroquinolones should be reserved for only severe cases, failure of first line options or β-lactam allergy in complicated cases due to the potential for increasing resistance, risk of Clostridium difficile infection

and their importance in the management of other infections• Empiric therapy for atypical organisms (Mycoplasma pneumoniae & Chlamydophilia pneumoniae) not recommended• Consider obtaining cultures if not improving after 72 hours of antimicrobial therapy• Consider systemic corticosteroids for moderate to severe exacerbations of COPD (prednisone 40 mg po once daily for 5 days)• Influenza vaccination and pneumococcal vaccination recommended

*Dose adjustment required in renal impairment10

Antimicrobial Therapy for Adult Community Acquired Pneumonia (CAP)(NB Provincial Health Authorities Anti-Infective Stewardship Committee, May 2018) Treatment Considerations: • Having taken antibiotics within the past 3 months significantly increases the risk of resistant S. pneumoniae. Choose an antibiotic from a different class, regardless of clinical success.• Exclusions: immunosuppression, acute exacerbation of COPD, bronchitis, macro-aspiration, chronic pneumonia syndromeβ, cystic fibrosis, bronchiectasis, or MRSA.Determine severity of pneumonia and assess risk of mortality; calculate DS-CRB65 score by adding one point if any of the following criteria are met:

D History of any of the following comorbid diseases: heart failure, chronic renal disease, chronic liver disease, cerebrovascular disease (or other chronic neurological diseases), or active malignancy

S Oxygen saturation (SpO2) less than 90% on room air C Confusion (new onset) R Respiratory rate greater than or equal to 30 breaths/minute B Systolic blood pressure less than 90 mmHg OR diastolic blood pressure less than or equal to 60 mmHg 65 Age 65 or older

Total

Severity DS-CRB65 Mortality Site of care Empiric Therapy∞ (start antibiotics as soon as possible) Comments

Low 0-1 Less than 1%

Home (unless

hospitalized for reason other than

pneumonia)

amoxicillin 1000 mg PO q8h* OR

doxycycline 100 mg PO q12h If at risk for Gram-negative bacilli or S. aureus (e.g. post-influenza, alcoholism, COPD,

nursing home):

amoxicillin-clavulanate 875/125 mg PO q12h* OR

cefuroxime axetil 500 mg PO q8h* (if true immediate penicillin allergy⌂)

Microbiology Tests: None routinely (unless hospitalized, see below)

- Amoxicillin is the oral beta-lactamthat offers the best coverageagainst S. pneumoniae.

Moderate 2-3 3-9% Hospital

ampicillin 2 g IV q6h* + [doxycycline 100 mg PO q12h OR Macrolide PO (see comments) OR (azithromycin 500 mg IV q24h x 3 days, then STOP)]

If true immediate penicillin allergy▲, OR if at risk for Gram-negative bacilli or S. aureus (e.g. post-influenza, alcoholism, COPD, nursing home):

cefuroxime 1.5 g IV q8h* + [doxycycline 100 mg PO q12h OR Macrolide PO (see comments) OR (azithromycin 500 mg IV q24h x 3 days, then STOP)]

Microbiology Tests: -Blood cultures (2 sets)-Sputum culture-Urine antigen for pneumococcusand legionellosis‡

(Depending on clinical context, consider investigation for atypical pathogens and viruses)

- Macrolide PO: clarithromycin 500 mgPO q12h* OR azithromycin 500 mg POday 1, then 250 mg PO q24h x 4 days- If Legionella strongly suspected,consider levoFLOXacin or azithromycin- Exercise caution if usinglevoFLOXacin or moxifloxacin:association with C. difficile and MRSA

High 4 or higher 15-29%Hospital (consider

ICU)

cefTRIAXone 2 g IV q24h + azithromycin 500 mg IV q24h OR

[levoFLOXacin 750 mg IV/PO q24h* or moxifloxacin 400 mg IV/PO q24h] +/- ampicillin 2 g IV q6h*

(consider adding ampicillin to levofloxacin or moxifloxacin for ICU-based therapy)

Duration of therapy • Treat for a minimum of 5 days, and then until the patient meets all clinical stability criteria (see page 2), then STOP antibiotics.• Longer treatment duration may be required in certain circumstances (e.g. extrapulmonary infections, empyema, infections caused by P. aeruginosa or S. aureus, etc.).

(continued on next page)11

IV to PO conversion (for more information, please refer to the IV-PO conversion policy and criteria) • Consider oral antibiotics when patients are able to tolerate PO medications and meet all the clinical stability criteria listed below:

Clinical stability criteria - community acquired pneumonia

Patient is afebrile (e.g. temperature lower than 38°C) for at least 48 hours Heart rate lower than or equal to 100 beats/minute Respiratory rate lower than or equal to 24 breaths/minute Systolic blood pressure higher than or equal to 90 mmHg Oxygen saturation (SpO2) higher than or equal to 90% on room air (or return to

baseline oxygen level for patients receiving long-term oxygen therapy) Normal mental state (compared to baseline) Patient is able to tolerate oral intake

Parenteral drug Suggested oral step-down

ampicillin amoxicillin (high dose; 1000 mg PO q8h*)

azithromycin azithromycin or clarithromycin

Cephalosporin (any) amoxicillin + clavulanic acid (or cefuroxime axetil if true penicillin allergy)

levoFLOXacin or moxifloxacin +/- ampicillin levoFLOXacin or moxifloxacin alone +/- amoxicillin

Please note: oral monotherapy vs. combined therapy (atypicals) → clinical judgment; see below.

Clinical pearls • Within the first 3 days of therapy, as many as 2/3 of patients will satisfy all clinical stability criteria. The majority of the remaining 1/3 of patients will satisfy all criteria by day 7 of therapy.• In low-risk patients, consider adding doxycycline or a macrolide to a beta-lactam regimen if high clinical suspicion of atypical pathogens (beta-lactams DO NOT cover atypicals).Clinical

features favouring “atypical” bacteria (Mycoplasma or Chlamydophila): gradual onset and presentation, absence of septic shock, non-lobar pneumonia, family cluster, cough persistingmore than 5 days without acute clinical deterioration, absence of sputum production, and normal or minimally elevated white-cell count.

• It is important to note that, although Legionella is defined as an “atypical” pathogen, the presentation is similar to “typical” pathogens (i.e. hyperacute and severe presentation).• Azithromycin dosing and duration of therapy depends on the route of administration and its indication for use: 1) When using 500 mg IV once daily in non-critically ill patients, 3 days of

therapy is adequate; 2) When using the PO formulation, or in patients that are critically ill, 5 days of therapy is adequate; 3) In patients with infections caused by Legionella, 7 to 10 daysof therapy may be required.

• Patients at high risk for pneumonia (e.g. age 65 and older, nursing home residents, COPD, etc.) should receive influenza and pneumococcal vaccines if vaccination not up to date.• While MRSA is rarely associated with CAP in New Brunswick, consider adding vancomycin empirically if severe pneumonia (i.e. DS-CRB65 score of 4 or higher) AND presence of one of

the following MRSA risk factors: history of MRSA infection or colonization, IV drug use, homelessness, member of First Nations community, incarcerated person, or recent travel to anMRSA endemic region.

• Recent literature suggests that corticosteroids could be considered in certain patients with a high inflammatory response due to severe CAP. However, it should be noted that preliminarydata suggests patients with influenza pneumonia may not benefit, and could be harmed by adding corticosteroids.

• Due to potential QTc prolongation, consider baseline ECG if prescribing macrolides or quinolones to certain patients (e.g. other QTc prolonging drugs, electrolyte abnormalities, etc.).*Dose adjustment required in renal impairment‡If antigen is positive for Legionella, efforts must be made to obtain sputum and advise laboratory that Legionella culture is required. This is important for epidemiological purposes in case of an outbreak. ∞If microbial cause of infection known, treat accordingly▲ True, immediate IgE-mediated allergies include, but are not limited to: anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, and pruritis. β Chronic pneumonia syndrome: pneumonia symptoms lasting more than 3 weeks

12

Antimicrobial Treatment of Hospital Acquired Pneumonia (HAP) (New Brunswick Provincial Health Authorities Anti-Infective Stewardship Committee, May 2018) Definition: Pneumonia that develops 48 hours or more after admission to hospital. ***Note: ventilator-associated pneumonia is excluded; please refer to ventilator-associated pneumonia guidelines.*** Probable pathogens: S. aureus (MSSA or MRSA), Gram-negative bacilli (e.g., E. coli, K. pneumoniae, P. aeruginosa), or S. pneumoniae. Microbiological analyses: Blood cultures x 2 sets (always) + sputum culture +/- S pneumoniae urinary antigen

Risk stratification Patient’s condition Empiric therapy∞ Comments

STABLE

First-line cefTRIAXone 2 g IV q24h

If true immediate allergy to a beta-lactam at risk for cross-reactivity with cefTRIAXone▲:

levoFLOXacin 750 mg IV/PO q24h* OR moxifloxacin 400 mg IV/PO q24h

• Consider adding empiric vancomycin (targettrough 15-20 mg/L) in patients with a risk factorfor MRSA:

o History of MRSA infection or colonizationo Injection drug use o Homelessness o Member of First Nations communityo Incarcerated person o Recent travel to an MRSA endemic region

• If history of infection or colonization with Gram-negative bacilli producing AmpC or ESBL beta-lactamases, empiric use of meropenem isencouraged (may consider fluoroquinolones ifstable and no risk factors).

• DO NOT use cefTRIAXone or moxifloxacin ifPseudomonas infection is confirmed orsuspected.

• If the patient received an antibiotic in the past 3months, choose an antibiotic from a differentclass, regardless of clinical success.

• Second anti-pseudomonal agents should befrom another class, and can include:

o tobramycin 7 mg/kg IV q24h*o ciprofloxacin 400 mg IV q8h*

UNSTABLE (or requiring higher

level of care)

First-line piperacillin-tazobactam 4.5 g IV q6h*

If true immediate penicillin allergy▲ meropenem 500 mg IV q6h*

If severe delayed reaction‡ to a beta-lactam: levoFLOXacin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h*

STABLE

First-linepiperacillin-tazobactam 4.5 g IV q6h*

If true immediate penicillin allergy▲ meropenem 500 mg IV q6h*

If severe delayed reaction‡ to a beta-lactam levoFLOXacin 750 mg IV/PO q24h* + tobramycin 7 mg/kg IV q24h*

UNSTABLE (or requiring higher

level of care)

First-linepiperacillin-tazobactam 4.5 g IV q6h* + 2nd anti-pseudomonal agent (+/- vancomycin 25 mg/kg IV x1 dose, then 15 mg/kg IV q8h*; see

comments)

If true immediate penicillin allergy ▲: meropenem 500 mg IV q6h* + 2nd anti-pseudomonal agent

(+/- vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h*; see comments)

If severe delayed reaction‡ to a beta-lactam levoFLOXcin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h* +

vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h*Duration of therapy

• Treat for no more than 7 days if good clinical response, regardless of bacterial etiology.• Treatment duration could be prolonged for more than 7 days in certain situations (e.g., empyema, extrapulmonary infections, S. aureus bacteremia, immunosuppression, etc.)

Risk factors for MDR pathogens or poor outcomes Use of IV antibiotics in past 90

days Immunosuppression Chronic lung disease (e.g.,

bronchiectasis, cystic fibrosis) In intensive care unit (ICU)

when symptoms appear, ortransferred from ICU in last48 hours

If NO risk factors (indicated below)

If presence of at least one risk factor (indicated above)


Clinical Pearls

• Recent studies have shown that, compared with standard treatment durations of 10 days or more, 7-day treatment durations were associated with fewer relapses caused bymultiresistant pathogens WITHOUT affecting mortality rate.

• To avoid prolonged use of broad-spectrum antibiotics, it is essential to de-escalate therapy according to the results of microbiologic analyses.• For patients with HAP requiring intubation, an endotracheal secretions culture is recommended.• Empiric coverage of atypical organisms (e.g., Legionella, Mycoplasma) is generally not recommended. Consider atypical coverage if nosocomial outbreak of Mycoplasma or Legionella.• Empiric double coverage of Pseudomonas aeruginosa is to maximize the likelihood of having at least one active agent (due to increased risk of resistance with Pseudomonas). If

Pseudomonas is isolated, step-down to monotherapy (according to susceptibility data). ***Use of aminoglycosides (e.g., tobramycin and gentamicin) as monotherapy for the treatment ofpneumonia is NOT recommended (even if susceptibility is confirmed).

• DO NOT use DAPTOmycin to treat pneumonia; DAPTOmycin is inactivated by pulmonary surfactant. If MRSA infection, use vancomycin (or linezolid if vancomycin is ineffective orinappropriate).

• Serial procalcitonin levels (if available), in combination with clinical evaluation, may assist in the decision to discontinue antibiotics.* Dose adjustment required in renal impairment.∞ If microbial cause of infection known, treat accordingly.▲ Immediate, IgE mediated allergies include, but are not limited to, anaphylaxis, urticaria, angiœdema, hypotension, bronchospasm, stridor, and pruritic rash. Refer to the

NB-ASC Beta-Lactam Allergy guidelines to determine which beta-lactams share similar side chains.‡ Severe delayed hypersensitivity reactions to beta-lactams are caused by mechanisms that are not well known and require that subsequent use of beta-lactams be avoided.

Severe delayed hypersensitivity reactions can include interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, severe cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS).

14

Antimicrobial Treatment of Ventilator-Associated Pneumonia (VAP) (New Brunswick Provincial Health Authorities Anti-Infective Stewardship Committee, May 2018) Definition: Pneumonia that develops 48 hours or more after endotracheal intubation. Probable pathogens: S. aureus (MRSA or MSSA), gram-negative bacilli (e.g., E. coli, K. pneumoniae, P. aeruginosa, A. baumannii) Microbiological analyses (always order): Blood cultures x 2 sets + endotracheal suctioning for culture

Risk stratification Empiric therapy∞ Comments

First-linepiperacillin-tazobactam 4.5 g IV q6h*

If true immediate penicillin allergy▲: meropenem 500 mg IV q6h*

If severe delayed reaction‡ to a beta-lactam levoFLOXacin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h*

• Consider adding empiric vancomycin (target trough 15-20mg/L) in patients with septic shock requiring vasopressors,or with a risk factor for MRSA:o History of MRSA infection or colonizationo Injection drug use o Homelessness o Member of First Nations communityo Incarcerated person o Recent travel to an MRSA endemic region

• If history of infection or colonization with Gram-negativebacilli producing AmpC or ESBL beta-lactamases, empiricuse of meropenem is encouraged.

• If the patient received an antibiotic in the past 3 months,choose an antibiotic from a different class, regardless ofclinical success.

• Second anti-pseudomonal agents should be fromanother class, and can include:

o tobramycin 7 mg/kg IV q24h*o ciprofloxacin 400 mg IV q8h*

First-linepiperacillin-tazobactam 4.5 g IV q6h* + 2nd anti-pseudomonal agent


If true immediate penicillin allergy▲ meropenem 500 mg IV q6h* + 2nd anti-pseudomonal agent


If severe delayed reaction‡ to a beta-lactam levoFLOXacin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h* +

vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h*

Duration of therapy

• Treat for no more than 7 days if good clinical response, regardless of bacterial etiology.• Treatment duration could be prolonged for more than 7 days in certain situations (e.g., empyema, extrapulmonary infections, S. aureus bacteremia, immunosuppression, etc.)

Risk factors for MDR pathogens or poor outcomes Septic shock requiring vasopressors Use of IV antibiotics in past 90 days Immunosuppression Chronic lung disease (e.g.,

bronchiectasis, cystic fibrosis) Acute renal replacement therapy before

VAP onset Hospitalization for at least 5 days before

VAP onset Acute respiratory distress syndrome

(ARDS) before VAP onset

If NO risk factors (indicated below)

If presence of at least one risk factor (indicated above)


Clinical Pearls

• Recent studies have shown that, compared with standard treatment durations of 10 days or more, 7-day treatment durations were associated with fewer relapses caused bymultiresistant pathogens WITHOUT affecting mortality rate.

• To avoid prolonged use of broad-spectrum antibiotics, it is essential to de-escalate therapy according to the results of microbiologic analyses.• The role of antimicrobials in the treatment of ventilator-associated tracheobronchitis¶ is controversial. Consider initiating antimicrobial therapy if clinical deterioration (e.g. progressive

hypoxemia).• Empiric double coverage of Pseudomonas aeruginosa is to maximize the likelihood of having at least one active agent (due to increased risk of resistance with Pseudomonas). If

Pseudomonas is isolated, step-down to monotherapy (according to susceptibility data). ***Use of aminoglycosides (e.g., tobramycin and gentamicin) as monotherapy for the treatment ofpneumonia is NOT recommended (even if susceptibility is confirmed).

• DO NOT use DAPTOmycin to treat pneumonia; DAPTOmycin is inactivated by pulmonary surfactant. If MRSA infection, use vancomycin (or linezolid if vancomycin is ineffective orinappropriate).

• Serial procalcitonin levels (if available), in combination with clinical evaluation, may assist in the decision to discontinue antibiotics.

* Dose adjustment required in renal impairment.∞ If microbial cause of infection known, treat accordingly.▲ Immediate, IgE mediated allergies include, but are not limited to, anaphylaxis, urticaria, angiœdema, hypotension, bronchospasm, stridor, and pruritic rash.‡ Severe delayed hypersensitivity reactions to beta-lactams are caused by mechanisms that are not well known and require that subsequent use of beta-lactams be avoided.

Severe delayed hypersensitivity reactions can include interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, severe cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS).

¶ Ventilator-associated tracheobronchitis: fever with no other identifiable cause with: significant purulent secretions, positive endotracheal aspirate culture, and ABSENCE of pneumonia on a chest X-ray.

16

Treatment of Cellulitis/Skin Infection(NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

Cellulitis/Erysipelas Severity

Preferred Empiric RegimensDuration of

Therapy Comments

Mild (no signs of systemic toxicity)

- Assess for risk factors1 orclinical evidence of MRSA(e.g. purulent boil withspreading cellulitis, previousMRSA infections orcolonization)

cephalexin 500 - 1000 mg PO q6h2

OR

cefadroxil 500 - 1000 mg PO q12h2,3

True immediate allergy4 to a beta-lactam at risk of cross-reactivity with cephalexin or

cefadroxil: cefuroxime 500 mg PO q8-12h2

Severe delayed reaction5 to a beta-lactam where their future use is not recommended:

clindamycin 300 - 450 mg PO q6h

MRSA Suspected: sulfamethoxazole/trimethoprim 800/160 mg to 1600/320 mg (1 or 2 DS tablets) PO q12h2,6

OR

doxycycline 100 mg PO q12h6

5 days (may extend duration if not improved)

Work-up: None, unless there is an associated fluctuant pustule that can be drained and sent for culture

Moderate(signs of systemic toxicity)

OR

Progression on oral therapy7

ceFAZolin 2 g IV q8h2

Alternative for outpatient management: probenecid 1 g PO followed 30 - 60 min later by ceFAZolin 2 g IV, repeated q24h2

OR

cefTRIAXone 2 g IV q24h

Severe delayed reaction5

where future use of β-lactams not recommended: clindamycin 600-900 mg IV q8h

MRSA suspected, add: vancomycin 25 to 30 mg/kg IV x 1 dose then 15 mg/kg IV q8-12h2

(adjust based on levels to a trough target of 15 - 20 mg/L)

5 days (may extend duration if not improved)

If on IV therapy assess every 48 hours for appropriateness for IV to PO conversion8 (seePO options available under mild severity)

Work-up: As above plus: Consider blood cultures (2 sets)

Severe(sepsis syndrome, Necrotizing Fasciitis [clinical features of NF include systemic toxicity, deep severe pain – more severe than expected for skin findings, violaceous bullae, rapid spread along fascial planes, gas in soft tissues])

ceFAZolin 2 g IV q8h with or without clindamycin 900 mg IV q8h

Risk of mixed bacterial infection: piperacillin-tazobactam 3.375 g IV q6h2 with or without

clindamycin 900 mg IV q8h

MRSA suspected, add: vancomycin 25 to 30 mg/kg IV x 1 dose then 15 mg/kg IV q8-12h2

(adjust based on levels to a trough target of 15 - 20 mg/L)

Consult with specialists

Work-up: As above plus: urgent surgical assessment for diagnostic biopsy and/or debridement

Clinical pearls: These guidelines are for basic skin infections only, any complicating features on history may require alternative management (Specific but not exclusive examples include:

immunocompromised patients, diabetic foot infections, cellulitis associated with a surgical site, trauma or animal/human bites) Consider looking for predisposing feature (e.g. Tinea pedis) as source of cellulitis1 Risk factors for MRSA infection include: known or previous colonization, recent hospitalization, homelessness, injection drug use, member of First Nations community and

incarcerated person 2 Dose adjustment required in renal impairment 3 Non-formulary agent not available within hospital 4 True, immediate IgE-mediated allergies include, but are not limited to: anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, and pruritis.5 Stevens-Johnson syndrome, toxic epidermal necrolysis, immune hepatitis, DRESS, serum sickness, hemolytic anemia or interstitial nephritis6 Poor coverage for beta-hemolytic streptococci, consider combining with cephalexin or cefadroxil 7 Assessment of clinical response within 48 hours should be based on pain and fever; mild progression of erythema expected during this timeframe8 IV to PO conversion appropriate when patient: afebrile, hemodynamically stable, clinically improving, and able to tolerate oral intake (see IV to PO conversion policy for more details)

17

When to Send a Urine for Culture and Urinalysis (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

UTI SymptomsCystitis

• Dysuria • ↑ frequency • ↑ urgency • Suprapubic

pain

Catheter-Associated UTI • Fever• Acute hematuria • Delirium• Rigors• Flank Pain • ± Lower tract symptoms

if catheter removed

Pyelonephritis • Fever• Nausea, vomiting • Costovertebral pain • Flank pain • ± lower tract

symptoms

Cloudy and/or foul smelling urine are NOT symptoms of UTI

Start

Does a non-UTI diagnosis likely account for the

symptoms?

Does the patient have

any UTI symptoms?

Consider empiric antibiotics*

Send urine for culture (if patient catheterised send culture

from new catheter)

Review urine culture results to tailor antibiotic

therapy

Do NOT send urine for culture and/or urinalysis

(Unless pregnant or for urologic procedure where mucosal bleeding

expected)

Work-up other cause for symptoms Yes

No

Yes

No Clinical Pearls • “Changes in cognitive function and declines in activities of

daily living REQUIRE careful clinical assessment. DO NOTassume they are secondary to UTI.” VCH/ASPIRES 2014

• Urine culture and susceptibility and urinalysis testing is NOT necessary orbeneficial in healthy, non-pregnant, premenopausal, non-diabetic women withacute cystitis (at least 2 of 3 cardinal symptoms – dysuria, urgency orfrequency) and NO vaginal discharge without functional or anatomicalabnormalities of the urinary tract.

• Always obtain a culture for: pregnant women; patients with sign and symptomsof pyelonephritis; premenopausal adult females with recurrent cystitis; urologicalprocedure; patients with complicated urinary tract infections (i.e. structuralabnormality, obstruction, recent urologic procedure, male sex,immunosuppression, poorly controlled diabetes, spinal cord injury orcatheterization)

*Refer to NB-ASC UTI Treatment Guideline for antibiotic selection

18

Positive Urine Culture

Catheter-Associated UTI

DefinitionPresence of symptoms with greater than 106 CFU/L of ≥ 1 bacterial species in a single catheter urine specimen or in a midstream voided urine after catheter removal for 48 hours, with a positive urinalysis for pyuria

Possible Signs & Symptoms:New onset or worsening fever, rigors, altered mental status, malaise, or lethargy with no other identified cause; flank pain; costovertebral tenderness; acute hematuria; pelvic discomfort and in those with catheter removed dysuria, urgent or frequent urination or suprapubic pain or tenderness.

· If spinal cord Injury, symptoms may also include increased spasticity, autonomic

dysreflexia OR a sense of unease

Symptomatic Bacteriuria

Cystitis (lower UTI)Dysuria, urgency, frequency, or suprapubic pain with no fever or flank pain; change in cognitive function or activities of daily living REQUIRE careful clinical assessment, never assume these are due to UTI

Pyelonephritis (upper UTI)Fever, flank pain, costovertebral tenderness, abdominal/pelvic pain, nausea,

vomiting with or without signs/symptoms of lower tract UTI

Asymptomatic Bacteriuria

See NB-ASC UTI Treatment Guideline1 for Treatment Options

(Adjust Antimicrobial Therapy According to Urine C&S Results)

Treat according to urine C&S only if

symptoms present (adjust according to C&S

results)

If catheter required, obtain urine culture and urinalysis through new catheter prior

to initiation of antimicrobial therapy OR

If catheter is not required, culture voided midstream urine prior to initiation of

antimicrobial therapy

Was the catheter changed immediately before urine culture

was collected?

YES

NO

Treat according to NB-ASC UTI Treatment Guideline1 if

symptoms present(adjust according to C&S results)

Urological Procedure

(mucosal bleeding expected)

Pregnant

Surgical Prophylaxis2

Do NOT Treat

Treat according to

urine C&S

YESYES

NO

NO

YES

1Treatment of Adult Urinary Tract Infections (NB Health Authorities Anti-Infective Stewardship Committee, May 2014)2Surgical Prophylaxis Guidelines (NB Health Authorities Anti-Infective Stewardship Committee, May 2015)*Urine culture may be contaminated by colonized bacteria.

Positive Urine Culture Assessment Algorithm(NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

19

Treatment of Adult Urinary Tract Infections (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

Indication Empiric Therapy (Tailor regimen based on urine/blood C&S results) Duration Comments

Asymptomatic Bacteriuria

Antibiotic therapy only recommended for: -Prophylaxis for urological procedures when mucosal bleedingexpected-Treatment in pregnancy

(Select antimicrobial therapy according to urine C&S)

Urological procedures: see surgical prophylaxis guideline

Pregnancy: 3 – 7 days

• Asymptomatic bacteriuria with pyuria is NOT an indication for antimicrobial therapyPregnancy • Repeat culture and urinalysis 1 week after therapy complete as a test of cure; if positive repeat

treatment according to urine C&S• Monthly repeat urine cultures recommended for screening until completion of pregnancy• Consider prophylactic/suppressive antibiotic therapy for persistent bacteriuria• Intrapartum prophylaxis of early-onset Group B Streptococcal (GBS) disease is recommended if

GBS is isolated in urine or vaginal swabUncomplicated Cystitis (Lower UTI) (Female patients with dysuria, urgency, frequency, or suprapubic pain with no fever or flank pain)

Preferred Regimen: nitrofurantoin monohydrate/macrocrystals 100 mg PO q12h (Not recommended if CrCl less than 40 mL/min; in pregnancy, avoid near term (36-42 weeks) due to risk of haemolytic anemia in the new born)

Alternative Regimens: cefuroxime 500 mg PO q8h OR fosfomycin 3 g PO once4 OR sulfamethoxazole/trimethoprim 800/160 mg PO q12h1,3 (Not recommended in pregnant women)

5 days

7 days One dose 3 days

Pregnancy • Repeat culture and urinalysis 1 week after therapy complete as a test of cure; if positive repeat

treatment according to urine C&S• Monthly repeat urine cultures recommended for screening until completion of pregnancy• Consider prophylactic/suppressive antibiotic therapy for persistent or recurrent cystitis• Intrapartum prophylaxis of early-onset Group B Streptococcal (GBS) disease is recommended if

GBS is isolated in urine or vaginal swab

Acute Uncomplicated Pyelonephritis (Upper UTI) (Signs/Sx: fever, flank pain, costovertebral tenderness, abdominal/pelvic pain, nausea, vomiting with or without signs/sx of lower tract UTI)

OR

Complicated UTI (Complicating Factors: structural abnormality, obstruction, recent urogenital procedure, male sex, immunosuppression, poorly controlled diabetes, spinal cord injury, catheterization or Signs/Sx greater than 7 days)

Systemically Well: Preferred Regimen: cefixime 400 mg PO q24h3 Alternative Regimens: amoxicillin/clavulanate 875/125 mg PO q12h3

Additional options if culture confirmed susceptibility: sulfamethoxazole/trimethoprim 800/160 mg PO q12h1,3 OR ciprofloxacin 500 mg PO q12h1,3

Systemically Unwell/Pregnant: cefTRIAXone 1 g IV q24h2 OR ampicillin 2 g IV q6h + (tobramycin OR gentamicin) 5 mg/kg IV once daily2,3,5 ORpiperacillin/tazobactam 3.375 g IV q6h2,3

See Comments

Acute Uncomplicated Pyelonephritis • Outpatient management an option if female, not pregnant, no nausea/vomiting, no evidence of

dehydration, sepsis or high fever• Treat for 14 days• May treat for 7 days if female, uncomplicated and using ciprofloxacin• For treatment using oral β-lactams, consider an initial single intravenous dose of cefTRIAXone 1

g IV and use a 14 day total duration of antimicrobial therapy

Complicated UTI: • Treat 7 days if prompt response, female and only lower urinary tract infection• Treat 14 days if male, delayed response, structural abnormality, or upper tract symptoms

Catheter-Associated UTI:• Pyuria not diagnostic, only treat if symptomatic• Catheters frequently colonized, obtain culture through new catheter• Change catheter if in place for greater than 2 weeks & still requiredPregnancy • Treat for 10 to 14 days• Prophylactic/suppressive antibiotic therapy recommended for the remainder of the pregnancy• Repeat culture and urinalysis 1 week after therapy complete as a test of cure; if positive repeat

treatment according to urine C&S• Monthly repeat urine cultures recommended for screening until completion of the pregnancy• Intrapartum prophylaxis of early-onset Group B Streptococcal (GBS) disease is recommended if

GBS is isolated in urine or vaginal swabClinical Pearls: • Cloudy and foul smelling urine alone are NOT considered signs of infection and are NOT an indication for a urine culture and sensitivity• Urinalysis interpretation:

o Presence of nitrites and leukocytes (leukocyte esterase positive or WBC) and new UTI symptoms: good positive predictive value of UTIo Absence of nitrites and/or leukocytes (negative leukocyte esterase or WBC): good negative predictive value

• Therapy should be adjusted according to culture and sensitivity results• Blood cultures should be drawn if febrile, septic, signs and symptoms suggestive of pyelonephritis or immunocompromised• Post-treatment culture not recommended except in case of persistent or recurrent symptoms or pregnancy• nitrofurantoin and fosfomycin are not appropriate for men, complicated UTI or systemic infections1CAUTION: Significant E.coli resistance (greater than 20%) to fluoroquinolones, sulfamethoxazole/trimethoprim and amoxicillin exist in some areas of the province; check local antibiogram and confirm urine C&S

results when available 2De-escalate according to urine/blood C&S and switch IV to PO based on conversion criteria 3Dose adjustment required in renal impairment 4Fosfomycin criteria for use: for multi-drug resistant E.coli or Enterococcus faecalis with limited oral options OR where recommended alternatives are not appropriate due to allergies, drug interactions, poor renal function or other considerations 5Please see aminoglycoside dosing guide for more details on appropriate dosing adjustments and monitoring

20

AMINOGLYCOSIDES DOSING AND MONITORING GUIDELINES

NB Provincial Health Authorities Anti-Infective Stewardship Committee

GENERAL COMMENTS

• Aminoglycosides (AG) include gentamicin, tobramycin, amikacin and streptomycin• AG exert bactericidal activity against gram-negative bacteria• Combination of gentamicin with a cell-wall active agent (i.e. beta-lactam) results in a synergistic

effect on certain gram-positive bacteria such as Enterococci and Streptococci in the treatment ofendocarditis

• Amikacin is generally reserved for infections due to organisms with documented resistance togentamicin and tobramycin; refer to amikacin section for dosing and monitoring information

• Streptomycin is used infrequently to treat drug resistant tuberculosis and nontuberculousmycobacterial infections; its dosage and monitoring are not included in these guidelines

• There are three dosing strategies for AG:o Conventional dosing of AG: weight-based dose administered three times a day, or less

frequently in decreased renal functiono Extended-interval dosing of AG (also called “once daily dosing”): a larger weight-based

dose (approximately triple conventional dosing) administered once a day, or lessfrequently in decreased renal function

o Synergistic dosing for gram-positive infections• AG exhibit concentration-dependent killing: higher serum concentrations result in higher rates and

extent of bacterial killing• AG demonstrate a post-antibiotic effect: suppression of bacterial growth is continued even after

serum concentrations have decreased below the minimum inhibitory concentration (MIC)• AG are nephrotoxic, ototoxic and can produce neuromuscular blockade (in patients with

myasthenia gravis, the use of AG is contraindicated)CLINICAL PEARLS • Use care when selecting the dosing interval in patients that are older and/or with multiple co-

morbidities (ex. diabetes, heart failure, etc.) or where estimated creatinine clearance would beexpected to be an overestimate (ex. low muscle mass in an elderly patient, dysmobility, paraplegia, etc.)

• The provided ranges for estimated creatinine clearance are only intended to be a guide for theselection of an empiric dosing interval and should not be used in isolation without consideringpatient and infection-related factors – especially when estimated creatinine clearance approachesthe either end of the range.

Approved: September 2018

21

GENTAMICIN AND TOBRAMYCIN IN ADULT PATIENTS

ADULT EXTENDED INTERVAL DOSING • Use extended interval dosing whenever possible • Takes advantage of concentration-dependent killing and post-antibiotic effect properties of AG with the goals

of enhancing efficacy with higher peaks and potentially decreasing toxicity with greater drug-free intervals • Extended interval AG dosing should NOT be used in:

o Patients requiring dialysis o Patients with rapid clearance of AG, including burns exceeding 20% of body surface area o Patients with gram-positive infections where AG is used for synergy (i.e. endocarditis)

• Extended interval AG dosing should be used with CAUTION in:o Patients with creatinine clearance (CrCl) less than 20 mL/mino Patients with chronic ascites or serious liver disease (altered volume of distribution)o Patients with known auditory or vestibular disease or pre-existing impairmento Pregnant women

Initial Dose • 5-7 mg/kg IV

o based on ideal body weight or dosing weight (see appendix B)o use 7 mg/kg for serious infections or infections due to Pseudomonas aeruginosa or multidrug

resistant organismso round dose to nearest 20 mg

• An initial dosing interval is chosen based on renal function as per the following table

Creatinine Clearance Dosing Interval greater than or equal to 60 mL/min q24h 40 to 59 mL/min q36h 20 to 39 mL/min q48h; consider conventional dosing less than 20 mL/min Give first dose then draw serial serum drug

levels to determine when to give next dose. Consider conventional dosing.

Levels • Monitoring of trough levels alone is generally sufficient with extended interval dosing• Trough levels verify that AG is being adequately eliminated and is not accumulating• Peak levels are typically NOT required, as the larger doses used are expected to produce concentrations well

above those required for clinical efficacy• Peak levels are done in the rare cases where individualized pharmacokinetic monitoring is requiredTarget serum concentrations: • Trough levels: less than 1 mg/L • Peak levels [only if indicated]: 15-25 mg/L

o Optimal bactericidal activity for AG is achieved when maximum serum concentrations areapproximately 8 to 10 times the MIC

Levels recommended are in: • Treatment anticipated to be longer than 3-5 days• Patients more than 65 years of age• Patients with renal dysfunction (CrCl less than 60 mL/min ) or significant changes in renal function from

baseline• Patients receiving other nephrotoxic drugs (i.e. vancomycin, NSAIDs, diuretics, ACE-I, ARBs, etc.)• Patients with a large volume of distribution (e.g., ascites, third spacing)• Pregnant women

22

Serum sampling: • Trough levels are taken immediately before a dose (within 30 minutes)• Peak levels are taken 90 minutes after the END of drug infusion, to allow for distribution• The timing and duration of drug administration and sample collection must be carefully documentedTiming of serum levels: • The notion of steady state does not apply with extended-interval dosing; therefore levels may be

taken prior to the 2nd doseInterpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time• Trough level result of 1 mg/L or more suggests accumulation; extend dosing intervalHartford Hospital Nomogram (see appendix D): • A random level taken between 8 to 12 hours after the START of drug infusion may be used to

determine appropriate dosing interval using the Hartford Hospital nomogram• Only to be used with a 7 mg/kg dose; has not been validated with other doses

Monitoring and patient counselling Subsequent serum levels: • After a change in dose • At least once a week for most patientsMonitor: • Clinical response• Renal function

o Serum creatinine (SCr) at baseline and every 2 to 3 days during therapyo AG can cause renal dysfunction; typically reversible if discontinued in a timely manner; close

monitoring is warranted• Ototoxicity

o Patients should be advised to watch for and report signs & symptoms of cochlear toxicity (e.g.,tinnitus, sense of fullness in ears, loss of hearing) and of vestibular toxicity (e.g., disequilibrium,oscillopsia, cognitive dysfunction, visual sensitivity, nausea/vomiting, vertigo, headache, nystagmus).

o AG should be discontinued immediately if any signs/symptoms of toxicity develop; ototoxicity causedby AG may be irreversible.

o Audiometry and vestibular testing recommended for patients receiving AG for 7 days or more, or atany time if ototoxicity suspected. Consult Audiology.

o If prolonged therapy expected (greater than 7 days) baseline audiometry may be consideredo Assess need for continued AG therapy based on microbial susceptibilities, clinical response, side

effects, duration of therapy, etc.

23

ADULT CONVENTIONAL DOSING • Use conventional dosing when extended-interval dosing is not indicatedInitial Dose Loading dose: • 2 mg/kg IV

o based on ideal body weight or dosing weight (see appendix B)o round dose to nearest 20 mgo loading doses DO NOT need to be adjusted in patients with renal dysfunction; only maintenance

dosing interval requires adjustmentMaintenance dose: • 1.5 to 2 mg/kg IV

o based on ideal body weight or dosing weight (see appendix B)o round dose to nearest 20 mg

Dosing interval: • Interval depends on patient’s renal function

Creatinine Clearance Dosing Interval greater than or equal to 80 mL/min q8h 50 to 79 mL/min q12h 20 to 49 mL/min q24h less than 20 mL/min q48-72h; give first dose and draw

serial serum drug levels to determine when to give next dose; close monitoring is recommended

Levels • Therapeutic drug monitoring of AG dosed conventionally is typically done by measuring both peak and trough

levels at steady state to confirm that therapeutic concentrations have been achieved and that drugaccumulation has not taken place

Target serum concentrations: Infection Desired minimal (trough)

plasma concentration (mg/L)

Desired maximum (peak) plasma concentration (mg/L)

Lower urinary tract infection less than 1 4-6Pelvic inflammatory disease (e.g., endometritis, salpingitis, tubo-ovarian abscess, pelvic peritonitis) Chorioamnionitis Pyelonephritis Peritonitis Soft tissue infections

less than 2 6-8

Sepsis Neutropenia Burns Pneumonia Infections due to Pseudomonas (non-urinary) Bone and joint infections

less than 2 8-10

Cystic fibrosis less than 2 10-15

Levels are recommended in: • Treatment anticipated to be longer than 3-5 days• Patients more than 65 years of age

24

• Patients with renal dysfunction (CrCl less than 60 mL/min) or significant changes in renal function frombaseline

• Patients receiving other nephrotoxic drugs (e.g., vancomycin, NSAIDs, diuretics, ACE-I, ARBs, etc.)• Patients with a large volume of distribution (e.g., ascites, third spacing)• Pregnant women Serum sampling: • Trough levels are taken immediately before a dose (within 30 minutes)• Peak levels are taken 30 to 60 minutes after the END of the IV infusion• The timing and duration of drug administration and sample collection must be carefully documentedTiming of serum levels: • Levels should be taken at steady state, typically before and after the 3rd dose in patients with normal renal

function • Steady state (SS) occurs in 4 to 5 half-lives and can be estimated by the following equations:

o Ke (gentamicin) = CrCl x 0.00285 + 0.015o Ke (tobramycin) = CrCl x 0.0031 + 0.01 o T½ = 0.693/Ke

o SS = 4 to 5 T½Interpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time and at steady state• Adjust AG dose if serum concentrations are not within the desired range as follows:

high trough extend dosing interval high peak decrease dose low peak increase dose

• AG exhibit linear kinetics; decreasing or increasing the dose by a specific percentage will result in an equaldecrease/increase in percentage of peak levels

• Pharmacokinetic calculations may be used determine the dose most likely to produce the desired levels, basedon the pre and post levels obtained from the patient. Contact Pharmacy.

Monitoring and patient counselling Subsequent serum levels: • After a change in dose, levels should be repeated at new steady state• At least once a week for most patientsMonitor: • Clinical response• Renal function

o Serum creatinine (SCr) at baseline and every 2 to 3 days during therapyo AG can cause renal dysfunction; typically reversible if discontinued in a timely manner; close

monitoring is warranted• Ototoxicity

o Patients should be advised to watch for and report signs & symptoms of cochlear toxicity (e.g.,tinnitus, sense of fullness in ears, loss of hearing) and of vestibular toxicity (e.g., disequilibrium, oscillopsia, cognitive dysfunction, visual sensitivity, nausea/vomiting, vertigo, headache, nystagmus).

o AG should be discontinued immediately if any signs/symptoms of toxicity develop; ototoxicity causedby AG may be irreversible.

o Audiometry and vestibular testing recommended for patients receiving AG for 7 days or more, or atany time if ototoxicity suspected. Consult Audiology.

o If prolonged therapy expected (greater than 7 days) baseline audiometry may be considered • Assess need for continued AG therapy based on microbial susceptibilities, clinical response, side effects,

duration of therapy, etc.

25

ADULT GENTAMICIN SYNERGISTIC DOSING • Used in combination therapy for endocarditis due to Viridans Group Streptococcus, Streptococcus gallolyticus

(formerly Streptococcus bovis) or Enterococcus (refer to most recent IDSA/AHA Endocarditis Clinical PracticeGuidelines for details)

• Only gentamicin is routinely used in this setting• Dose: gentamicin 1 mg/kg q8h or 3 mg/kg q24h, depending on the organism identified

o dosing based on IBW (see appendix B)o no initial loading doseo round dose to nearest 20 mgo in patients with renal impairment, consider using 1 mg/kg dosing strategy and lengthening the

interval based on the table belowCreatinine Clearance Dosing Interval

greater than or equal to 80 mL/min

q8h

50 to 79 mL/min q12h 20 to 49 mL/min q24h less than 20 mL/min q48-72h; give first dose then draw serial serum

drug levels to determine when to give next dose; close monitoring is recommended

• Draw gentamicin trough level before the 3rd dose and at least once a week thereafter if patient is stableo Goal of monitoring is to avoid toxicity o Target trough level : less than 1 mg/Lo If trough more than 1 mg/L, increase interval

• Peaks are NOT routinely recommendedo If done, target peak level: 3 to 5 mg/L

26

GENTAMICIN AND TOBRAMYCIN IN PEDIATRIC PATIENTS

DEFINITIONS • Neonate: 0-4 weeks of age

o Gestational age: number of weeks from first day of the mother’s last menstrual period until the birthof the baby

o Postnatal age: chronological age since birth o Corrected Gestational Age: gestational age plus postnatal age

Ex.: baby born at 28 weeks, presently 21 days old corrected gestational age = 31 weeks (28 weeks + 3 weeks)

• Infant: 1 month to 1 year of age• Child: 1-12 years of age

PEDIATRIC EXTENDED INTERVAL DOSING • Extended interval AG dosing should NOT be used in pediatric patients who

o have renal insufficiency at baseline (CrCl less than 50 mL/min)o require dialysis o have gram-positive infections where AG is used for synergy (use conventional dosing)o have endocarditis (use conventional dosing)o have rapid clearance of drug (e.g., burns exceeding 20% of body surface area)o have altered volume of distribution (e.g., ascites)o have meningitis o are receiving AG for surgical prophylaxis

• Use conventional dosing if any of the above exclusion criteria for extended interval dosing are metNeonates Initial dose in neonates (less than 1 month of age):

Corrected Gestational Age (weeks)

Postnatal Age (days) mg/kg/dose IV Interval

(hours)

29* or less 0-7 5 48

8-28 4 36 29 or more 4 24

30-34 0-7 4.5 36 8 or more 4 24

35 or more all 4 24 *or significant asphyxia, Patent Ductus Arteriosus (PDA) or treatment with indomethacin or ibuprofen

• round dose to nearest 5 mgLevels Target serum concentrations at 22 hours: • 1.2 mg/L or lessLevels recommended in: • Treatment anticipated to be longer than 48hSerum sampling: • A random level (or interval level) should be drawn 22 hours after the first dose regardless of the dosing

interval• The timing and duration of drug administration and sample collection must be carefully documented

27

Interpreting serum levels and adjusting dose: Level at 22 hours (mg/L) Suggested dosing interval 1.2 or less q24h 1.3 to 2.6 q36h 2.7 to 3.5 q48h 3.6 or more hold dose and repeat level in 24 hours; base dosing interval on

time to achieve a level less than 2 mg/L

Infants and children Initial dose of gentamicin/tobramycin • Infants and children 1 month – up to 9 years:

o 7-9 mg/kg IV q24h • Children 9 years and older:

o 7 mg/kg IV q24hInitial dose of tobramycin for Febrile Neutropenia • Infants and children 1 month – up to 6 years:

o 10 mg/kg IV q24h • Children 6 years and older:

o 8 mg/kg IV q24h Dose: • based on actual body weight, unless 20% above IBW, in which case use dosing weight (appendix C)• maximum of 400 mg/24h prior to levels • round dose to nearest 5 mgLevels • Monitoring of trough levels alone are generally sufficient with extended interval dosing of AG

o verifies that AG is being adequately eliminated• Peak levels are typically NOT required, as the larger doses used are expected to produce concentrations well

above those required for clinical efficacyo may be done in the rare cases where individualized pharmacokinetic monitoring is required

Target serum concentrations: • Trough level : less than 1 mg/L• Peak level [only if indicated]: 15-25 mg/LLevels recommended in: • Treatment anticipated to be longer than 48hSerum sampling: • Trough levels are taken immediately before a dose (within 30 minutes)• Peak levels are taken 90 minutes after the END of drug infusion• The timing and duration of drug administration and sample collection must be carefully documentedTiming of serum levels: • The notion of steady state does not apply with extended-interval dosing; therefore trough levels may be taken

prior to the 2nd doseInterpreting serum levels and adjusting dose: • Trough level of 1 mg/L or more suggests accumulation; extend dosing intervalMonitoring • Serum creatinine every 2 to 3 days while on therapy; daily if unstable renal function• Coordinate blood work when possible to minimize the number of times the child has blood drawn

28

PEDIATRIC CONVENTIONAL DOSING Initial dose Neonates (less than 1 month of age):

Weight (kg) Postnatal Age (days) mg/kg/dose IV Interval

(hours) Less than 1.2 0-28 2.5 18-24

1.2 to 2 less than 7 2.5 12 7 or more 2.5 8 to 12

more than 2 less than 7 2.5 12 7 or more 2.5 8

• round dose to nearest 5 mg

Infants and children: • 1 month to less than 5 years of age: 2.5 mg/kg IV q8h• children 5 years of age and older: 2 to 2.5 mg/kg IV q8h• for treatment of cystic fibrosis: 2.5 to 3.3 mg/kg IV q6-8h • for synergy: 1 mg/kg IV q8h • dose based on actual body weight, unless 20% above IBW, in which case use dosing weight (appendix C)• round dose to nearest 5 mg

Levels • Therapeutic drug monitoring of AG dosed conventionally is typically done by measuring both peak and trough

levels at steady state to confirm that therapeutic concentrations have been achieved and that drugaccumulation has not taken place

Target serum concentrations: Infection Desired minimal (trough)

plasma concentration (mg/L)

Desired maximum (peak) plasma concentration (mg/L)

Synergy for gram-positive infections

less than 1 3-5

Lower urinary tract infection and mild-moderate infections

less than 2 4-8

Severe infections (Pneumonia, Sepsis, etc.)

less than 2 8-10

Cystic Fibrosis less than 2 10-15

Levels are recommended in: • Treatment anticipated to be longer than 48hSerum sampling: • Trough levels are taken immediately before a dose (within 30 minutes)• Peak levels are taken 30 to 60 minutes after the END of drug infusion.• The timing and duration of drug administration and sample collection must be carefully documentedTiming of serum levels: • Level should be taken at steady state, typically before and after 3rd dose in patients with normal renal functionInterpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time and at steady state• Adjust AG dose if serum concentrations are not within the desired range as follows:


• AG exhibit linear kinetics; decreasing or increasing the dose by a specific percentage will result in an equaldecrease/increase in percentage of peak levels.

29

• Pharmacokinetic calculations may be used determine the dose most likely to produce desired levels, based onthe pre and post levels obtained from the patient. Contact Pharmacy.

Monitoring • Serum creatinine every 2 to 3 days while on therapy; daily if unstable renal function• Coordinate blood work when possible to minimize the number of times the child has blood drawn

30

EXTENDED-INTERVAL TOBRAMYCIN IN CYSTIC FIBROSIS (PEDIATRIC and ADULT)

GENERAL COMMENTS • Patients with Cystic Fibrosis (CF) will have increased AG requirements secondary to increased clearance• Extended interval dosing is as efficacious as conventional dosing of tobramycin in the treatment of CF

pulmonary exacerbations in adults and children• Amikacin may also be used to treat CF; data is limited with gentamicin. There are insufficient data in CF

patients for guiding extended interval dosing of AG apart from tobramycin. If other AG is needed, useconventional dosing.

• For conventional dosing, refer to previous adult and pediatric sections. Target peak levels are 10 to 15 mg/L,while target trough levels are less than 2 mg/L.

DOSE AND LEVELS Dose (pediatric and adults; from 1 months of age) • Treatment naïve:

Creatinine Clearance Initial tobramycin dose greater than or equal to 50 mL/min 10 mg/kg IV q24h 30-49 mL/min 10 mg/kg IV q36h 20-29 mL/min 10 mg/kg IV q48h less than 20 mL/min avoid maximum tobramycin dose of 600 mg/day prior to levels

• Previously treated with tobramycin: dose based on previous therapeutic drug monitoring• Dose based on ideal body weight (see appendix B)Levels: • Monitoring of trough levels alone are generally sufficient with extended interval dosing of AG; trough levels

verify that AG is being adequately eliminated• Peak levels are NOT routinely measured, but may be ordered to allow for individualized pharmacokinetic

monitoring if concern about clinical progresso Because CF patients have more rapid clearance of AG, extrapolated peaks can be substantially higher

than reported values.Target serum concentrations: • Trough levels: less than 1 mg/L • Peak levels [only if indicated]: 20-30 mg/L, peaks NOT to exceed 50 mg/LSerum sampling: • Trough levels are taken immediately before a dose (within 30 minutes)• Peak levels are taken 90 minutes after the END of drug infusion• The timing and duration of drug administration and sample collection must be carefully documentedTiming of serum levels: • notion of steady state does not apply in extended-interval dosing; trough levels may be taken before 2nd doseInterpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time• If tobramycin is being administered via inhalation in addition to IV, absorption of inhaled tobramycin may

contribute to tobramycin serum concentrations• If trough is less than 1 mg/L, continue current dose• Adjust AG dose if serum concentrations are not within the desired range as follows:


Subsequent serum levels: • Trough levels should be monitored every 7 days or sooner if clinically necessary

31

GENTAMICIN AND TOBRAMYCIN IN INTERMITTENT HEMODIALYSIS

GENERAL COMMENTS • Extended interval dosing not indicated for patients on hemodialysis; use conventional dosing • In patients on intermittent hemodialysis, AG is given on dialysis days, typically 3 times a week • AG doses are administered after dialysis • Give the first dose of AG the day it is ordered and subsequent doses on dialysis days• AG are removed by hemodialysis (to a greater extent than vancomycin)

o High-flux dialyzers reduce AG serum concentrations by approximately 50%Example: pre-dialysis gentamicin serum concentration is 5 mg/L; following a 4h hemodialysis session,post-dialysis gentamicin serum concentration is approximately 2.5 mg/L

DOSE Loading dose: • 1.5-2 mg/kg IV

o based on dry weight/dosing weight (see appendix B)o round dose to nearest 20 mg

Initial maintenance dose: • 1 mg/kg IV

o based on dry weight/dosing weight (see appendix B)o round dose to nearest 20 mgo administered at the end of dialysis session

Dosing weight: Patient’s dry weight…. Use as dosing weight is less than ideal body weight dry weight is less than 20% above ideal body weight dry weight is more than 20% above ideal body weight adjusted weight

Adjusted weight = 0.4 x (actual body weight – IBW) + IBW

LEVELS Trough levels: • Draw trough level within 30 minutes before the start of the hemodialysis session• Target pre-hemodialysis level: 1.5 to 3 mg/LPeak levels: • NOT commonly done• Measure peak level 60 minutes after END of drug infusion, if required• Target peak: 6-10 mg/L, depending on the indication (refer to section “Adults-Conventional Dosing of

Gentamicin and Tobramycin”: target serum concentrations)

32

GENTAMICIN AND TOBRAMYCIN IN PREGNANCY

CONSIDERATIONS ON THE USE OF AMINOGLYCOSIDES IN PREGNANCY • Glomerular filtration rate can be increased by up to 50% in pregnant and post-partum patients, resulting in a

shorter half-life compared to nonpregnant women • Volume of distribution is increased in pregnancy, while the post-partum period is associated with increased

mobilization of fluid followed by diuresis as the body eliminates the increased fluid volume of pregnancy• Extended interval dosing

o Data limited on extended interval dosing of AG in pregnancy; use with caution o More data on extended-interval dosing of AG is available in post-partumo For pregnant and post-partum patients, the actual body weight should be used. For obese pregnant

and post-partum patients, use maximum 500 mg dose prior to levels.o Initial dose and interval

5 mg/kg IV q24h (if CrCl greater than or equal to 60 mL/min) dose based on actual body weight maximum 500 mg/24h prior to levels dosing interval adjusted based on renal function

o Monitoring Trough levels, taken within 30 minutes before 2nd dose

• target less than 1 mg/L• Conventional dosing

o Initial dose and interval 2 mg/kg IV x 1 loading dose, then 1.5-2 mg/kg IV q8h (if CrCl greater than or equal to 80 mL/min) dose based on actual body weight dosing interval adjusted based on renal function

o Monitoring target levels – refer to “Adults-Conventional Dosing of Gentamicin/Tobramycin” section

33

AMIKACIN

GENERAL COMMENTS, DOSING AND MONITORING • Amikacin is a less commonly used AG with similar spectrum of activity and toxicity profile as gentamicin and

tobramycin • Dosing and serum concentrations are different compared to gentamicin and tobramycin• Determination of serum concentration is sent to a laboratory outside the province; expect delays in obtaining

results • Extended interval dosing

o Initial dose 15 mg/kg IV; dose based on IBW or dosing weight (see appendix B); rounded to nearest 25

mgo Initial interval

Creatinine Clearance Dosing Interval greater than or equal to 60 mL/min q24h 40 to 59 mL/min q36h 20 to 39 mL/min q48h; consider conventional dosing less than 20 mL/min Give first dose then draw serial serum drug levels

to determine when to give next dose. Consider conventional dosing.

• Conventional dosingo Initial dose

7.5 mg/kg IV x 1 loading dose may be considered, then 5 to 7.5 mg/kg IV; dose based on IBW or dosing weight; rounded to nearest 25 mg

o Initial intervalCreatinine Clearance Dosing Interval

greater than or equal to 80 mL/min q8h 50 to 79 mL/min q12h 20 to 49 mL/min q24h less than 20 mL/min q48-72h; give first dose then draw serial serum

drug levels to determine when to give next dose; close monitoring is recommended

• For extended interval dosing of amikacin,o Target trough level: less than 4 mg/Lo Target peak level [only if indicated]: 35-50 mg/Lo Hartford Hospital nomogram may be used to determine appropriate dosing interval based on a

random level taken 8-12h after the first dose, provided a 15 mg/kg dose was used Divide serum amikacin level obtained in half, then plot on graph (see Appendix D)

• For conventional dosing of amikacin, target serum concentrations:Desired minimal (trough) concentration (mg/L)

Desired maximum (peak) concentration (mg/L)

Moderate infections less than 4 20-25Severe infections less than 4 25-30

34

APPENDIX A: Calculation of Creatinine Clearance (CrCl)

Women Men CrCl = (140-age) x weight (in kg)†

SCr (in mcmol/L) CrCl = (140-age) x weight (in kg)† x 1.2

SCr (in mcmol/L) IBW = 45.5 Kg + (0.92 x cm above 150 cm) or

45.5 kg + (2.3 x inches above 60 inches) IBW = 50 kg + (0.92 x cm above 150 cm) or

50 kg + (2.3 x inches above 60 inches) †use ideal body weight unless actual body weight is more than 20% above ideal body weight (IBW), in such case use dosing weight: Dosing weight = 0.4 x (actual body weight – IBW) + IBW

APPENDIX B: Adult Ideal Body Weight, Dosing Weight and Dry Weight

Patient’s weight…. Use is less than ideal body weight actual body weight is less than 20% above ideal body weight ideal body weight is more than 20% above ideal body weight dosing weight =

0.4 x (actual body weight – IBW) + IBW

Ideal body weight (IBW)

Women Men IBW = 45.5 kg + (0.92 x cm above 150 cm) or


50 kg + (2.3 x inches above 60 inches)

Dry body weight in hemodialysis: defined as the lowest tolerated post-dialysis weight at which there are minimal signs or symptoms of hypovolemia or hypervolemia

APPENDIX C: Pediatric Ideal Body Weight and Dosing Weight

Child’s weight…. Use is less than 20% above ideal body weight actual body weight is more than 20% above ideal body weight dosing weight =

0.4 x (actual body weight – IBW) + IBW

Ideal body weight (1 to 18 years of age):

• Children less than 5 feet tall: height (cm)2 x 1.65 1000

• Boys 5 feet and taller: 39 kg + (2.3 x inches above 60 inches)• Girls 5 feet and taller: 42.2 kg + (2.3 x inches above 60 inches)

35

APPENDIX D: Hartford Hospital nomogram

• This nomogram is only to be used for a 7 mg/kg dose of gentamicin or tobramycin• This nomogram assumes a Vd of 0.3 L/kg• If interval falls in areas marked as q24h, q36h, q48h, dosing interval should be every 24,

36, or 48 hours respectively.• If the interval level is on one of the sloping lines, choose the longer interval.• If the interval level is above the q48h dosing interval area, stop extended interval dosing

and switch to conventional dosing.• If the interval level is below the nomogram (i.e., less than 2 mg/L), AG dosing/therapy

should be reassessed if patient not improved.• For amikacin the Hartford Hospital nomogram may be used to determine appropriate

amikacin dosing interval based on a random level taken 8-12h after the first dose,provided a 15 mg/kg dose was used

o Divide serum amikacin level obtained in half, then plot on graph

36

Introduction

The dosing recommendations presented here are for adults with moderate-to-severe infections and are based on published literature, the Clinical & Laboratory Standards Institute’s reference dosing for susceptibility interpretation and clinical experience. The recommended doses should only be used as a reference tool. Patient dosing should be individualized and based on pharmacokinetic and clinical evaluation where possible.

Recommendations for renal dose adjustment are made according to estimated creatinine clearance (CrCl) calculated using the Cockroft-Gault equation, which is used in practice. Estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease 4 (MDRD4) equation, commonly reported with most serum creatinine levels, is NOT interchangeable with CrCl calculated using the Cockroft-Gault equation. The two equations may result in different antimicrobial dosing recommendations in up to 20 to 36% of cases with potential clinical significance.20 Recommendations for renal dose adjustment in the table below are for modifications of the maintenance doses; no adjustments are required for loading doses where applicable.

For patients on intermittent hemodialysis (IHD), antimicrobial dosages and administration times may need to be adjusted. If an antimicrobial is significantly removed by hemodialysis (HD) and recommended to be given post-HD then administration of the dose prior to or during HD should be avoided because drug loss could result in subtherapeutic levels post-HD. The dosing schedule should be adjusted on dialysis days so that the scheduled dose is administered immediately after dialysis. Other strategies may include supplementary doses administered post-HD to replace the amount of antimicrobial removed during HD or intermittent post-HD administration (ex. ceFAZolin 2 g IV post-HD 3 times weekly). Please consult your local pharmacy department for guidance in patients receiving peritoneal dialysis, continuous veno-venous hemofiltration, continuous veno-venous hemodiafiltration or continuous renal replacement therapy. Dosing adjustment may also be necessary in patients with severe liver impairment.

In critically ill patients (ex: sepsis), antimicrobial pharmacokinetics can be significantly altered and unstable potentially resulting in sub-optimal dosing. Critically ill patients may also suffer from acute renal failure (ARF) that can be rapidly reversible; therefore, since the serum creatinine level is not stable, the Cockroft-Gault equation should NOT be used to estimate renal function in ARF. A pharmacy consultation could be considered to optimize antimicrobial doses in this patient population.

ADULT ANTIMICROBIAL DOSING TOOL (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

37

Penicillins

amoxicillin (PO)1,2,3,4,5,6 500 mg – 1 g q8h 500 mg q12h 500 mg q24h 500 mg q24h;

administer dose after dialysis on dialysis days

amoxicillin/clavulanate (PO)1,2,7

- Dose listed as amoxicillin component

- Do not use 875 mg tablets if CrCl less than 30 mL/min

- Less diarrhea with 875 mg given q12h vs.500 mg q8h

500 mg q8h

500 mg q12h 500 mg q24h 500 mg q24h;

administer dose after dialysis on dialysis days 875 mg q12h

ampicillin (IV)1,3,5 Dose 2 g q4h for endocarditis and other deep space infections‡

1 – 2 g q4-6h 1 – 2 g q6-8h 1 – 2 g q8-12h 1 – 2 g q12-24h 1 – 2 g q12-24h;


cloxacillin (PO)1,5 500 – 1000 mg q6h

cloxacillin (IV)1,2,5 Dose 2 g q4h for endocarditis and deep space infections‡

1 – 2 g q4-6h

penicillin G (IV)1,5 Dose 4 million units q4h for endocarditis and deep space infections‡

2 – 4 million units q4-6h 75% of usual dose q4-6h 20 – 50% of usual

dose q4-6h

20 – 50% of usual dose q4-6h; administer dose after dialysis on

dialysis days

penicillin V (PO)2,5,8,9 300 – 600 mg q6h 300 – 600 mg q8h 300 – 600 mg q12h

piperacillin/tazobactam (IV)1,2,3,5

Dose listed as piperacillin plus tazobactam components

3.375 g q6h (CrCl greater than

40 mL/min) 2.25 g q6h (CrCl 20 – 40 mL/min)

2.25 g q8h (CrCl less than 20

mL/min)

2.25 g q12h; administer supplementary dose of 0.75 g after dialysis session

Hospital acquired pneumonia, febrile neutropenia and Pseudomonas spp infections

4.5 g q6h (CrCl greater than

40 mL/min) 3.375 g q6h (CrCl 20 – 40 mL/min)

2.25 g q6h (CrCl less than 20

mL/min)

2.25 g q8h; administer supplementary dose of 0.75 g after dialysis session

piperacillin (IV)1,3,5 3 – 4 g q6h

(CrCl greater than 40 mL/min)

3 – 4 g q8h (CrCl 20-40mL/min)

3 – 4 g q12h (CrCl less than 20 mL/min)

2 g q8h; administer supplementary dose

of 1 g after dialysis session

Cephalosporins

ceFAZolin (IV)1,5,19 (1st generation) 2 g q8h 2 g q12h 1 – 2 g q24h

1 – 2 g q24h; administer dose after dialysis on dialysis days

OR 2 g after dialysis three times

weekly if receiving dialysis three times weekly

cephalexin (PO)1,3,5 (1st generation) 500 mg – 1 g q6h 500 mg q8h 500 mg q12h 500 mg q12-24h

500 mg q12-24h; administer dose after dialysis on

dialysis days

ADULT ANTIMICROBIAL DOSING TOOL

Drug General Comments

Usual Adult Dose (CrCl greater

than or equal to 50 mL/min)

CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min

CrCl less than 10 mL/min

Intermittent Hemodialysis (IHD)

38

cefadroxil£ (PO)1,3,5 (1st generation)

Dose 1 g twice daily for complicated UTI 500 mg – 1 g q12h 500 mg – 1 g q24h 500 mg q36h

500 mg – 1 g three times weekly after dialysis if receiving dialysis

three times weekly

cefaclor£ (PO)1,3,5

(2nd generation) 250 - 500 mg q8h 250 mg q8h 250 mg q8h ; administer

supplementary dose of 250 mg after dialysis session

cefuroxime axetil (PO)1,2,3,5, 22, 23 (2nd generation) 500 mg q8-12h 500 mg q12h 500 mg q24h

500 mg q24h; administer dose after dialysis on

dialysis days

cefuroxime (IV)1,2,5 (2nd generation)

1.5 g q8h (CrCl greater than 20 mL/min)

1.5 g q12h (CrCl 10-19

mL/min) 1.5 g q24h

1.5 g q24h; administer dose after dialysis on

dialysis days

cefOXitin (IV)1,5,10 (2nd generation)

Dose 2 g q6h for moderate to severe infections such as intra-abdominal infections

1 – 2 g q6-8h 1 – 2 g q8h 1 – 2 g q12h 1 – 2 g q24h 1 – 2 g q24h;


cefprozil (PO)1,3,5 (2nd generation) 500 mg q12h 250 mg q12h

250 mg q12h; administer supplementary dose of 250 mg after dialysis session

cefixime (PO)2,3 (3rd generation) 400 mg q24h 200 mg q24h 200 mg q24h

cefTRIAXone (IV)1 (3rd generation)

Dose 2 g q12h for CNS infections or Enterococcus faecalis endocarditis in combination with ampicillin

1 – 2 g q24h

cefotaxime (IV)1,2,3 (3rd generation)

Moderate to severe infection 1 – 2 g q6-8h 1 – 2 g q12h 1 – 2 g q24h 1 – 2 g q24h;


CNS infection 2 g q4h 2 g q6h 2 g q8h 2 g q12h 2 g q12-24h;


cefTAZidime (IV)1,3,5 (3rd generation)

2 g 8h 2 g q12h 2 g q24h 1 g q24h

1 g q24h; administer dose after dialysis on

dialysis days OR

2 g after dialysis three times weekly if receiving dialysis three

times weekly

cefepime£ (IV)1,2 (4th generation)

Uncomplicated mild to moderate infections 1 – 2 g q8-12h 1 – 2 g q12 – 24h

(ClCr 30-59 mL/min 1 – 2 g q24h 1 g q24h

1g q24h; administer dose after dialysis on

dialysis days OR





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



39

cefepime£ (IV)1,2 (4th generation)

Severe infections including febrile neutropenia, hospital acquired pneumonia, deep space infections‡ or coverage for Pseudomonas aeruginosa

2 g q8h 2 g q12h (ClCr 30-59 mL/min

2 g q24h 1 g q24h

2 g after dialysis three times weekly if receiving dialysis three

times weekly

Carbapenems

ertapenem£ (IV/IM)13,5 1 g q24h 500 mg q24h

500 mg q24h; administer supplementary dose of 150 mg after dialysis session if daily dose given less than 6 hr

before start of HD

imipenem/cilastatinR (IV)1,11 Meropenem preferred for CNS infections and when CrCl less than 30 mL/min

500 – 1000 mg q6h (CrCl greater than

70 mL/min)

500 mg q6-8h (CrCl 31 – 70

mL/min)

500 mg q8-12h (CrCl 21 – 30

mL/min)

250 – 500 mg q12h (CrCl less than 20

mL/min)

250 – 500 mg q12h; administer dose after dialysis on

dialysis days

meropenemR (IV)1,2,3,5

q6h dosing regimen: Caution: do NOT use this regimen for CNS infections

500 mg q6h 500 mg q8h

(CrCl 26 – 50 mL/min)

500 mg q12h (CrCl 10 – 25

mL/min) 500 mg q24h

500 mg q24h; administer dose after dialysis on

dialysis days

q8h dosing regimen: Dose 2 g q8h for CNS infections

1000 – 2000 mg q8h 1000– 2000 mg q12h 500 mg – 1000 mg q24h

500 mg – 1000 mg q24h; administer dose after dialysis on

dialysis days Aminoglycosides – Adjust dose for serum drug levels where applicable. For prolonged therapies consider pharmacy consult for appropriate dosing and monitoring

gentamicin/tobramycin (IV) Extended Interval Dosing2,4,14

- 7 mg/kg for seriousinfections

- Dosing based on IBW, unless actual body weight greater than 20% above IBW, then use dosing weight

5 – 7 mg/kg q24h (CrCl greater than or equal to 60 mL/min)

5 – 7 mg/kg q36h (CrCl 40 – 59

mL/min)

5 – 7 mg/kg q48h (CrCl 20 – 39

mL/min) OR

Consider conventional

dosing

5 – 7 mg/kg IV to start then use serial serum drug levels to

adjust (CrCl less than 20 mL/min)

OR Consider

conventional dosing

1.5 – 2 mg/kg loading dose followed by 1 mg/kg

maintenance dose at the end of each dialysis session;

dose adjustments based on pre-dialysis levels

(dosing based on patient’s dry weight if not obese; if dry weight is greater than 20% above IBW

then use dosing weight) gentamicin/tobramycin (IV) Conventional Dosing 2,4,14


- Consider a loading dose of 2 mg/kg to start

1.5 – 2 mg/kg q8h (CrCl greater than or equal to 80 mL/min)

1.5 – 2 mg/kg q12h (CrCl 50 – 79

mL/min)

1.5 – 2 mg/kg q24h (CrCl 20 – 49

mL/min)

1.5 – 2 mg/kg q48-72hrs OR

Single dose, then use serial drug levels to adjust; close monitoring recommended

(CrCl less than 20 mL/min)





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



40

gentamicin/tobramycin (IV) Synergy Dosing2,3,14

- For Gram positive infectionsonly; tobramycin not for synergy against Enterococcus spp infections

- Dosing based on IBW, unless actual body weightgreater than 20% above IBW, then use dosing weight

1 mg/kg q8h (CrCl greater than or

equal to 80 mL/min)

1 mg/kg q12h (CrCl 50 – 79 mL/min)

1 mg/kg q24h (CrCl 20 – 49

mL/min)

1 mg/kg q48-72hrs OR

Single dose, then use serial drug levels to adjust; close monitoring recommended


1 mg/kg at the end of each dialysis session;



then use dosing weight)

amikacin (IV) Extended Interval Dosing1,2,4

Dosing based on IBW, unless actual body weight greater than 20% above IBW, then use dosing weight

15 mg/kg q24h (CrCl greater than or

equal to 60 mL/min)

15 mg/kg q36h (CrCl 40 – 59 mL/min)

15 mg/kg q48h (CrCl 20 – 39

mL/min) OR

Consider conventional

dosing

15 mg/kg to start then use serial

serum drug levels to adjust (CrCl less than 20 mL/min)

OR Consider

conventional dosing

5 – 7.5 mg/kg at the end of each dialysis session;



then use dosing weight) amikacin (IV) Conventional Dosing1,2,4


- Consider a loading dose of 7.5 mg/kg to start

5 – 7.5 mg/kg q8h (CrCl greater than or equal to 80 mL/min)

5 – 7.5 mg/kg q12h (CrCl 50 – 79

mL/min)

5 – 7.5 mg/kg q24h (CrCl 20 – 49

mL/min)

5 – 7.5 mg/kg q48-72hrs OR

use serial serum drug levels to adjust; close monitoring recommended


Macrolides erythromycin (IV)1,2 500 – 1000 mg q6h 50 – 75% dose q6h

erythromycin (PO)1,2,3

Formulary product: •erythromycin 250 mg capsules containing EC pellets

250 – 500 mg q6h 50 – 75% dose q6h

azithromycin (IV)1 500 mg q24h x 3-5 days

Use with caution – No dose adjustment provided azithromycin (PO)1

500 mg q24h x 3 days OR

500 mg on day one, then 250 mg daily for days 2 to 5

clarithromycin (PO)1,3,4 500 mg q12h 500 mg q24h 500 mg q24h;


clarithromycin XL£ (PO)1,3 1000 mg q24h 500 mg q24h 500 mg q24h;






CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



41

Quinolones

ciprofloxacin (IV)1,2,8

400 mg q12h

400 mg q24h 400 mg q24h;

administer dose after dialysis on dialysis days Severe infections; infections

due to Pseudomonas aeruginosa

400 mg q8h 400 mg q12h

ciprofloxacin (PO) (regular release oral solid )1,2,9

500 mg q12h

500 mg q24h 250 – 500 mg q24h;


Infection of the bone or skin, infections due to Pseudomonas spp or severe infections

750 mg q12h 500 mg q12h

levofloxacin (PO/IV)1

500 mg q24h

500 mg once then 250 mg q24h (CrCl 20 – 49

mL/min)

500 mg once then 250 mg q48h (CrCl less than 20 mL/min or IHD)

High dose for bacteremia, complicated UTI, pyelonephritis, complicated skin infection, nosocomial pneumonia, intra-abdominal infections, infections due to Pseudomonas spp

750 mg q24h 750 mg q48h (CrCl 20 – 49

mL/min) 750 mg once then 500 mg q48h (CrCl less than 20 mL/min or IHD)

moxifloxacin(PO/IV)1 400 mg q24h

norfloxacin£ (PO)1,3 400 mg q12h 400 mg q24h

Tetracyclinesdoxycycline (PO)1 100 mg q12h

minocycline£ (PO)1,3,5 200 mg then 100 mg q12h Usual dose (Doxycycline preferred)

tetracycline (PO)1,3,5

250 – 500 mg q6h (CrCl greater than

80 mL/min)

250 – 500 mg q8-12h

(CrCl 50 to 80 mL/min)

250 – 500 mg q12 – 24h (doxycycline preferred)

250 – 500 mg q24h (doxycycline preferred)

Use not recommended

tigecyclineR (IV)1 100 mg initially, then 50 mg q12h





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



42

Other

clindamycin (IV)1 600 – 900 mg q8h

clindamycin (PO)1,12 300 – 450 mg q6-8h

DAPTOmycinR (IV)1,3

Skin and soft tissue infections: 4 mg/kg q24h

Severe infections: 8-10 mg/kg q24h

Monitor baseline and weekly creatine kinase levels

6 – 8 mg/kg q24h Usual dose q48h if CrCl less than 30 mL/min

Usual dose q48h Administer dose after dialysis on

dialysis days

fosfomycin (PO) Uncomplicated UTI 3 g ONCE

linezolidR (PO/IV)1,2,3 600 mg q12h 600 mg q12h

Administer dose after dialysis on dialysis days

metroNIDAZOLE (PO/IV)1,2 Dose 500 mg q8h for Clostridium difficile infection or CNS infection

500 mg q12h

500 mg q12h Consider a supplemental dose after dialysis if administration cannot be separated from the

dialysis session

nitrofurantoin monohydrate/macrocrystal sustained release capsules (MACROBID) (PO)1

100 mg q12h

Contraindicated if CrCl less than 40 mL/min (will NOT be effective in these patients)

nitrofurantoin regular release oral solidR,1

50 – 100 mg q6h





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



43

sulfamethoxazole + trimethoprim (IV) •Each mL of injectable containssulfamethoxazole 80 mg andtrimethoprim 16 mg1,2,8

- Dose listed as trimethoprim(TMP) component

- Use of sulfamethoxazole + trimethoprim in moderate to severe renal dysfunction has not been not adequately studied, close monitoring of patient response, electrolytes and serum creatinine recommended

8 – 20 mg TMP/kg/day divided q6-12h

Pneumocystis jiroveci Treatment: 15 – 20 mg/kg/day divided q6-8h

50% of usual dose (CrCl 15 – 29

mL/min)

Pneumocystis jiroveci

Treatment (CrCl 15 – 30 mL/min): 15 – 20 mg/kg/day divided q6-8h for 48 hr then 7 – 10 mg/kg/day divided

q12h

Generally not recommended, but if

required: 4 – 6 mg/kg/day divided

q12-24h (CrCl less than 15

mL/min)

Pneumocystis jiroveci Treatment (CrCl less than15

mL/min): 7 – 10 mg/kg/day divided q12-24h

2.5 – 10 mg/kg q24h; administer dose after dialysis on dialysis

days OR

4-6 mg/kg 3 times weekly after dialysis if receiving dialysis three

times weekly

Pneumocystis jiroveci Treatment:

7 – 10 mg/kg after dialysis three times weekly if receiving dialysis

three times weekly

sulfamethoxazole + trimethoprim (PO) • Each regular strength tablet

contains sulfamethoxazole 400mg and trimethoprim 80 mg

• Each double-strength (DS) tabletcontains sulfamethoxazole 800mg and trimethoprim 160 mg

• Each mL of oral suspensioncontains sulfamethoxazole 40 mgand trimethoprim 8 mg1,2,8

sulfamethoxazole/trimethoprim 800/160 to 1600/320 mg q12h

Pneumocystis jiroveci Treatment: 15 – 20 mg/kg/day divided q6-8h

trimethoprim (PO)2 100 mg q12h 50 mg q12h


Generally not recommended if CrCl less than 15

mL/min, but if required: 50 mg

q24h

50 mg q24h Administer dose after dialysis on

dialysis days

vancomycin (IV)2,8,13

- Consider a loading dose of 25-30 mg/kg if severe infection, adjusting maintenance doses based on renal function

- Dosing based on actual body weight

- Maximum of 2 g per dose for maintenance doses

- Adjust dose for serum drug levels where applicable. For prolonged therapiesconsider pharmacy consult for appropriate dosing and monitoring

Target Trough 10 – 15 mg/L

15 mg/kg q12h (CrCl greater than

80 mL/min)

15 mg/kg q24h (CrCl 40 – 80

mL/min)


15 mg/kg q36h



15 mg/kg q48h (CrCl 10 –19

mL/min) Consider loading dose of 25 – 30 mg/kg; then use

serial serum drug levels to adjust

Less than 70 kg: 1000 mg loading dose then 500 mg maintenance dose infused after dialysis on dialysis days;

70-100 kg: 1250 mg loading dose then 750 mg maintenance dose infused after dialysis on dialysis days;

Greater than 100 kg: 1500 mg loading dose then 1000 mg maintenance dose

infused after dialysis on dialysis days

(Adjust maintenance doses based on pre-dialysis

vancomycin trough levels)


15 mg/kg q8h (CrCl greater than

80 mL/min)

15 mg/kg q12h (CrCl 40 – 80

mL/min)


15 mg/kg q24h (CrCl 20 – 39

mL/min)


15 mg/kg q48h (CrCl 10 – 19

mL/min)





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



44

vancomycin (PO)1 C. difficile infection ONLY See NB-ASC Clostridiumdifficile Infection treatment guidelines for more details

125 – 500 mg q6h

Antivirals

acyclovir (IV)1,2,3,9

Dose based on ideal or dosing body weight Herpes zoster (shingles)/ Herpes simplex/ Varicella-zoster (chickenpox) in an immunocompromised host or patient with severe disease or encephalitis: 10 - 15 mg/kg q8h

5 – 10 mg/kg q8h 5 – 10 mg/kg q12h


5 – 10 mg/kg q24h (CrCl 10 – 24

mL/min) 2.5 – 5 mg/kg q24h

2.5 – 5 mg/kg q24h Administer after dialysis on

dialysis days

acyclovir (PO)1 Herpes zoster, and Varicella zoster: 800 mg five times a day

400 – 800 mg q8h to five times a day 400 – 800 mg q8h 200 – 800 mg q12h 200 - 800 mg q12h


famciclovir£ (PO)1,2,3,8

Herpes zoster (shingles) 500 mg q8h

(CrCl greater than or equal to 60 mL/min)

500 mg q12h (CrCl 40 – 59

mL/min)

500 mg q24h (CrCl 20 – 39

mL/min)

250 mg q24h (CrCl less than 20

mL/min)

250 mg after each dialysis session

Primary genital herpes 250 mg q8h


250 mg q12h (CrCl 20 – 40 mL/min)

250 mg q24h (CrCl less than 20

mL/min)

250 mg after each dialysis session

Recurrent Genital herpes

1000 mg q12h x 1 day


500 mg q12h x 1 day


500 mg as a single dose


250 mg as a single dose (CrCl <20

mL/min)

250 mg as a single dose after a dialysis session

ganciclovir (IV)1,8

Induction

5 mg/kg q12h or 2.5 mg/kg q12h if


2.5 mg/kg q24h 1.25 mg/kg q24h 1.25 mg/kg 3 times weekly (following dialysis, if receiving dialysis three times weekly)

Maintenance

5 mg/kg q24h or 2.5 mg/kg q24 h if


1.25 mg/kg q24h 0.625 mg/kg q24h 0.625 mg/kg three times weekly (following dialysis, if receiving dialysis three times weekly)

oseltamivir (PO)1,2,15

Treatment (for 5 days)

75 mg q12h (CrCl greater than

60 mL/min)

30 mg q12h (CrCl 30 – 60

mL/min) 30 mg q24h Use with caution:

75 mg ONCE 75 mg after each dialysis

session over a period of 5 days

Prophylaxis (for 10 to 14 days)

75 mg q24h (CrCl greater than

60 mL/min)

30 mg q24h (CrCl 30 – 60

mL/min) 30 mg q2days Use with caution:

30 mg ONCE

An initial 30 mg dose may be given prior to HD if exposed during the 48 hours between

dialysis sessions. Then administer 30 mg after alternate dialysis sessions over a period

of 10-14 days





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



45

valACYclovir (PO)1,2,16

Herpes zoster (shingles) 1 g q8h 1 g q12h 1 g q24h 500 mg q24h 1 g three times weekly after dialysis, if receiving dialysis

three times weekly

Herpes labialis 2g q12h x 2 doses 1 g q12h x 2 doses 500 mg q12h x 2 doses

500 mg as a single dose

500 mg as a single dose Administer dose after a dialysis

session

Primary genital herpes 1g q12h 1g q24h 500 mg q24h 500 mg PO q24h


Recurrent genital herpes 500 mg q12h x 3 days or 1g q24h x 5 days 500 mg q24h

500 mg PO q24h Administer dose after dialysis on

dialysis days

Herpes simplex/ Varicella zoster treatment in oncology patients

1 g q8h 1 g q12h 1 g q24h 500 mg q24h 1 g three times weekly after dialysis, if receiving dialysis

three times weekly

Herpes simplex/ Varicella zoster prophylaxis in oncology patients

500 mg q8-12h 500 mg q12h 500 mg q24h 500 mg PO q24h


valGANciclovir (PO)1,2,8

Induction

900 mg q12h (CrCl greater than or equal to 60 mL/min)

450 mg q12h (CrCl 40 – 59

mL/min)

450 mg q24h (CrCl 25 – 39

mL/min)

450 mg q48h (CrCl 10 – 24

ml/min) Consider ID or Transplant consult

Maintenance

900 mg q24h (CrCl greater than or equal to 60 mL/min)

450 mg q24h (CrCl 40 – 59

mL/min)

450 mg q2days (CrCl 25-39 mL/min)

450 mg 2x/week (CrCl 10 – 24

ml/min) Consider ID or Transplant consult

zanamivir£ (inhaled)1,15 Treatment 10 mg inhaled orally q12h

Prophylaxis 10 mg inhaled orally q24h

Antifungals amphotericin B (IV)1,2,4,8 (FUNGIZONE) 0.5-1 mg/kg q24h

amphotericin B, lipid complex£ (IV)1,4,8

(ABELCET) 5 mg/kg q24h

amphotericin B, liposomal (IV)1,8 (AMBISOME) 3 – 6 mg/kg q24h

anidulafungin£ (IV)1 200 mg once then 100 mg q24h

caspofungin£ (IV)1 70 mg once, then 50 mg q24h





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



46

micafungin (IV)1,17

100 mg q24h

Esophageal candidiasis OR invasive aspergillosis 150 mg q24h

Prophylaxis of Candida infection in hematopoietic stem cell transplantation

50 mg q24h

fluconazole (PO/IV)1 Candidemia: 800 mg loading dose on day 1 then 400 mg daily

200 – 800 mg q24h 50% of the dose if CrCl 50 mL/min or less

Administer usual dose after dialysis on dialysis days; on

non-dialysis days, reduce dose by 50 %

itraconazole (PO)1

*Capsules and oral solution are NOTbioequivalent; favor the oral solution

Aspergillosis: Consider loading dose of 200 mg q8h x 3 days; then 200 mg q12h

100 – 200 mg q24h

posaconazole (IV)1,8,9

Loading dose, 300 mg IV infusion q12h on day 1, followed

by 300 mg IV infusion q24h

starting on day 2

Accumulation & resultant toxicity of the diluent can occur if CrCl less than 50 mL/min.

posaconazole (PO)1,8,9

Delayed release tablet and oral suspension are NOT bioequivalent; favor the delayed release tablet.

Delayed-Release Tablet Loading dose of 300 mg q12h on day 1 followed by 300 mg q24h starting on day 2

Oral Suspension Prophylaxis: 200 mg three times daily

Treatment of invasive fungal infections: 400 mg q12h or 200 mg four times daily for patients unable to tolerate a meal or nutritional supplement

voriconazole (IV)1

Therapeutic drug monitoring may be considered

6 mg/kg q12h x 2 doses then 4 mg/kg

q12h thereafter

Accumulation & resultant toxicity of the diluent can occur if CrCl less than 50 mL/min. Use oral voriconazole at normal doses

voriconazole (PO)1,18 Therapeutic drug monitoring may be considered

For patients weighing greater than or equal to 40 kg: 400 mg q12h x 2 doses then 200 mg q12h ; OR for patients less than 40 kg: 200 mg q12h x 2 doses then 100 mg q12h

IDSA recommendations for invasive aspergillosis: may consider oral therapy in place of IV with dosing of 4 mg/kg rounded up to convenient tablet dosage form every 12 hours. IV administration preferred in serious infections as comparative efficacy with

the oral route has not been established.





CrCl 30 - 49 mL/min

CrCl 10 - 29 mL/min



47

Legend: R: restricted antimicrobial £: antimicrobial not listed on NB Hospital Formulary ‡: deep space infections include meningitis, septic arthritis,complicated abscesses, etc IBW: ideal body weight Dry body weight in hemodialysis: defined as the lowest tolerated post-dialysis weight at which there are minimal signs or symptoms of hypovolemia or hypervolemia.21 Obesity: defined as an actual body weight greater than 20% above patient’s calculated ideal body weight.

Cockcroft-Gault equation for estimated creatinine clearance (mL/min): CrCL (females) = (140 – age) x weight (kg)*

serum creatinine (mcmol/L)

CrCl (males) = CrCl (females) x 1.2

*For weight, use ideal body weight unless actual body weight is greater than 20% of ideal body weight, inwhich case use dosing body weight.

Ideal body weight (IBW): IBW (females) = 45.5 kg + 0.92 x (height in cm – 150 cm) OR 45.5 kg + 2.3 × (height in inches – 60 inches) IBW (males) = 50 kg + 0.92 x (height in cm – 150 cm) OR 50 kg + 2.3 × (height in inches – 60 inches) Dosing weight (kg) = IBW + 0.4 × (actual body weight – IBW)

ADULT ANTIMICROBIAL DOSING TOOL (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

48

Management of Penicillin and Beta-Lactam Allergy (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

Key Points • Beta-lactams are generally safe; allergic and adverse drug reactions are over diagnosed and over reported• Nonpruritic, nonurticarial rashes occur in up to 10% of patients receiving penicillins. These rashes are usually not allergic and are

not a contraindication to the use of a different beta-lactam• The frequently cited risk of 8 to 10% cross-reactivity between penicillins and cephalosporins is an overestimate based on studies

from the 1970’s that are now considered flawed• Expect new intolerances (i.e. any allergy or adverse reaction reported in a drug allergy field) to be reported after 0.5 to 4% of all

antimicrobial courses depending on the gender and specific antimicrobial. Expect a higher incidence of new intolerances inpatients with three or more prior medication intolerances1

• For type-1 immediate hypersensitivity reactions (IgE-mediated), cross-reactivity among penicillins (table 1) is expected due tosimilar core structure and/or major/minor antigenic determinants, use not recommended without desensitization

• For type-1 immediate hypersensitivity reactions, cross-reactivity between penicillins (table 1) and cephalosporins is due tosimilarities in the side chains; risk of cross-reactivity will only be significant between penicillins and cephalosporins with similarside chains

• Only type-1 immediate hypersensitivity to a penicillin manifesting as anaphylaxis, bronchospasm, angioedema, hypotension,urticaria or pruritic rash warrant the avoidance of cephalosporins with similar side chains and other penicillins

• Patients with type-1 immediate hypersensitivity to a penicillin may be safely given cephalosporins with side chains unrelated tothe offending agent (See figure 1 & 2 below)o For example, ceFAZolin does not share a side chain with any beta-lactam and is not expected to cross react with other

agents• Cross-reactivity between cephalosporins is low due to the heterogeneity between side chains; therefore, a patient with a

cephalosporin allergy may be prescribed another cephalosporin with a dissimilar side chain• Cross-reactivity between penicillins and carbapenems is low. Carbapenems would be a reasonable option when antibiotics are

required in patients with type-1 immediate hypersensitivity reaction to penicillins• Patients with reported Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic

symptoms, immune hepatitis, hemolytic anemia, serum sickness or interstitial nephritis secondary to beta-lactam use should avoidbeta-lactams and not receive beta-lactam skin testing, re-challenging or desensitization

• Penicillin skin tests can be used to predict penicillin sensitivity and have a 97-99% negative predictive value• Any patient with possibility of type-1 immediate hypersensitivity to a beta-lactam should be referred for allergy confirmation

Management of the Beta-Lactam Allergy (Figure 1 & Figure 2) 1,2,3,4 1. Avoid the unnecessary use of antimicrobials, particularly in the setting of viral infections.2. Complete a thorough investigation of the patient’s allergies, including, but not limited to: the specific drug the patient

received, a detailed description of the reaction, temporal relationship of the onset of the reaction with respect towhen the drug was given, concomitant drugs received when the reaction occurred, the time elapsed since thereaction occurred and tolerability of any structurally related compounds. If the patient:

a. reports intolerance (e.g. nausea, vomiting, diarrhea, headache) – likely not allergic, attempt beta-lactamtherapy

b. has a documented severe non-IgE mediated hypersensitivity reaction to a beta-lactam (e.g. interstitialnephritis, immune hepatitis, hemolytic anemia, serum sickness, severe cutaneous reactions such asStevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia andsystemic symptoms (DRESS), etc…) – avoid all beta-lactam antibiotics including their use for allergytesting, desensitization and re-challenge.

Treatment options include non-beta-lactam antibioticsc. has a documented severe type-1 immediate (IgE-mediated) hypersensitivity reaction to a penicillin (e.g.

anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis) – avoid other penicillinsand cephalosporins with similar side chain, unless patient undergoes desensitization.

Treatment options include cephalosporins with dissimilar side chains or carbapenems or non-beta-lactam antibiotics – Note: ceFAZolin does not share a side chain with any beta-lactam agent.

d. has a documented severe type-1 immediate (Ige-mediated) hypersensitivity reaction to a cephalosporin(e.g. anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis) – avoidcephalosporins with similar side chains and penicillins with similar side chains (see figure 2) unlessdesensitization is performed.

Treatment options include penicillins with dissimilar side chains, cephalosporins with dissimilarside chains, carbapenems or non-beta-lactam antibiotics.

49

Figure 1: Management Diagram

Reported Penicillin Allergy

Assess the nature of the allergy

Onset within 1-72 hours of administration

of: Anaphylaxis, hypotension,

bronchoconstriction, allergic rhinitis,

early onset urticaria, stridor,

angioedema

Intolerance such as: Diarrhea, Nausea, Vomiting, Headache

Onset after more than 72 hours of

administration of: non-pruritic

morbiliform rash, maculopapular rash

Onset after more than 72 hours of

administration of: Stevens-Johnson syndrome, toxic

epidermal necrolysis, immune hepatitis, DRESS, serum

sickness, hemolytic anemia or interstitial

nephritis

Avoid testing, desensitizing and re-challenging with all

beta-lactam antibiotics

Ok to attempt beta-lactam

therapy

Further assess the allergy

How long ago? What specific agent?

Re-challenged? Penicillin skin testing available?

Positive Penicillin Skin Test

Avoid all penicillins as well as beta-lactams

with a similar side chain (see figure 2) or

consider desensitization or select a non-beta-lactam antibiotic

Convincing history of an IgE-mediated

reaction: Avoid all penicillins as well as beta-lactams

with a similar side chain (see figure 2) or

consider desensitization or select a non-beta-lactam antibiotic.

Yes No

Negative Penicillin Skin test

Consider oral challenge in a

monitored setting; if negative, penicillin

class antibiotics may be used

Ok to attempt therapy with a different beta-

lactam

50

Beta-lactam cross-allergy

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PENICILLINS

penicillin X X X X X X X

amoxicillin X X X X X X X X X

ampicillin X X X X X X X X X

cloxacillin X X X X X

piperacillin X X X X X

ticarcillin X X X X X

1ST GENERATION

CEPHALOSPORION

cefadroxil X X X X X

ceFAZolin

cephalexin X X X X X

cephalothin X X X

2ND GENERATION

CEPHALOSPORIN

cefaclor X X X X X

cefprozil X X X X X

cefuroxime X

cefOXitin X X X

3RD GENERATION

CEPHALOSPORIN

cefixime

cefotaxime X X X

cefTAZidime X

cefTRIAXone X X

4TH GEN CEPH cefepime X X

CARBAPENEMSmeropenem X X

imipenem X X

ertapenem X X

Monobactam aztreonam X

Each ‘X’ in the matrix indicates side-chain and/or major/minor antigenic similarity between two antibiotics. For type-1 immediate hypersensitivity there is a risk of cross-allergenicity between pairs due to similar side-chains and/or major/minor antigenic determinants, use NOT recommended without desensitization.

For example: a patient allergic to amoxicillin would likely manifest a reaction to ampicillin, cloxacillin, piperacillin, ticarcillin, cefadroxil, cephalexin, cefaclor and cefprozil but NOT to ceFAZolin, cefuroxime or cefTRIAXone, etc.

Figure 2: Matrix of Beta-Lactam Cross Allergy (based on similar core and/or side chains) 5,6,7,8,9:

*Please note that the Matrix of Beta-Lactam Cross Allergy should only be used to evaluate the risk ofcross-reactivity in patients with type 1 immediate (IgE-mediated) hypersensitivity reactions to a beta-lactam (e.g. anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis). Pleaserefer to figure 1 for all other types of reactions.

51

Therapeutic Review

Beta-lactam antibiotics are the most commonly prescribed class of antimicrobials and include penicillins, cephalosporins, carbapenems and monobactams (table 1).9 Due to similarities in their beta-lactam ring structure it has been widely accepted that penicillins, cephalosporins and carbapenems have significant cross-reactivity with other classes of beta-lactams.5,9,10,11 Historically it has been reported that approximately 10% of patients allergic to penicillins are also allergic to cephalosporins and up to 50% cross-reactivity has been reported between penicillins and carbapenems.4,5,9,10,11 Therefore, it has been commonly recommended that patients with a severe allergic reaction to one class of beta-lactam antibiotic should not receive any beta-lactam antibiotic.9 This historic over-estimation of cross-sensitivity between classes of beta-lactams is inaccurate and based on flawed methodologies.12

Studies have shown that physicians are more likely to prescribe antimicrobials from other classes when patients have a documented penicillin or cephalosporin allergy.13,14 Non beta-lactam alternatives may be: less effective, more toxic, broader spectrum, more expensive and more likely to lead to infection or colonization with resistant organisms.4,13,15,16,17 The inaccurate documentation of a penicillin allergy can lead to undesirable patient outcomes. For example, one study showed that patients with a documented penicillin allergy at admission spend more time in hospital and are more likely to be exposed to antibiotics associated with C.difficile and vancomycin resistant Enterococcus.18 In addition they had increased prevalence rates for infections secondary to C.difficile, vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus.18 Another study showed that patients with an “allergy” label (to any antimicrobial) in their medical record were more likely to have longer hospital stays, to be admitted to an intensive care unit, to receive more than one antibiotic during their hospitalisation, and to die during hospitalisation.36

Practice however is changing because allergies have been better defined and the role of the chemical structure on the likelihood of cross-reactivity is now better understood. Recent data shows that the rate of allergic cross-reactivity between penicillins and other beta-lactams is much lower than previous estimates.4,5,9,11

Determining the nature of the patient’s reaction is an important step in differentiating between an allergic reaction and an adverse drug reaction such as nausea, vomiting, diarrhea and headache.5,9 Immunologic reactions to medications are generally classified according to the Coombs and Gell classification of hypersensitivity reactions (see table 2).5,9 The onset and presentation of the reaction can be used to help classify the reaction and determine whether or not a beta-lactam antibiotic may be used (table 2).5,9 Type-1, immediate hypersensitivity reactions, are immunoglobulin (Ig) E-mediated reactions and are the only true allergic reactions where the potential risk of cross-reactivity between beta-lactams should be considered.5,9 Type-1 immediate hypersensitivity reactions usually occur within 1 hour of exposure and typically manifest as anaphylaxis, bronchospasm, angioedema, stridor, wheezing, hypotension, urticaria or a pruritic rash.5 The incidence of these reactions is very low.19 Nonurticarial and nonpruritic rashes are almost certainly not IgE-mediated.5

Penicillins

Penicillin is the most frequently reported drug allergy and is reported in 5-10% of the population.20,21,22 Studies have shown that between 80 and 95% or more of those patients reporting a penicillin allergy

52

do not in fact have true hypersensitivity reactions and the vast majority of these patients can tolerate beta-lactams.1,10,21,22,23,24,25

The use of penicillins can be associated with a nonimmediate, nonpruritic, nonurticarial rash in up to 10% of patients that is unlikely to be IgE-mediated and most often idiopathic or T-cell mediated.5,26 While inconvenient, these reactions have not been associated with anaphylaxis and pose no risk of cross reactivity with other beta-lactams.26 An example is the nonpruritic maculopapular rash commonly seen after the administration of ampicillin or amoxicillin to children suffering from infectious mononucleosis secondary to the Epstein-Barr virus.27

Only a type-1 immediate (IgE-mediated) hypersensitivity reaction to a penicillin manifesting as: anaphylaxis, bronchospasm, angioedema, hypotension, urticaria or pruritic rash warrants the avoidance of other penicillins and cephalosporins with similar side chains.4,5,9,11 Cross-reactivity between penicillins (figure 2) may be due to shared common antigenic determinants based on similarities in their core ring structure that is common to all penicillins and/or the side chains that distinguish different penicillins from one another; therefore, cross-reactivity cannot be based on side chain similarities alone.

Currently, there is one Health Canada-approved standardized penicillin skin test. PRE-PEN contains the major antigenic determinant of penicillin and is used to rule out a type-1 immediate (IgE-mediated) penicillin allergy. Available literature suggests that the skin test using both major and minor antigenic determinants are roughly 50-60% predictive of penicillin hypersensitivity with a 97-99% negative predictive value.4 When penicillin skin testing is not available, the approach to penicillin allergic patients is based on their reaction history and the need for treatment with a penicillin.28 While patients with a convincing reaction history are more likely to be allergic, those with vague histories cannot be discounted as they may also be penicillin allergic.28 The time passed since the reaction is useful because 50-80% of penicillin allergic patients lose their sensitivity after 5 and 10 years respectively.2,29,30

Skin testing, desensitization or re-challenge with a beta-lactam should not be performed in those patients with a history of Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, serum sickness, immune hepatitis, hemolytic anemia or interstitial nephritis.5

Cephalosporins

Cephalosporin-induced skin reactions, described as urticarial, rash, exanthema and pruritus, occur in approximately 1 to 3% of patients.31

Early analysis of cephalosporin use in penicillin allergic patients was complicated by the uncritical evaluation of “allergic reaction”.5,9,11 Any adverse reaction to cephalosporins was often classified as “allergic”.5,9,11 This, accompanied with possible penicillin contamination in early cephalosporin production, resulted in overestimations of cross-sensitivity.5,9 In addition, penicillin allergic patients are more likely to have an allergy to any drug when compared to other patients.4,5,9,10,11 Investigations have shown that individuals with a penicillin allergy are three times more likely to develop new allergies to unrelated compounds, leading to further overestimations of cross-reactivity.5,9,10

Cross-reactivity between penicillins and cephalosporins is due to similarities in side chains at the C-3 or C-7 position as shown in table 3 and not similarities in beta-lactam ring structure as previously speculated.4,5,9,11 The American Academy of Pediatrics states that the likelihood of a penicillin allergic

53

patient reacting to a cephalosporin with a different side chain is similar to that of a non-penicillin allergic patient.5 A prospective study with skin test or challenge dose confirmed penicillin allergy demonstrated a 0% cross-reactivity to ceFAZolin, cefuroxime and cefTRIAXone. None of these agents share a side chain with penicillin.32 Meanwhile the risk of cross-reactivity may be up to 40% between penicillins and cephalosporins with the similar R-group side chains.3,33 A retrospective population based analysis of 3.9 million patients revealed that there was no significant difference between the rates of anaphylaxis to a cephalosporin in patients with and without documented penicillin “allergy”. This study also highlighted that the practice of avoiding 1st and 2nd generation cephalosporins and using 3rd or 4th generation cephalosporins instead was associated with higher rates of C. difficile infection. The authors go on to say: “Warnings against the administration of cephalosporins to patients with unconfirmed penicillin allergy should be removed from electronic medical record systems.The public would be better served by warnings that the use of cephalosporins, particularly third- or higher generation parenteral cephalosporins, is associated with an increased risk of C difficile infection within 90 days.”38

Cross-reactivity between cephalosporins is low because of the significant heterogeneity of the side chains at the C-3 and C-7 positions.9,34 Therefore, if a patient has a cephalosporin allergy, one can safely prescribe another cephalosporin that has dissimilar side chains at both C-3 and C-7 positions.34 A prospective study evaluating the possibility of using alternative cephalosporins in patients with confirmed cephalosporin allergy demonstrated that cephalosporin allergies are not a class effect, and that patients with confirmed cephalosporin allergy can safely receive cephalosporins with dissimilar side chains.37

CeFAZolin is not expected to cross react with any penicillin or cephalosporin as it does not share a side chain with any beta-lactam.4,34

Carbapenems

Early studies evaluating the risk of cross-reactivity between penicillin and carbapenems found rates upwards of 47%. However, these studies had poor definitions of allergy and variable methods for determining allergy status.9 A more recent systematic review was completed to collect and combine all published data on pediatric and adult patients reported to have a clinical history of type-1 immediate hypersensitivity (IgE-mediated) to a penicillin and/or cephalosporin who were then given a carbapenem.35 Within the study allergic reactions were classified as proven, suspected or possible IgE-mediated and non-IgE-mediated.35 Overall, for patients with a history of proven, suspected or possible IgE-mediated reaction to a penicillin; 4.3% (36/838) had a suspected hypersensitivity reaction to a carbapenems but only 20 were compatible with an IgE-mediated reaction and only one was considered to be proven.35 The authors concluded that carbapenems would be a reasonable option when antibiotics are required in patients with IgE-mediated reactions to penicillins.35 They advise that clinicians proceed with caution by administering the first dose of carbapenem in a setting where anaphylaxis can be managed and to consider giving via a graduated challenge.35 If at any stage the patient reacts then the options are to use a carbapenem desensitization protocol or switch to a non-beta-lactam antibiotic.35

54

Desensitization

Desensitization, or temporary induction of drug tolerance, is used for patients with a documented or convincing history of type-1 immediate (IgE-mediated) beta-lactam allergy and/or positive skin test and a serious infection where non-cross-reacting alternatives are not appropriate.2,28 The goal of desensitization is to modify a patient’s immune response to allow safe treatment with the allergenic drug.28

Desensitization will not prevent non-IgE mediated reactions and should never be attempted in patients with reactions involving major organs or severe cutaneous reactions (e.g. interstitial nephritis, SJS, TEN, DRESS, etc.).2

Desensitization is performed by administering incremental doses of the allergenic drug.3 Usually the procedure is complete within hours and starts in the microgram range.28 Dosages are usually doubled every 15 to 30 minutes until therapeutic doses are achieved.28 When the desensitization process is complete, treatment with the select beta-lactam should be started immediately and must not be interrupted during the treatment course.2,28 Desensitization is usually lost within two days of cessation and must be repeated if the beta-lactam is required in the future.2,28

Graduated Challenge

Graduated challenges are used when there is a low likelihood of drug allergy and differ from desensitization in that they do not alter the patient’s underlying immune response to the drug in question.28 Their purpose is to allow cautious administration in patients unlikely to be allergic when there is no intention to alter the patient’s immune response.28 If the graduated challenge is tolerated the patient is then considered not to be allergic and not at increased risk for future reactions.28 Graduated challenges should never be performed in patients with reactions involving major organs or non-IgE mediated severe cutaneous reactions (e.g. interstitial nephritis, SJS, TEN, DRESS, etc…).28

The starting dose of a graduated challenge is often higher than that used for desensitization and usually only involves 2 to 3 steps and completed within hours.28 For a graduated challenge for an intravenous antibiotic, 1% of the full dose is administered, then 10 % of the full dose, then the full dose, separated by 30 minutes to 1 hour each and under careful observation.2,3 If at any point a reaction occurs the graduated challenge is stopped.

The decision to use a graduated challenge is based on the risk of cross-reactivity and the description and remoteness of the allergic reaction in question. Treatment options requiring desensitization or graduated challenge should be avoided in severe infections (ex. febrile neutropenia, sepsis, meningitis, etc.) where delays in appropriate drug therapy are associated with poor patient outcome, in these scenarios a non-beta lactam treatment option should be considered for empiric therapy.

Allergy assessment

Allergy evaluation and “de-labelling” is emerging as a new antimicrobial stewardship intervention. Recent IDSA guidelines recommend that antimicrobial stewardship programs promote allergy assessments and penicillin skin testing when appropriate, as these may enhance the use of first-line agents.39 A multicenter prospective trial demonstrated that antimicrobial stewardship pharmacists performing beta-lactam allergy skin testing and graduated challenge at the point of care was

55

associated with greater use of preferred beta-lactam therapy without increasing the risk of adverse drug reactions.40

Table 1: Classification of Beta-Lactams

Penicillins Cephalosporins

Carbapenems Monobactam First Generation

Second Generation

Third Generation

Fourth Generation

penicillin ampicillin amoxicillin cloxacillin piperacillin ticarcillin

cefadroxil cefaclor cefOXitin cefprozil cefuroxime

cefTAZidime cefixime cefTRIAXone cefotaxime

cefepime ertapenem aztreonam ceFAZolin imipenem cephalexin meropenem

Table 2: Coombs and Gell Classification of Hypersensitivity Reactions4,5,31,38,41,42,43,44 Type Mediator Onset Clinical Reaction Comments

I - Immediate and Acute hypersensitivity

IgE antibodies Less than 1hr (Rarely up to 72 hours)

Anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis

Anaphylaxis: Penicillins 0.015 – 0.2%

Cephalosporins 0.0001 – 0.1%

Avoid the offending agent and side chain related agents (See Figure 2)

II – Delayed cytotoxic antibody-mediated hypersensitivity

IgG and IgM antibodies

Greater than 72 hours

Hemolytic anemia, thrombocytopenia, neutropenia

Drug specific, avoid the offending agent

III – Antibody complex-mediated hypersensitivity

IgG and IgM complexes


Serum sickness, glomerulonephritis, small vessel vasculitis, drug fever

Antibody-antigen complexes precipitate in tissues and potentially affect any end organ

IV – Delayed type hypersensitivity

T-Cells Greater than 72 hours

Contact dermatitis, pustulosis

Incidence is low. Ex: Eosinophilia, bullous exanthems, severe exfoliative dermatoses (ex. SJS/TEN), interstitial nephritis, immune hepatitis and some morbilliform or maculopapular rashes

Idiopathic Reactions Unknown Usually greater than 72 hours

Maculopapular or morbilliform rashes

1 – 4% of patients receiving beta-lactams Not a contraindication to future use of beta-lactam antibiotics

*Anaphylaxis: defined as serious hypersensitivity reaction that is rapid in onset and may cause death, typically involving theskin, mucosal tissue or both and either respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced peakexpiratory flow, hypoxemia) or reduced blood pressure or the associated symptoms and signs of end-organ dysfunction.

56

Table 3: Beta-Lactam Groups with Similar Side-Chains Similar C-7 Side Chain

(Cross Reactions between agents within one group is possible)

Similar C-3 Side Chain (Cross reactions between agents within one group is possible)

Group 1 Group 2 Group 3 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 penicillin cefOXitin

amoxicillin ampicillin cefaclor cephalexin cefadroxil cefprozil

cefepime cefotaxime cefTRIAXone

cefadroxil cephalexin

cefotaxime cephalothin

cefuroxime cefOXitin

cefixime cefTAZidime aztreonam

Note: • CeFAZolin does not share a side chain with any beta-lactam and is not expected to cross react with other agents• Amoxicillin, ampicillin, penicillin, cloxacillin, piperacillin and ticarcillin share common major allergic determinants

based on similarities in their core structure and/or side chains; therefore, cross-reactivity cannot be based on sidechain similarities alone

57

Antimicrobial Allergy Evaluation Tool (NB Provincial Health Authorities Anti-Infective Stewardship Committee, May 2016)

Reaction (as indicated in the patient’s chart or described by the patient )

Personal history Asthma Autoimmune disease Atopic dermatitis Latex allergy Prior anaphylaxis Multiple drug intolerance syndrome Multiple drug allergy syndrome Food allergy: ________________Other:_________________________________________________________________________________

Patient questionnaire 1. When did the reaction take place? _________________________________________________________

2. How old was the patient at the time of the reaction? ___________________________________________

3. Does the patient recall the reaction? If not, who informed them of the reaction? ___________________________________________________________________________________________________________

4. Does the patient remember which medication? _______________________________________________

5. What was the medication prescribed for? ____________________________________________________

6. What was the route of administration? ______________________________________________________

7. How long after starting the medication did the reaction begin? ________________________________________________________________________________________________________________________

8. Describe the reaction: ________________________________________________________________________________________________________________________________________________________

9. Did the patient seek medical care due to the reaction? _________________________________________

10. Was the medication discontinued? If so, what happened after it was discontinued? ________________________________________________________________________________________________________

11. Did the patient have any other ongoing medical problem at the time of the reaction? _______________________________________________________________________________________________________

12. What other medications was the patient taking? Why and when were they prescribed? _____________________________________________________________________________________________________

13. Has the patient taken any similar medications before or after the reaction? If so, what was the result? _________________________________________________________________________________________

14. Has the patient ever experienced this reaction without intake of the suspected medication? _________________________________________________________________________________________________

Assessment Probable non-severe delayed hypersensitivity

reaction (non-IgE mediated) Probable non-allergic adverse reaction or

intolerance

Probable type 1 immediate hypersensitivity reaction(IgE mediated)

Probable severe delayed hypersensitivity reaction(non-IgE mediated)

Completed by:___________________________________________ Date/time:_______________________ 58

Table 1: Patient questionnaire1,2,4,5,6,7,12,13,14

Question Comments When did the reaction take place? Patients with type 1 immediate (IgE-mediated) hypersensitivity reactions

to penicillin may lose their sensitivity over time (50% after 5 years, and 80% after 10 years)

How old was the patient at the time of the reaction?

Certain confounding factors may be more common depending on the patient’s age. (Example: viral exanthems in pediatric patients)

Does the patient recall the reaction? If not, who informed them of the reaction?

Vague histories do not rule out serious reactions. However, it is less likely to be a serious hypersensitivity reaction if the patient or family cannot recall the specifics of the reaction.

Does the patient remember which medication? Knowing the specific antimicrobial which caused the reaction can help in determining safe alternatives.

What was the medication prescribed for? Sometimes patients confuse symptoms of the condition with adverse reactions of the medication. (e.g.: Strep. pyogenes scarlet fever rash being confused as a drug-reaction)

What was the route of administration? Hypersensitivity reactions can be more common when medications are administered intravenously compared to orally.

How long after starting the medication did the reaction begin?

Timeframe is essential to distinguish between an IgE-mediated immediate hypersensitivity reaction or non-IgE mediated delayed reaction.

Describe the reaction. Obtain specific information from the patient. (Ex: if a rash; determine location, morphology, etc.)

Did the patient seek medical care due to the reaction?

Can be of value to stratify how severe the reaction was.

Was the medication discontinued? If so, what happened after it was discontinued?

Discontinuing the medication will have varying results. (e.g.: depending on the type of skin reaction, symptoms may or may not improve after discontinuation)

Did the patient have any other ongoing medical problem at the time of the reaction?

Certain viral infections [e.g. Epstein-Barr virus (EBV), Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV)] are associated with non-IgE mediated cutaneous drug reactions that are often misdiagnosed as “allergic reactions”.

What other medications was the patient taking? Why and when were they prescribed?

Concomitant medications could cause or contribute to the reaction.

Has the patient taken any similar medications before or after the reaction? If so, what was the result?

Tolerance of structurally similar medications is not always indicative of tolerance of the suspected medication; however, it can assist in determining safe alternatives.

Has the patient ever experienced this reaction without intake of the suspected medication?

If the same reaction has occurred without exposure to the suspected medication, it may be caused by other factors.

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Therapeutic review

Allergy evaluation is an essential component of patient care. Beta-lactams, as a class, are generally safe; allergic and adverse reactions are over diagnosed and over reported. For example, up to 10% of the population will report a penicillin allergy; but up to 95% (or more) of these patients do not have a true allergy.4,6,11

Fearing a potential anaphylaxis secondary to beta-lactam use, many clinicians will over diagnose penicillin allergy or simply accept a diagnosis of penicillin allergy from patients without a proper history of the reaction.2 Studies have shown that physicians are more likely to prescribe antimicrobials from other classes when patients have a documented penicillin or cephalosporin allergy.2,9 Non beta-lactam alternatives may be: less effective, more toxic, broader spectrum, more expensive and more likely to lead to infection or colonization with resistant organisms.6,9 Unfortunately, a penicillin allergy label is not benign. Simply being labelled as having an allergy to penicillin increases the likelihood of prolonged hospital stay and increases the risk of infections due to Clostridium difficile, vancomycin-resistant Enterococcus (VRE), and methicillin-resistant Staphylococcus Aureus (MRSA).10

Most patients have no current physical findings that can either prove or disprove their allergy label.2 The initial probability of a true allergy is almost always determined by the allergy history.2 The included patient questionnaire can assist clinicians in obtaining a detailed allergy history.

A detailed investigation of the patient’s allergy history is necessary to differentiate between true type 1 (IgE-mediated) immediate hypersensitivity reactions (true allergic reactions) and non IgE-mediated hypersensitivity reactions or intolerances/adverse reactions. While some of the non IgE-mediated reactions are minor, other types of reactions can be severe (e.g. interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, etc.). Table 2 below subdivides the reactions based on the Coombs and Gell classification of hypersensitivity reactions:

Table 2: Coombs and Gell Classification of Hypersensitivity Reactions 6,7

Type Mediator Onset Clinical Reaction Comments I - Immediate and Acute hypersensitivity

IgE antibodies Within 1hr (Rarely up to 72 hours)

Anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis

Anaphylaxis: Penicillins 0.01-0.05%

Cephalosporins 0.0001-0.1%

II – Delayed cytotoxic antibody-mediated hypersensitivity

IgG and IgM antibodies


Hemolytic anemia, thrombocytopenia, neutropenia

Drug specific

III – Antibody complex-mediated hypersensitivity

IgG and IgM complexes


Serum sickness, glomerulonephritis, small vessel vasculitis, drug fever

Antibody-antigen complexes precipitate in tissues and potentially affect any end organ

IV – Delayed type hypersensitivity

T-Cells Greater than 72 hours

Contact dermatitis, pustulosis

Incidence is low. Ex: Eosinophilia, bullous exanthems, severe exfoliative dermatoses (ex. SJS/TEN), interstitial nephritis, immune hepatitis and some morbilliform or maculopapular rashes

Idiopathic Reactions Unknown Usually greater than 72 hours

Maculopapular or morbilliform rashes

1 – 4% of patients receiving beta-lactams

The time to onset of the reaction can be a helpful tool in determining if the reaction was in fact a true type 1 immediate (IgE-mediated) hypersensitivity reaction. Type 1 reactions usually occur within an hour of exposure, with the possibility of occurring up to 72 hours post-exposure, and can include anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor and pruritis.5,6,7

60

Cutaneous reactions

Many patients may report a “rash” as an allergic reaction; however more information should be sought to assist in defining the true nature of the reaction. Cutaneous reactions can range from non-severe delayed maculopapular rashes to life-threatening toxic epidermal necrolysis; therefore it is essential to further question the patient.

Certain infections can either cause cutaneous reactions or predispose patients to reacting to antimicrobials. Patients suffering from certain bacterial infections (e.g. Streptococcus pyogenes, Mycoplasma pneumoniae) can develop cutaneous symptoms, irrespective of which antibiotic is used.18,22 Certain viral infections [e.g. Epstein-Barr virus (EBV), Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV)] can also directly cause cutaneous symptoms.14,18,22 Patients suffering from these viral infections may also be at a higher risk to react to certain antimicrobials.2,4,12,13 A notable example is the delayed morbilliform rash that often develops when patients suffering from EBV are treated with an aminopenicillin, such as amoxicillin.4,18

Please see table 3 below for a brief description of certain cutaneous reactions.

Table 3 – Cutaneous reactions 1,2,15,16,18,19,20,21 Type of skin reaction Chronology Description

Angioedema Onset: Usually immediate (0-6 hours)

Duration: Resolution within 24-72 hours

Region(s) affected: Lips, eyelids, earlobes, tongue, mouth, larynx, genitalia

Morphology: Skin-coloured circumscribed edema involving the subcutaneous tissues. (can be asymmetrical/unilateral)

More details: Non-pruritic; often very frightening for patients; can be painful

DRESS syndrome (Drug Rash with

Eosinophilia and Systemic Symptoms)

Onset: 1-8 weeks after exposure

Duration: Weeks- months (even after discontinuing the suspected medication)

Region(s) affected: Classic distribution: Face, upper trunk, extremities (but can progress anywhere on the surface of the skin and can sometimes have mucosal involvement)

Morphology: Most commonly begins as an erythematous, pruritic, morbilliform rash

More details: Pruritis and fever usually precede cutaneous eruptions. Can cause facial edema, which can be mistaken for angioedema.

Systemic systems involved: - Lymphatic: lymphadenopathy is very common- Hematologic: leukocytosis, eosinophilia, lymphocytosis- Hepatic: hepatosplenomegaly, hepatitis, elevated livertransaminases, elevated alkaline phosphatase- Renal: hematuria, proteinuria, elevated BUN and creatinine- Other: pulmonary, cardiac, neurologic

Erythema multiforme Onset: Within 3-5 days (May include prodromal symptoms of an upper respiratory infection)

Duration: Approximately 2 weeks

Region(s) affected: Often appear on the extremities (hands, palms, extensor of the forearms, soles of the feet, etc.) and can spread inwards towards the trunk. May involve mucous membranes of the mouth and genitalia.

Morphology: Well-demarcated, circular, erythematous papules; often “target” or “iris”-like.

More details: - Can be difficult to discern from Stevens-Johnson Syndrome- Often associated with HSV or mycoplasma infections- Fever, if present, is usually mild

61

Type of skin reaction Chronology Description Maculopapular rash /

Morbilliform rash / Exanthems

Onset: Delayed (often more than 72 hours), within the first 2-4 weeks following the initial dose

Duration: Usually fades within 2 weeks

Region(s) affected: Commonly begin on head, neck or upper torso, and progress downward to the extremities.

Morphology: Often bilateral and symmetrical. Usually flat, barely raised, erythematous patches (one to several mm in diameter). Can also include papules.

More details: - With or without pruritis- Can develop into confluent areas- Can be the result of several mechanisms (ex: viral infection,idiopathic, etc.)- Mild eosinophilia is possible, but not common- Fever rarely associated; but is mild if present

Photosensitivity / Phototoxicity

Onset: 5-20 hours after drug + UV light exposure

Duration: N/A

Region(s) affected: Areas most often exposed to the sun (ex: face, back of the hands, back and sides of the neck, extensor surfaces of the forearm, etc.). Classical presentation spares shaded areas, such as under the chin, under the nose, behind the ears.

Morphology: Often resembles exaggerated sunburn, sometimes with blisters. Sharp demarcation at sites where clothing or jewelry were present during light exposure.

More details: Not common with beta-lactam antibiotics

Pruritis Onset: N/A

Duration: N/A

Region(s) affected: Localized or generalized itching; more often generalized when drug induced.

Morphology: Does not require visible cutaneous signs of a reaction.

More details: Mechanism not always clear

Stevens-Johnson syndrome

Onset: Delayed (within 8 weeks of first exposure), but with abrupt onset of symptoms.

Duration: Up to 6 weeks

Region(s) affected: Less than 10% of the body surface is affected. Can affect the skin, eyes, and mucous membranes; such as the lips, mouth, and genital mucous membranes.

Morphology: Often begins with dusky red, flat lesions (sometimes target-like, similar to erythema multiforme), progressing to bullae and necrotic lesions. Leads to blisters and dislodgement of the epidermis.

More details: - Is accompanied by any (or all) of: high fever, malaise, myalgia,arthralgia, headache, ocular involvement, painful stomatitis- A medical emergency; in-hospital mortality = 5-12 %

Toxic epidermal necrolysis Onset: Delayed (within 8 weeks of first exposure), but with abrupt onset of symptoms.

Duration: Up to 6 weeks

Region(s) affected: Greater than 30% of the body surface is affected. Can affect the skin, eyes, and mucous membranes; such as the lips, mouth, and genital mucous membranes. Hairy regions of the skin are often spared.

Morphology: See Stevens-Johnson Syndrome; eventually can resemble extensive second degree burns

More details: - Is accompanied by any (or all) of: high fever, fatigue, vomiting,diarrhea, malaise, myalgia, angina, arthralgia, headache, ocularinvolvement, painful stomatitis- A medical emergency; in-hospital mortality more than 30%

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Type of skin reaction Chronology Description Urticaria Onset: Immediate,

usually within 36 hours

Duration: Rarely persist for more than 24 hours

Region(s) affected: Can occur in any location. Involves the superficial portion of the dermis, and not subcutaneous tissues.

Morphology: Raised, erythematous areas of edema (wheals), sometimes with central pallor. Will often blanch with pressure.

More details: - Often pruritic- May or may not be accompanied by angioedema, can progress toanaphylaxis

For more information, please see the Management of Penicillin and Beta-Lactam Allergy guideline prepared by the NB Provincial Health Authorities Anti-Infective Stewardship Committee.

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http://uptodate.z1b.nbhealthlibrary.ca/contents/drug-reaction-with-eosinophilia-and-systemic-symptoms-dress/abstract/2

http://uptodate.z1b.nbhealthlibrary.ca/contents/drug-reaction-with-eosinophilia-and-systemic-symptoms-dress/abstract/2

Antimicrobial Route of Administration (IV to PO) Therapeutic Conversion

Patients on the targeted IV antimicrobials should be assessed within 72 hours of the start of IV therapy and regularly thereafter for the appropriateness of IV to PO conversion based on the following criteria (see below for list of targeted antimicrobials and their renal dose adjustments).

GENERAL CRITERIA The patient:

� is tolerating food, enteral feeds and/or other oral medications AND � is not showing evidence of malabsorption (e.g.diarrhea/vomiting) AND � does not have continuous nasogastric suctioning, gastrectomy, malabsorption syndrome, GI obstruction or

ileostomy

ANTIMICROBIAL CRITERIA The patient:

� is clinically improving (which may include documented improved clinical signs and symptoms of infection, normalizing white blood cell count, etc…) AND

� is hemodynamically stable AND � has been afebrile for at least 48 hours (i.e. temperature less than 38°C) AND � is not being treated for a condition where parenteral therapy is clinically indicated, including but not

limited to: endocarditis, CNS infection, osteomyelitis, S. aureus bacteremia, undrained or complicated abscess, cystic fibrosis, febrile neutropenia AND

� doesn’t have a pathogenic isolate showing resistance to the suggested antibiotic

Version: 20160317

Table 1: Route of Administration (IV to PO) Conversion Protocol for Targeted Antimicrobials

Drug IV dose PO drug/dose Interval azithromycin 250 or 500 mg q24h azithromycin 250 mg q24h

ceFAZolin1 1000 mg q8h cephalexin1,2 500 mg q6h 2000 mg q8h cefTRIAXone (For community-acquired pneumonia or acute exacerbation of COPD)

1000 mg q24h amoxicillin/clavulanate1,2 875/125 mg q12h 2000 mg q24h

ciprofloxacin1 400 mg q12h or q24h ciprofloxacin1 500 mg Same as IV 400 mg q8h ciprofloxacin1 750 mg q12h

clindamycin 600-900 mg q8h or q12h clindamycin 450 mg q6h metroNIDAZOLE1 500 mg q8h or q12h metroNIDAZOLE1 500 mg Same as IV moxifloxacin 400 mg q24h moxifloxacin 400 mg q24h levofloxacin1 500-750 mg q24h levofloxacin1 (dose same as IV) Same as IV 1Dose adjustment required in renal impairment 2Assess for true penicillin allergy

Table 2: Antimicrobial Dosing in Renal Impairment

Drug Usual adult dose

(CrCl equal to or greater than 50 mL/min)

CrCl 30 - 49 mL/min CrCl 10 - 29 mL/min CrCl less than 10 mL/min

amoxicillin + clavulanate 875/125 mg q12h no adjustment 500/125 mg q12h 500/125 mg q24h cephalexin 500 mg q6h 500 mg q8h 500 mg q12h 500 mg q24h

ceFAZolin 1000 mg q8h no adjustment 1000 mg q12h 1000 mg q24h 2000 mg q8h no adjustment 2000 mg q12h 2000 mg q24h

ciprofloxacin PO 250–500 mg q12h no adjustment extend interval to q24h extend interval to q24h 750 mg q12h 500 mg q12h 500 mg q24h 500 mg q24h

ciprofloxacin IV 400 mg IV q12h no adjustment 400 mg q24h 400 mg q24h 400 mg IV q8h 400 mg q12h 400 mg q24h 400 mg q24h

metroNIDAZOLE 500 mg q8h or q12h no adjustment no adjustment 500 mg q12h

levofloxacin 750 mg q24h CrCl 20-49 mL/min

750 mg q48h CrCl less than 20 mL/min

500 mg q48h

500 mg q24h CrCl 20-49 mL/min 250 mg q24h

CrCl less than 20 mL/min 250 mg q48h

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Surgical Prophylaxis Guidelines Prepared by:

NB Provincial Health Authorities Anti-Infective Stewardship Committee

2018

65

Surgical Prophylaxis GuidelinesSection 1: General Principles Page

General Principles 67 Timing of Prophylaxis 67 Duration of Antibiotic 67 Choice of Prophylactic Antibiotic 68 Antibiotic Dosing 69

• Intra-operative Dosing 69 • Renal or Hepatic Impairment 69 • Aminoglycoside Dosing 69 • Vancomycin Dosing 70 • Dosing in Obesity 70 • Pediatric Dosing: 70

Section 2: Surgical Prophylaxis Recommendations Cardiac 70 Gastrointestinal

• Appendectomy 71 • Colorectal 71 • Small Intestinal 71 • Gastroduodenal 72 • Hernia Repair 72 • Hepatic/Pancreatic/Biliary 72

Head and Neck 74 Neurosurgery 74 Obstetrics and Gynecology 75 Ophthalmology 76 Oral and Maxillofacial 76 Orthopedics 77 Plastic Surgery 77 Spine 79 Thoracic 79 Trauma 80 Urology 81 Vascular 82

References 109

66

These guidelines provide general recommendations for appropriate prophylactic antibiotic use for common surgical procedures; the list of surgical procedures is not all inclusive.

SECTION 1: GENERAL PRINCIPLES OF ANTIMICROBIAL PROPHYLAXIS1,2,3,4,6,7,8,10,11

• Antimicrobial prophylaxis should be provided for surgical procedures for which it has beendemonstrated to be beneficial.

• Antimicrobial surgical prophylaxis is administered to achieve serum and tissue antibioticconcentrations that exceed the minium inhibitory concentration of the majority of organismslikely to be encountered, at the time of the incision and for the duration of the procedure. Keyto achieving this goal is:

appropriate dosing timely administration of first dose antimicrobial within 60 to 120 minutes of

surigical incision repeat dosing for prolonged procedures or in the event of major blood loss.

• It is estimated that 50% of surgical site infections are preventable by application of evidence-based strategies.

• General patient-related risk factors for surgical site infection include extremes of age,compromised nutritional status, obesity, diabetes mellitus, tobacco use, co-existent remotebody site infection, altered immune response, corticosteroid therapy, recent surgical procedure,length of preoperative hospitalization and colonization withmicroorganisms

TIMING OF PROPHYLACTIC ANTIMICROBIAL DOSE:

• Preoperative doses of antimicrobials must be given in the 60 minutes before the first surgicalincision. Some agents, such as fluoroquinolones and vancomycin, require administration overone to two hours; therefore, the administration of these agents should begin within 120minutes before surgical incision.

• Patients receiving therapeutic antimicrobials for an infection before surgery should be givenadditional antimicrobial prophylaxis before surgery.

DURATION OF PROPHYLACTIC ANTIBIOTIC:

• Post-operative doses of prophylactic antibiotics are generally unnecessary.

• If antimicrobial prophylaxis is continued post-operatively, the duration should be less than 24hours, regardless of the presence of intravascular catheters or indwelling drains.

• If the surgery is contaminated, it should be indicated that the post-operative antibiotic ordersare for treatment.

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CHOICE OF PROPHYLACTIC ANTIMICROBIAL:

• Antimicrobial prophylaxis is generally unnecessary for “clean” surgical procedures.

• For the majority of surgical procedures in which antimicrobial prophylaxis is indicated, a singledose of ceFAZolin 2 g IV given within the 60 minutes before the first surgical incision isappropriate.

• Beta-lactam allergy: Obtain a reliable history and document exact nature of the reaction.Approximately 10% of the population report having a penicillin allergy; however, greater then90% of these individuals are not truly allergic. Non-beta-lactam options may be more toxic andless effective. For example, there is an increasing rate of gram-positive resistance toclindamycin. In addition, a study by Blumenthal et al. found that patients with a reportedpencillin allergy had a 51% increased risk of surgical site infection that was primarily related toreceiving a non-beta-lactam antibiotic.17

o For immediate or Type 1 (IgE-mediated) hypersensitivity reactions (e.g. anaphylaxis,urticaria, angioedema, hypotension, bronchospasm, stridor, pruritus), cross-reactivitybetween cephalosporins and penicillins is due to similarity in side-chains and wasoverestimated in the past. There is only significant risk of cross-reactivity among penicillinsand between penicillins and cephalosporins with similar side-chains.

o Immediate or Type 1 (IgE-mediated) hypersensitivity reaction to penicillin warrants theavoidance of cephalosporins with similar side chains and other penicillins.

o Cross-reactivity among cephalosporins is low due to heterogeneity among side chains.Cephalosporin allergic patients may safely receive another cephalosporin with dissimilar sidechains.

o CeFAZolin does not share a side chain with any beta-lactam and is not expected to crossreact with other beta-lactams. CeFAZolin is the only systemic beta-lactam included in thisguide and may safely be given to patients with immediate or Type 1 (IgE-mediated)hypersensitivity reactions to penicillins or other cephalosporins. It should only be avoided inpatients allergic to ceFAZolin or who have a severe non-IgE mediated reaction to a beta-lactam antibiotic (see below).

o Severe non-IgE mediated hypersensitivity reactions (Stevens-Johnson syndrome, toxicepidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, immunehepatitis, hemolytic anemia, serum sickness, interstitial nephritis, small vessel vasculitis)-warrant the avoidance of all beta-lactams.

o Idiopathic reactions are not clearly immune-mediated (non-pruritic morbilliform rash) andare not a contraindication to taking a different beta-lactam such as ceFAZolin.

o For more information on assessing beta-lactam allergies, please see the “Management ofPenicillin and Beta-Lactam Allergy” Guide on the NB-ASC website.

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• Known MRSA colonization:

• Consider administration of pre-op vancomycin prophylaxis in addition to recommendedroutine surgical prophylaxis regimen. Vancomycin ALONE is less effective than ceFAZolin forpreventing surgical site infections due to MSSA.

o Consider pre-procedural MRSA decolonization

o Consider consult to infectious diseases/medical microbiology for recommendations

DRUG DOSING

Intra-operative dosing: • For antimicrobials with short half-lives, intra-operative dosing recommended for patients with

normal renal function if: prolonged surgical procedure (> 2 half-lives of the antimicrobial) ORmajor blood loss (>1.5L). If massive blood loss occurs, a second dose should be given promptly.See Table 1.

Table 1. Intra-operative Antibiotic Prophylaxis

Prophylactic Antibiotic Half-life (hours) Recommended re-dosing interval (from time of administration of

the pre-op dose) ceFAZolin 1.2–2.2 Q4h clindamycin 2-4 Q6h aminoglycoside 2-3 N/A* metroNIDAZOLE 6-8 N/A* vancomycin 4-8 N/A* *Recommended redosing intervals marked as “not applicable” (N/A) are based on typical case length; for unusually long procedures, redosingmay be needed except for aminoglycoside dosed at 5 mg/kg.

Renal or Hepatic Impairment: • Antimicrobial prophylaxis for patients with renal or hepatic dysfunction often does not need to

be modified when given as a single dose pre-operatively.

Aminoglycoside dosing: • Aminoglycoside 5 mg/kg (extended interval dose) provides at least 24 hours of antimicrobial

coverage.

• Tobramycin is an acceptable alternative for the indication of surgical prophylaxis in the eventthat gentamicin is not available. Dose based on ideal body weight (IBW), unless actual bodyweight (ABW) is greater than 20% above IBW, then use dosing body weight, calculated asfollows:

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• Ideal body weight (males) = 50 kg + (0.92 x cm above 150 cm) OR 50 kg + (2.3 kg x inches above60 inches)

• Ideal body weight (females) = 45.5 kg + (0.92 x cm above 150 cm) OR 45.5 kg + (2.3 kg x inchesabove 60 inches)

• Dosing body weight = IBW + 0.4 (ABW –IDW)

Vancomycin Dosing:

• Vancomycin 15 mg/kg based on patient’s ABW and rounded to the nearest 250 mg.

Drug dosing in obesity: • Conclusive recommendations for weight-based dosing for antimicrobial prophylaxis in obese

patients cannot be made because data demonstrating clinically relevant decreases in SSI ratesfrom the use of such dosing strategies instead of standard doses are not available in thepublished literature.

• Considering the low cost and favourable safety profile of ceFAZolin, the minimum dose shouldbe 2 g. Increasing the dose to 3 g for those weighing 120 kg or more can easily be justified. Forsimplification, these guidelines recommend 2 g ceFAZolin doses for all adult patients.

Pediatric Dosing:

• Note: This guideline is intended for adults only. Pediatric dosing provided in Table 2.

aThis table applies only to pediatric patients weighing 40kg or less bThe maximum pediatric dose should not exceed the usual adult dose cThis table does not specifically address new born infants

Table 2. Pediatric Prophylactic Antibiotic Dosing a,b,c,

Antibiotic Recommended Dose ampicillin 50 mg/kg ceFAZolin 30 mg/kg cefTRIAXone 50-70 mg/kgciprofloxacin 10 mg/kg clindamycin 10 mg/kg aminoglycoside 2.5 mg/kg based on dosing weight metroNIDAZOLE 15 mg/kg piperacillin-tazobactam

Infants 2 – 9 months: 80 mg/kg of the piperacillin component Children greater than 9 months and less than or equal to 40kg: 100mg/kg of the piperacillin component

vancomycin 15 mg/kg

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SECTION 2: SURGICAL PROPHYLAXIS RECOMMENDATIONS

Patient Selection Pre-Operative Antibiotic Recommendation Post-Operative IV

Antibiotic Duration Preferred Alternate (See Principles)

CARDIAC1,2,3,7,9,12

• Cardiac device insertion(pacemaker implantation)

• Ventricular assist devices

ceFAZolin 2 g* vancomycin 15 mg/kg OR clindamycin 900 mg

No Antibiotics

• CABG• Prosthetic valve• Open heart surgery• Other cardiac procedures


Less than 24 hours

• Cardiac catheterization +/-stenting

No Antibiotics N/A N/A

APPENDECTOMY1,2,7,12

Appendectomy for uncomplicated appendicitis

metroNIDAZOLE 500 mg Plus ceFAZolin 2 g*

metroNIDAZOLE 500 mg Plus aminoglycoside 5 mg/kg

• No Antibiotic• If gangrenous or

perforatedappendicitis orintestine, initiatetreatment course

COLORECTAL1,2,3,7,9,12

All patients metroNIDAZOLE 500 mg Plus ceFAZolin 2 g*

[metroNIDAZOLE 500 mg Plus aminoglycoside 5 mg/kg

No Antibiotics

SMALL INTESTINE SURGERY 1,3

Non-obstructed ceFAZolin 2 g* clindamycin 900 mg Plus aminoglycoside 5 mg/kg

Less than 24 hours

Obstructed or emergency surgery ceFAZolin 2 g* Plus metroNIDAZOLE 500 mg

[metroNIDAZOLE 500 mg OR clindamycin 900 mg] Plus aminoglycoside 5 mg/kg

Less than 24 hours

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg71



GASTRODUODENAL 1,2,3,7,9,12

• Procedures involving entryinto lumen of GI tract(including bariatric surgery,pancreaticduodenectomy,gastric carcinoma, perforatedulcer, and percutaneousendoscopic gastrostomy)

• Procedures not involvingincision in GI tract (ex.antireflux, highly selectivevagotomy), High risk patientsonly• Decreased gastric acidity• Decreased GI motility• Obstruction• Hemorrhage• Gastric ulcer or

malignancy• morbid obesity• Gastroduodenal

perforation• ASA classification of ≥3

ceFAZolin 2 g* clindamycin 900 mg Plus aminoglycoside 5 mg/kg

No Antibiotics

High risk gastroesophageal endoscopy • esophageal dilation• variceal sclerotherapy


No Antibiotics

HERNIA REPAIR1,2,3,9,12

All patients • Herniorraphy• Hernioplasty


No Antibiotics

HEPATIC PANCREATIC BILIARY TRACT (HPB) – Major Procedures2,3,7

Major Procedures metroNIDAZOLE 500 mg Plus ceFAZolin 2 g*


No Antibiotics




HEPATIC PANCREATIC BILIARY TRACT (HPB) – Minor Procedures1,2,3,7,9,12

Low Risk Procedures • Elective laparoscopic

cholecystectomy without riskfactors (see below for risk factors)

• Liver biopsy

No Antibiotics (Note: many risk factors may not be known until intra-operatively, so may be reasonable to give every patient a single pre-op dose of antibiotic)

N/A N/A

High risk Procedures • Laparoscopic

cholecystectomy with riskfactors which include:(emergency procedures, diabetes,anticipated procedure duration exceeding 120 minutes, intra-operative gallbladder rupture, agegreater than 70 years, open cholecystectomy, risk of conversion from laparoscopic to open cholecystectomy, American Societyof Anesthesiologists Physical StatusClassification System (ASA) of 3 ormore, episode of colic within 30days before the procedure, re-intervention in less than a monthfor non-infectious complications ofprior biliary operation, acutecholecystitis, anticipated bile spillage, jaundice, pregnancy, non-functioning gallbladder, biliaryobstruction, obstructive jaundice orcommon bile duct stones and immunosuppression)

• Open cholecystectomy• Insertion of prosthetic device• ERCP (if biliary obstruction, known

pancreatic pseudocyst, or ifcomplete biliary drainage isunlikely)

• Liver Resection


No antibiotics for most patients except • Acute cholecystitis:

• 2 – 5 days• Emphysematous

cholecystitis:• 5 – 7 days

• Gangrene orperforated gallbladder:• change to broad

spectrum antibioticfor treatment




HEAD AND NECK (MAJOR)1,2,3,7,9,12

Clean procedures: •No incision of the oral or

pharyngeal mucosa•No implantation of prosthetic

material• Lymph node excisions• Exceptions (no antibiotics):

o Thyroidectomyo Parotidectomyo Submandibular gland

excisiono all of above with no neck

dissections and/or skullbase involvement


Clean procedures: • Cancer surgery

• Placement of prosthesis(except tympanostomy tubes)

ceFAZolin 2 g* clindamycin 900 mg 24 hours

Clean-contaminated procedures: • Require penetration of the

oral/nasal/pharyngeal mucosa• Complex resection with

reconstruction procedures• Revision and salvage surgeries• Cancer surgery•Mandibular surgery (if

tobacco/alcohol/drug use)

ceFAZolin 2 g* Plus metroNIDAZOLE 500 mg

clindamycin 900 mg Plus aminoglycoside 5 mg/kg

24 hours

• Tonsillectomy• Functional endoscopic sinus

procedure• Nasal Septoplasty


NEUROSURGERY1,2,3,7,9,12

• Craniotomy (elective, clean,non-implant)

• Elective implantation ofintrathecal pump


No Antibiotics

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg

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Craniotomy • clean-contaminated• crosses sinuses or

naso/oropharynx• emergency surgery• operation ≥2 hours• CSF leakage• Subsequent operation• Transsphenoidal surgery (All

patients)


vancomycin 15 mg/kg Plus metroNIDAZOLE 500 mg

No Antibiotics

CSF Shunting Procedures ceFAZolin 2 g* clindamycin 900 mg OR vancomycin 15 mg/kg

Less than 24 hours

OBSTETRICS AND GYNAECOLOGY 1,2,3,5,7,9,12,13,14,15

Therapeutic termination of pregnancy

doxycycline 100 mg PO 1 hr pre-op

azithromycin 1 g PO If doxycycline used pre-op: doxycycline 200 mg PO 30 min post-op

Caesarean section • Administer antibiotics prior

to skin incision NOT aftercord clamping

Elective Procedure: ceFAZolin 2 g*

Elective Procedure: clindamycin 900 mg Plus aminoglycoside 5 mg/kg

No Antibiotics

Nonelective Procedure: ceFAZolin 2 g* Plus azithromycin 500 mg

Nonelective Procedure : clindamycin 900 mg Plus aminoglycoside 5 mg/kg Plus azithromycin 500 mg

No Antibiotics

• Radical and totalhysterectomy (abdominal,laparoscopic or vaginal)

• Vulvectomy with or withoutlymphadenectomy

• Vaginectomy• Urogynecological procedures

o Laparoscopic Burcho 2-Team sling

ceFAZolin 2 g* [clindamycin 900 mg OR metroNIDAZOLE 500 mg] Plus aminoglycoside 5 mg/kg

No Antibiotics




• Endometrial ablation• Dilatation and curettage• Laparoscopic procedures that

do not enter uterus and/orvagina

No antibiotics N/A N/A

Endometriosis (laparoscopic and open)



No antibiotics

OPHTHALMIC1,3,12

Ophthalmic Procedures: • Cataract extractions• Vitrectomy• Keratoplasty• Intraocular lens implantation• Glaucoma procedures• Strabotomy• Retinal detachment repair• Laser in situ keratomileusis• Laser-assisted subepithelial

keratectomy• Corneal transplant• Eyelid surgery• Dacryocystorhinostomy• Enucleation

4th generation topical fluoroquinolones (moxifloxacin) given as 1 drop every 5-15 min for 5 doses within the hour before the start of the procedure

Addition of ceFAZolin 100 mg by subconjunctival injection or intracameral ceFAZolin 1 – 2.5 mg or cefuroxime 1 mg at the end of the procedure is optional

ORAL AND MAXILLOFACIAL2,7

• No oral or sinus cavityinvolvement

ceFAZolin 2 g* clindamycin 900 mg No Antibiotics

• Oral cavity or sinus cavityinvolvement

• Comminuted andcompounded fractures

• Implants/prosthesis; bonegraft

• Orthognathic


clindamycin 900 mg No Antibiotics

• Gunshot wound• Animal or human bite injuries• Grossly contaminated and

dirty injury

ceFAZolin 2 g* Plus aminoglycoside 5 mg/kg Plus metroNIDAZOLE 500 mg


• 24 hours• For grossly

contaminated/dirtywounds, consider acourse of treatmentwith broad spectrumantibiotics




ORTHOPEDIC1,2,3,7,9,12

Major procedures: • Difficult fracture

reconstruction• Closed fracture with internal

fixation• Total hip and knee

replacement• Other procedures requiring

prophylaxis• Total joint replacement• Implantation of internal

fixation devices• Hip fracture repair

Fasciotomy

ceFAZolin 2 g* clindamycin 900 mg OR vancomycin 15 mg/kg

24 hours or less

Minor procedures: • Arthroscopy• Procedures not involving

implantation of prostheticmaterial

• Clean operations involvingfoot, hand, or knee


PLASTIC SURGERY1,2,3,7

Clean Procedures (Low Risk) • Dermatologic• Facial bone fracture• Tumor excision• Simple rhinoplasty or

septoplasty• Simple lacerations• Flexor tendon injuries• Hand surgery (simple)


Clean Procedures (High Risk) • Placement of prosthetic

material• Skin irradiation• Procedures below waist


No Antibiotics


77



Clean Contaminated Procedures • Contaminated

skin/mucosa/intertriginousareas (oral cavity, upperrespiratory tract, axilla,groin, perineum)

• Wedge excision lip/ear• Flaps on nose/head/neck• Grafts


No Antibiotics

Breast: High risk patients only14,15 • Breast cancer procedures• Recent neoadjuvant

chemotherapy or radiationtherapy

• Prosthetic material or mesh• Re-operation or recent prior

breast surgery• Reconstruction surgeries• Operation duration ≥2 hours• Immunocompromised

patients (diabetics, steroids, etc) • Morbid obesity (> 100 kg)• Skin irradiation


No Antibiotics Except Autologous breast reconstruction: Consider 24 hours or less

Hand: Complex Clean Procedures: • Mutilating and crushing

injuries from home &industrial source

• Bone, joint, tendon (exceptopen flexor tendon injuries –see below) and nerveinvolvements

• Implants/ prosthesis• Flap reconstruction• Injuries require amputations• High risk patients with

medical comorbidities and/orimmunosuppressive drugs


24 hours


78



Hand: Clean-contaminated and Contaminated Procedures: • Mutilating and crushing

injuries from farmenvironment

• Grossly contaminated anddirty injuries

• Animal and human bites• Open fractures• Use of leeches



• 24 hours• For grossly

contaminated/ dirtywounds and injurieslonger than 6 hoursconsider a course oftreatment with broadspectrum antibiotics

SPINE1,2,3,7,12

• Fusion• Decompression• Laminectomy• Microdiscectomy• Insertion of foreign material• Instrumentation


Less than 24hours

THORACIC1,2,3,7,12 • Thoracentesis• Chest tube insertion for

spontaneous pneumothorax


Non-cardiac procedures: • Lobectomy• Pneumonectomy• Lung resection• Thoracotomy• VATS (video assisted

thorascopic surgery)• Chest tube insertion for chest

trauma withhemo/pneumothorax

ceFAZolin 2 g* vancomycin 15 mg/kg OR clindamycin 900 mg]

Less than 24 hours

Esophageal resection ceFAZolin 2 g* Plus metroNIDAZOLE 500 mg


24 hours




TRAUMA – Gunshot2,7

Gunshot fracture wound ceFAZolin 2 g* vancomycin 15 mg/kg

48 hours

Gunshot fracture wound with • Large soft tissue defects or

cavitary lesionsAND/OR

• Fracture of the extremities(in area of the hand, foot andankle)

ceFAZolin 2 g* Plus aminoglycoside 5 mg/kg

vancomycin 15 mg/kg Plus aminoglycoside 5 mg/kg

48 hours

Gunshot fracture wound with • Large soft tissue defects or

cavitary lesionsAND/OR

• Fracture of the extremities(in area of the hand, foot andankle)PLUS

• Gross contamination of thewound and environment:

o Occurred in rural/woodedarea

o Grossly dirty skin andclothes

o Bowel communication


vancomycin 15 mg/kg Plus aminoglycoside 5 mg/kg Plus metroNIDAZOLE 500 mg

48 hours For grossly contaminated/dirty wounds and injuries longer than 6 hours consider a course of treatment with broad spectrum antibiotics.

TRAUMA – Abdomen2,7

Penetrating abdominal trauma • Hollow viscus injury



24 hours

Penetrating abdominal trauma • Non-hollow viscus injury



No Antibiotics

TRAUMA – Orthopedic3,18,19,20 Closed Fractures with internal fixation

ceFAZolin 2 g* Vancomycin 15 mg/kg

No Antibiotics




Open/Compound Fractures • Administer parenteral

antibiotics as soon aspossible after injury.Consider time of first doseand delay to surgicalintervention whendetermining appropriaterepeat dosing schedule

ceFAZolin 2 g*

If heavily soiled or contaminated complex open fracture: ADD aminoglycoside 5 mg/kg

Vancomycin 15 mg/kg

If heavily soiled or contaminated complex open fracture: ADD aminoglycoside 5 mg/kg

24 to 48 hours post-op

URINARY DIVERSION PROCEDURES INVOLVING BOWEL SEGMENTS2,3,7,12 (assuming all patients have urine culture performed and all positive urine culture patients are treated before surgery)

• Ileal conduit procedures orprocedures involving bowelsegments


[metroNIDAZOLE 500 mg Plus aminoglycoside 5 mg/kg

Less than 24 hours

UROLOGY1,2,3,7,12,16

(assuming all patients have urine culture performed and all positive urine culture patients are treated before surgery) • Lower tract instrumentation,

including transrectal prostatebiopsy, cystoscop, etc.

High Risk only o Advanced ageo Poor nutritional statuso Diabetes mellituso Smokingo Obesityo Coexisting infection at a

remote body siteo Colonization with

microorganismso Anatomical anomalies of

the urinary tracto Urinary obstruction or

stoneo Chronic steroid useo Immunodeficiencyo Externalised catheterso Colonized

endogenous/exogenousmaterial

o Prolonged hospitalization

ciprofloxacin 500 mg PO OR sulfamethoxazole/ trimethoprim 800/160mg PO OR ceFAZolin 2 g* IM/IV OR aminoglycoside 5 mg/kg

Note: PO regimens, give 1 – 2 hours pre-op

aminoglycoside 5 mg/kg with or without clindamycin 900 mg

Less than 24 hours




Clean without entry into urinary tract


Less than 24 hours

Clean without entry into urinary tract + prosthesis

ceFAZolin 2 g* with or without aminoglycoside 5 mg/kg

(clindamycin 900 mg OR vancomycin 15 mg/kg) with or without aminoglycoside 5 mg/kg

Less than 24 hours

Clean with entry into urinary tract

ceFAZolin 2 g* with or without aminoglycoside 5 mg/kg (only if prosthesis involved)

ciprofloxacin 500 mg OR (aminoglycoside 5 mg/kg with or without clindamycin 900 mg)

Less than 24 hours

Clean Contaminated ceFAZolin 2 g* Plus metroNIDAZOLE 500 mg

ciprofloxacin 500 mg OR (aminoglycoside 5 mg/kg Plus metroNIDAZOLE 500 mg)

Less than 24 hours

VASCULAR 1,2,3,7,12

• Lower limb amputation• Abdominal and lower limb

vascular surgery• Procedures involving groin

incision or insertion ofprosthetic material

• Carotid endarterectomy andbrachial arterial repair withprosthetic graft only


24 hours or less

• Native AV fistula• Peritoneal dialysis catheter

placement• Artificial AV graft


No antibiotics




Low risk carotid endarterectomy, brachial artery repair, endovascular stenting without implantation of prosthetic graft material


83

VANCOMYCIN DOSING AND MONITORING GUIDELINES (NB Provincial Health Authorities Anti-Infective Stewardship Committee)

GENERAL COMMENTS • Vancomycin is a glycopeptide antibiotic with bactericidal activity • It is active against gram-positive bacteria, including methicillin-resistant staphylococcus (MRSA) • Vancomycin is less effective than beta-lactams against Staphylococcus aureus that is susceptible to

cloxacillin/methicillin • Vancomycin exhibits time-dependent killing: its effect depends primarily upon the time the concentration

exceeds the organism’s Minimum Inhibitory Concentration (MIC) • These guidelines pertain to IV vancomycin only; they do not apply to PO vancomycin, which is not absorbed • Ensure that an adequate mg/kg dose and appropriate interval are ordered initially. Adjust the dose if

necessary immediately; do not wait for a confirmatory trough level. • When managing a severe Staphylococcus aureus infection (e.g., bacteremia), an Infectious Diseases

consultation is strongly encouraged.

VANCOMYCIN IN ADULT PATIENTS

ADULT INITIAL DOSE Loading dose: • Consider using a loading dose in patients with:

o severe infections where rapid attainment of target level of 15-20 mg/mL is desired o significant renal dysfunction in order to decrease the time required to attain steady state

• Recommended dose: 25-30 mg/kg IV o based on actual body weight, for 1 dose, followed by maintenance dose separated by recommended

dosing interval o consider capping the loading dose at a maximum of 3.5 g o loading doses DO NOT need to be adjusted in patients with renal dysfunction; only maintenance

dosing interval requires adjustment • If loading dose not used then proceed with administration of a maintenance dose at recommended dosing

interval Maintenance dose: • 15-20 mg/kg IV

o based on actual body weight; maximum of 2g/dose for initial maintenance doses (prior to vancomycin levels)

o doses greater than 500 mg – round to the nearest 250 mg o doses less than 500 mg – round to the nearest 50 mg

Approved: September 2018

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Dosing interval: • Interval depends on patient’s renal function and targeted serum vancomycin concentration

Target trough of 15 to 20 mg/L Target trough of 10 to 15 mg/L Creatinine Clearance Dosing Interval Creatinine Clearance Dosing Interval

greater than 80 mL/min q8 – 12h greater than 80 mL/min q12h 40 to 80 mL/min q12h 40 to 80 mL/min q24h 20 to 39 mL/min q24h 20 to 39 mL/min q36h 10 to 19 mL/min q48h 10 to 19 mL/min q48h less than 10 mL/min consider a loading dose,

then adjust maintenance dose based on serial serum drug levels to target trough

less than 10 mL/min consider a loading dose, then adjust maintenance dose based on serial serum drug levels to target trough

• Estimated creatinine clearance (CrCl)Women Men CrCl = (140-age) x weight (in kg)†

SCr (in mcmol/L) CrCl = (140-age) x weight (in kg)† x 1.2

SCr (in mcmol/L) IBW = 45.5 kg + (0.92 x cm above 150 cm) or


50 kg + (2.3 x inches above 60 inches) †Use ideal body weight unless actual weight is 20% above ideal body weight (IBW), in such case use adjusted body weight. Adjusted body weight = 0.4 x (actual body weight – IBW) + IBW If actual weight is less than ideal body weight, use actual weight.

Clinical Pearls: • Use care when selecting patients for q8h dosing – recommend to avoid in patients that are older and/or with

multiple co-morbidities (ex. diabetes, heart failure, etc.) or where estimated creatinine clearance would beexpected to be an overestimate (ex. low muscle mass in an elderly patient, dysmobility, paraplegia, etc.)

• Consider q8h dosing for patients who are younger and otherwise well with few medical co-morbidities• The provided ranges for estimated creatinine clearance are only intended to be a guide for the selection of an

empiric dosing interval and should not be used in isolation without considering patient and infection-related factors – especially when estimated creatinine clearance approaches either end of the range

LEVELS • The ratio of Area Under the Curve to Minimum Inhibitory Concentration (AUC/MIC) is thought to be the best

pharmacokinetic parameter associated with a clinical and bacterial response to vancomycin; however,because of its relative impracticality to determine in clinical practice, trough levels are used as a surrogate forefficacy.

• Peak (post) levels are generally NOT recommended because they are not correlated with improved clinicaloutcome; they should only be ordered in rare circumstances to facilitate individualized patientpharmacokinetic analysis.

• Vancomycin’s efficacy depends primarily upon the time above the MIC

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Target serum concentrations:

Infection Desired minimal (trough) plasma concentration

-All MRSA infections -Invasive and/or deep space infections, including but

not limited to: o Osteomyelitis o Pneumonia o CNS infection o Endocarditis o Bacteremia o Prosthetic joint infection

15-20 mg/L

Uncomplicated skin and soft tissue infections Urinary tract infections 10-15 mg/L

vancomycin levels should always be maintained above 10 mg/L to avoid development of resistance

Levels are recommended in: o patients who are severely ill and/or require target trough of 15-20 mg/Lo patients with anticipated therapy duration of 7 days or greatero patients with impaired renal function (CrCl 50 mL/min or less) or unstable renal function (change in

baseline serum creatinine (SCr) of 40 mcmol/L or greater, or change of 50% or more from baseline)o patients on dialysis o concomitant use of other nephrotoxic drugs (i.e. aminoglycoside, NSAID, diuretics, ACEI, ARB, etc.)o patients with altered volume of distribution or clearance of vancomycin, including

morbidly obese patients (190% or greater of ideal body weight or BMI 40 kg/m2 or greater) cystic fibrosis burns more than 20% BSA pregnancy

• Routine trough (pre) levels are generally not necessary when:o vancomycin is used for empiric therapy as it may be discontinued once final culture results are

availableSerum sampling: • Trough (pre) levels are taken immediately before a dose (within 30 minutes)• The timing of drug administration and sample collection must be carefully documented• Do not hold next vancomycin dose while waiting for results of vancomycin levels unless there is a specific

reason to do so, e.g. significant decline in renal functionTiming of serum levels: • First trough level should be taken at steady state, typically

o prior to 4th dose if q12h intervalo prior to the 5th dose if q8h interval

• Steady state (SS) occurs in 4 to 5 half-lives and can be estimated for vancomycin by the following equations:o Ke = CrCl x 0.00083 + 0.0044 o T½ = 0.693/Ke

o SS = 4 to 5 T½• Vancomycin clearance is enhanced in obesity. Consider drawing first level sooner (i.e. before the 3rd dose if

normal renal function) in morbidly obese patients

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INTERPRETING TROUGH LEVELS AND ADJUSTING DOSE • Verify the timing of the trough in relations to the dose that preceded it and the dose that followed• Verify if the trough was taken at steady state• Verify for changes in renal function since the trough was drawn• Consider alternate sources of vancomycin that may be contributing to measured serum concentrations (e.g.,

vancomycin instilled intra-operatively, or added to cement during orthopedic surgery)• If the trough is below the target level, ensure the dose is 15-20 mg per kg actual body weight, and consider

shortening the dosing interval (e.g., if was dosed q12h, change to q8h)• If the trough is above 20-25 mg/L, consider decreasing the dose and/or lengthening the dosing interval• If trough level is significantly elevated (i.e. greater than 30 mg/L) hold vancomycin and use repeat levels to

determine when to restart vancomycin and new dosing regimenMONITORING Subsequent serum levels: • With dosage change: trough should be repeated at new steady state as described in “Levels” section• Once target trough achieved: trough should be taken approximately every 7 days in hemodynamically stable

patients; more frequently if hemodynamically unstable, renal function changing, if concurrent nephrotoxicdrugs, or underlying renal dysfunction

Monitor: • patient’s clinical response to vancomycin• CBC at least weekly on long-term vancomycin therapy• SCr at least twice a week initially, then at least weekly on long-term therapy; more frequent monitoring should

be considered if renal function changing, if concurrent nephrotoxic drug, underlying renal dysfunction or agegreater than 60.

o If SCr increases significantly (i.e. greater than 15 – 20% from baseline), draw trough level to assess forneed for dosage adjustment as vancomycin accumulation may occur

Adverse effects of vancomycin include: • Nephrotoxicity: 5-43%; more common with higher trough levels, longer durations, critically ill patients,

concomitant nephrotoxic drugs, elderly patients or pre-existing renal dysfunction; rise in SCr usually reversibleupon discontinuation of vancomycin

• Red Man Syndrome: 5-10%; ensure appropriate duration of infusion to minimize risk (refer to Parenteral DrugManual)

• Neutropenia: less than 2%, delayed onset (15-40 days), reversible

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VANCOMYCIN IN PEDIATRIC PATIENTS

DEFINITIONS • Neonate: 0-4 weeks of age

o Gestational age: number of weeks from first day of the mother’s last menstrual period until the birthof the baby

o Postnatal age: chronological age since birth o Corrected Gestational Age: gestational age plus postnatal age

Ex.: baby born at 28 weeks, presently 21 days old corrected gestational age = 31 weeks (28 weeks + 3 weeks)

• Infant: 1 month to 1 year of age• Child: 1-12 years of age

PEDIATRIC INITIAL DOSE Initial dose in neonates (less than 1 month of age):

Corrected Gestational Age (weeks)

Postnatal Age (days) mg/kg/dose IV Interval

(hours)

29 or less 0-14 10 - 15 18 15 or more 10 - 15 12

30-36 0-14 10 - 15 12 15 or more 10 - 15 8

37-44 0-7 10 - 15 12 8 or more 10 - 15 8

45 or more all 10 - 15 6

Initial dose in infants and children (1 month to 12 years of age): • Traditional:

o 40-60 mg/kg/day, divided in q6h-8h o max dose of 2g/day prior to levels

• Alternative (for more severe infections):o 15 mg/kg/dose IV q6h o max dose of 4g/day prior to levels

LEVELS • Trough levels are taken 30 minutes or less prior to the next dose• Peak levels are generally NOT recommendedTarget trough levels in neonates (less than 1 month of age):

o 5-15 mg/Lo up to 20 mg/L for severe infections where vancomycin penetration to the site may be poor or high

MIC is suspected (osteomyelitis, meningitis and endocarditis or infection with MRSA)Target trough levels in infants and children (1 month to 12 years of age):

o 15-20 mg/L for most infections o 10-15 mg/L for less severe infections

• First trough level should be taken at steady state, typically prior to 4th doseINTERPRETING TROUGH LEVELS AND ADJUSTING DOSE • Verify the timing of the trough in relations to the dose that preceded it and the dose that followed• Verify if the trough was taken at steady state• Verify for changes in renal function since the trough was drawn• If the trough is below the target level, consider shortening the dosing interval• If the trough is high, consider lengthening the dosing intervalSUBSEQUENT TROUGH LEVELS AND MONITORING • See Adults section for guidance

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VANCOMYCIN IN INTERMITTENT HEMODIALYSIS

GENERAL COMMENTS • In patients undergoing intermittent hemodialysis, vancomycin IV is given on dialysis days, typically 3 times a

week • Give the first dose of vancomycin the day it is ordered and subsequent doses on dialysis days • Vancomycin doses are administered during the last portion of the hemodialysis session (intradialytic

administration) or after hemodialysisDOSE • Patient with weight less than 70 kg:

vancomycin 1000 mg IV for the first dose, then 500 mg IV for subsequent doses• Patient with weight 70 to 100 kg:

vancomycin 1250 mg IV for the first dose, then 750 mg IV for subsequent doses • Patient with weight above 100 kg:

vancomycin 1500 mg IV for the first dose, then 1g IV for subsequent dosesLEVELS Target pre-dialysis vancomycin levels:

o 15-20 mg/Lo 10-15 mg/L may be acceptable for uncomplicated skin and soft tissue infections and urinary tract

infections; see Adults section for more information • Vancomycin levels are drawn before the beginning of the hemodialysis session• Do not hold post-dialysis vancomycin dose while waiting for results of pre-dialysis vancomycin levels unless

there is a specific reason to do so • If the trough is below the target level, consider a top-up dose and increase the next maintenance dose

accordingly • If the trough is high, consider decreasing the next maintenance dose• Vancomycin trough levels should be obtained before each dialysis until desired trough is attained. After that,

vancomycin trough levels should be obtained once a week before dialysis.

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VANCOMYCIN IN PREGNANCY

CONSIDERATIONS ON THE USE OF VANCOMYCIN IN PREGNANCY • Pregnancy is associated with accelerated renal clearance of vancomycin due to increased renal blood flow• Pregnancy is associated with higher volumes of distribution• Pharmacokinetic changes become more pronounced in the later stages of pregnancy and gradually return to

pre-pregnancy values a few days following delivery • Dose and target trough levels same as other adults • Will likely achieve steady state sooner• May require higher dosage and shorter dosing intervals to achieve target levels compared to non-pregnant

individuals • Recommend routine trough levels in pregnant patients• If target levels difficult to achieve, consider drawing two levels (trough and peak) to enable individualized

pharmacokinetic calculations

OUTPATIENT VANCOMYCIN IV THERAPY

NOTES FOR TRANSITIONS TO OUTPATIENT IV VANCOMYCIN THERAPY • Prior to discharge on outpatient IV vancomycin therapy, the healthcare team should:

o Review the treatment plan to confirm that oral alternatives are not available or appropriate forpatient management

o Review the feasibility and safety of the treatment and care plan o Review the patient’s concomitant medications to identify any nephrotoxic agents (e.g.

aminoglycoside, NSAID, diuretic, ACEI, ARB, etc.) and evaluate whether any should be held for theduration of treatment

o Communicate the treatment and care plan to the patient and/or care givers and communityhealthcare providers; including necessary blood work, target levels and duration of therapy

o Communicate the importance of proper timing of blood work in relation to administration of thevancomycin dose to allow interpretation of vancomycin serum concentrations

o Educate and inform the patient and their caregivers on the signs and symptoms of potential adversereactions to report or act on

o Arrange all necessary monitoring test and follow-up appointments o Avoid scheduling blood work on Fridays because interpretation may be delayed

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Prevention of Overwhelming Postsplenectomy Infection in Adults

Introduction The spleen is the largest lymphatic organ in the body and its primary functions are to filter damaged red blood cells and micro-organisms from the blood and to aid in the production of antibodies to enhance the immune response.1 Asplenic patients or patients who suffer from functional asplenia have an increased risk of infection and are at risk of contracting a syndrome known as overwhelming postsplenectomy infection (OPSI).2Overwhelming postsplenectomy infection has been defined as ”septicaemia and/or meningitis, usually fulminant but not necessarily fatal, occurring at any time after removal of the spleen”.3 The incidence of OPSI has been difficult to establish due to a wide variation in occurrence rates among different groups of patients, but lifetime risk has been estimated at 5%.2 Risk of OPSI has been found to be dependent on age at which splenectomy occurs, time interval from splenectomy, cause for asplenia and immune status of the patient.4

Although the incidence of OPSI is low, the estimated mortality is high (38 – 69%).2 Therefore, prevention and early identification of OPSI have been identified as key strategies to improve patient outcome.2 Some of the current strategies being used and recommended to decrease a patient’s risk of OPSI include vaccination, communication of hyposplenic state to other healthcare providers and patient education.1,2,5 In addition, some groups recommend either short term or lifelong prophylactic antibiotics to reduce the risk of OPSI.8 However, the use of antibiotics for the prevention of OPSI is often limited by poor compliance and antibiotic resistance; therefore, its use should be assessed on a case-by-case basis.8 Recommendations from the Canadian Pediatric Society include the administration of prophylactic antibiotics until the patient is 60 months of age with consideration to be given for lifelong prophylaxis.14 Experts and some guidelines also recommend that patients have a home supply of antibiotics for urgent use.15,16

The Provincial Anti-infective Stewardship Committee (ASC) has prepared resources to facilitate recommended vaccination orders, vaccine distribution, patient education and communication to the primary care provider. Recommendations regarding the prophylactic or as needed use of antibiotics are beyond the scope of these guidelines, please consult a local infectious disease specialist for recommendations.

Vaccinations Asplenic patients are at risk of OPSI with any micro-organism but particularly encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.2,4 Encapsulated bacteria are more difficult for the body to clear because they resist antibody binding and their clearance is primarily completed by the spleen.4 Therefore, it is important that attention be paid to providing optimal protection against encapsulated bacteria using appropriate immunizations.6 The National Advisory Committee on Immunization (NACI) and the Canadian Immunization Guideline currently recommend the following vaccines for adult asplenic or hyposplenic patients: pneumococcal 13-valent conjugate vaccine (PNEU-C-13), pneumococcal 23-valent polysaccharide vaccine (PNEU-P-23), Haemophilus influenzae type b conjugate (Hib) vaccine, meningococcal ACYW-135 conjugate (Men-C-ACYW) vaccine, all routine immunizations and yearly influenza vaccine.6,7 NACI also recommends multi-component meningococcal serogroup B (4CMenB) vaccination for active immunization of patients with anatomical or functional asplenia who are greater than 2 months of age.11

Streptococcus pneumoniae is responsible for 50 – 90% of all cases of OPSI. 4 Pneumococcal polysaccharide vaccine (PNEUMOVAX 23) provides protection against 23 serotypes of Streptococcus pneumoniae and is the vaccine of choice for adult patients at high risk of invasive pneumococcal disease (IPD). 6 The pneumococcal polysaccharide vaccine has been found to have an efficacy of 50 to 80% against IPD among the elderly and high risk groups.6 However, after immunization with PNEU-P-23 vaccine, antibody levels begin to decline after 5 to 10 years and the duration of immunity is unknown.6 In an effort to improve the duration of immunity the current NACI guidelines recommend for adults with asplenia or hyposplenia one dose of PNEU-C-13 vaccine (PREVNAR 13) followed at least 2 months later by one dose of PNEU-P-23 vaccine.6 If PNEU-P-23 vaccine has been previously received, then wait 1 year before giving PNEU-C-13 vaccine. 10 In the case where only one vaccine can be given then it should be the PNEU-P-23 vaccine. A single booster of PNEU-P-

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23 vaccine is recommended 5 years after the initial dose.6 Due the increased risk of invasive pneumococcal disease and rapid decline in antibodies following PNEU-P-23 vaccination, patients age 65 years and over, regardless of previous vaccination history, should receive one dose of PNEU-P-23 vaccine as long as 5 years have passed since the previous PNEU-P-23 vaccine dose.12 The Center for Disease Control and Prevention’s Advisory Committee on Immunization Practices released a statement in October 2012 with similar recommendations for all adult patients 19 years of age or greater.10

A single dose of Haemophilus influenzae type b (HiB) conjugate vaccine is recommended in all patients who are functionally or anatomically asplenic and greater than 5 years of age regardless of previous Hib immunization.5,6 Current Hib vaccine should be given at least one year after any previous dose.6 This is despite limited efficacy data and a low overall risk of Haemophilus influenzae sepsis in patients greater than 5 years of age.6

Meningococcal ACYW-135 conjugate vaccine, NIMENRIX, MENACTRA or MENVEO, is recommended for all groups at high risk of invasive meningococcal infection when long-term protection is required.6,7 MENVEO (Men-C-ACYW-CRM) has the A, C, Y and W-135 serogroup oligosaccharides conjugated to the CRM197 protein. 6,13

Men-C-ACYW-CRM (MENVEO) can be administered concomitantly with routine childhood vaccines but furtherstudies are needed with respect to concomitant administration with other CRM197 conjugate vaccines such asthe pneumococcal 13-valent conjugate vaccine (PREVNAR); therefore, Men-C-ACYW-CRM vaccine has been leftoff the clinical order set to avoid this concomitant administration.6,13 Recommendations are to give 2 doses ofmeningococcal ACYW-135 conjugate vaccine at least 8 weeks apart for patients with anatomic or functionalasplenia between the ages of 1 – 55.6 Based on limited evidence and expert opinion, current NACI guidelinesrecommend that 2 doses of meningococcal ACYW-135 conjugate vaccine given 8 weeks apart is alsoappropriate for individuals greater than 55 years of age, despite lacking authorization for use in this agegroup.6,7 Booster doses are recommended every 3 - 5 years in individuals vaccinated at 6 years of age oryounger and every 5 years for individuals vaccinated at greater than 6 years of age.6 Multi-componentmeningococcal serogroup B (4CMenB) vaccine (BEXSERO) given as a 2 dose series 4 weeks apart is alsorecommended.11

In addition, all routine immunizations and yearly influenza vaccination should be given as there are no contraindications to the use of any vaccine in patients with functional or anatomical hyposplenia. 6 When an elective splenectomy is planned, the necessary vaccines are recommended to be given two weeks before removal of the spleen. 6 In the case of an emergent splenectomy, vaccines should be given two weeks post-splenectomy or prior to hospital discharge if there is a concern that the patient may not return for vaccination. 6

Asplenic patients are at increased risk of travel related infectious diseases, including malaria and babesiosis.9Expert advice should be sought prior to travel to endemic areas.

Patient Education Education has also been cited as an essential component for successful prevention of OPSI. 2 Patients should be educated regarding their increased risk of developing life threatening sepsis, what to do at the first sign of infection, to inform all healthcare providers of their hyposplenic state and to take appropriate precautions to prevent OPSI.2 Education may be provided through thorough discussion and provision of appropriate reading materials.2

Document Updated by: Tim MacLaggan, BSc(Pharm), ACPR Document reviewed and approved by: New Brunswick Anti-infective Stewardship Committee – May 2018

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**The following clinical order set is provided as a sample only and would have to be modified to an individual zone’s format for local use**

Clinical Order Set Post-Splenectomy Vaccinations – Adult Provincial Anti-infective Stewardship Committee

Patient: INSTRUCTIONS

Allergies:

1. The following orders will be carried out by a nurse only on the authority of a physician/nurse practitioner.2. A bullet preceding an order indicates the order is standard and should always be implemented. 3. A check box preceding an order indicates the order is optional and must be checked off to be implemented. 4. Applicable boxes to the right of an order must be checked off and initialed by the person implementing the order.5. Date and time of administration must be recorded

Contraindications

• Hypersensitivity to any vaccine component• Anaphylactic reaction to previous dose of any of the vaccines listed below

Vaccinations (if not received pre-operatively for elective surgeries or if not received previously)

• Haemophilus influenzae type b conjugate vaccine (ACT-HIB) 0.5 mL intramuscularly in deltoid

• Meningococcal ACYW-135 conjugate vaccine (N IME N RIX , MENACTRA) 0.5 mL intramuscularly indeltoid (additional dose of meningococcal ACYW-135 conjugate vaccine required in 2 monthsfollowed by a booster every 5 years)

• Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine (BEXSERO) 0.5 mLintramuscularly in the deltoid (additional dose of Multicomponent Meningococcal Serogroup B(4CMenB) Vaccine required in 1 month)

Pneumococcal Vaccination: � If pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) not previously

received or received greater than one year ago then give Pneumococcal 13-valent conjugate vaccine (PREVNAR 13) 0.5 mL intramuscularly in deltoid (Pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) required 8 weeks later if not previously received. Single lifetime booster of Pneumococcal 23-valent polysaccharide (PNEUMOVAX23) required 5 years after first dose.)

OR � If Pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) previously received but less

than one year ago then wait 1 year from that date to give Pneumococcal 13-valent conjugate vaccine (PREVNAR 13). Single lifetime booster of Pneumococcal 23-valent polysaccharide (PNEUMOVAX 23) required 5 years after first dose.

• Seasonal Influenza Vaccine (if not already received)

Notes

-Vaccinations should be given two weeks post-operatively or on hospital discharge if there is aconcern that he or she might not return for vaccination.-All vaccinations may be administered simultaneously. Separate syringes and separate injection sitesshould be used if more than one vaccine is administered on the same day.

Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Revised and Approved May 2018

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Adult Splenectomy Vaccines Documentation for Primary Care Provider and Public Health Please complete and forward to patient’s primary care provider and local Public Health office on discharge.

Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Revised and Approved May 2018

Asplenic patients are known to be at risk of infection, and are particularly susceptible to encapsulated organisms. Vaccinations are recommended to reduce the risk of infection in this patient population.

Your patient received the following vaccinations while in hospital after splenectomy. Please update your records, and note the patient’s need for future vaccinations.

Meningococcal ACYW-135 conjugate vaccine (N IM E N RIX , MENACTRA) (2 doses, 2 months apart) Date 1st dose given: Lot#: Dose: Administration Site: Date 2nd dose given: Lot#: Dose: Administration Site: A booster is recommended every 5 years

Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine (BEXSERO) (2 doses, 1 month apart) Date 1st dose given: Lot#: Dose: Administration Site: Date 2nd dose given: Lot#: Dose: Administration Site:

Haemophilus influenzae type b conjugate vaccine (ACT-HIB) Date given: Lot#: Dose: Administration Site:

Pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Lot#: Dose: Administration Site:

Pneumoccocal polysaccharide vaccine (PNEUMOVAX 23) due 8 weeks after pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Lot#: Dose: Administration Site: A single booster dose of pneumococcal polysaccharide vaccine is recommended after 5 years.

- Yearly influenza vaccine recommended.

If you have any questions regarding these vaccinations please call the numbers above, or contact the Department of Public Health for further information.

Thank you. This message is CONFIDENTIAL. If you received this fax by mistake, please notify us immediately.

From:

Phone: Fax:

To: Local Public Health Office

Fax #:

Re. Patient Name:

HCN:

D.O.B:

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Splenectomy Information for Patients

Role of the spleen: • The spleen has many functions, including removal of damaged

blood cells. It also plays an important role in removal of certaintypes of bacteria.

• The spleen may be removed (splenectomy) if it becomesoveractive, stops working or is ruptured in an accident.

Life without a spleen: • Adults can live a normal life without a spleen. However, you

may be at risk of developing infections caused by certaintypes of bacteria which are normally removed by the spleen.

• The most serious possible infection is called overwhelming post-splenectomy infection(OPSI). This infection is rare, but can progress rapidly and may result in the loss of limbs ordeath.

How to reduce the risk of infection: • Inform all doctors, dentists and other health care professionals that you do not have a

spleen.• A series of vaccinations is recommended for patients who have their spleen removed.

These vaccines are two doses of meningococcal quadrivalent conjugate vaccine,pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine (due 2 monthsafter pneumococcal conjugate vaccine), two doses of multi-component meningococcalserogroup B vaccine and Haemophilus influenzae type b conjugate vaccine.

• You should receive a single booster of pneumococcal polysaccharide vaccine in 5 years.• You should receive a booster dose of meningococcal conjugate vaccine every 5 years.• You should receive a yearly flu shot.• Your primary care provider will receive a letter explaining the vaccinations you received in

hospital, as well as recommendations for future vaccinations.• Seek expert medical advice before travel. Patients without a spleen are at increased risk of

travel-related infectious diseases, including severe malaria. Additional vaccines and/or oneor more medications may be recommended to prevent or treat travel-related infectiousdiseases. Where malaria is endemic, preventative measures including antimalarialmedications, insect repellent and barrier precautions should be used.

Identification: • Wallet card (included with this information) includes information on vaccinations you have

received.• Medic-Alert™ bracelet should be worn. It should indicate that you had your spleen

removed.

When to seek medical attention: • If you receive a tick or animal bites/scratches. You may be at risk of developing a serious

infection.• Fever, shakes and/or chills may be a sign of a serious infection. Proceed immediately to the

nearest emergency department for further evaluation and care. If you have been providedantibiotics to use on an as needed basis for infection, take one dose immediately and thenproceed to the nearest emergency department.

Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved May 2018

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Wallet card for Asplenic Patients Please complete card and give to patient on hospital discharge.


Medical AlertAsplenic Patient

Patient Name: Name: Phone:

Patient is at risk of potentially fatal, overwhelminginfections. Medical attention required for:

Signs of infection- fever > 38ºC, sore throat, chills,unexplained cough. Tick and animal bites/scratches.

Vaccination Record Patient has received the following vaccinations:

Meningococcal ACYW-135 conjugate vaccine (NIMENRIX, MENACTRA) 2 doses 8 weeks apart Date 1st dose given: Date 2nd dose given:

Meningococcal ACYW-135 conjugate vaccine booster (NIMENRIX, MENACTRA or MENVEO)

Dates due: every 5 yearsDates given:

Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine (BEXSERO) 2 doses 4 weeks apart

Date 1st dose given: Date 2nd dose given: Pneumococcal 13-valent conjugate vaccine (PREVNAR 13)

Date given: Pneumococcal polysaccharide vaccine (PNEUMOVAX 23)

Date due: 8 weeks after pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given:

Pneumococcal polysaccharide booster (PNEUMOVAX 23) Date due: single dose 5 years after initial vaccineDate given:

Haemophilus influenzae type b conjugate vaccine (ACT-HIB) Date given:

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Splenectomy Vaccine Checklist

1) Post-Splenectomy Vaccinations Clinical Order Set

2) Vaccines as per clinical order set plus package inserts

3) Splenectomy Vaccines – Documentation for Primary Care Providerand Public Health Form

4) Splenectomy – Information for Patients Sheet

5) Wallet Card for Asplenic Patients Sheet


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References Clostridium difficile Infection McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Sammons JS, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), Clinical Infectious Diseases. 2018. cix1085, https://doi.org/10.1093/cid/cix1085

Sirbu BD et al. Vancomycin Taper and Pulse Regimen with Careful Follow-up for Patients With Recurrent Clostridium difficile Infection. Clinical Infectious Diseases. 2017;65(8):1396–9

Loo VG, Davis I, Embil J, et al. Association of Medical Microbiology and Infectious Disease Canada treatment practice guidelines for Clostridium difficile infection. Official Journal of the Association of Medical Microbiology and Infectious Disease Canada 3.2, 2018. doi:10.3138/jammi.2018.02.13

Adapted from Vancouver Coastal Health Antimicrobial Stewardship Treatment Guidelines for Common Infections (2011)

Intra-Abdominal Infections Ball, C., Hansen, G., Harding, G., Kirkpatrick, A., Weiss, K. & Zhanel, G. (2010). Canadian practice guidelines for surgical intra-abdominal infections. Canadian Journal of Infectious Disease and Medical Microbiology, 21(1), 11-37.

Doyle, J., Nathens, A., Morris, A., Nelson, S., & McLeod, R. (2011). Best practice in general surgery guideline #4: Management of Intra- abdominal infections. Toronto, ON: University of Toronto, Faculty of Medicine.

INESSS. Antibiotic Treatment Guide: Intra-abdominal Infections in Adults. June 2012

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