antimicrobial de-escalation (ade) · e. vancomycin plus pip/tazo. case 1: a 45 years old male with...

Antimicrobial De-escalation (ADE)

Wilawan Thipmontree, MD.

A. CloxacillinB. CeftriaxoneC. Ceftriaxone plus ClindamycinD. PGS plus ClindamycinE. Vancomycin plus Pip/Tazo

Case 1: A 45 years old male with alcoholic cirrhosis presented with acute fever and right leg & foot pain for 3 days. PE: BT 39C, BP 80/50 mmHg, PR 110 bpm, RR 24 /min, Right leg as shownWhat is the most appropriate empiric antibiotics?

Terminology for antimicrobial recommendations

Empiric therapy

Initial therapy started in the absence of definitive microbiologic pathogen identification. Empiric therapy may be mono-, combination, or broad-spectrum, and/or multidrug in nature.

Broad-spectrum Rx

The use of one or more ATB with the specific intent of broadening the range of potential pathogens covered, usually during empiric therapy.

Multidrug therapy

Therapy with multiple ATB to deliver broad-spectrum therapy for empiric therapy (i.e., where pathogen is unknown) or to potentially accelerate pathogen clearance (combination therapy) with respect to a specific pathogen(s) where the pathogen(s) is known or suspected

Combination therapy

The use of multiple antibiotics (usually of different mechanistic classes) with the specific intent of covering the known or suspected pathogen(s) with more than one antibiotic to -accelerate pathogen clearance (main purpose)-inhibition of bacterial toxin production (e.g., clindamycin with

β-lactams for streptococcal toxic shock) - potential immunomodulatory effects (macrolides with a β-lactamfor pneumococcal pneumonia)

Targeted/definitive therapy

Therapy targeted to a specific pathogen (usually after microbiologic identification). Targeted/definitive therapy may be mono- or combination, but is not intended to be broad-spectrum.

Surviving Sepsis Campaign 2016, Intensive Care Med (2017) 43:304–377

Antibiotic Therapy : Regimen• We recommend empiric broad-spectrum therapy

with one or more ATB to cover all likely pathogens

Kumar A et al. Crit Care Med 2010; 38(9): 1773-85

IDSA guideline for skin soft tissue infection 2014

Necrotizing Fasciitis Rt leg with MODS STSS

• Managememt– Empiric RX: Ceftriaxone 2 g iv OD plus

Clindamycin 900 mg q 8 h– Debridement– Retain foley catheter

• Laboratory– H/C: NG– Pus G/S: GPC in chain, Pus C/S: S. pyogenase– BUN/Cr: 34/2.2, AST/ALT 110/98– CBC: Hct 30 mg%, Plt 76,000, WBC 23,000, N 90%, L10%

• Diagnosis: S. pyogenase Toxic shock syndrome

Streptococcal Toxic Shock Syndrome (STSS) (Streptococcus pyogenes) 2010 Case DefinitionClinical Criteria: An illness with the following clinical manifestationsHypotension (SBP ≤ 90 mmHg)Multi-organ involvement characterized by ≥ 2 of the following:

-Renal impairment: Cr ≥ 2 mg/dL or ≥ twice the UNL, In patients with preexisting renal disease, ≥ twofold elevation over the baseline level.-Coagulopathy: Platelets ≤ 100,000/mm3 or DIC -Liver involvement: ALT, AST, or TB ≥ twice UNL. In patients with preexisting liver disease, ≥ twofold increase over the baseline level.-ARDS -A generalized erythematous macular rash that may desquamate.-Soft-tissue necrosis, including NF or myositis, or gangrene.

Laboratory Criteria for Diagnosis: Isolation of group A Streptococcus

Case ClassificationProbableClinical case definition in the absence of another identified etiology for the illness and with isolation of group A Streptococcus from a non-sterile site.ConfirmedClinical case definition and with isolation of group A Streptococcus from a normally sterile site (e.g., blood or cerebrospinal fluid or, less commonly, joint, pleural, or pericardial fluid)

S. pyogenase Toxic Shock Syndrome

• Empiric ATB: Ceftriaxone plus Clindamycin

• What is the most appropriate de-escalation therapy?A. Ceftriaxone plus ClindamycinB. PGS plus ClindamycinC. PGSD. Doxycyclin plus CeftazidimeE. Imipenem plus Vancomycin

“Empiric Broad-Spectrum Therapy” cover all likely pathogens

Inappropriate initial therapy

Too Broad-Spectrum Regimen

Surviving Sepsis Campaign 2016

Antibiotic De-escalation

• No consensual definition of DE is currently available

• DE purpose was to reduce both the spectrum of antimicrobial therapy and the selective pressure on microbiota (84% of the experts)

• DE included switching from combination to monotherapy (92% of the experts)

E. Weiss, Clin Microbiol Infect 2015; 21: 649.e1–649.e10

Antimicrobial De-escalation: Definition

Narrowing spectrum

Switching from combination tomonotherapy

Shortening duration

Stop if infection is unlikely

Therapy aimed at causative pathogen

Switching

Antimicrobial De-escalation: Goals

Reduce selection of MDR bacteria

Reduce colonization of MDR bacteria

Reduce infection with MDR bacteria

Reduce antibiotic use (DDD)

Reduce cost

Reduce time LOS, mortality

Reduce ATB related adverse events

Tabah A. et al. CID 2016:62 (15 April) Schuts EC et al. Lancet Infect Dis 2016; 16: 847–56

Tabah A. et al. CID 2016:62 (15 April)

Definition of Antimicrobial De-escalation in Included 14 Studies


Difference in patient mortality rate in ADE and non-ADE

Effect on mortality of prescribing empirical ATB according to guidelines

Schuts EC et al. Lancet Infect Dis 2016; 16: 847–56

• Effect of ADE on the Duration of Antimicrobial Therapy– 4 studies compared the duration of ATB therapy – There was no reduction in antibiotic days with ADE

• Effect of ADE on Microbiological Flora and Antimicrobial Resistance– None of the studies were designed to investigate the effect

of ADE (or non-ADE) on the acquisition of MDR bacteria• Cost Analysis

– 2 studies reported lower costs in patients with ADE

Algorithm for de-escalation decision making at day 3 in improving patient

Patient on empiric ATB and improving

De-escalation antibioticStop antibiotic Maintain antibiotic

Clinical & Investigations do not support presence of infection

Clinical assessment of patient show infection improving

Microbiology cultures positive & show evidence of de-escalation opportunity

Other investigations show that infection is improving


Microbiology cultures negative or positive MDR pathogen

Masterton RG. Crit Care Clin 2011;27:149-162

Nosocomial infection : CA-UTI

• S. pyogenase Toxic Shock Syndrome• Rx. PGS plus Clindamycin• New onset fever with sepsis• Suspected Catheter related UTI (UA: WBC 30-50, RBC 5-10)• Off foley cathter

• What is the most appropriate empiric ATB ?A. AmikacinB. CiprofloxacinC. Piperacillin/TazobactamD. ErtapenemE. Imipenem

P.-L. Lu et al. International Journal of Antimicrobial Agents 40S1 (2012) S37–S43

Distribution of GNB causing UTI by country in the Asia-Pacific region

• Community-acquired infections– Penicillin-resistant Streptococcus pneumoniae (PRSP)– Community- acquired methicillin resistant Staphylococcus aureus

(CA-MRSA)– Quinolone-resistant Neisseria gonorrhoeae (QRNG)– Quinolone-resistant Salmonella (QRS)– Community-acquired Extended-Spectrum B lactamase (ESBL)

producing Enterobacteriaceae• Hospital-acquired infections

– ESBL producing Enterobacteriaceae– Carbapenemase-producing Enterobacteriaceae– Multidrug resistant (MDR) P.aeruginosa, A. baumanii– Pandrug resistant P.aeruginosa, A. baumanii– Methicillin resistant Staphylococcus aureus (MRSA)

Antibiotic-Resistant Bacteria

J Pediatr Pharmacol Ther 2014; 19 (3): 156-164

Consensus statement guidelines for empirical antimicrobial therapy of complicated bacterial urinary tract infections in Asia-Pacific region.

Hsueh Po-R. et al., J of Infect 2011;63: 114-123

All-cause mortality of patients with ESBL bacteremia: Empirical treatment

Carbapenems VS BL/BLIs Carbapenems VS non BL/BLIs

Vardakas K Z. J Antimicrob Chemother 2012; 67: 2793-2803

Catheter Associated Urinary Tract Infection

• S. pyogenase Toxic Shock Syndrome• Persistent fever with sepsis, wound at Rt. Leg is improve• Suspected Catheter related UTI (UA: WBC 30-50, RBC 5-10)

• Empiric ATB: Imipenem 500 mg iv q 6 hoff PGS plus Clindamycin

• Urine culture: > 105 E.coli ESBL+– Susceptible to Ertapenem, Imipenem, Meropenem,

Pip-Tazocin– Resistant to Ciproflox, Ceftriaxone, Ceftazidime

• Hemoculture: E.coli ESBL+

Pharmacokinetic parameters of carbapenems after a single intravenous (IV) dose

Drugs 2007; 67 (7): 1027-1052

Major Mechanisms of Resistance by Antimicrobial Class

Mechanism B-lactams Aminoglycoside

Macrolide Quinolone TMP SMX Tetracycline

Polymyxin

Glycopeptide

1.Enzymaticinactivation

+++ +++ +(Gram-neg)

- - - + - -

2.1 Decreased permeability

+ (Gram-neg)

+(Gram-

neg)

+ +(Gram-neg)

+ (Gram-neg)

+(Gramneg)

- + (Gram-

neg)

+ +(Gram-

neg)

+ +(Gram-

neg)

2.2 Efflux + + ++ + - - +++ - -

3.1 Alteration of target site

++ ++ +++ +++ +++ ++ + (H.pylori)

- +++

3.2 Protection of target site

- - - + - - ++ - -

3.3 Overproduction of target

- - - - ++ ++ - - +

4. Bypass of inhibited process

- - - - + + - - -

5.Bind up ATB - - - - - - - - ++

Mandell, Principles and practice of infectious 2015

Plasmid-mediatedbeta-lactamase

Amber

Substrate Inhibitor Phenotypic testing

Clinical use: beta-lactam

ESBLs A,D All beta-lactam except carbapenems

Clavulanate, Sulbactam, Tazobactam

Double disk, combined disk

Carbapenems

Amp C beta-lactamase

C, D All beta-lactam except carbapenems

Boronic acid Amp C disk, boronic disk

Carbapenems

Carbapenemases A,D All beta-lactam May be inhibit by Clavulanate, Boronicacid, Tazobactam

Modified Hodge

No

Mechanisms of Antimicrobial Resistance in MDR Gram negative

Susceptibility Testing1. Disk Diffusion: Zones of inhibition Susceptibility, Intermediate, Resistant

2. Tube dilution method: MIC (first tube with no visible growth)

3. Agar dilution method4. E-test: MIC

CLSI 2012 : Changes in ESBL ReportAntibiotics MIC

breakpointZone

breakpointOld New Old New

Cefazolin ≤ 8 ≤ 2 ≥ 18 ≥ 23

Cefotaxime ≤ 8 ≤ 1 ≥ 23 ≥ 26

Ceftriaxone ≤ 8 ≤ 1 ≥ 21 ≥ 23

Ceftazidime ≤ 8 ≤ 4 ≥ 18 ≥ 21

ESBL report: E.coli, K.pneumoniae, K.oxytoca, Proteus mirabilis

All-cause mortality of patients with ESBL bacteremia: Definitive treatment

Carbapenems VS BL/BLIs Carbapenems VS non BL/BLIs

Vardakas K Z. J Antimicrob Chemother 2012; 67: 2793-2803

De-escalation Therapy

• S. pyogenase Toxic Shock Syndrome• E. coli ESBL Catheter related UTI and bacteremia• What is the most appropriate de-escalation ATB?

A. ErtapenemB. MeropenemC. Piperacillin/TazobactamD. AmikacinE. Fosfomycin

Leone M et al. Intensive Care Med (2014) 40:1399–1408

Methods:This was a multicenter nonblinded randomized noninferiority trial of patients with severe sepsis who were randomly assigned to de-escalation (n = 59) or continuation of empirical antimicrobial treatment (n=57).

• Recruitment began in February 2012 and ended in April 2013 in 9 ICUs in France. • Primary outcome was to measure the duration of ICU stay (non-inferiority margin define as 2 days)• Secondary outcomes included mortality at 90 days, occurrence of organ failure, number of

superinfections, and number of days with antibiotic during the ICU stayResults:• The median duration of ICU stay was 9 [IQR 5–22] days in the de-escalation group and 8 [IQR 4–15]

days in continuation group, respectively (P = 0.71). Mean difference was 3.4 (95 % CI -1.7 to 8.5)• A superinfection occurred in 16 (27 %) patients in the de-escalation group and six (11 %) patients in

the continuation group (P = 0.03). • The numbers of ATB days were 9 [7–15] and 7.5 [6–13] in the de-escalation group and continuation

group, respectively (P = 0.03). • Mortality was similar in both groupsConclusion:• As compared to the continuation of the empirical antimicrobial treatment, a strategy based on de-

escalation of antibiotics resulted in prolonged duration of ICU stay. However, it did not affect the mortality rate.

Randomized (n=66)

Ertapenem (n=32) Group2 Carbapenem (n=34)

Rattanaumpawan et al. BMC Infectious Diseases (2017) 17:183

Characteristics of patients in the de-escalation group (intervention) and in the non-de-escalation group (control)

Efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-β-lactamase producingEnterobacteriaceae: an open label randomized controlled trial

Results: Characteristics of both groups were comparable• Most common sites of infection were UTI (42%) • By using a 15% predefined margin, Ertapenem was non-inferior to control group

– Clinical cure rate (%Δ = 14.0 [95% confidence interval: −2.4 to 31.1])– Microbiological eradication rate (%Δ = 4.1[−5.0 to 13.4])– Superimposed infection rate (%Δ = −16.5 [−38.4 to 5.3])

• Patients in the de-escalation group had – significantly lower 28-day mortality rate (9.4% vs. 29.4%; P = .05) – significantly shorter median LOS (16.5 d [4.0–73.25] vs. 20 d [1.0–112.25]; P = .04)

– significantly lower defined daily dose of carbapenem use (12.9 ± 8.9 vs. 18.4 ± 12.6; P = .05)

Conclusions: Ertapenem could be safely used as de-escalation therapy for ESBL-producing Enterobacteriaceae infections

Rattanaumpawan et al. BMC Infectious Diseases (2017) 17:183

N.-Y. Lee et al. / Diag Microbiol Infect Dis 70 (2011) 150–153

Algorithm for de-escalation decision making at day 3 in not improving patient

Patient on empiric ATB and not improving

Escalate antibiotic & Repeat microbiology investigation

Maintain antibiotic and Repeat microbiology investigation

Clinical assessment of patient demonstrates infection getting worse

•Microbiology cultures positive & show evidence of escalation opportunity or

•Microbiology investigation negative

Other investigations demonstrate that infection is getting worse

Clinical assessment of patient demonstrates that infection is not improving

•Microbiology cultures positive and appear to be covered pathogen

•Microbiology investigation negative

Other investigations demonstrate that patient is not improving


Positively associated Negatively associatedInitially appropriate empiric therapy Isolation of a MDR pathogen

Broad-spectrum empiric therapy Polymicrobial infectionsCompliance with national prescribing guidelines

Intra-abdominal infections

Treatment with multiple and “companion” antimicrobialsPositive microbiological cultures

Lower severity of illness scores at-Baseline

-Time of ADE-Day 5 of therapy

Factors Associated with Antibiotic De-escalation


A. CiprofloxacinB. AmikacinC. CeftriaxoneD. Piperacillin/TazobactamE. Ertapenam

Case 2: A middle aged diabetic male presented with acute fever, dysuria, and frank pain for 3 days

PE: BT 38.5C, BP 80/50 mmHg, PR 102 , RR 16 /min tender at right frank area

UA: WBC 50-100 cells, RBC 5-10, Epithelium 0-5

What is the most appropriate antibiotic?

Complicated/ uncomplicated Urinary tract infection

• Structural abnormalities (e.g. urinary obstruction)

• Metabolic & Hormonal abnormalities (Pregnancy, DM, renal impairment, etc.)

• Impaired host responses (transplant recipients, neutropenic patients etc.)

ESBL producing organisms

• E. coli• K. pneumoniae• K. oxytoca• Other Enterobacteriaceae

(Enterobacter, Proteus, Providentia, Serratia, Citrobacter)

• P. aeruginosa• Acinetobacter spp.

Hsueh Po-R. J of Infect 2011; 63: 114-123 Bush K. et al. AAC 1995;39:1211

P.-L. Lu et al. International Journal of Antimicrobial Agents 40S1 (2012) S37–S43

Distribution of GNB causing UTI by country in the Asia-Pacific region

• Community-acquired infections– Penicillin-resistant Streptococcus pneumoniae (PRSP)– Community- acquired methicillin resistant Staphylococcus aureus

(CA-MRSA)– Quinolone-resistant Neisseria gonorrhoeae (QRNG)– Quinolone-resistant Salmonella (QRS)– Community-acquired Extended-Spectrum B lactamase (ESBL)

producing Enterobacteriaceae• Hospital-acquired infections

– ESBL producing Enterobacteriaceae– Carbapenemase-producing Enterobacteriaceae– Multidrug resistant (MDR) P.aeruginosa, A. baumanii– Pandrug resistant P.aeruginosa, A. baumanii– Methicillin resistant Staphylococcus aureus (MRSA)

Antibiotic-Resistant Bacteria

• Rodriguez-Bano J et al. Arch Intern Med 2008;168:1897-902.

Risk factors for all type Community ESBL E.coli

Risk factors for Community ESBL E.coli UTI

Multivariate analysis:• > 3 UTI episodes in the preceding year (OR 3.8, 95% CI 1.8–8.1, p <0.001), •Use of a b-lactam ATB in the preceding 3 mo (OR 4.6, 95% CI 2.0–0.7,p <0.001)•Prostatic disease (OR 9.6, 95% CI 2.1–44.8, p 0.004)

Azap O.K. et al Clin Microbiol Infect 2010; 16: 147-151

Community acquired acute pyelonephritis with shock

• Hx. Recurrent UTI last 2 months• Empiric ATB: Ertapenem 1 g iv OD • Urine Culture: > 105 E. coli ESBL+

-Susceptible: Amikacin, Ertapenem, Imipenem, Meropenem-Resistant: Ampicillin, Ceftriaxone, ceftazidime,

ciprofloxacin• Hemoculture: E. coli ESBL+

• De-escalation therapy: Ertapenem 1 g iv OD (Outpatient Parenteral Antimicrobial Therapy;OPAT)

IDSA Guideline, Clinical Infectious Diseases 2004; 38:1651–72

Properties of commonly prescribed ATB at various temperatures

Tice AD et al. Clinical Infectious Diseases 2004; 38:1651–72

Treatment Regimens and Expected Early Efficacy Rates for Acute Uncomplicated Cystitis

Gupta et al. IDSA Guideline, CID 2011:52 (1 March)

Switching Therapy

Advantages of Intravenous to Oral switch therapy

Current Opinion in Infectious Diseases 2000, 13:599±607

Types of IV to oral conversions

• Sequential therapy: Replacing an IV medication to oral counterpart of the same compound

• Switching therapy: Conversion from IV medication to a oral equivalent; within the same class and has the same level of potency – e.g. switch from ceftriaxone 1 g to tab cefixime 200 mg

• Step down therapy: Conversion from IV medication to an oral agent in another class or to a different medication without the same class– e.g. conversion of IV cefotaxime to tab ciprofloxacin

Consideration for early switch to oral therapy COMS (review at 24-48 hours)

• C: Clinical improvement observed• O: Oral route is not compromised

(vomiting, malabsorptive disorder, NBM, swallowing problems, unconscious, severe diarrhoea)

• M: Markers showing a trend towards normal: – Patient should be apyrexial for the last 24 hours

(Temp>36 o C and <38 o C) and – NOT have more than one of the following, HR >90/min,

RR>20/min, BP unstable, WBC<4 000 or>12000 • S: Specific indication/deep seated infection

S: Specific indication/deep seated infection

High risk infections requiring prolong IV therapy

Deep seated infections that may require an initial 2 weeks of IV therapy

Meningitis/encephalitis Cavitating pneumonia Intracranial abscesses Empyema Endocarditis Liver abscess Mediastinitis Osteomyelitis, Septic arthritisS. aureus bacteraemia Severe infections during chemotherapy related neutropenia Severe necrotising soft tissue infections Infected implants/prosthesis Inadequently drained abscesses/empyema Exacerbation of cystic fibrosis/ bronchiectasis

Sequential therapyAntimicrobial agent Bioavailability

IV dose Equivalent PO dose

Ciprofloxacin* 70-80% 400 mg q 12 h 500 mg q 12 h (Pseudomonas spp. infection) 400 mg q 8 h 750 mg q 12 h Levofloxacin* 99% 500-750 mg q 24 h 500-750 mg q 24 h Moxifloxacin 90% 400 mg q 24 h 400 mg q 24 h Azithromycin 37% 500 mg q 24 h 500 mg q 24 h Metronidazole 100% 500 mg q 8 h 500 mg q 8 h Clindamycin 75-90% 600 mg q 8 h 300 mg q 6 h Amoxy/clavulonic 70-99% 1.2 g q 8 h 1 g q 12 h or

625 mg q 8 h Linezolid 100% 600 mg q 12 h 600 mg q 12 h Trimethroprim/sulfamethoxazole

90-100% Depend on diseases

Depend on diseases

Current Opinion in Infectious Diseases 2000, 13:599±607

Switch TherapyParenteral ATB Dose Oral ATB Dose

Cloxacillin 1-2 g q 6 h Dicloxacillin 250-500 mg q 6 h

Cloxacillin 500 mg q 6 h

Ampicillin 1 g q 6 h Amoxycillin 500 mg q 8 h

Cefazolin 1-2 g q 8 h Cephalexin 500 mg q 6 h

Dicloxacillin 250-500 mg q 6 h

Ceftriaxone 2 g q 24 h Cephalexin 200 mg q 12 h

Cefdinir 200-300 mg q 12 h

Ofloxacin 400-800 mg q 12 h

Ciprofloxacin 500 mg q 12 h

Levofloxacin 500-750 mg q 24 h

Norfloxacin 400 mg q 12 h

Doxycyclin 100 mg q 12 h

Ceftazidime 2 g iv q 8 h Ciprofloxacin 750 mg q 12 h

Amikacin 15 mg/kg q 24 h Cefdinir 200-300 mg q 12 h

Ofloxacin 400-800 mg q 12 h

Ciprofloxacin 500 mg q 12 h

Levofloxacin 500-750 mg q 24 h

Ertapenem (ESBL+) Sitafloxacin 50-100 mg q 12 h

Antibiotic optionDiseases Parenteral antimicrobial Oral antimicrobial Leptospirosis PGS, Ceftriaxone Doxycycline Scrub typhus Doxycycline (not available in

Thailand), Chloramphenicol, Azithromycin (mild case)

Doxycycline, azithromycin

Diptheria PGS Erythromycin Salmonellosis Ciprofloxacin, Ceftriaxone,

Carbapenem Ciprofloxacin

Melioidosis Ceftazidime, Cefo/Sulbactam, Imipenem, Meropenem

TMP/SMX, Amoxy/clav

BW GFR > 30 GFR <30

> 60 kg TMP/SMX (80/400) 4 tab bid TMP/SMX (80/400) 3 tab bid

40-60 kg TMP/SMX (80/400) 3 tab bid TMP/SMX (80/400) 2 tab bid

< 40 kg TMP/SMX (80/400) 2 tab bid TMP/SMX (80/400) 1 tab bid

Thank you for your attention

antimicrobial de-escalation (ade) · e. vancomycin plus pip/tazo. case 1: a 45 years old male with...

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