febrile neutropenia by dr saqib ahmad shah pg radiation oncology skims kashmir

GRANULOPOIESIS

GM-CSF(+)

G-CSF

CT

Neutrophils in the body

• 3-8,000/mL of blood

• ~70% of WBC

• T1/2 = 4-7 hours in blood

• T1/2 = 5-6 days in tissues

Guyton text book of physiology

Neutropenia

• Normal ANC 1500 to 8000 cells/mm³

• Neutropenia: ANC < 1500 cells / mm3

• Mild Neutropenia: 1000-1500 cells / mm3

• Moderate Neutropenia: 500-999 cells / mm3

• Severe Neutropenia: < 500 cells / mm3

• Profound Neutropenia: <100 cells/ mm³

• Ganong text book of physiology…

Infection + ABX + Immune system = cure

• Normal Gross Anatomy

• Skin Integrity

• Intact mucous membranes

• Intact ciliary function

• Absence of Foreign Bodies

• Innate Immunity

PMN,

Macrophages, NK cells, Mast cells and

basophils)

• Complement

• Adaptive immunity

T cells CD 4 and CD 8

B cells

• The life of the granulocytes after beingreleased from the bone marrow is normally 4to 8 hours circulating in the blood and another4 to 5 days in tissues where they are needed.In times of serious tissue infection, this totallife span is often shortened to only a fewhours because the granulocytes proceed evenmore rapidly to the infected area, performtheir functions,and, in the process, arethemselves destroyed.

When Does Neutropenia Occur?

• Most chemotherapy agents/protocols cause neutropenia nadir at 10-14 days

• But can see anytime from a few days after chemotherapy to up to 4-6 weeks later depending on the agents used

• Neurtopenia is one of the risk factors in cancerpatients(others host factors hematological /solidmalignancies,aspelenia, treatment related factorsneutropenia,mucosistis ,steriods,monocolnal antibodies,RTETC)

Why is this an Oncologic emergency ??

EPIDEMIOLOGY

Morbidity and Financial Burden of Infections in Patients with Neoplasia

• Number of patients with cancer and infectious complications hospitalized (USA): 60,000 / year

• Average cost of hospitalization: $10,372

• Motality due to infection: 10%

– Solid tumors: 8% (lung: 13.4%, breast: 3.6%)

– Leukemia: 14%, Lymphoma: 9%

• Motality higher in confirmed infections:

invasive aspergillosis (39%), candidiasis (37%),

Gram (-)ve sepsis (34%), Gram (+)ve sepsis(21%)

Cagiarro et al. Cancer 2005;103:1916Kuderer et al. Cancer 2006;106:2258

Febrile Neutropenia• Appears in 10 % - 30 % of patients with solid tumors• Often characteristic signs and symptoms of infection are absent• 50% of febrile neutropenic patients have infection• 20% of febrile neutropenic patients + PMN <100 /mm3 have

septicemia• Frequent inability to identify the pathogen(motality rate 10% in solid

tumors and 14% in hematological malignancies)

• Neutopenia depends on patient factors(individalised),type of chemo/number of cycles./type of tumor.

• Crawford et al fould 96% of patients treated with CAE IN SCCLexperienced neutropenia

• Blay et al over all incidence of neutropenia (grade 4) in 51% ofpatients treated for lymphoma and solid tissue malignancies.

Sepkowitz K.A. Clin Infect Dis 2005;40 Suppl 4:S253-6Pizzo P.A. N Engl J Med 1993;328:1323

• 2142 patients with febrile neutropenia from

cancer chemotherapy

– 499 (23%) patients with bacteremia

– Gram-positive: 57%

– Gram-negative: 34%

– Polymicrobial bacteremias: 10%

Bacteremia in febrile neutropenic cancer patients

Klastersky et al. Int J Antimicrob Agents 2007; 30(Suppl 1): S51–9.

Epidemiology contd

• Changing etiology of bacteremiaIATG-EORTC 1973-2000 trials of febrile neutropenia

Gram positive dominant since mid 1980s1) More intensive chemoTx

•Mucositis2) In-dwelling catheters

• Cutaneous-IV portal3) Selective antiBx pressure

•Fluoroquinolones• Co-trimoxazole

4) Antacids•Promote oro-oesophagealcolonisation with GPC

Viscoli et al, Clin Inf Dis;40:S240-5

Gram negative resurgence

Epidemiology --NEJM, 1979;284:1061

Retrospective data have shown that

– ~ 50 % of Pseudomonas Aeruginosa Bacteremia result in death within 72 hours when ANC is < 1000

– Early trials aimed at Pseudomonas showed thatCarbapenicillin /Gentamicin decreased Mortality by 33 %

Common Microbes

Gram-positive cocci and bacilli

• Staph. aureus

• Staphylococcus epidermidis

• Enterococcus faecalis/faecium

• Corynebacterium species

Gram-negative

• bacilli and cocci

• Escherichia coli

• Klebsiella species

• Pseudomonas aeruginosa

FUNGI

• Candida- Non albicans emerging

• Aspergillus >> in HSCT

Anerobic Bacteria

• Bacteroides spp

• Clostridium spp

• Fusobacterium spp

• Propionibacterium spp

• Peptococcus spp

• Veillonella spp

• Peptostreptococcus spp

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines IndexTable of Contents

Discussion

NCCN Guidelines Version 1.2014

Prevention and Treatment of Cancer-Related Infections

CLINICAL PRESENTATION INITIAL EVALUATION OF FEVER AND NEUTROPENIA MICROBIAL EVALUATION

Fever:

• Single temperature

equivalent to

≥ 38.3°C orally

or

• Equivalent to ≥ 38.0°C

orally over 1 h period

Neutropenia:

• < 500 neutrophils/mcL

or

< 1,000 neutrophils/mcL

and a predicted decline

to ≤ 500/mcL over the

next 48 h

Site speciic H&P including:

• Intravascular access device

• Skin

• Lungs and sinus

• Alimentary canal

• Perivaginal/perirectal

• Urologic

• Neurologic

Supplementary historical information:

• Major comorbid illness

• Time since last chemotherapy administration

• History of prior documented infections

• Recent antibiotic therapy/prophylaxis

• Medications

• HIV status

• Exposures:

O t h e r s at home with similar

symptoms

P e t s

Travel

Tuberculosis exposure

Recent blood product administration

Laboratory/radiology assessment:

• CBC including differential, platelets, BUN,

electrolytes, creatinine, and LFTs

• Consider chest x-ray, urinalysis,

pulse oximetry

• Chest x-ray for all patients with respiratory

symptoms

• Blood culture x 2 sets (one set

consists of 2 bottles). Options

include:

One peripheral + one catheter

(preferred)a

or

Both peripheral

or

Both catheter

• Urine culture (if symptoms,

urinary catheter, abnormal

urinalysis)

• Site-speciic culture:

Diarrhea (Clostridium dificile

assay, enteric pathogen screen)

Skin (aspirate/biopsy of skin

lesions)

Vascular access cutaneous site

with inlammation (consider

routine/fungal/mycobacterial)

• Viral cultures:

Vesicular/ulcerated lesions on

skin or mucosa

Throat or nasopharynx for

respiratory virus symptoms,

especially during outbreaks

See Initial

Risk

Assessment

(FEV-2)

aPreferred for distinguishing catheter-related infections from secondary sources.

FEV-1

Version 1.2014, 06/17/2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCNGuidelines

Printed by saqib shah on 7/28/2014 9:25:19 AM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

• Definition developed by infection disease society of america(IDSA) and the u.s food and drug adminstration deptt(FDA)

• Patient with neutropenia but signs and symptoms of infection (eg abdominal pain,mucositis,perirectal pain ) without fever is to be taken as active infection..

• Patient on steriods may also blunt fever response and localising signs of infection..

Febrile NeutropeniaTreatment

• Emergency situation• Treatment initiation within 2 hours

• Morbidity >70% if delay of initiation of antimicrobial chemotherapy

• A) Risk assessment

• B) Antimicrobial coverage• Wide spectrum

• Local microbial flora susceptibility pattern

• Previous antimicrobial therapy

Sepkowitz K.A. Clin Infect Dis 2005;40:S253Schimpff SC et al. N Engl J Med 1971;284:1061

Febrile NeutropeniaPatient Risk Assessment

Low risk patients• Outpatient status at time of fever development

• No acute comorbidity indicating hospitalization

• ≤ 100 cells / mm 3 for < 7 days

• ECOG: 0-1

• No hepatic / renal insufficiency

Or

• MASCC Risk Index score ≥ 21 (MULTINATIONAL ASSESMENT FOR SUPPORTIVE CARE OF CANCER)

Freifeld et al. Clin Infect Dis 2011;52:427-31National Comprehensive Cancer Network (NCCN) Guidelines, version 1.2013

Febrile NeutropeniaPatient Risk Assessment

High risk patients• Inpatient status at time of fever development

• Significant medical comorbidity (ex. GI, CNS) / clinically unstable

• ≤ 100 cells / mm 3 for > 7 days

• Suspected / proven catheter - relater infection

• Hepatic insufficiency (LFT ≥ 5 UNL)

• Renal insufficiency (creatinine clearance <30 mL/min)

• Uncontrolled / progressive cancer

• Pneumonia or other complex infection at presentation

• Alemtuzumab

• Mucositis grade 3-4

Or

• MASCC Risk Index score < 21

Freifeld et al. Clin Infect Dis 2011;52:427-31National Comprehensive Cancer Network (NCCN) Guidelines, version 1.2014


Discussion



RISK ASSESSMENT RESOURCES

USING THE MASCC RISK-INDEX SCORE

• Using the visual analogue score, estimate the patient's burden of illness at the time of

initial clinical evaluation. No signs or symptoms or mild signs or symptoms are scored

as 5 points, moderate signs or symptoms are scored as 3 points. These are mutually

exclusive. No points are scored for severe signs or symptoms or moribund.

• Based upon the patient's age, past medical history, present clinical features and site of

care (input/output when febrile episode occurred), score the other factors in the model

and total the sum.

MASCC RISK-INDEX SCORE/MODEL1

Characteristic

• Burden of illness

No or mild symptoms

M o d e r a t e

symptoms

• No hypotension

• No COPD

• Solid tumor or

Weight

Hematolo

gic malignancy with no

previous fungal infection

• No dehydration

• Outpatient status

• Age <60 years

BURDEN OF ILLNESS

How sick is the patient at presentation?

No signs Mild signs Moderate Severe Moribund

or or signs or signs or

symptoms symptoms symptoms symptoms

Estimate the burden of illness

considering all comorbid conditions

5

3

5

4

4

3

3

2

1Klastersky J, Paesmans M, Rubenstein EJ et al. The Multinational Association for Supportive Care in Cancer Risk Index: A Multinational Scoring System forIdentifying Low-Risk Febrile Neutropenic Cancer Patients. J Clin Oncol 2000;18:3038-51.



FEV-D




Duration of Neutropenia

• < 7 days LOW risk

• > 7 days HIGH RISK

• Problem with MASCC index:- duration of neutropenia not included..

Duration Of Neutropenia1988,Rubin and colleagues (cancer invest journal)

• < 7 days of neutropenia

~ response rates to initial antimicrobial therapy was 95%, compared to only 32% in patients with more than 14 days of neutropenia ( <.001)

~ patients with intermediate durations of neutropenia between 7 and

14 days had response rates of 79%

Advantages of Outpatient Therapy

• Improved quality of life

• Lower incidence of nosocomial infections

• Simplification of antimicrobial therapy

• Lower cost

Uzun O and Anaizzie E.J. J Antimicrob Chemother 1999;43(3):317-320


Discussion



OUTPATIENT THERAPY FOR LOW-RISK PATIENTS

INDICATION ASSESSMENTMANAGEMENT

Patient determined to be in low-risk

category on presentation with fever

and neutropeniab

• Careful examination

• Review lab results: no critical

values

• Review social criteria for home

therapy

Patient consents to home care

24 h home caregiver available

Home telephone

Access to emergency facilities

Adequate home environment

Distance within approximately

one hour of a medical center

or treating physician's ofice

• Assess for oral antibiotic

therapy

No nausea and vomiting

Able to tolerate oral

medications

N o t o n p r i o r

luoroquinolone

prophylaxis

Observation period (2-12 h) (category

2B) in order to:

• Conirm low-risk status and ensure

stability of patient

• Observe and administer irst dose

of antibiotics and monitor for

reaction

• Organize discharge plans to home

and follow-up

• Patient education

• Telephone follow-up within 12-24 h

See Treatment

and Follow-up

(FEV-4)



FEV-3Version 1.2014, 06/17/2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCNGuidelines

bRisk categorization refers to risk of serious complications, including mortality, in patients with neutropenic fever. See Risk Assessment Resources (FEV-D).



ORAL vs IV

• For patients who are low risk for developing infection-related complications during the course of neutropenia,

~ Oral ciprofloxacin plus amoxicillin/clavulanate

~ Oral ciprofloxacin plus clindamycin

for PCN allergy

• Oral versus intravenous empirical antimicrobial therapy for fever inpatients with granulocytopenia who are receiving cancer chemotherapy.International Antimicrobial Therapy Cooperative Group of the EuropeanOrganization for Research and Treatment of Cancer(NEJM).

• Abstract• BACKGROUND:Intravenously administered antimicrobial agents have been the standard choice for the

empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost.

• METHODS:In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less.

• RESULTS:Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency.

• CONCLUSION:- In low-risk patients with cancer who have fever andgranulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate isas effective as intravenous therapy.

Bacteremia due to viridans streptococci in neutropenic patients: areview.(Bochud et al)

• Abstract:-Viridans streptococci have long been considered, with theexception of the ability to cause endocarditis, as minor pathogenic agents.More recently, however, these bacteria have become a major concern inneutropenic patients undergoing a chemotherapeutic treatment. In thishigh-risk population, they can be responsible for up to 39% of bacteremiacases and are the most frequent cause of this type of infection. The mostfrequently isolated species in blood cultures are Streptococcus mitis andStreptococcus sanguis II. Viridans streptococcus bacteremia can beaccompanied by serious complications, like adult respiratory distresssyndrome (ARDS) (3% to 33%), shock (7% to 18%) or endocarditis (7% to8%). Mortality rates range from 6% to 30%. Case-control studies haveidentified the following risk factors: severe neutropenia (< 100neutrophils/mm3), prophylactic antibiotic treatments with quinolone orco-trimoxazole, absence of intravenous antibiotics at the time ofbacteremia, high doses of cytosine arabinoside, oropharyngeal mucositis,and heavy colonization by viridans streptococci. The introduction ofpenicillin in prophylactic antibiotic treatments has reduced the incidenceof these infections, but the long-term use of penicillin could becompromised by the emergence of resistant strains.


Discussion



OUTPATIENT THERAPY FOR LOW-RISK PATIENTS

TREATMENT OPTIONS FOLLOW-UP

• IV antibiotics at home

• Daily long-acting intravenous

agent ± oral therapyd

H o m e o r ofice

• Oral therapy onlye:

Ciproloxacinf plus

amoxicillin/clavulanateg

(category 1)

Moxiloxacinf,h (category 1)

hNot active against Pseudomonas.




• Patient should be monitored daily

• Daily examination (clinic or home visit) for the

irst 72 h to assess response, toxicity, and

compliance; if responding, then telephone

follow-up daily thereafter.

• Speciic reasons to return to clinic:

Any positive culture

New signs/symptoms reported by the patient

P e r s i s t e n t or recurrent fever at

days 3-5

Inability to continue prescribed antibiotic

regimen (ie, oral intolerance)

Ofice visit for infusion of IV antibiotics

dAgents active against Pseudomonas should be included.eCriteria for oral antibiotics: no nausea or vomiting, patient able to tolerate oral medications, and patient not on prior fluoroquinolone prophylaxis.fThe fluoroquinolone chosen should be based on reliable Gram-negative bacillary activity, local antibacterial susceptibilities, and the use of quinolone prophylaxis of

fever and neutropenia.gUse clindamycin for penicillin-allergic patients.




Discussion



• Intravenous antibiotic monotherapy (choose one):

Imipenem/cilastatin (category 1)

M e r o p e n e m (category 1)

Piperacillin/tazobactamk (category 1)

Cefepime (category 1)l

Ceftazidimem (category 2B)

• Oral antibiotic combination therapy for low-risk

patients:

Ciproloxacin + amoxicillin/clavulanate

(category 1)

Moxiloxacin (category 1)f,h

Oral antibiotic regimen recommended should

not be used if quinolone prophylaxis was used

INITIAL EMPIRIC THERAPY FOR UNCOMPLICATED FEVER AND NEUTROPENIAi,j

Site-Speciic Evaluation

and Therapy:

Initial antibiotic therapy should be based on:

• Infection risk assessment

(See FEV-2)

• Broad spectrum coverage including

antipseudomonal activity

• Potential infecting organisms include multi-

drug resistant organisms (MDROs)

• Colonization with or prior infection with

methicillin-resistant Staphylococcus

aureus (MRSA)

• Site of infection

• Local antibiotic susceptibility patterns

• Organ dysfunction/drug allergy

• Previous antibiotic therapy

• Bactericidal

• IV combination therapy not routinely

recommended except for complicated cases

or resistance

Mouth, Esophagus and

Sinus/Nasal (FEV-6)

Abdominal Pain, Perirectal

Pain, Diarrhea, Urinary Tract

Symptoms (FEV-7)

Lung Iniltrates (FEV-8)

Cellulitis, Vascular Access

Devices, Vesicular Lesions,

Disseminated Papules or

Other Lesions, Central

Nervous System Symptoms

(FEV-9)

OR

Follow-up (FEV-10)

fThe fluoroquinolone chosen should be based on reliable Gram-negative bacillary activity, local antibacterial susceptibilities, and the use of quinolone prophylaxis offever and neutropenia.

hNot active against Pseudomonas.iConsider local antibiotic susceptibility patterns when choosing empirical therapy. At hospitals where infections by antibiotic resistant bacteria (eg, MRSA ordrug resistant gram-negative rods) are commonly observed, policies on initial empirical therapy of neutropenic fever may need to be tailored accordingly.jSee Antibacterial Agents (FEV-A) for dosing, spectrum, and specific comments/cautions.kMay interfere with galactomannan measurement.lMeta-analysis reported increased mortality associated with cefepime in randomized trials of neutropenic fever. Based on the results of the FDA’s meta-analyses, the

FDA has determined that cefepime remains an appropriate therapy for its approved indications.mWeak Gram-positive coverage and increased breakthrough infections limit utility.






~ A meta analysis of 33 RCTs until Feb 2005 on

Antipseudomonal B lactams as MONOtherapies showedthat ~CEFEPIME increases 30 day all cause mortality.. Asubsequent meta-analysis by the FDA, using additional databeyond what was used in the Yahav study, did not find astatistically significant increase in mortality for cefepime-treated patients compared with controls. Thus, the FDAconcluded that cefepime remains appropriate therapy forits approved indications

~ Carbapenems were associated with increased

Pseudomembranous colitis..

Febrile NeutropeniaEmpiric Monotherapy

• Ceftazidime is no longer reliable as monotherapy

decreasing potency against gram (-) ves

poor activity against gram (+)ves (streptococci)

• Aminoglycosides not to be used as monotherapy empirically due to rapid emergence of resistance

Freifeld et al. Clin Infect Dis 2011;52:427-31


Discussion



INITIAL CLINICAL

PRESENTATION

(DAY 0)

FINDING EVALUATION ADDITIONS TO INITIAL EMPIRIC REGIMENn,o,p

All febrile neutropenic patients should receive broad-spectrum antibiotics (FEV-5)

Mouth/

mucosal

membrane

Necrotizing

ulceration

Thrush

Vesicular lesions

• Culture and Gram stains

Viral - Herpes simplex virus

(HSV)

Fungal

C o n s i d e r

l e u k e m i c iniltrate

• Biopsy suspicious lesions

• Ensure adequate anaerobic activity

• Consider anti-HSV therapy

• Consider systemic antifungal therapy

• Antifungal therapy

F l u c o n a z o l e irst-line

therapy

Voriconazole, posaconazole, or

echinocandin if refractory to luconazole

Anti-HSV therapy (category 1)

Viral cultures or PCR or

other diagnostics and DFA

direct luorescent antibody

test for HSV and Varicella-

zoster virus (VZV)

• Culture suspicious oral

lesions

HSV

Fungal

• Consider endoscopy, if no

response to therapy

• Consider CMV esophagitis

in patients at high risk for

CMV disease

Esophagus•Retrosternal burning

•Dysphagia/

odynophagia

• Initial therapy guided by clinical indings

(eg, thrush or perioral HSV)

• Antifungal therapy for thrush

F l u c o n a z o l e , irst-line

therapy

Voriconazole, posaconazole, or

echinocandin if refractory to luconazole

• Consider acyclovir for possible HSV

Sinus/

nasal

• Sinus tenderness

• Periorbital cellulitis

• Nasal ulceration

• Unilateral eye tearing

• High resolution sinus

CT/orbit MRI

• ENT/ophthalmological

urgent evaluation

• Culture and stains/

biopsy

• Add vancomycin if periorbital cellulitis noted

• Add lipid amphotericin B preparation to

cover possible aspergillosis and

mucormycosis in high-risk patients with

suspicious CT/MRI indingsq

See

Follow-up(FEV-10)

nSee Antibacterial Agents (FEV-A) for dosing, spectrum, and specific comments/cautions.oSee Antifungal Agents (FEV-B) for dosing, spectrum, and specific comments/cautions.pSee Antiviral Agents (FEV-C) for dosing, spectrum, and specific comments/cautions.qPosaconazole can be considered for patients who have invasive, refractory infections or who have intolerance to amphotericin B formulations. Posaconazole is not

approved by the FDA as either primary or invasive, refractory therapy for invasive fungal infections.






PEARLS(NCCN guidelines)

A trial of fluconazole and acyclovir (5 mg/kg IV every 8 hours in patients withnormal renal function) should be considered in neutropenic patients andother highly immunocompromised persons with symptoms that suggestesophagitis..

Fluconazole is recommended as first If patients do not respond, the dose offluconazole can be increased up to 800 mg daily (in adults with normal renalfunction)

The sinuses are a common site of bacterial infection. Patients with severeand prolonged neutropenia (e.g., more than 10 days) and allogeneic HSCTrecipients with GVHD are particularly susceptible to invasive mold infections.


Discussion



INITIAL CLINICAL

PRESENTATION

(DAY 0)

EVALUATIONs ADDITIONS TO INITIAL EMPIRIC REGIMENn,o,p

All febrile neutropenic patients should receive broad-spectrum antibiotics (FEV-5)

Abdominal

painr

• Abdominal CT (preferred) or ultrasound

• Alkaline phosphatase, transaminases,

bilirubin, amylase, lipase

• Oral vancomycin or

metronidazole if C. dificile

suspected

• Ensure adequate anaerobic

therapy

• Ensure adequate anaerobic

therapy

• Consider enterococcalt

coverage

• Consider local care (sitz baths,

stool softeners)

Perirectal

pain

• Perirectal inspection

• Consider abdominal/pelvic CT

Diarrhea

• C. dificile assay

• Consider testing for rotavirus and

norovirus in winter months and during

outbreaks

• Consider stool bacterial cultures and/or

parasite exam if travel/lifestyle history or

community outbreak indicate exposure

• Consider testing for adenovirus

If C. dificile suspected,

consider adding oral

metronidazole or oral

vancomycin pending assay

results: IV metronidazole

should be used in patients who

cannot take oral agents

Urinary tract

symptoms• Urine culture

• UrinalysisNo additional therapy until

speciic pathogen

identiied

SeeFollow-up(FEV-10)

nSee Antibacterial Agents (FEV-A) for dosing, spectrum, and specific comments/cautions.oSee Antifungal Agents (FEV-B) for dosing, spectrum, and specific comments/cautions.pSee Antiviral Agents (FEV-C) for dosing, spectrum, and specific comments/cautions.rSurgical and other subspecialty (eg, gastroenterology, interventional radiology) consultations should be considered for these situations as clinically indicated.sLab studies include CMV antigens/PCR and abdominal/pelvic CT.tEnterococcal colonization must be differentiated from infection. Vancomycin use must be minimized because of the risk of vancomycin resistance.







Discussion



PRINCIPLES OF DAILY FOLLOW-UP FOLLOW-UP THERAPY

• Daily site-speciic H&P

• Daily review of

laboratory tests and

cultures: document

clearance of

bacteremia, fungemia

with repeat blood

cultures

• Evaluate for response

to therapy (in 3-5 d) and

drug toxicity:

F e v e r trends

Signs and symptoms

of infection

• Evaluation of drug

toxicity including end-

organ toxicity (LFTs and

renal function tests at

least 2x/wk)

Responding/clinically stable

• Decreasing fever trend

• Signs and symptoms of

infection are stable or

improving

• Patient is

hemodynamically stable

No change in initial

empiric regimen.

If initially started

appropriately on

agent for gram-

positive resistant

infection,aa continue

course of therapy.

Initial antibiotic

regimen should be

continued at least

until neutrophil count

is ≥ 500 cells/mcL

and increasing

Documented

infection

See Duration(FEV-11)

Fever

resolved,

unknown

origin

Neutrophils

≥ 500 cells/mcL

Discontinue

therapy

Neutrophils

< 500 cells/mcLbb

Continue

current

regimen until

neutropenia

resolvescc

Non-responding/clinically unstable

• Persistently or intermittently

febrile

• Signs and symptoms of infection

are not improving

• Patient may be hemodynamically

unstable

• Persistent positive blood cultures

• Broaden coverage to

include anaerobes,

resistant Gram-negative

rods, and resistant Gram-

positive organisms, as

clinically indicated

• Consider reevaluation

with CT scans

• Consider adding G-CSF or

GM-CSF (category 2B)

• Ensure coverage for

Candida

• ID consult

• Consider antifungal

therapy with activity

against molds for fever

continuing ≥ 4 days

of empiric antibiotic

therapyaa

• Duration of therapy

depends on clinical

course, neutropenia

recovery, toxicity,

and opinions of ID

consultants

aaSee Appropriate Use of Vancomycin and Other Agents for Gram-positive Resistant Infections (FEV-F).bbIn the case of prolonged neutropenia (>14d), consider judicious assessment of empiric therapy.ccIn patients who defervesced, it may be appropriate in some cases to de-escalate to fluoroquinolone.ddThe timing to add empirical antifungal therapy varies with the risk of invasive mold infection but generally ranges between 4-7d of neutropenic fever. In patients at

high-risk for mold infection (neutropenia > 10d, allogeneic stem cell transplant recipients, high-dose corticosteroids), the Panel recommends adding empirical


antifungal therapy after 4th d unless patient is receiving prophylaxis directed against molds.



FEV-10



Evaluation and Follow-up Therapy in Non-responding Patients

Non infectious etiology(drug fever) nonbacterial infection (fungal or viral) abacterial infection that is resistant to empiric antibiotics, a venous access orclosed space infection, or inadequate antimicrobial serum levels,deep tissueinfections may take longer than fever of unknown etiology to respond to

antimicrobial therapy. unusual infections (e.g., toxoplasmosis) may complicateneutropenia, particularly if immunosuppressive agents (e.g., high-dosecorticosteroids) are alsoused. the panel strongly recommends an infectiousdisease consultation for these patients.

•Broaden coverage to include anaerobes, resistant Gram-negative

rods, and resistant Gram- positive organisms, as clinically indicated

•Consider reevaluation with CT scans

•Consider adding G-CSF or GM-CSF (category 2B)

•Ensure coverage for Candida

•ID consult

NCCN GUIDELINES FOR NRPs


Discussion



FOLLOW-UP THERAPY FOR

RESPONDING DISEASE

SUGGESTED MINIMUM DURATION OF THERAPY FOR DOCUMENTED INFECTIONn,o,p

These are general guidelines and may need to be revised for individual patients.

Documented

infection

• Initial antibiotic regimen should

generally be continued until

neutrophil count is ≥ 500 cells/

mcL and increasing

• Duration of antimicrobial therapy

may be individualized based

upon:

Neutrophil recovery

Rapidity of defervescence

Speciic site of infection

Infecting pathogen

Patient's underlying illness

• Skin/soft tissue: 7-14 d

• Bloodstream infection (uncomplicated)

G r a m - n e g a t i v e : 10-14 d

G r a m - p o s i t i v e : 7-14 d

S. aureus: at least 2 weeks after irst negative blood culture; treatment

may need to be prolonged in cases of endovascular involvement

Yeast: ≥ 2 wks after irst negative blood culture

Consider catheter removal for bloodstream infections with Candida,

S. aureus, Pseudomonas aeruginosa, Corynebacterium jeikeium,

Acinetobacter, Bacillus organisms, atypical mycobacteria, yeasts,

molds, vancomycin-resistant enterococci, and Stenotrophomonas

maltophilia

• Sinusitis: 10-21 d

• Catheter removal for septic phlebitis, tunnel infection, or port pocket

infection

• Bacterial pneumonia: 10-21 d

• Fungal (mold and yeast):

Candida: minimum of 2 wks after irst negative blood culture

Mold (eg, Aspergillus): minimum of 12 wks

• Viral:

HSV/VZV: 7-10 d (category 1); acyclovir, valacyclovir, or famciclovir

(uncomplicated, localized disease to the skin)

nSee Antibacterial Agents (FEV-A) for dosing, spectrum, and specific comments/cautions.oSee Antifungal Agents (FEV-B) for dosing, spectrum, and specific comments/cautions.pSee Antiviral Agents (FEV-C) for dosing, spectrum, and specific comments/cautions.eeSome centers use higher dose (for example 150 mg).



FEV-11




Febrile NeutropeniaGram positive antimicrobial coverage

Gram Positive organisms

Increasing in frequency

Central Venous Catheters (?)

Antimicrobial Chemotherapy

– vancomycin

– linezolid

– quinopristin - dalfopristin

– tigecycline

– daptomycin

• Discontinuation of empiric gram(+)ve Rx post 72 hours if susceptible bacteria are not isolated from the patient

Freifeld et al. Clin Infect Dis 2011;52:427-31Hughes at al. Clin Infect Dis 2002;34:730

• Vancomycin should be considered in thefollowing clinical situations

• Clinically apparent, serious IV catheter-related infection (tocovercoagulase-negative staphylococcal isolates, which areusually betalactam antibiotic-resistant and MRSA).

• Blood cultures positive for Gram-positive bacteria beforefinal identification and susceptibility testing;

• Known colonization with penicillin/cephalosporin–resistantpneumococci or MRSA;

• Clinical instability (e.g., hypotension or shock), pending theresults of cultures.

• Soft tissue infection (particularly in regions where MRSAinfection is common).

• management of complicated cases of Clostridium difficileinfections, oral vancomycin can be considered.

The NCCN Guidelines panel strongly recommendsthat vancomycin should not be routinely added to anempiric regimen solely based on persistentneutropenic fever of unknown etiology.(2 trials)

• In patients with neutropenic fever and severe mucositis who receivingimipenem/cilastatin, meropenem, or piperacillin/tazobactam antibiotics withactivity against oral flora), it does not appear that the addition of vancomycin is

advantageous .

• A smaller randomized, placebo-controlled study did not show any advantage after adding teicoplanin (a glycopeptide antibiotic similar to vancomycin) in patients with neutropenic fever that persisted after 3 to 4 days of empiric imipenem/cilastatin

MultiDrug Resistant (MDR) organisms

Risk Factors

– Previous infection

– Colonization

– Admission in hospital with endemic resistant bacteria

• MRSA: vancomycin, linezolid, daptomycin

• VRE: linezolid, daptomycin

• ESBLs: carbapenem

• KPCs: colistin, tigecycline


Discussion



ANTIBACTERIAL AGENTS: GRAM-POSITIVE ACTIVITY

aThese drugs are not recommended as monotherapy for fever in the setting of neutropenia and should only be added for documentedinfection with resistant Gram-positive organisms or if certain risk factors are present. (See FEV-F)

bRequires dose adjustment in patients with renal insufficiency.


Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. FEV-A

(Page 1 of 4)


Continued on next page


Gram-positiveAgentsa

DOSE SPECTRUM COMMENTS/PRECAUTIONS

Dalfopristin/

Quinupristin

7.5 mg/kg IV every 8 h • Gram-positive

organisms

including most VRE

• Not active against

Enterococcus faecalis

• Signiicant drug interactions

• Use limited by myalgias/arthralgias (up to 47%)

• Requires central venous access delivery

• Avoid use due to toxicity although coverage is good

• Musculoskeletal pain syndrome is a potential toxicity

Daptomycin 6 mg/kg/d IV b • Gram-positive organisms

• Has in vitro activity against

VRE but is not FDA-

approved for this indication

• Weekly CPK to monitor for rhabdomyolysis

• Not indicated for pneumonia due to inactivation by

pulmonary surfactant

• Myositis is a potential toxicity

Linezolid 600 mg PO/IV

every 12 h

Gram-positive

organisms, including

VRE

• Hematologic toxicity (typically with prolonged cases, > 2 wks) may occur,

thrombocytopenia most common (0.3% to 10%)

• Serotonin syndrome rare, use cautiously with SSRI's1

• Not routinely used in fever and neutropenia although, does not impair

neutrophil recovery

• Treatment option for VRE and MRSA

• Peripheral/optic neuropathy with long-term use

Vancomycin 15 mg/kg IV every12 hb

For C.dificile: 125mg PO every 6 h

Gram-positive organisms,

with exception of VRE

and a number of rare

Gram- positive organisms

• Should not be considered as routine therapy for

neutropenia and fever unless certain risk factors present

(See-FEV-F)

• Dosing individualized with monitoring of levels



Discussion



ANTIBACTERIAL AGENTS: ANTI-PSEUDOMONALc

bRequires dose adjustment in patients with renal insufficiency.cEmerging data may support continuous infusion use for higher potency against resistant cases.dNone of these agents are active against MRSA or VRE.



(Page 2 of 4)



ANTI-PSEUDOMONAL AGENTSd DOSE SPECTRUM COMMENTS/PRECAUTIONS

Cefepime 2 grams IV every 8 hb • Broad spectrum activity against most

Gram-positive and Gram-negative

organisms


most anaerobes and

Enterococcus spp

• Use for suspected/proven CNS infection

with susceptible organism

• Increased frequency of resistance among

Gram-negative rod isolates at some centers

• Empiric therapy for neutropenic

fever (category 1)

Ceftazidime 2 grams IV every 8 hb • Relatively poor Gram-

positive activity

• Breakthrough

streptococcal infections

reported


most anaerobes and

Enterococcus spp.

• Use for suspected/proven CNS

infection with susceptible organism

• Increased frequency of resistance among Gram-

negative rod isolates at some centers

• Empiric therapy for neutropenia fever

(category 2B; due to resistance

among certain Gram-negative rods)

Imipenem/cilastatin sodium 500 mg IV every 6 hb • Broad spectrum activity against most

Gram-positive, Gram-

negative and

anaerobic organisms

• Preferred against extended

spectrum beta-lactamase (ESBL) and

serious Enterobacter

infections.

• Carbapenem-resistant Gram-

negative rod infections are an

increasing problem at a

number of centers

• Use for suspected intra-

abdominal source

• Meropenem is preferred over imipenem

for suspected /proven CNS infection

• Carbapenems may lower seizure threshold in

patients with CNS malignancies or infection or with

renal insuficiency

• Effective in nonsocomial pneumonia and

intra- abdominal infections

• Empiric therapy for neutropenic

fever (category 1)

• Data is limited but we would expect that Doripenem

like Meropenem as an anti-pseudomonal

beta-lactam would be eficacious

Meropenem 1 gram IV every 8 hb

(2 g IV every 8 h for

meningitis)

Doripenem 500 mg IV every 8 hb

Piperacillin/tazobactam 4.5 grams IV every 6 hb

Some institutions use

extended infusion: 3.375

g IV every 8 h

• Broad spectrum activity

against most Gram-positive,

Gram- negative and anaerobic

organisms

• Use for suspected intra-abdominal source

• Not recommended for meningitis

• May result in false positive galactomannan2

• Empiric therapy for neutropenic fever (category 1)


NCCN Guidelines Index

eConsider adding a second agent in cases of severe infection based on local susceptibility pattern.



(Page 3 of 4)Version 1.2014, 06/0172014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Table of Contents

Discussion



ANTIBACTERIAL AGENTS: OTHER

bRequires dose adjustment in patients with renal insufficiency.


OTHER ANTIBACTERIAL

AGENTS

DOSE SPECTRUM COMMENTS/CAUTIONS

Aminoglycosides

• Amikacin

• Gentamicin

• Tobramycin

Dosing

individualized with

monitoring of levelsb

• Activity primarily against Gram-negative

organisms

Often used as empiric therapy

in seriously ill or

hemodynamically unstable

patients

Ciproloxacine 500-750 mg PO every

12 hours or 400 mg

IV

every 8-12 hb

For low risk: 500

mg PO every 8 h +

amoxicillin/

clavulanate 500 mg

every 8 h

• Good activity against Gram-negative and

atypical (e.g., Legionella spp.) organisms

• Less active than “respiratory”

luoroquinolones against Gram-positive

organisms

• No activity against anaerobic organisms

• Avoid for empiric therapy if patient

recently treated with luoroquinolone

prophylaxis

• Increasing Gram-negative resistance in

many centers

• Oral antibiotic combination therapy in

low-risk patients (with

amoxicillin/clavulanate or clindamycin)

Levoloxacin 500-750 mg oral

or IV dailyb• Good activity against Gram-negative and

atypical (e.g., Legionella spp.) organisms

• Improved Gram-positive activity

compared to ciproloxacin

• Limited activity against anaerobes

• Prophylaxis in neutropenic patients3,4

• Prophylaxis may increase

bacterial resistance and

superinfection5

• Limited studies as empirical

therapy in patients with fever

and neutropenia

Trimethoprim/

sulfamethoxazol

e (TMP/SMX)

Single or double strength

daily

or

Double strength 3 times

per wk

Activity against P. jiroveccii Highly effective as prophylaxis against

P. jirovecii in high risk

patients (See INF-6)



Discussion


Prevention and Treatment of Cancer-Related InfectionsANTIFUNGAL AGENTS: AZOLES

bTherapeutic drug monitoring (TDM) is an ongoing area of research; TDM should be considered in consultation with ID specialists. (See Discussion).


Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.FEV-B

(Page 1 of 4)


aAzoles inhibit fungal cell membrane synthesis and inhibit cytochrome P450 isoenzymes that may lead to impaired clearance of other drugs metabolized by this pathway. Fluconazole is a

less potent inhibitor of cytochrome P450 isoenzymes than the mold-active azoles. Drug-drug interactions are common and need to be closely monitored (consult package inserts for

details). Reversible liver enzyme abnormalities are observed.


AZOLESa DOSE SPECTRUM COMMENTS/CAUTIONS

Fluconazole In adults with normal renal

function: 400 mg IV/PO

daily

• Active against Candida

• Active against dimorphic fungi (eg,

histoplasmosis, coccidioidomycosis)

and C. neoformans

• Candida glabrata is associated with variable resistance

in vitro and Candida krusei is always resistant

• Inactive against molds (eg, Aspergillus

species, Zygomycetes)

Itraconazoleb Oral 400 mg daily (aim for

trough of > 0.25 mcg/mL

after 7 d of therapy)

• Active against Candida, Aspergillus

sp. and some of the rarer molds

• Active against dimorphic fungi and

C. neoformans

• Itraconazole has negative inotropic properties and is

contraindicated in patients with signiicant cardiac

systolic dysfunction

Posaconazoleb • Prophylaxis: 200 mg POTID among high-riskpatients (See INF-2)

• Treatment of refractoryinfection: 400 mg POBID with high fat meal or200 mg PO QID if unableto eat, preferably withacidic beverage

• EC 300mg BID on day1 and then 300 mg POQ day

• Effective as prophylaxis in neutropenic

patients with myelodysplastic

syndrome and acute myelogenous

leukemia4, and in HSCT recipients with

signiicant GVHD5


sp., some Zygomycetes sp., and some

of the rarer molds


C. neoformans

• Evaluated as treatment of refractory infection (but not

FDA-approved) in several invasive fungal diseases.

• Data on posaconazole as primary therapy for invasive

fungal infections are limited.

• Should be administered with a full meal or liquid

nutritional supplement or an acidic carbonated

beverage. For patients who cannot eat a full meal or

tolerate an oral nutritional supplement alternative

antifungal therapy should be considered.

• Proton pump inhibtors decrease posaconazole plasma

concentration

Voriconazoleb • IV 6 mg/kg every 12 h

x 2 doses, then 4 mg/

kg every 12 h; oral 200

mg PO BID (for invasive

aspergillosis);1

• IV 6 mg/kg every

12 h x 2, then 3

mg/kg every 12 h

for non-

neutropenic patients with

candidemia2


sp. and some of the rarer molds


C. neoformans

• Standard of care as primary therapy for

invasive aspergillosis (category 1)1,3

• Effective in candidemia in

non- neutropenic patients2

• Poor activity against Zygomycetes

• IV formulation should be used with caution in patients

with signiicant pre-existing renal dysfunction based

on potential to worsen azotemia



effective but less toxic than 10 mg/kg/d as initial therapy for invasive mold infections.


Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. FEV-B

(Page 2 of 4)


Table of Contents

Discussion



ANTIFUNGAL AGENTS: AMPHOTERICIN B FORMULATIONS


cBroad spectrum of antifungal activity. Significant infusional and renal toxicity, less so with lipid formulations.dThe vast majority of subjects in this trial had invasive aspergillosis; optimal dosing of L-AMB for other mold infections (such as mucormycosis with 3mg/kg/d IV) was as


AMPHOTERICIN

B

FORMULATIONSc

DOSE SPECTRUM COMMENTS/CAUTIONS

Amphotericin

B colloidal

disper- sion

(ABCD)

5 mg/kg/d IV for invasive

mold infections

Broad spectrum of

antifungal activity

including Candida,

Aspergillus sp (excluding

Aspergillus terreus)

Zygomycetes, rarer molds,

Cryptococcus neoformans,

and dimorphic fungi

Substantial infusional toxicity; other lipid

formulations of amphotericin B are

generally preferred

Amphotericin

B

deoxycholate

(AmB-D)

Varies by indication,

generally 0.5 to 1.5 mg/kg/d

• Substantial infusional and renal toxicity

including electrolyte wasting

• Saline loading may reduce nephrotoxicity

• Infusional toxicity may be managed with anti-pyretics,

an anti-histamine, and meperidine (for rigors)

Amphotericin B

lipid complex

(ABLC)

5 mg/kg/d IV for invasive

mold infections

Reduced infusional and renal toxicity

compared to AmB-D

Liposomal amphotericin

B (L-AMB)

≥ 3 mg/kg/d IV6,d Reduced infusional and renal toxicity

compared to AmB-D





FEV-B(Page 3 of

4)Version 1.2014, 06/17/2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN

Guidelines

Table of Contents

Discussion



ANTIFUNGAL AGENTS: ECHINOCANDINS


eA number of centers use combination voriconazole and an echinocandin for invasive aspergillosis based on in vitro, animal, and limited clinical data.


ECHINOCANDINSe DOSE SPECTRUM COMMENTS/CAUTIONS

Anidulafungin 200 mg IV x 1 dose,

then 100 mg/d IV

Active against Candida

and Aspergillus sp. Not

reliable or effective

against other fungal

pathogens.

• Primary therapy for candidemia and

invasive candidiasis (category 1)

• Superior eficacy compared to luconazole as primary

therapy for candidemia and invasive candidiasis11

• Excellent safety proile

Caspofungin • 70 mg IV x 1 dose, then 50 mg

IV daily; some investigators use

70 mg IV daily as therapy for

aspergillosis

• 70 mg IV x 1 dose, followed by

35 mg IV daily for patients

with moderate liver disease


invasive candidiasis (category 1)7

• Treatment for invasive, refractory aspergillosis.

Similar eficacy compared to AmB-D as primary

therapy for candidemia and invasive

candidiasis, but signiicantly less toxic7

• 45% success rate as therapy for invasive, refractory

aspergillosis8

• Similar eficacy, but less toxic compared with L-AMB

as empirical therapy for persistent neutropenic fever7


Micafungin • 100 mg/d IV for

candidemia and 50-100

mg/d IV as prophylaxis

• 150 mg/d IV used at some

centers for Aspergillus

sp. infection


invasive candidiasis (category 1)

• Similar eficacy compared to caspofungin9 and

compared to L-AMB10 as primary therapy for

candidemia and invasive candidiasis





Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. FEV-C

(Page 1 of 4)


Table of Contents

Discussion



ANTIVIRAL AGENTSa

aRequires dose adjustment in patients with renal insufficiency.bAntiviral prophylaxis should be targeted to specific high-risk patients (see INF-3). In non-transplant high-risk patients, prophylaxis should be administered to patients

seropositive for HSV or VZV (or with a history of chicken pox). In HSCT recipients, prophylaxis is only indicated if either the donor or recipient is seropositive for the virusin question. The indicated doses for antiviral agents are for adults with normal renal function; consult package insert for dose modification in pediatric patient and inpatients with renal impairment. Prophylactic antiviral doses may be higher than those routinely used in immunocompetent persons (for example, for recurrentcold sores); there is substantial variability in the prophylactic doses of acyclovir used in different clinical trials in patients with hematologic malignancies and HSCTrecipients.

cHigh-dose acyclovir and valacyclovir have been used as prophylaxis for CMV. Because these agents have weak activity against CMV, a strategy of CMV surveillanceand pre-emptive therapy with ganciclovir, valganciclovir, or foscarnet is required among patients at high risk for CMV disease.

dIn general, the strategy of CMV surveillance testing by antigenemia or PCR followed by pre-emptive anti-CMV therapy for a positive result is favored over universallong-term prophylaxis in allogeneic HSCT patients.


AGENT TREATMENT SPECTRUM COMMENTS/CAUTIONS

Acyclovir • Prophylaxisb: HSV (400-800 mg PO BID); VZV in allogeneic HSCT recipients (800 mg PO

BID)1; CMV in allogeneic HSCT recipients (800 mg PO QID)c,2; for patients unable to

tolerate oral therapy, 250 mg/m2 IV every 12 h.

• Post-exposure prophylaxis: 800 mg PO 5 times daily

• Treatment: signiicant mucocutaneous HSV (5 mg/kg IV every 8 h for 7-10 days); single

dermatomal VZV (800 mg PO 5 times daily or 5 mg/kg IV every 8 h for 7-10 days);

disseminated HSV or VZV including viral encephalitis (10 mg/kg IV every 8 h)3

HSV

,

VZV

• Hydration to avoid crystal

nephropathy with high dose

• Dosing based upon

ideal body weight.

Famciclovir Prophylaxis: HSV or VZV (250 mg PO BID)

Treatment: HSV (250 mg PO TID) or VZV (500 mg PO TID)5,6HSV

,

VZV

No data for

oncologic related

prophylaxis

Ganciclovir • Prophylaxis for CMV: 5-6 mg/kg IV every day for 5 days/week from engraftment until day

100 after HSCTd,7

• Pre-emptive therapy for CMV: 5 mg/kg every 12 h for 2 weeks; if CMV remains detectable,

treat with additional 2 weeks of ganciclovir 6 mg/kg daily 5 days per week.

• Treatment: CMV disease (5 mg/kg every 12 h for 2 weeks followed by 5 to 6 mg/kg daily

for at least an additional 2-4 weeks and resolution of all symptoms). Add IVIG for CMV

pneumonia. Formulations and dosages of IVIG vary in different series

CMV,

HSV,

VZV,

HHV-

6

May cause bone

marrow

suppression


SPECIAL CASES

NEUTROPENIC SEPTIC SHOCK

Source: Adapted from the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee

• IST HOUR OF ANTIBIOTIC THERAPY PREDICTS MOTALITY. Broad spectrum beta-lactam (e.g.,imipenem/cilastatin, meropenem,or piperacillin-tazobactam) plus an aminoglycoside and vancomycin.

• Addition of fluconazole or an echinocandin should be strongly considered in patients not receiving antifungal prophylaxis.

• Rapid interventions are needed. Fluid resuscitation, oxygen, invasive hemodynamic monitoring, and vasopressor agents may be required. Stress doses of hydrocortisone (IV 50 mg every 6 hours with or without fludrocortisone oral 50 mcg daily) have been associated with decreased mortality in patients with septic shock and with insufficient adrenal reserve.

• Stress-dose corticosteroids are recommended for patients with septic shock who require vasopressor support. High-dose corticosteroids have not shown any benefit in the setting of septic shock or severe sepsis, and may be associated with increased risks for secondary infections.(NCCN GUIDE LINES 2014)

• Stress doses of hydrocortisone reverse hyperdynamic septicshock: a prospective, randomized, double-blind, single-center study(Briejel et al) :critical care med:1999

• CONCLUSION:-Infusion of stress doses of hydrocortisone reduced the timeto cessation of vasopressor therapy in human septic shock. This wasassociated with a trend to earlier resolution of sepsis-induced organdysfunctions

• Effect of high-dose glucocorticoid therapy on mortality in patients withclinical signs of systemic sepsis. The Veterans Administration SystemicSepsis Cooperative Study Group.(NEJM:1988)

• CONCLUSION:-NO ADVANTAGES

Neutropenic Enterocolitis or Typhilitis

• Inflammatory process involving colon and/or small bowel

• ischemia, necrosis, bacteremia

• ( translocation from gut) hemorrhage, and perforation.

• Fever and abdominal pain ( typically RLQ).

• Bowel wall thickening on ultrasonography or CT imaging.

Treatment( 50-70% mortality)

• Initial conservative management • bowel rest,

• intravenous fluids,

• TPN,

• broad-spectrum antibiotics

• and normalization of neutrophil counts.

• Surgical intervention • obstruction, perforation, persistent gastrointestinal

bleeding despite correction of thrombocytopenia and coagulopathy, and clinical deterioration.

Consider Pseudomonal and Clostridial coverage in Empiric therapy

• Clostridium SepticumClostridium SordelliCover with PEN G ,AMP, Clindamycin*Broad Spectrum Abx ( carbapenem )include Metronidazole if unsure of Cdiff

* resistance of Clostridia to clindamycin

reported.

Neutropenic Pneumonia

• In neutropenia, consolidation and sputum production may be absent.(lack of inflimatory response)

• Blood cultures, a chest radiograph, and, if possible, a sputum sample for Gram stain and culture should be obtained.

• (a) If community-acquired pneumonia is suspected (i.e., pneumonia present before admission or developing within 3 to 4 days of hospitalization), addition of a macrolide or fluoroquinolone to an antipseudomonal beta-lactam is warranted to treat atypical pathogens.

• (b)For nosocomial pneumonia, therapy with an antipseudomonalbetalactam is advised, and addition of an aminoglycoside and fluoroquinolone should be considered. For cases of nosocomialpneumonia in which hospital-acquired legionellosis is suspected, empiric addition of a macrolide or fluoroquinolone is also warranted.

• (C) Vancomycin or linezolid should be added for pneumonia in patients colonized with MRSA and for nosocomial pneumonia at centers in which MRSA is common..

Pcp Pneumonia• Diffuse infiltrates have a broad differential diagnosis:-

PCP,viral infections, hemorrhage, and drug-inducedpneumonitis. A diagnosis of PCP should be considered inpatients with significantly impaired cellular immunity notreceiving PCP prophylaxis who present with diffusepulmonary infiltrates. BAL is the standard approach fordiagnosing PCP. In patients with substantial respiratorydisease (e.g., labored breathing, requiring supplementaloxygen), empiric therapy should be initiated before BAL.Pending BAL results, an initial regimen can include arespiratory fluoroquinolone against community-acquiredpathogens and TMP-SMX (TMP component: 5 mg/kg every 8hours) against possible PCP. In patients with suspected PCPand with room air PaO2 of 75 mmhg or less, corticosteroids(initially prednisone 40 mg twice daily, then tapered) shouldbe added based on studies of patients withAIDS–associatedPCP.(NCCN GUIDELINES)

CVC related infections

• Diagnosis and treatment is a challenge

• Usual microorganisms:

CNS, S. aureus, Candida spp., gram (-)ve

• Local and disseminated complications (septic thrombophlebitis, endocarditis)

• Challenging question: Catheter removal

• Prevention is feasible

Fungal Infections

• More frequent in AML patients

• Candida spp. more likely pathogen in the first days of neutropenia if no administered prophylaxis

• If fluconazole prophylaxis then more likely – fluconazole resistant Candida (C. krusei, C. glabrata)

– Mold (Aspergillus spp., Zygomyces spp. , Fusarium spp.)

• Invasive mold infections in patients with severe (ANC ≤ 100 cells/mm 3) and prolonged (>10-15 days) neutropenia


Antifungal Therapy

• Added on the 5th - 7th day of fever and neutropenia

• Increased incidence of fungal infection post day 7 of fever and neutropenia

• 40% - 50% of patients will defervesce post initiation of antifungal chemotherapy


Febrile NeutropeniaEmpirical Antifungal Therapy

• Liposomal amphotericin B

• Azoles (with mold activity)

Itraconazole

Voriconazole

• Micafungin

• Caspofungin


Antibacterial Prophylaxis During

Neutropenia(afebrile neutropenia)Patients with cancer and chemotherapy-induced neutropenia are at risk forsevere bacterial infections. Fluoroquinolones are the most commonly usedprophylactic antibacterial agents in adults with chemotherapy inducedNeutropenia.

In a meta-analysis that evaluated 18 trials(N=1408) in which fluoroquinoloneswere compared to either placebo or TMP/SMX, fluoroquinolone prophylaxissignificantly reduced the incidence of Gram-negative infections by about 80%compared with those without prophylaxis (relative risk=0.21; 95% CI, 0.12-0.37),leading to an overall reduction in total infections:ENGLS et al:cl oncojournal.

The NCCN Guidelines panel advises that fluoroquinolone prophylaxis(levofloxacin is preferred) be considered in patients with expected duration ofneutropenia (ANC less than 1000/mcL) for more than 7 days. In patients withneutropenia expected to last less than 7 days who are not receivingimmunosuppressive regimens (e.g., systemic corticosteroids), the panelsuggests no antibiotic prophylaxis

Antifungal Prophylaxis During Neutropenia(afebrile neutropenia)

INTERMEDIATE RISK GROUP (MM,LYMPHOMAS,AUTOLOGUSHSCT,NEUTROPENIA 7-10 DAYS AND FURADABINE BASED CHEMO) AND HIGH-RISK PATIENTS ( LONGER DURATIONS OF NEUTROPENIA(>10 DAYS) OR WITHGVHD AFTER ALLOGENEIC HSCT,ALL ):- USE FLUCONAZOLE PROPHYLAXIS ifNEUTROPENIA till recovery AND MUCOSITIS.

The NCCN Guidelines panel recommends posaconazole (category 1) for antifungalprophylaxis in neutropenic patients with AML and MDS receiving induction orreinduction chemotherapy.

Antiviral Prophylaxis During Neutropenia(afebrile neutropenia)

HSV infection/reactivation in intermediate andhigh risk use viral prophylaxis(acyclovir /famicyclovar)for neutropenia or during active therapy

Same applies for vzv.

In low risk group use only if prior hsv episode..

You can be a victim of cancer, or a survivor of cancer. It’s a mindset.” All u need brave efforts– Dave Pelzer

THANK YOU

febrile neutropenia by dr saqib ahmad shah pg radiation oncology skims kashmir

Health & Medicine