Sumit Bhutani

8/6/2019 Sumit Bhutani

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Sumit Bhutani

Neutropenic Fever


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Fever

Fever is defined as a single oral

temperature measurement of >38.3C

(101F) or a temperature of >38.0C(100.4F) sustained over a 1-h period


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Neutropenia

Neutropenia is defined as an ANC of ,500

cells/mm3 or an ANC that is expected to

decrease to ,500 cells/mm3 during thenext 48h

Profound neutropenia

Functional neutropenia


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Primary aim of the practice guideline is to

assist practitioners in making decisions about

appropriate care for neutropenic patients

No specific drug or duration can be

unequivocally recommended for all patients

Recommendations are derived from well-

tested patterns of clinical practice that haveemerged from cancer therapy clinical trials


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History

The role played by the rapid institution of

empirical, broad-spectrum antibacterial therapy

for fever and neutropenia in reducing mortality is

now unquestioned, following the report bySchimpff et al and Klastersky et al.

Observed a 53% success rate and 67%

respectively

1. Schimpff S, Satterlee W, Young VM, Serpick A Empiric therapy with carbenicillin and

gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med

1971;284:1061-5

2. Klastersky J, Cappel R, Debusscher L Evaluation of gentamicin with carbenicillin in

infections due to Gram-negative bacilli. Curr Ther Res 1971;13:174-233.


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NEW GRAM-POSITIVE

PATHOGENS

Viridans streptococci

Leuconostocspecies

Enterococcus species,esp. vancomycin-

resistant

Corynebacterium

jeikeium, C.urealyticum

Rhodococcus equi

Bacillus cereus

Stomatococcus

mucilaginosus Lactobacillus

rhamnosus

Clostridium septicum,

C. tertium

Zinner S. CID 1999:29;490


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NEW GRAM-NEGATIVE

PATHOGENS

Stenotrophomonousmaltophilia

Alteromonas

putrefaciens Legionella

pneumophilia, L.micdadei

Vibrio parahemolyticus

Capnocytophagaspecies

Alcaligenesxylosoxidans

Chrysebacteriummeningosepticum

Burkholderia cepacia

Fusobacteriumnucleatum Leptotrichia buccalis Methylobacterium

species Moraxella-like

organisms

Zinner S. CID 1999:29;490


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2010 guidelines

Major change in the current guideline is a morestructured consideration of the level of risk forserious infectious complications that a given

patient with fever and neutropenia might face. Prevention of infection in neutropenic patients isalso an important focus of this guideline

Bacterial, viral, and fungal prophylaxisrecommendations

new sections on the management of indwellingCVCs and environmental precautions forneutropenic patients


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I. What Is the Role of Risk Assessment and What Distinguishes

High-risk and Low-risk Patients with Fever and Neutropenia?

Risk for complications of severe infection

should be undertaken at presentation of

fever

1. Type of empirical antibiotic therapy (oral

vs intravenous [IV])

2. Venue of treatment (inpatient vs

outpatient)

3. Duration of antibiotic therapy


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High-risk patients

Anticipated prolonged (>7 days duration)

Profound neutropenia (absolute neutrophil

count [ANC] 100 cells/mm3 followingcytotoxic chemotherapy)

Significant medical co-morbid conditions,

including hypotension, pneumonia, new-

onset abdominal pain, or neurologic

changes.


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Low-risk patients, including those with

anticipated brief (7 days duration)

neutropenic periods or no or few co-

morbidities, are candidates for oral

empirical therapy


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Formal risk classification may be performed

using the

MASCC scoring system High-risk patients have a MASCC score

21


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High-risk patients have a MASCC score


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II What Specific Tests and Cultures Should

be Performed during the Initial Assessment?

CBC count with differential leukocyte count and

platelet count; BMP and LFTs

At least 2 sets of blood cultures are

recommended, with a set collectedsimultaneously from each lumen of an existing

CVC, if present, and from a peripheral vein site;

2 blood culture sets from separate

venipunctures should be sent if no central

catheter is present

chest radiograph is indicated for patients with

respiratory signs or symptoms


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III In Febrile Patients With Neutropenia, What

Empiric

Antibiotic Therapy Is Appropriate and in What

Venue? Monotherapy with an anti-pseudomonal -

lactam agent, such as cefepime, acarbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, isrecommended

Other antimicrobials (aminoglycosides,fluoroquinolones, and/or vancomycin) may beadded to the initial regimen for managementof complications (eg, hypotension andpneumonia) or if antimicrobial resistance issuspected or proven


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Vancomycin (or other agents active against

aerobic gram-positive cocci) is not

recommended as a standard part of the initial

antibiotic regimen for fever and neutropenia(A-I).

These agents should be considered for

specific clinical indications, includingsuspected catheter-related infection, skin or

soft-tissue infection, pneumonia, or

hemodynamic instability.


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MRSA: Consider early addition of

vancomycin, linezolid, or daptomycin.

VRE: Consider early addition of linezolidor daptomycin.

ESBLs: Consider early use of a

carbapenem.

KPCs: Consider early use of polymyxin-

colistin or tigecycline.


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Allergy issues

Most penicillin-allergic patients tolerate

cephalosporins, but those with a history of

an immediate-type hypersensitivity

reaction (eg, hives and bronchospasm)

should be treated with a combination that

avoids -lactams and carbapenems, such

as ciprofloxacin plus clindamycin oraztreonam plus vancomycin


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Low risk patients

Low-risk patients who have initiated IV or oral antibiotics in thehospital may have their treatment approach simplified if they areclinically stable (A-I).

An IV-to-oral switch in antibiotic regimen may be made if patients

are clinically stable and gastrointestinal absorption is felt to beadequate (A-I).

Selected hospitalized patients who meet criteria for being at low riskmay be transitioned to the outpatient setting to receive either IV ororal antibiotics, as long as adequate daily follow-up is ensured (B-III).

If fever persists or recurs within 48 h in outpatients, hospital re-admission is recommended, with management as for high-riskpatients (A-III).


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Oral Options

Ciprofloxacin plus amoxicillin-clavulanate incombination.

levofloxacin or ciprofloxacin monotherapy

ciprofloxacin plus clindamycin

(Patients receiving fluoroquinolone prophylaxisshould not receive oral empirical therapy with afluoroquinolone)


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When to stop antibiotics?

Once blood culture results and organismsusceptibilities are availableusually withinseveral days after blood samples are

drawnthey may direct a more specificchoice of antibiotics.

In a majority of cases, however, blood cultureresults are negative. In these cases,

empirical antibiotics are generally continueduntil ANC recovery is imminent or until aninfection requiring alternative antimicrobialcoverage is identified.


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Certain facts!

Only 23% of febrile neutropenic episodes

are associated with bacteremia

Frequencies of gram-positive, gram-negative, and polymicrobial bacteremia

were approx 57%, 34%, and 9%,

respectively

greater mortality (5% vs 18%) with gram

negativesKlastersky J, Ameye L, Maertens J, et al. Bacteraemia in febrile neutropenic

cancer patients. Int J Antimicrob Agents 2007


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Vancomycin is not a standard part of empiricalantibiotic therapy for fever and neutropenia.

Despite the predominance of gram-positive

organisms as the cause of bacteremia during

fever and neutropenia, randomized studiescomparing empirical regimens with and without

vancomycin as part of the initial empirical

regimen have shown no significant reductions in

either the duration of fever or overall mortalityVancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients.

European Organization for Research and Treatment of Cancer (EORTC) International Antimicrobial Therapy

Cooperative Group and the National Cancer Institute of Canada-Clinical Trials Group. J Infect Dis 1991; 163:951

8.

Paul M, Borok S, Fraser A, et al. Empirical antibiotics against gram-positive infections for febrile neutropenia:

systematic review and meta-zanalysis of randomized controlled trials. J Antimicrob

Chemother 2005; 55:43644.


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If vancomycin or another gram-positive activeagent is added to the initial regimen forclinical reasons, it should be discontinued 2

or 3 days later if susceptible bacteria are notrecovered from the patient

The primary reason for the judicious use ofvancomycin has been the epidemiological

link between its overuse and thedevelopment of drug resistance inEnterococcus species and S. aureus


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VRE bloodstream infection is difficult to treatin the setting of fever and neutropenia,particularly in leukaemic patients and/or

HSCT recipients, and it is an independentrisk factor for death

Local and even individual patient patterns of

bacterial colonization and resistance must betaken into account when choosing an initialempirical regimen for neutropenic patients ata given institution


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IV. When and How Should Antimicrobials be

Modified During the Course of Fever and

Neutropenia? Modifications to the initial antibiotic regimen

should be guided by clinical andmicrobiologic data

Patients who remain hemodynamicallyunstable after initial doses with standardagents for neutropenic fever should have

their antimicrobial regimen broadened toinclude coverage for resistant gram-negative,gram-positive, and anaerobic bacteria andfungi


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Empirical antifungal coverage should be

considered in high-risk patients who have

persistent fever after 47 days of a broad-

spectrum antibacterial regimen and no

identified fever source (A-II)


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Recurrent or persistent fever > 3 days in durationdespite empirical antibiotic therapy should prompt athorough search for a source of infection, including anew set of blood cultures and symptom-direction

collection of other diagnostic tests

recurrent or persistent fever, consideration should alsobe given to noninfectious sources, such as drugrelated fever, thrombophlebitis, the underlying canceritself, or resorption of blood from a large hematoma. Inmany cases, no source of persistent fever is identifiedbut the patient defervesces nonetheless, when theANC increases to .500 cells/mm3


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V. How Long Should Empirical

Antibiotic Therapy be Given? In patients with clinically or microbiologically

documented infections, the duration of therapy isdictated by the particular organism and site;appropriate antibiotics should continue for at least

the duration of neutropenia (until ANC > 500cells/mm3) or longer if clinically necessary (B-III).

In patients with unexplained fever, it isrecommended that the initial regimen be continued

until there are clear signs of marrow recovery; thetraditional endpoint is an increasing ANC thatexceeds 500 cells/mm3 (B-II).


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VI. When Should Antibiotic Prophylaxis be

Given, and With What Agents?

Fluoroquinolone prophylaxis should be

considered for high-risk patients with

expected durations of prolonged and

profound neutropenia (ANC 7 days)

Antibacterial prophylaxis is not routinely

recommended for low-risk patients whoare anticipated to remain neutropenic for 72 h oftherapy with appropriate antibiotics

For documented CLABSI caused by

coagulase negative staphylococci, thecatheter may be retained using systemictherapy with or without antibiotic lock therapy


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XII. What Environmental Precautions Should be

Taken When Managing Febrile Neutropenic

Patients?

Hand hygiene is the most effective means of preventingtransmission of infection in the hospital (A-II).

Standard barrier precautions should be followed for all patients, andinfection-specific isolation should be used for patients with certain

signs or symptoms (A-III).

HSCT recipients should be placed in private (ie, singlepatient)rooms (B-III). Allogeneic HSCT recipients should be placed in roomswith .12 air exchanges/h and HEPA filtration (A-III).

Plants and dried or fresh flowers should not be allowed in the roomsof hospitalized neutropenic patients

Hospital work exclusion policies should be designed to encourageHCWs to report their illnesses or exposures

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