2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer Walter T, Hughes, Donald Armstrong, Gerald P. Bodey, Eric J. Bow,

2002 Guidelines for the Use of Antimicrobial Agents in

Neutropenic Patients with Cancer

Walter T, Hughes, Donald Armstrong, Gerald P. Bodey, Eric J. Bow, Arthur E. Brown, Thierry Calandra, Ronald Feld, Philip A. Pizzo, Kenneth V. I. Rolston, Jerry L. Shenep, and Lowell S. Young

St. Jude Children’s Research Hospital, Memphis, Tennessee; Memorial Sloan-Kettering Cancer Center, New York, New York; University of Texas M. D. Anderson Cancer Center, Houston; Harvard Medical School, Boston, Massachusetts; Stanford University School of Medicine, Palo Alto, and Kuzell Institute for Arthritis, San Francisco California; University of Manitoba, Winnipeg, and Princess Margaret Hospital, Toronto, Canada; and Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Management of Antibiotic Regimen during the First Week of Therapy

• At least 3-5 days required to determine efficacy

• After which, decisions based on:– Bacteremia or pneumonia– Resolution of fever– Deterioration of condition

• Recent analysis of 488 patients, median time to clinical response was 5-7 days *– May wait 5 days to make any changes

*Elting LS, Rubenstein EB, Rolston K, et al. Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care. J Clin Oncol 2000;18:3699-706

Patient Afebrile within 3-5 Days of Treatment

• If causative microbe identified, regimen may be changed– Optimal treatment with minimal adverse

effects, lowest cost

• Broad-spectrum coverage maintained– Prevent breakthrough bacteremia

• Continued minimum 7 days, or negative culture, and patient free of significant symptoms

• Desirable for neutrophil count >500 cells/mm3

• In absence of discernible cause, compliant adults may be changed after >2 days– IV therapy to oral ciprofloxacin and

amoxicillin-clavulanic acid *

• Controlled studies done with inpatients– Cannot be assured similar results if patients

are discharged

• Comprehensive assessment essential for each patient

*Freifeld A, Marchigiani D, Walsh T et al. A double- blind comparison of empirical oral and intravenous antibiotic therapy for low risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med 1999; 341: 305-11.

Afebrile within first 3-5 days of treatment

No etiology identified

Etiology identified

Adjust to most

appropriate treatment

Low risk High risk

Continue same

antibiotics

Change to ciprofloxacin + amoxicillin-clavulanate (adults) or cefixime (child) Discharge

Persistent Fever throughout the First 3-5 Days of Treatment

• Nonbacterial infection• Resistant bacterial infection or slow to

respond• Emergence of second infection• Inadequate serum and tissue levels of

antibiotics• Drug fever• Cell-wall deficient bacteremia*• Infection at an avascular site

*Woo PC, Wong SS, Lum PN, et al. Cell wall-deficient bacteria and culture-negative febrile episodes in bone marrow recipients. Lancet 2001;357:675-9

Reassessment

• Review of all previous culture results

• Meticulous physical examination

• Chest radiography

• Ascertain status of IV lines

• Specimens of specific sites of infection

• Diagnostic imaging of any organ

• Determination of serum concentrations

• Ultrasonography and high-resolution CT

• If reassessment does not yield a cause, 1 of 3 choices should be made:

– Continue with initial antibiotics

• If no discernible changes in patient’s condition

• Especially if neutropenia expected to resolve within ensuing 5 days

– Change or add antibiotics

– Add an antifungal drug

Change or add antibiotics• If evidence of progressive disease or

complication

• Add appropriate antibiotic or change to different antibiotic

• Vancomycin considered if not included in initial treatment

• Consideration to withdrawal if included in initial treatment– Minimize anti-bacterial resistance

Add an antifungal drug• Up to 1/3 febrile neutropenic patients who

do not respond to 1-week antibiotics have systemic fungal infections*– Candida or Aspergillus in most cases

• Effort made to determine whether systemic fungal infection exists

• Lipid formulations of amphotericin B can be used as alternatives to amphotericin B deoxycholate*

*EORTC International Antimicrobial Therapy Cooperative Project Group. Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 1989;86:668-72

Persistent fever during first 3-5 days of treatment

Reassess patient on days 3-5

If no change in patient’s condition (consider stopping

vancomycin)

Continue initial antibiotics

•If progressive disease

•If criteria for vancomycin are met

Change or add antibiotics

If febrile through days 5-

7 and resolution of neutropenia

not imminent

Antifungal drug, with or

without antibiotic change

Duration of Antimicrobial Therapy

• Most important determinant is neutrophil count• Therapy may be stopped if:

– Neutrophil count >500 cells/mm3 for 2 consecutive days– No infection identified after 3 days– Patient afebrile for >48 hours

• Antibiotics stopped after 5-7 afebrile days if:– Neutropenic patients who appear healthy– Low risk category– No discernible infectious lesions– No radiographic or laboratory evidence of infection

• Continuous administration in:– Patients with profound neutropenia (<100 cells/mm3)– Mucous membrane lesions– Unstable vital signs– Other identified risk factors

Afebrile by Days 3-5

Afebrile by days 3-5

ANC >500 cells/mm3 for 2

consecutive days

Stop antibiotics 48h after afebrile +

ANC >500 cells/mm3

ANC <500 cells/mm3 by day 7

Initial low risk

Clinically well

Stop when afebrile for 5-7

days

Initial high risk

•ANC <100 cells/mm3

•Mucositis

•Unstable signs

Continue antibiotics

Persistent Fever• Febrile after recovery of neutrophil count

to >500 cells/mm3

– Despite receipt of broad-spectrum antibacterial therapy

– Reassessment for undiagnosed fungal, mycobacterial and viral infections

– Antibiotic therapy can be stopped 4-5 days after neutrophil count reaches >500 cells/mm3

– Ultrasound, CT or MRI abdomen to detect systemic fungal infections

Persistent fever

ANC >500 cells/mm3

Stop 4-5 days after ANC >500 cells/mm3

Reassess

ANC <500 cells/mm3

Continue for 2 weeks

Reassess

Stop if no disease and condition is stable

Duration of Amphotericin B Therapy• Course of antifungal therapy determined by:

– Causative agent– Extent of disease

• May be discontinued when:– Neutropenia has resolved– Patient clinically well– CT abdomen and chest reveals no suspicious lesions

• 2 weeks of daily doses for:– Clinically well with prolonged neutropenia– No discernible lesions

• Continuation with antibiotics and amphotericin B throughout neutropenic episode in ill or high risk patients

Other Drugs

Use of Antiviral Dugs• Usually no indication for empirical use

– Only if there is clinical or laboratory evidence of viral disease

• Acyclovir indicated if skin or mucous membrane lesions due to herpes simplex or varicella-zoster*– More favourable febrile response than in untreated

patients

• Cytomegalovirus uncommon cause, except in bone marrow transplantation– Ganciclovir or foscarnet

*Baglin TP, Gray JJ, Marcus RE, Wreghitt JG. Antibiotic resistant fever associated with herpes simplex virus infection in neutropenic patients with haematological malignancy. J Clin Pathol 1989;42:1255-8

Use of Colony-Stimulating Factors• G-CSF (filgrastim) or granulocyte-

macrophage colony-stimulating factor (sargramostim)*– Consistently shorten duration of neutropenia– Have not consistently or significantly reduced

other measures of febrile morbidity– No decrease in infection-related mortality

rates

• Not recommended for routine use to treat febrile or afebrile neutropenic patients

*Anaissie EJ, Vartivarian S, Bodey GP, et al. Radomized comparison between antibiotics alone and antibiotics plus granulocyte-macropahe colony-stimulating factor in cancer patients with fever and neutropenia. Am J Med 1996;100:17-23

Granulocyte Transfusions• May be useful in:

– Profound neutropenia where documented causative bacteria cannot be controlled with optimal antibiotic therapy or G-CSF

– Cases of severe uncontrollable fungal infections• Significant toxicities

– Transmission of CMV– Alloimmunization associated with fever– Graft-versus-host reactions– Progressive platelet refractoriness– Respiratory insufficiency with concomitant

amphotericin B• No specific indications for standard use of

granulocyte transfusionsHubel K, Dale DC, Engert A, Liles WC. Current status of granulocyte (neutrophil) transfusion therapy for infectious diseases. J Infect Dis 2001;183:321-8

Comparison with Practice in Singapore

Singapore IDSA

Definition Temperature greater than 38oC

ANC <1000 cells/mm3

Temperature greater than 38.3oC

ANC <500 cells/mm3

Initial Treatment

IV ceftazidime Cefepime, ceftazidime or carbapenem

If obvious skin source, add IV cloxacillin, ciproflozacin or clindamycin

--

If patient looks unwell, add IV gentamicin

Aminoglycoside plus antipseudomonal penicillin, cefepime, ceftazidime, or carbapenem

Antibiotic Prophylaxis for Afebrile Neutropenic Patients

• Not routine because of emerging antibiotic resistance

• Except trimethoprim-sulfamethoxazole to prevent Pneumocystis carinii pneumonitis*

• Fluconazole^ and acyclovir or ganciclovir for patients undergoing allogenic hematopoietic stem cell transplantation

• Should be administered for as short a period as possible, to as few patients as possible

*Hughes WT, Rivera GK, Schell MJ, et al. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1987;316:1627-32

^Rotstein C, Bow EG, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic patients. Clin Infect Dis 1999;28:331-40