Duke University Hospital Guideline for Empiric Inpatient Treatment of Cancer- Related Neutropenic Fever in Adult Patients PURPOSE Fever among neutropenic patients is common and a significant cause of morbidity and mortality. Rapid empiric treatment of these patients is critical. These guidelines shall be used by prescribers and pharmacy personnel to aid in the initiation and discontinuation of anti-infectives for adult patients with fever and neutropenia. POLICY This policy provides a systematic approach to evaluation and empiric treatment of neutropenic patients with fever based upon clinical symptoms, laboratory results, and imaging as set forth by the Antimicrobial Stewardship and Evaluation Team and Oncology Formulary Evaluation Team. The practitioner may deviate from this guideline based on clinical indication, if appropriate and documented, or in emergency or unusual circumstances. DEFINITIONS Fever-Core body (equivalent to oral) temperature 38.3 C (101 F) once or 38.0 C (100.4 F) for 1 hour or on two separate measurements over an hour apart. Neutropenia-Absolute Neutrophil Count (ANC) <500/mm 3 or ANC <1000/mm 3 with a predicted decline to <500/mm 3 [calculated ANC = WBC*(%neutrophilsbands)/100] Severe sepsis-presence of sepsis-induced organ dysfunction, hypotension not responsive to fluids RESPONSIBILITY Medical staff (Hematology, Oncology, Infectious Diseases) Inpatient Pharmacy staff PROCEDURES 1. Initial evaluation a. Immediately assess for localizing signs or symptoms of b. Administer antibiotics STAT (within 30 min) for fever or other signs of (i.e. chills, rigors) c. Initial workup should include blood cultures x 2, urine cultures, urinalysis, chest x- ray, CBC with differential, BMP, and LFTs d. Other site-specific imaging, cultures and diagnostics (i.e. respiratory viral panel, C.diff PCR) should be performed based on history and clinical examination findings. 2. Refer to the Empiric Antimicrobial Therapy pathway for initial empiric coverage recommendations 3. Refer to the Antibiotic Therapy: Duration and Subsequent Care pathway for follow up recommendations 4. Refer to the Empiric Antifungal Therapy pathway for patients with persistent febrile neutropenia unresponsive to broad-spectrum antibacterial agents 5. Restricted antimicrobial approval process a. Restricted antimicrobial use outlined in this protocol (daptomycin, meropenem, micafungin, voriconazole) may be ordered per Febrile Neutropenia Protocol b. All other restricted antimicrobials or non-protocol directed use of the above restricted antimicrobials require Infectious Diseases (ID) approval by contacting Transplant ID (pager 970-7221) c. Consultation with ID for patients with persistent fevers or clinical deterioration is recommended 6. Colony stimulating factors (i.e. GCSF) are not routinely recommended in the treatment of febrile neutropenia. DUH P&T Approved 8.7.14
2 7. EMPIRIC ANTIMICROBIAL THERAPY DRAW CULTURES PRIOR TO ADMINISTRATION OF ANTIBIOTICS REMOVE central lines for patients with suspected central line-associated bacteremia with organisms that adhere to central lines FOR PATIENTS ON FLUOROQUINOLONE PROPHYLAXIS, the fluoroquinolone should be discontinued upon initiation of empiric therapy. OPTION 1: febrile neutropenia without known or suspected source/site of : OPTION 2: febrile neutropenia with any of the following: 1. Vascular line site suspected 2. History of MRSA colonization or 3. Pneumonia 4. Positive blood cultures for gram bacteria before final identification and susceptibility testing OPTION 3: febrile neutropenia from suspected intra-abdominal source: Metronidazole 500 mg IV q8h OPTION 4: febrile neutropenia with severe sepsis: Meropenem 500 mg IV q6h. Infuse each dose over 30 min. Reassess meropenem at 72 hrs. ID telephone approval required for continuation beyond 72 hrs. *Ok to infuse first dose over 30 min. All antibiotic dosing is assuming normal renal function; dose adjustments may be required for antibiotics in patients with renal dysfunction with the exception of metronidazole
3 EXCEPTIONS/MODIFICATIONS TO OPTIONS 1-4 ABOVE: BETA-LACTAM ALLERGIC PATIENTS: Penicillin Allergy, Non Type 1: minor reaction (e.g. rash) Use cefepime-based regimen above Penicillin Allergy Type 1- immediate hypersensitivity (hives, anaphylaxis) or unknown: Aztreonam 2g IV q8h vancomycin IV Add metronidazole 500mg IV q8h if suspect abdominal Cephalosporin Allergy, Non Type 1 or Type 1: refer to Penicillin Allergy Type 1 HISTORY OF VRE INFECTION OR POSITIVE VRE SURVEILLANCE CULTURE (EXCEPT FOR COEXISTING PNEUMONIA): Daptomycin 6 mg/kg IV in place of vancomycin in the above regimens (note: all other uses for daptomycin require ID consult) Reassess daptomycin at 72 hrs. ID consult required for continuation beyond 72 hrs in absence of active vancomycin resistant enterococcus. OTHER INITIAL EMPIRIC ANTIMICROBIAL CONSIDERATIONS: Healthcare-associated pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia with Pseudomonas risk factors: add double coverage with an aminoglycoside (double coverage with ciprofloxacin may be considered in patients not on fluoroquinolone prophylaxis) Potential or witnessed aspiration: consider using piperacillin-tazobactam 3.375g q8h extended infusion in place of cefepime Possible atypical pneumonia: add azithromycin Possible influenza (pending respiratory viral panel): add oseltamivir Concern for C.difficile colitis (based on history, pending PCR): add oral metronidazole or oral vancomycin (based on severity and institutional guidelines) All antibiotic dosing is assuming normal renal function; dose adjustments may be required for antibiotics in patients with renal dysfunction with the exception of metronidazole
4 ANTIBIOTIC THERAPY: DURATION & SUBSEQUENT CARE REASSESS AT 48-96 HOURS Defervesced Persistent fever, clinically stable (persistent fever in hemodynamically stable patient) Persistent fever, clinically unstable (i.e. hypotension, tachypnea, new or worsening tachycardia, mental status changes, organ dysfunction) Modify antibiotics according to culture Continue for standard duration indicated for the specific and until ANC 500 and rising If patient has been afebrile x 2 days and ANC 500 and rising, antibiotics may be discontinued Continue to culture & assess sites of No antibiotic changes unless new clinical, micro-biological or radiographic data supporting new Discontinue vancomycin if no s/sx of a gram Modify antibiotics according to culture Monitor for resolution of Discontinue antibiotics if patient becomes clinically stable, afebrile, adequate course has been complete, and ANC 500 and rising. Modify antibiotics according to culture Monitor for resolution of Continue for standard duration indicated for the specific and until ANC 500 and rising Continue antibiotics until ANC 500 and rising If no response 1. /biopsy/drain sites of proven or probable 2. Broaden antibiotic coverage -Add vancomycin if not part of initial regimen -Expand to meropenem (call ID for approval) 3. Examine and reimage (CT/MRI) 4. Consider empirical antifungal Clinical judgment should remain paramount and used in conjunction with these guidelines
5 EMPIRIC ANTIFUNGAL USE IN FEBRILE NEUTROPENIA Persistent fever > 4 days on broad spectrum antibiotics Daily examination and history Blood cultures: repeat q48-72h at minimum s according to suspected sites of s Consider CT of sinuses/lungs Removal of foci of resolved (i.e. lines) Check serum galactomannan Patient received voriconazole, posaconazole (anti-mold) prophylaxis Yes No Check voriconazole/ posaconazole trough concentration Start micafungin 100 mg IV q24h Consider Transplant ID consult Load voriconazole 6 mg/kg IV q12h x 2 doses, then 4 mg/kg IV q12h OR Liposomal amphotericin B (Ambisome) 5 mg/kg IV q24h (use requires ID consult) Monitor for fungal process & continue antibiotics/antifungals until ANC 500 and rising, or consult with ID regarding treatment duration ID consult required for documented candidal or proven or probable mold Note: Azole antifungals (fluconazole, itraconazole, voriconazole, posaconazole) have multiple drug-drug interactions and use is contraindicated for certain drugs. Consult pharmacy with questions. References: 1. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical Practice Guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis 2011; 52:e56 2. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancerrelated s. Version 1.2013. http://www.nccn.org (Accessed on May 8, 2014) 3. Rosa RG and Goldani LZ. Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia. Antimicrob Agents Chemother. 2014, 58: 3799-3803