Case
A 63-year-old woman with acute myeloid leukemia (AML) is admitted to the hospital for fevers up to 39.2°C and shortness of breath. Her current home medications consist of levofloxacin 500 mg daily by mouth, posaconazole 200 mg 3 times daily by mouth with meals, and valacyclovir 500 mg daily by mouth. The medical team would like assistance in choosing an empiric antimicrobial therapy.

Answer
Febrile neutropenia (FN) is a medical emergency that affects patients with malignancies. It is defined as an absolute neutrophil count <500 cells/mm3 in the setting of a single oral temperature of ≥38.3°C or a sustained temperature of ≥38.0°C.1 Although the majority of patients with FN never have an identifiable source of infection, patients with documented Gram-negative and Gram-positive bacteremia have mortality rates of 18% and 5%, respectively.1,2 It is for this reason that patients with FN should receive broad-spectrum antibiotics within 2 hours of presentation.1

When selecting an empiric antimicrobial for a patient with FN, an anti-pseudomonal agent must be chosen. Monotherapy with piperacillin-tazobactam, cefepime, or a carbapenem (such as meropenem, doripenem, or imipenem-cilastatin) is an appropriate empiric therapy option for most patients.1 Ceftazidime has been shown to have higher resistance rates against both Gram-negative and Gram-positive organisms and therefore should not be used as empiric monotherapy.3,4 Aminoglycosides are not routinely used empirically; however, they may be added in the case of a Gram-negative culture before species and sensitivities have been identified.1

Patients should also be evaluated for their need for vancomycin. Indications for empiric vancomycin include hemodynamic instability, pneumonia, positive blood culture for Gram-positive bacteria, suspected catheter-related infection, skin or soft-tissue infection, severe mucositis, and colonization with methicillin-resistant Staphylococcus aureus.1 A study evaluating the efficacy of levofloxacin for bacterial prophylaxis found that FN patients had an increased incidence of fluoroquinolone-resistant Gram-positive infections.5 For this reason, FN patients who have received fluoroquinolone prophylaxis should be empirically treated with vancomycin.

Invasive fungal infections are not commonly seen at the onset of fevers, thus antifungal therapy should only be initiated in the setting of persistent fevers or clinical suspicion of a fungal infection. If a patient remains febrile for 96 hours despite broad-spectrum antibiotics, antifungal treatment is warranted. Voriconazole has been found to be non-inferior to liposomal amphotericin B in preventing breakthrough fungal infections in patients with FN and persistent fevers.6 When compared with amphotericin B, voriconazole has also been shown to have higher response rates and improved overall survival when treating proven and probable invasive aspergillosis.7

For this particular patient, the most appropriate empiric regimen is vancomycin and an antipseudomonal agent such as cefepime. If the patient is persistently febrile on broad-spectrum antibiotics, antifungal therapy with voriconazole should be added. Once culture and sensitivity data are available, therapy should be narrowed to treat the identified source of infection.


Meredith Deal Keisler, PharmD, CPP, is an oncology clinical pharmacist at UNC Health Care. She earned her doctor of pharmacy degree from UNC Eshelman School of Pharmacy.


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(4):e56-e93.
  2. Klastersky J, Ameye L, Maertens J, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents. 2007;30(suppl 1):S51-S59.
  3. Paterson D, Ko W, Gottberg A, et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum β-lactamases: implications for the clinical microbiology laboratory. J Clin Microbiol. 2001;39:2206-2212.
  4. Fritsche T, Sader H, Jones R. Comparative activity and spectrum of broad-spectrum B-lactams (cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam) tested against 12,295 staphylococci and streptococci: report from SENTRY antimicrobial surveillance program (North-America: 2001-2002). Diagn Microbiol Infect Dis. 2003;47(2):435-440.
  5. Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353(10):977-987.
  6. Walsh T, Pappas P, Winson D, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:225-234.
  7. Herbrecht R, Denning D, Patterson T, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415.