Presenter: Amber B. Clemmons, BCOP, PharmD, Clinical Professor, University of Georgia College of Pharmacy, Augusta, GA
Co-Authors: Rachel Shelley, PharmD Candidate, University of Georgia College of Pharmacy; Vayou Chittavong, PharmD Candidate, University of Georgia College of Pharmacy; Huimin Hu, PhD Candidate, Department of Statistics, University of Georgia; Xianyan Chen, PhD, Statistician, Department of Statistics, University of Georgia; Andrew Chao, MD, Physician, Infectious Disease, Augusta University Medical Center; Daniel Anderson, PharmD, BCIDP, Infectious Disease Pharmacist, Pharmacy, Augusta University Medical Center; Joshua Eudy, PharmD, BCIDP, Infectious Disease Pharmacist, Pharmacy, Augusta University Medical Center
BACKGROUND: Appropriate empiric antibiotic use for patients with febrile neutropenia (FN) must balance adequate coverage per local antibiogram and patient factors (eg, history of resistance, clinical presentation), as well as principles of antimicrobial stewardship.1,2 Based on antibiogram reports showing poor susceptibility of Pseudomonas to cefepime, our institution requires the addition of empiric tobramycin therapy for 48 hours (or longer if there is growth of gram-negative organism) for initial management of FN. There is a paucity of data regarding dual antipseudomonal strategy in this setting.3-6
OBJECTIVE: To evaluate the benefit of tobramycin therapy added to cefepime for empiric treatment of adult patients with FN.
METHOD: This retrospective review included adult patients with FN between January 2019 and July 2020. Patients were divided into 3 treatment cohorts: cefepime monotherapy; early dual therapy plus tobramycin therapy added within 48 hours of cefepime initiation, per protocol; and delayed dual therapy plus tobramycin therapy added after 48 hours of cefepime. The primary outcome was adherence to institutional protocol requiring empiric dual treatment with cefepime plus tobramycin. The secondary end points were a comparison of the 3 cohorts regarding hospital length of stay (LOS) and intensive care unit (ICU) LOS; incidence of gram-negative and cefepime-resistant bacteremia, and any gram-negative infection; acute kidney injury; and in-hospital mortality. Statistical analysis included logistic regression, chi-square test, or nonparametric test.
RESULTS: Of the 350 patients who received cefepime for FN, 146 (42%) received dual therapy with tobramycin, per protocol. Of those, approximately 80% of the patients discontinued tobramycin therapy by 48 hours. The patient demographics were similar among the 3 groups, except for fewer cases of hematology or transplant, and fewer cases of concomitant vancomycin and hypotension in the cefepime monotherapy group. Overall, the incidence of gram-negative bacteremia was 10%, with resistance to cefepime in 13% of available susceptibility reports. No difference was found among the groups regarding the incidence of gram-negative bacteremia, other gram-negative infections, cefepime resistance, acute kidney injury, ICU admission, or ICU LOS (all P >.05). Patients in the cefepime monotherapy group had shorter hospital LOS (6 days + 9.6 days) compared with the early dual-therapy (15 days ± 12.1 days) and delayed dual-therapy (22 days + 14.1 days) groups. Mortality was lower in the cefepime monotherapy cohort compared with the delayed dual-therapy (P = .04) but not compared with the early dual-therapy (P >.05) groups.
CONCLUSION: Overall, no benefits were seen with dual therapy compared with monotherapy groups. Patients who received dual therapy were more likely to have had a transplant or a hematological diagnosis, which might have confounded the LOS and mortality results. In addition, the incidence of gram-negative bacteremia and cefepime resistance was low. Optimal antimicrobial(s) therapy should be dictated by antibiogram, the patient history, and by any risk factors for treatment resistance.
- Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical Practice Guideline 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-e93.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prevention and Treatment of Cancer-Related Infections. Version 1.2021. July 2, 2021. www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed October 7, 2021.
- Lee NH, Kang JM, Lee JW, et al. Cefepime versus cefepime plus amikacin as an initial antibiotic choice for pediatric cancer patients with febrile neutropenia in an era of increasing cefepime resistance. Pediatr Infect Dis J. 2020;39:931-936.
- Zengin E, Sarper N, Çakı Kılıç S. Piperacillin/tazobactam monotherapy versus piperacillin/tazobactam plus amikacin as initial empirical therapy for febrile neutropenia in children with acute leukemia. Pediatr Hematol Oncol. 2011;28:311-320.
- Ponraj M, Dubashi B, Harish BH, et al. Cefepime vs. cefoperazone/sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia. Support Care Cancer. 2018;26:3899-3908.
- Legrand M, Max A, Peigne V, et al. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med. 2012;40:43-49.