Management of Febrile Neutropenia: Single Agent or Combination Therapy?.

Joana Caldas, Teresa Fernandes, Alexandra Monteiro, Luisa Carande, Madalena Silva, Ernesto Cruz and Aida B. Sousa


The best strategy for the empirical treatment of fever in profoundly neutropenic patients (pts) remains unclear. We retrospectively compared the efficacy and safety of 2 antibacterial regimens consecutively used in our center for febrile neutropenia (FN) in pts undergoing intensive chemotherapy for acute leukemia or autologous stem cell transplantation. From 1/99 to 6/01, 374 episodes of FN in 179 pts were treated with piperacillin-tazobactam plus amikacin (PTA, 4.5 g q6h and 20 mg/kg q24h respectively), then from 7/01 to 12/03, 428 episodes in 223 pts were treated with cefepime (CEF, 2g q8h). Any modification of the initial regimen was evaluated as a failure. Pts were nursed in HEPA-filtered rooms and received prophylactic aciclovir (and ciprofloxacin until 12/99) with no antifungal primary prophylaxis. There were no significant differences between the PTA and CEF episodes regarding median age of the pts, median days with neutrophils <500/μl or presence of an intravenous central catheter. The proportion of documented bacteremias was similar (33/30%) with a Gram negative predominance in both periods (60/66%), mainly due to E. coli (61/64%) and P. aeruginosa (14/14%). As for Gram positive bacteremias, there was an increase in S. aureus (18% in PTA vs 27% in CEF) and a marked decrease in S. viridans (24/4%). Resistance of Gram negative bacteria to the protocol drugs remained low (7% to PT and 4% to A in the first period, 5% to CEF in the second); resistance of coagulase negative staphylococci to ciprofloxacin dropped from 33 to 15%. Success rates were 35% for PTA and 32% for CEF. The reasons for modification of the initial empirical regimen were similar in the 2 periods, the most frequent being persistent fever (56/59%) followed by progression of infection (20/18%), relapsing fever (19/14%), withdrawal due to toxicity (3/6%) and resistant pathogen (1/3%). The addition of an antifungal was the most usual modification, occuring in 44% of PTA and 39% of CEF episodes. Vancomycin (for which a restriction policy had been introduced in 1995 after an outbreak of vancomycin-resistant enterococci) was added in 17 and 15% of the episodes. Amikacin was added in 38% of the CEF episodes. The occurence of further infections did not differ between the 2 periods (26 and 29%) nor did the mortality due to infection (7.7 and 6%). The proportion of severe adverse events (CTC-NCI grades 3/4) was low in both periods (4 and 1%). Cutaneous allergic reactions were less frequent with PTA than with CEF (5 vs 9%). We conclude that monotherapy with CEF was as effective as the combination of PTA for empirical treatment of FN. Both regimens resulted in a low infectious mortality and a very low emergence of resistance, and both were well tolerated.