A. Cometta

Oral versus Intravenous Empirical Antimicrobial Therapy for Fever in Patients with Granulocytopenia Who Are Receiving Cancer Chemotherapy

BACKGROUND Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

Piperacillin-tazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

Gram-positive bacteria have become the predominant infecting organisms in granulocytopenic cancer patients. Empiric antibiotic regimens used in febrile neutropenic patients often include an extended-spectrum cephalosporin, but the response to therapy in gram-positive coccal bacteremia has been unsatisfactory. Thus, new antibiotics with better activity against gram-positive bacteria should be tested. The objective of this prospective randomized controlled study was to evaluate and compare the efficacy and tolerance of piperacillintazobactam plus amikacin with that of ceftazidime plus amikacin, the standard regimen of the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer, in the empiric treatment of febrile granulocytopenic cancer patients. A total of 858 episodes were eligible for this study, and 706 episodes were assessable for efficacy. The antibiotic treatment was successful in 210 (61%) of 342 episodes in the piperacillin-tazobactam-amikacin group compared with 196 (54%) of 364 episodes treated with ceftazidime plus amikacin (P = 0.05). The time to defervescence was significantly shorter (P = 0.01) and the time to failure was significantly longer (P = 0.02) in the piperacillin-tazobactam-amikacin group. A significant difference in response to bacteremic infections between the two patient groups was found: piperacillin-tazobactam plus amikacin was successful in 40 of 80 episodes (50%), and ceftazidime plus amikacin was successful in 35 of 101 episodes (35%) (P = 0.05). A multivariate analysis showed that the probability of failure was significantly greater with ceftazidime plus amikacin than with piperacillin-tazobactam plus amikacin (P = 0.02). This trial suggests that piperacillin-tazobactam plus amikacin is more effective than ceftazidime plus amikacin for the empiric treatment of fever and bacteremia in granulocytopenic cancer patients. Although cutaneous reaction was more frequently associated with piperacillin-tazobactam plus amikacin than with ceftazidime-amikacin, this unwanted effect was relatively mild and its incidence was comparable to that of other penicillin compounds.

Vancomycin versus Placebo for Treating Persistent Fever in Patients with Neutropenic Cancer Receiving Piperacillin-Tazobactam Monotherapy

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

In vitro antimicrobial activity of moxifloxacin against bacterial strains isolated from blood of neutropenic cancer patients

The use of fluoroquinolones has increased in neutropenic cancer patients over the past two decades. With respect to empiric treatment of fever in neutropenic patients, the poor activity of older quinolones against gram-positive cocci prompted physicians to add specific anti-gram-positive agents to provide better activity against streptococci, which are frequently isolated from these patients. The efficacy and safety of oral antibiotic regimens that include fluoroquinolones for the treatment of low-risk febrile neutropenic patients have been documented in two large studies [1, 2]. The widespread use of fluoroquinolones as prophylactic agents in cancer patients has been associated with the occurrence of resistance in E. coli and coagulase-negative staphylococci, organisms which are most often responsible for bacteremia in these patients [3]. Moxifloxacin is an 8-methoxyquinolone that has enhanced activity against gram-positive bacteria relative to ciprofloxacin and other older fluoroquinolones. Oral moxifloxacin is 90% bioavailable, and its mean half-life of 12 h allows once-a-day dosing. Peak serum concentrations of 3.2–4.5 μg/ml have been achieved following oral doses of 400 mg of moxifloxacin, and the agent is widely distributed throughout the body [4]. The aim of the present study was to assess the in vitro activity of moxifloxacin against grampositive and gram-negative bacteria isolated from the blood of neutropenic cancer patients and to compare it with other fluoroquinolones and reference antibiotics. The collection of bacterial strains isolated from the blood of febrile neutropenic cancer patients randomized in two trials conducted by the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (EORTC-IDG) between 1993 and 2000 [5, 6] yielded 152 gram-positive isolates, including 71 coagulase-negative staphylococci, 29 S. aureus, 19 S. mitis, 19 S. oralis, and 14 E. faecalis, and 85 gram-negative strains, including 44 E. coli, 30 K. pneumoniae and 11 P. aeruginosa. These strains were used in the present study. Bacterial identification was confirmed at the Microbiological Reference Center (CHUV, Lausanne) using standardized methods [7]. Minimal inhibitory concentrations (MICs) of four fluoroquinolones (moxifloxacin, levofloxacin, gatifloxacin, ciprofloxacin), as well as cefepime, meropenem, amikacin, vancomycin, penicillin for streptococci and oxacillin for staphylococci were determined using a microbroth dilution Eur J Clin Microbiol Infect Dis (2006) 25:537–540 DOI 10.1007/s10096-006-0175-2