Comment on: empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials.

Sir, The meta-analysis conducted by Paul et al. regarding empirical antibiotic monotherapy for febrile neutropenia illustrates the dangers of relying on such analyses to make therapeutic recommendations in an area characterized by rapid changes. We are particularly concerned with the conclusions that ceftazidime is suitable as monotherapy in such patients. In the meta-analysis, the authors included studies in which a glycopeptide was part of the regimen if it was administered in all arms of the study and considered this approach to be ‘monotherapy’ based on current guidelines issued by the Infectious Diseases Society of America (IDSA). Having helped co-author these guidelines, we wish to point out that monotherapy is defined as the use of a ‘single’ broad-spectrum agent whereas the use of broad-spectrum b-lactams with vancomycin is considered combination therapy. Current epidemiological trends indicate that Gram-positive organisms account for 44–76% of documented bacterial infections in neutropenic patients. By the authors own account, several agents including cefepime, piperacillin/tazobactam and the carbapenems offer better Gram-positive coverage than ceftazidime. Considering glycopeptide/b-lactam combinations as monotherapy is a serious methodological flaw which obscures the advantage of the superior Gram-positive coverage provided by other broad-spectrum agents. An additional area of concern is that a large number of studies with ceftazidime were conducted before the emergence of extended-spectrum b-lactamases (ESBLs) as a significant problem [15 of 19 studies (79%) with ceftazidime in this analysis were conducted before 2001]. There are reports of increasing resistance to ceftazidime among the Enterobacteriaceae due to ESBLs, which have been detected worldwide and are increasing in frequency. Based on in vitro data from the SENTRY surveillance programme, Jones et al. concluded that the carbapenems and fourth-generation cephalosporins represent the best agents for empirical therapy against Klebsiella spp. and Enterobacter spp. which are frequent pathogens in febrile neutropenic patients. Another report from the MYSTIC surveillance programme indicated that the carbapenems were the most active agents against Gram-negative bacilli. This meta-analysis demonstrated advantages of carbapenems over ceftazidime including fewer treatment failures and fewer modifications of the original regimen. A recent, evidence-based evaluation of empirical therapy in febrile neutropenic patients does not support the use of ceftazidime monotherapy (without modification) since it was associated with significantly inferior response rates when compared with other antibiotics. Selection of appropriate agent(s) for empirical therapy of fever in neutropenic patients is a complex process that continues to evolve. Epidemiological trends and susceptibility/resistance patterns vary considerably between institutions. Making general therapeutic recommendations based solely on statistical analysis of old data, without duly considering current epidemiology and resistance patterns, can be misleading. Based on current local information and the proper definition of monotherapy, ceftazidime is not a suitable agent for this indication at our institution. We strongly urge colleagues at other institutions to make therapeutic decisions based on current epidemiological/resistance patterns as well.