Fluoroquinolone prophylaxis: worth the cost?

Results of the retrospective study by Shinohara et al. published in this issue of Leukemia and Lymphoma, suggest that moxifloxacin may be more efficient in reducing febrile neutropenia episodes than tosufloxacin, particularly in patients with acute myeloid leukemia and prolonged neutropenia [1]. While fluoroquinolone prophylaxis with ciprofloxacin [2] and levofloxacin [3] has been investigated in a number of studies, few have explored the role of moxifloxacin or tosufloxacin for afebrile neutropenia [4].

The aim of antibiotic prophylaxis during chemotherapy-induced neutropenia is to prevent infectious complications, particularly in high-risk patients. However, the data supporting its use are controversial [5]. As such, differences exist between guidelines, with some regions advocating antibiotic prophylaxis [6] and others recommending against it [7]. Central to this controversy is the issue of antimicrobial resistance, with rates of fluoroquinolone use in adult and pediatric patients paralleling fluoroquinolone resistance trends in many regions [8].

Resistance to fluoroquinolones is transmitted vertically, through mutations in chromosomal genes, or horizontally, via mutations in transferable genes or plasmids [5,9]. The impact of these mutations on the inhibitory ability of fluoroquinolones is additive, with in vitro data supporting an association with intensity and duration of therapy [10]. Of particular concern is plasmid mediated co-transmission of aminoglycoside modifying enzymes, beta-lactamases and/or carbapenemases, which, combined with with fluoroquinolone resistance genes, confer high-level antibiotic resistance [9].

Bacterial resistance in hematology patients was reviewed at the 4th European Conference on Infections in Leukaemia (ECIL) in 2011. Updated ECIL guidelines for empirical and targeted antibiotics for febrile neutropenia are available online and formal publication is awaited [11]. To combat the increasing rates of antibiotic resistance observed in some parts of Europe, the guideline introduces a “de-escalation strategy” for febrile neutropenia. This strategy, recommended for complicated presentations, or in individuals or centers with risk factors for resistant pathogens, suggests a very broad initial regimen, with coverage of resistant gram-positive and gram-negative pathogens and de-escalation to a narrower spectrum (“targeted”) therapy once microbiology is available. Although designed to avoid the morbidity and mortality associated with inappropriate initial antibiotic therapy [12], this approach may lead to unnecessary use of very broad-spectrum antibiotics with associated adverse effects of toxicity, cost and resistance.

There is a shortage of new agents to combat the steady rise of antibiotic resistance around the world [13]. Strategies to curb this increasing resistance must be employed, with an emphasis on optimizing infection control practices and antimicrobial stewardship [13]. Continual monitoring of local epidemiology and bacterial resistance patterns, both at the hospital and on an individual level, is essential and should inform local prescribing policies. While the proposed ECIL “de-escalation strategy” may be necessary in some centers with a high prevalence of antibiotic resistant organisms, it should not be routinely adopted in centers with low resistance rates.

The precise threshold of resistance for which an antibiotic should no longer be used empirically is unknown. Available recommendations, based largely on expert opinion, range between a prevalence of 10% and 30% and vary according to bacteria and antibiotic class [14]. Regarding prophylaxis, an observational study found that a prevalence of fluoroquinolone resistance exceeding 20% in general medicine patients was associated with a significant reduction in the efficacy of ciprofloxacin prophylaxis in patients with cancer admitted to the same institution [15].

The appearance of carbapenems, colistin and rifampicin, for empiric treatment of febrile neutropenia in the new ECIL guidelines is a direct reflection of escalating antibiotic resistance. Unrestricted use of fluoroquinolones has contributed to this multifactorial problem. Although fluoroquinolone prophylaxis during afebrile neutropenia may have shown a survival benefit in certain high-risk groups in the past, its current role must be questioned. Attention should now be directed toward reducing unnecessary antibiotic exposure in an attempt to preserve the increasing limited agents available for the treatment of established infections.

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