Use of antibacterial prophylaxis for patients with neutropenia
Funding: Victorian Integrated Cancer Services, administered by Western and Central Melbourne Integrated Cancer Services.
Conflict of interest: The following authors are consultants or advisory committee members or receive honoraria, fees for service, or travel assistance (independent of research-related meetings) from; or have research or other associations with the organisations listed: Monica Slavin – Gilead, Merck Sharp & Dohme, Pfizer, Schering Plough; Senthil Lingaratnam – Victorian Integrated Cancer Services; Andrew Wei – Celgene, Hospira, Novartis; Karin Thursky – Gilead, Merck Sharp & Dohme, Pfizer, Schering Plough.
Monica Slavin, Department of Infectious Diseases, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Vic. 3002, Australia. Email: firstname.lastname@example.org
The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by this group because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. Recent evidence has demonstrated non-significant but consistent, improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. However, the consensus was that this evidence was not strong enough to recommend prophylaxis. The evidence base for FQ prophylaxis is presented alongside current consensus opinion to guide the appropriate and judicious use of these agents. Due consideration is given to patient risk, as it pertains to specific patient populations, as well as the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. The potential costs and consequences of emerging FQ resistance, particularly among Escherichia coli, Clostridium difficile and Gram-positive organisms, are considered. As FQ prophylaxis has been advocated in some chemotherapy protocols, specific regard is given to whether FQ prophylaxis should be used to support these regimens. The group also provides recommendations for monitoring and surveillance of emerging resistance in those centres that have adopted FQ prophylaxis.
Previous guidelines (IDSA, 2002) have advised against the use of oral prophylactic antibiotics in patients with afebrile neutropenia because of a lack of evidence showing a reduction in mortality, and concerns that such practice promotes antimicrobial resistance.1 This recommendation continues to be supported by findings from a more recent meta-analysis that could not demonstrate a mortality benefit.2
In practice, findings from the clinical survey administered prior to the development of these guidelines revealed that 81% of respondents would not use fluoroquinolone (FQ) prophylaxis for the described oncology case (stage II (T2, N1) non-small cell lung cancer patient presenting with neutropenic fever on day 7 of cycle 2 for whom future cycles of chemotherapy were planned) while 70% would not for the haematology case (patient with relapsed acute myeloid leukaemia (AML) due for re-induction chemotherapy following induction with fludarabine and cytarabine).3 Of the 70% who avoided use of FQ prophylaxis in the hospitalized haematology case, a further 5% responded that they would use FQ prophylaxis in an outpatient setting for other groups of haematology patients; the most common considerations for using prophylaxis were allogeneic transplants and an absolute neutrophil count <0.5 × 109 cells/L for more than 10 days.3
While a 2005 systematic review (including studies of oral co-trimoxazole or FQ prophylaxis from 1981 to 2002) showed improvements in infection-related mortality with oral antibiotic prophylaxis, it did not include all relevant studies and reported negative studies incorrectly.4 However, a meta-analysis from the same year (which mostly included trials of patients with haematologic cancer) did show that FQ prophylaxis specifically reduced the risk for all-cause mortality (RR 0.52 (95% CI: 0.35–0.77)), as well as infection-related mortality, fever, clinically documented infections and microbiologically documented infections.5 Both meta-analyses were limited by the quality of the available studies. Many of the included studies were small, of variable quality (i.e. not always blinded) and spanned over a long time period (e.g. 1973–2005) during which practices related to empiric antibiotic therapy are likely to have changed.
Two subsequent large RCTs – one involving patients with autologous bone marrow transplant (BMT) or treatment for haematological malignancy,6 the other solid tumour patients only7– also demonstrated statistically non-significant, yet consistent, improvement in all-cause mortality resulting from FQ prophylaxis (using levofloxacin as the study drug). An updated meta-analysis incorporating outcomes from these studies found that FQ prophylaxis reduced the risk of death from any cause by 33% (95% CI: 2–54%) in patients at high risk of developing neutropenic fever (with expected duration of neutropenia more than 7 days).8 With regard to low-risk patients (e.g. solid tumours or lymphoma), the authors of this meta-analysis concluded that while existing evidence points towards an advantage from prophylaxis during the first cycle of chemotherapy, the evidence is much less clear for the whole duration of therapy.8
Although this meta-analysis was the most inclusive of all relevant comparative studies, the studies included were a mixture of level II and level III-1 evidence with a variety of methodological qualities. The overall findings of the meta-analysis though have prompted commentators9,10 and cancer networks to update their practice guidelines (NCCN guidelines)11 to include the recommendation to use FQ prophylaxis in patients who have an expected duration of neutropenia of more than 7 days, such as patients receiving treatment for AML or undergoing BMT.
Risk of emerging fluoroquinolone resistance with fluoroquinolone prophylaxis
In developing these guidelines, the consensus group gave due consideration to the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. Unfortunately, the risk and effect of emerging resistance with use of FQ prophylaxis for afebrile neutropenia has not been well researched. Only a few reports and studies exist in the literature.12–14 However, the association between antimicrobial resistance and FQ use in other settings is well documented,15–31 restricting its prophylactic use in only highly select patient populations32,33 as per the above recommendations. Consideration is given below to some of the clinically important resistance issues likely to impact patients with neutropenia receiving FQ prophylaxis. The likely clinical effect of resistance in a high-risk haematology cancer population has recently been reviewed in detail.34
Escherichia coli and Gram-negatives
Emergence of E. coli resistance with FQ use is well documented.12 In Australia, rates of FQ resistance among E. coli are low, but low-level increases were observed in the late 1990s to 2001.35 Recent data are lacking, but at one Victorian hospital, FQ use was associated with increases in FQ resistance among E. coli from 0% in 2006 to 11% in 2008 (personal communication with Australian-based infectious diseases physician). In one US cancer hospital employing FQ prophylaxis, FQ use was associated with the emergence of methicillin-resistant Staphylococcus aureus (MRSA), multi-drug-resistant E. coli and multi-drug-resistant Pseudomonas aeruginosa.36 Emergence of FQ-resistant E. coli was seen in stool samples of 35% (n= 8/23) of cancer patients receiving FQ prophylaxis on average 10 days after commencing the drug (range: 3–35 days),37 indicating that changes in susceptibility occur within a short period. Indeed, Kern et al. showed that within 6 months of re-instituting FQ prophylaxis, resistance rates for E. coli causing bacteraemia in cancer patients had increased from 15% to 50%.12
Resistant E. coli strains have been associated with poor clinical outcomes.24,38–40 Further, in centres with a 20% prevalence of FQ-resistant E. coli isolates among general medical patients, FQ prophylaxis has recently been shown to have little or no preventative effect on bacteraemia or fever.41–44
With regard to Enterobacteriaceae, FQ resistance results mainly from mutations in topoisomerase genes or changes in the expression of efflux pumps. However, it may be transmitted horizontally by plasmids, which can also confer extended spectrum beta-lactamase resistance.45,46
Rapid development of FQ resistance among coagulase-negative staphylococci is associated with low or no fitness cost in these organisms47,48, such that high FQ resistance still occurs in patients not receiving FQ prophylaxis presumably through patient-to-patient transmission.49,50 Although FQ consumption has caused a sharp rise in FQ-resistant S. pneumoniae,51 of greater concern to patients with or at risk of neutropenic fever is the association between FQ use and development of MRSA16,23,26,27 and resistant Viridans group streptococci.52–55
Emergence of life-threatening Clostridium difficile (C. difficile) has also been associated with FQ use. Findings from a retrospective cohort and case–control study found FQs to be more strongly associated with C. difficile-associated diarrhoea than any other antibiotic studied and to result in high fatality rates (adjusted hazard ratio, 3.44 (95% CI: 2.65–4.47) and odds ratio, 3.9 (95% CI: 2.3–6.6)).15,20 New strains of FQ-resistant C. difficile appear to be particularly virulent.22
Potential costs and consequences of fluoroquinolone resistance
The potential costs and consequences of FQ resistance may be summarized as follows:
- 1Fluoroquinolone prophylaxis reduces the number of febrile episodes6 and thereby reduces the selective pressure exerted from reduced need of empiric therapies; hence, consideration must be given for the selective pressure exerted by FQ prophylaxis relative to empiric therapy. However, it is also likely that when neutropenic fever occurs in a patient receiving FQ prophylaxis a broader empiric regimen may be chosen.
- 2Fluoroquinolone prophylaxis is known to alter colonizing flora (particularly of the gut) of individual patients. Horizontal transmission is also known to occur (for certain organisms, such as MRSA, P. aeruginosa, E. coli), such that over time, the majority of a hospital's patient population may also be affected.56–60
- 3Mucositis and central venous catheters are potential portals for bacterial invasion of the bloodstream; thus, bacteraemia involving FQ-resistant organisms is a real possibility in AML or BMT patients receiving high-dose chemotherapies.
- 4There is likely to be a lag time (one or more months) between FQ use and emergence of resistance strains.11,44
- 5If a patient colonized with FQ-resistant organisms subsequently develops an infection, last resort antibiotics (e.g. carbapenems) are likely to be initiated as empiric therapy.56 There are fewer last resort antibiotics for Gram-negative organisms compared with Gram-positive.60
- 6For most pathogens, resistance contributes to increases in mortality, as has been demonstrated in bacteraemia caused by VRE, MRSA and extended-spectrum beta-lactamase producing Gram-negative organisms.61 Australian baseline resistance rates are high for MRSA, and show emergence of resistance in Gram-negative pathogens.35,62–64
- 7The duration of colonization by FQ-resistant organisms is thought to persist for a period of time after cessation of the FQ. This time relationship is thought to be complex and dependant on changes in FQ resistance mechanisms.13,65
- 8There are some emerging data that a threshold for prevalence of FQ resistance in general internal medicine patients with E. coli exists where benefits of FQ prophylaxis are lost in cancer patients. This threshold has been estimated at 20% and may reflect prevalence of FQ resistance in the community.44
Recommendations for use of antibacterial prophylaxis in the setting of neutropenia
Given the current evidence base and the resistance concerns described, the following recommendations use patient risk to guide use of FQ prophylaxis (see Table 1 for summary). As levofloxacin is currently not licensed (not Therapeutic Goods Administration (TGA)-approved) for use in Australia, the recommendations presented refer to ciprofloxacin. As levofloxacin is known to have a broader spectrum of activity against Gram-positive organisms than ciprofloxacin,2 the clinical advantages documented in studies for levofloxacin cannot be wholly assumed for ciprofloxacin. This limitation was taken into consideration when developing these guidelines, as was the risk of emerging antimicrobial resistance and associated costs to the individual patient and institution (see later discussion). Ciprofloxacin is not TGA-approved for this indication.
Table 1. Key practice points – prophylaxis
|• There is currently insufficient evidence to recommend routine use of FQ prophylaxis in patients at low risk of developing neutropenic fever (grade C)|
|• FQ prophylaxis should also not be routinely used in high-risk haematology patients (grade C)|
|• FQ prophylaxis could be considered in outpatient SCT and palliative patients with bone marrow failure (grade C)|
|• Appropriate surveillance (detailed within text) should be undertaken by centres using FQ prophylaxis (grade C)|
|• When the prevalence of FQ resistance in E. coli in internal medicine patients at an institution approaches 20%, FQ prophylaxis is unlikely to be effective (grade C)|
Use of fluoroquinolone prophylaxis in patients at intermediate to high risk of developing neutropenic fever
Level II evidence strongly suggests that FQ prophylaxis substantially reduces the number of febrile episodes and microbiologically documented infections in patients at high risk of developing neutropenic fever (more than 7 days' neutropenia).6 However, while FQ prophylaxis is associated with a reduction in overall mortality, this has not always been statistically significant. Furthermore, the meta-analyses showing this benefit have limitations. In addition, follow-up studies have not adequately measured the effect of resistance; the duration of many of the included surveillance studies was too short to account for the likely lag time (a few months to 1 year) between FQ use and emergence of resistant strains.11,44
Given the concerns about the quality of the data presented in the available systematic reviews (and issues regarding resistance and loss of efficacy), the majority view of the current consensus panel is that FQ prophylaxis should not be routinely used in high-risk haematology patients (grade C recommendation), although discussion pertaining to patients with stem cell transplant (SCT) and acute leukaemia was particularly contentious. Some thought that the meta-analyses of Gafter Gvili et al. were sufficiently strong to support the use of prophylaxis in these patient groups. Following rigorous debate, the group agreed that it may be reasonable to consider the use of FQ prophylaxis in outpatient SCT and palliative patients with bone marrow failure (grade C recommendation).
Use of fluoroquinolone prophylaxis in patients at low risk of developing neutropenic fever
There is currently insufficient evidence to recommend routine use of FQ prophylaxis in patients at low risk of developing neutropenic fever (typically patients with solid tumour). The clinical benefits in this patient group are generally much smaller compared with patients with an expected duration of neutropenia more than 7 days (level I–II evidence).7,9 Further, many low-risk patients who develop neutropenic fever can be successfully managed in the outpatient setting with oral antibiotics, of which the best-documented treatment regimens include FQs (please see earlier section of these guidelines for recommendations relating to ambulatory care of low-risk patients). If FQs were to be used prophylactically, they would not be appropriate for use as empiric therapy in the ambulatory care setting, which might necessitate parenteral antibiotics and hospitalization.
Use of fluoroquinolone prophylaxis to support specific chemotherapy protocols
Fluoroquinolone prophylaxis has been advocated in some head and neck, breast, and lung cancer chemotherapy protocols. The following recommendations pertain to specific regimens.
Use of fluoroquinolone prophylaxis with TPF for head and neck cancer
Fluoroquinolone prophylaxis has been incorporated into the docetaxel, cisplatin, 5-FU (TPF) protocol for head and neck cancer to minimize neutropenic fever, a dose-limiting toxicity.66 However, it is likely that the risk of neutropenic fever is greater in the first treatment cycle compared with any other (personal communication Dr M. Posner). Given TPF is an induction regimen generally used to treat fitter patients with the aim of achieving significant disease-free survival, consensus opinion supports use of FQ prophylaxis particularly in the first cycle of TPF. In subsequent cycles, prophylaxis with recombinant human glanulocyte colony stimulating factor (rHu-GCSF) may be used if fever and neutropenia occurred previously and the role of FQ prophylaxis is less clear. (grade D recommendation).
Use of fluoroquinolone prophylaxis with TAC for breast cancer
Docetaxel, doxorubicin, cyclophosphamide (TAC) is associated with high incidences of grade 4 neutropenia and neutropenic fever.67 Several studies have shown that the addition of ciprofloxacin to rHu-GCSF prophylaxis provides minimal additive protection against neutropenic fever during use of this protocol.67–69 In the GEPARTRIO study, addition of ciprofloxacin to pegfilgrastim resulted in a 2% reduction in incidence of febrile neutropenia (7% vs 5%; P < 0.001) and no survival benefit.67 The consensus opinion is to avoid use of FQ prophylaxis during TAC in the presence of rHu-GCSF primary prophylaxis (grade B recommendation).
Recommended surveillance during use of fluoroquinolone prophylaxis
The group acknowledges that some centres currently use FQ prophylaxis and provide the following recommendations for surveillance of resistant microorganisms and superinfections:
- • Monitor rates of VRE, C. difficile, MRSA and FQ-resistant Gram-negative organisms, noting that FQ prophylaxis is unlikely to be effective when general hospital rates of FQ resistance in E. coli is greater than 20%;
- • Adapt antibiotic policies while using FQ prophylaxis, for example, avoid using an FQ as first-line therapy or for outpatient treatment of neutropenic fever
- • Monitor antibiotic usage patterns (grade D recommendation).
There is currently insufficient evidence to recommend routine use of FQ prophylaxis in patients at low risk of developing neutropenic fever. Moreover, in high-risk patients the majority of the consensus group members were not convinced of a mortality benefit. However, targeted use of FQ prophylaxis among some high-risk haematology patients may be of benefit. The group supports the use of FQ prophylaxis during the first cycle of TPF chemotherapy, when rHu-GCSF prophylaxis is not used. Clinicians should give due consideration to the prevalence of FQ resistance in E. coli; FQ prophylaxis is unlikely to be effective when the level of resistance within E. coli isolated from internal medicine patients at an institution approaches 20%. Centres using FQ prophylaxis should undertake appropriate surveillance.
See those for entire neutropenic fever guidelines, as detailed in introduction by Lingaratnam et al.3