JAC Advance Access originally published online on October 30, 2006
Journal of Antimicrobial Chemotherapy 2007 59(1):5-22; doi:10.1093/jac/dkl425
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Systematic review |
Effect of quinolone prophylaxis in afebrile neutropenic patients on microbial resistance: systematic review and meta-analysis
1 Department of Medicine E, Beilinson Campus, Rabin Medical Center Petah-Tiqva, Israel 2 Sackler Faculty of Medicine, Tel-Aviv University Ramat-Aviv, Tel-Aviv, Israel 3 Department of Social Medicine, University of Bristol Bristol, UK
*Corresponding author. Tel: +972-39376500; Fax: +972-39376512; E-mail: anatga2{at}clalit.org.il
Received 19 July 2006; returned 18 August 2006; revised 13 September 2006; accepted 21 September 2006
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Abstract |
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Objectives: To assess the effect of quinolone prophylaxis following chemotherapy for malignancies on the emergence of resistant bacteria in neutropenic patients.
Methods: Systematic review and meta-analysis of randomized controlled trials comparing quinolone prophylaxis with placebo or no intervention, or another antibiotic, for the prevention of bacterial infections in afebrile neutropenic patients. The Cochrane Library, PubMed, Embase, conference proceedings and references were searched. Two reviewers independently applied selection criteria, carried out quality assessment and extracted the data. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Primary outcomes were rates of colonization and infection by quinolone-resistant bacteria.
Results: The search yielded 56 trials, 22 compared quinolones with placebo or no intervention. Data on colonization by resistant organisms could be extracted from 27 trials (48%). When compared with placebo or no intervention, there was a statistically non-significant increase in colonization with organisms resistant to quinolones (RR 1.68; 95% CI 0.71–4.00). There was no difference in the number of patients developing infections caused by resistant pathogens (RR 1.04; 95% CI 0.73–1.50). In trials comparing quinolones with trimethoprim/sulfamethoxazole, there were fewer incidents of colonization by bacteria resistant to the prophylactic agent in the quinolone arm than in the trimethoprim/sulfamethoxazole arm (RR 0.49; 95% CI 0.37–0.66). Data on baseline resistance of colonizing isolates, resistance development and cross-resistance to ß-lactam antibiotics were too scarce to analyse.
Conclusions: Patients treated with quinolones have a non-significant increase in colonization by quinolone-resistant bacteria. There is no difference in the number of infections caused by pathogens resistant to quinolones. As quinolone prophylaxis reduces the risk of death in neutropenic patients, the risk associated with colonization and infections caused by quinolone-resistant organisms does not outweigh the gain. Future trials should focus on better documentation of infections caused by resistant organisms.
Keywords: quinolones , neutropenia , antibiotic prophylaxis , antibiotic resistance
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Introduction |
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Bacterial infections are a major cause of morbidity and mortality in neutropenic patients following chemotherapy for malignancy. Pooled results from randomized controlled trials show that antibiotic prophylaxis, started at the time of chemotherapy or neutropenia onset reduces all-cause mortality.1,2 Similarly, substantial reductions in infection-related mortality, febrile episodes and bacteraemias have been demonstrated. The main argument against the use of antibiotic prophylaxis is induction of resistance.3–6
Quinolones are currently the primary antibiotics considered for prophylaxis given results from recent trials.7,8 Therefore the aim of this systematic review and meta-analysis was to extend our previous systematic review in an attempt to summarize and evaluate existing evidence of the effect of quinolone prophylaxis on the development of antimicrobial resistance. Our primary objective was to quantify the effect of quinolone prophylaxis on antibiotic resistance. Secondary objectives were to examine how studies assessed and reported data on resistance development.
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Methods |
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We updated our previous1 search of randomized controlled trials assessing antibiotic prophylaxis using quinolones for afebrile neutropenic patients and extended it to include secondary publications describing surveillance methods and surveillance results. We recorded the methods used for surveillance for antibiotic resistance in each study and extracted all data regarding resistance development in relation to pre-treatment resistance profiles.
The full search strategy and the methods used for identifying the trials included in this review were described previously.1,2 In brief, we combined the search terms ‘neutropenia’ and similar, ‘antibiotic’ and similar, and ‘prophylaxis’ and similar. Relevant trials were identified from electronic searches of Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966-6/2006), EMBASE (1980–2005), and the following conference proceedings: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) (1995–2004), Annual Meetings of the Infectious Diseases Society of America (IDSA) (2001–2004), and the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (2001–2006) and hand searches of references from relevant publications. No language restriction was set. To retrieve secondary publications of included trials describing surveillance methods and results we searched the same databases using the terms ‘surveillance’ and ‘colonization’ and ‘resistance’ and similar.
We included all randomized or quasi-randomized controlled trials comparing quinolone prophylaxis with placebo or no intervention, or with another antibiotic, for the prevention of bacterial infections in afebrile neutropenic patients.
The primary outcomes assessed were (i) rates of colonization; and (ii) microbiologically documented infections (hereafter referred to as ‘infection’), both caused by quinolone-resistant bacteria. Secondary outcomes included colonization by resistant bacteria in relation to the presence of resistant bacteria prior to antibiotic prophylaxis; any colonization during and following treatment, as well as in relation to pre-treatment colonization; and infections resistant to antibiotics other than quinolones following prophylaxis. We also aimed to collect the percentage of colonization and infection with bacteria resistant to the ß-lactam drugs used for treatment of febrile neutropenia in each study.
We recorded whether trials reported data regarding resistance, whether surveillance cultures were performed and the methods used for surveillance and microbiological assessment of cultures. We also recorded baseline and end colonization profiles of bacteria in stool and oropharynx, including the type/s of bacteria isolated and their antibiotic susceptibilities.
Two reviewers independently applied inclusion criteria, selected the studies, and extracted data and outcomes.
Data analysis and statistical methods
Trial results were expressed as relative risks (RR) with 95% confidence intervals (CIs) (Review Manager [RevMan], version 4.2 for Windows, The Cochrane Collaboration, Oxford, UK). We used a fixed-effect model to pool trial results throughout the review. We assessed heterogeneity of trial results by inspecting graphical presentations and calculating a 
2 test of heterogeneity and the I2 measure of inconsistency. We predefined significant heterogeneity as a 2 test P value <0.1 or an I2 measure >50%.9
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Results |
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Our search yielded 56 trials, which randomized 7878 patients. Twenty-two compared quinolones with placebo or no treatment7,8,10–29 and 34 compared quinolones with other antibiotics30–63 (Table 1): quinolones versus trimethoprim/sulfamethoxazole in 11 trials, quinolones versus non-absorbable antibiotics in 8 trials, quinolones versus fluoroquinolones with additional antibiotics for coverage against Gram-positive infections in 8 trials, quinolones plus trimethoprim/sulfamethoxazole versus trimethoprim/sulfamethoxazole in 2 trials, and quinolones versus other quinolones in 5 trials. The trials were published between 1987 and 2005. Most trials included patients with haematological malignancies or undergoing bone marrow transplantation (48 trials). In most trials the patients were hospitalized throughout the duration of antibiotic prophylaxis.
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Less than half of the trials in our study conducted microbiological surveillance (26 trials, 46%). Of these, most started surveillance with treatment and performed weekly or twice-weekly cultures until the end of treatment (Table 1). The methods for microbiological evaluation of surveillance cultures were reported in 16 trials. Selective media for Gram-negative bacteria were used in eight trials, while non-selective media were used by nine trials reporting on microbiological methods (including one trial that used both selective and non-selective media).
Colonization by bacteria resistant to quinolones at any time during the trial (baseline, during or end) was reported in 27 trials performing surveillance cultures (48%). Susceptibility data permitting the assessment of infections caused by bacteria resistant to quinolones were reported in 23 trials (41%).
Quinolones versus placebo or no intervention
Primary outcome. Of the 22 trials comparing quinolones with placebo or no intervention, only three trials reported on colonization by resistant organisms at the end of follow-up. Compared with placebo or no intervention, there was a statistically non-significant increase in the rate of colonization by quinolone-resistant organisms with prophylaxis at the end of the study (RR 1.68; 95% CI 0.71–4.0) (3 trials) (Figure 1).
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There was no difference in the proportion of patients who developed infections caused by bacteria resistant to quinolones (RR 1.04; 95% CI 0.73–1.5) (8 trials) (Figure 2). Of the 154 episodes of microbiologically documented infections in the quinolone arm, 54 were caused by quinolone-resistant organisms (30%) versus 51/308 (16%) without prophylaxis (Figure 3). There was no difference in the number of patients who developed infections caused by quinolone-resistant Gram-negative bacteria (RR 1.3; 95% CI 0.63–2.67) or by quinolone-resistant Gram-positive bacteria (RR 0.93; 95% CI; 0.61–1.42) in the quinolone arm versus placebo/no treatment.
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Results did not differ between trials of varying quality. Of the three trials that reported colonization by resistant organisms, only one had adequate allocation generation and concealment. Of the eight trials that reported infection by resistant organisms, three had adequate allocation generation and concealment. There was no difference in the relative risk for infection caused by resistant organisms between trials that reported adequate allocation concealment (RR 0.99; 95% CI 0.66–1.48) compared with trials that did not report adequate allocation concealment (RR 1.31; 95% CI 0.56–3.08). No evidence of association between trial years and the relative risk for infections caused by resistant organisms was found by meta-regression.
Secondary outcomes. None of the trials reported on colonization by resistant organisms at baseline or during the trial. Furthermore, there were no data on the susceptibility of bacteria causing infections to antibiotics other than quinolones or bacteria resistant to ß-lactam drugs used for treatment of febrile neutropenia, in the eight trials that reported infections caused by organisms resistant to quinolones.
None of the trials reported the composition of faecal flora or oropharyngeal flora at baseline (e.g. Gram-negative and Gram-positive colonization profiles of bacteria) and one trial reported end colonization profiles of bacteria15 and stated a reduction in the total count of aerobic bacteria in stool specimens, without providing numerical data.
Quinolones versus other antibiotics
Primary outcome. Of the 34 trials comparing quinolones with other antibiotics, 12 reported colonization by resistant organisms at the end of follow-up. In trials comparing quinolones with trimethoprim/sulfamethoxazole, there were fewer colonizations by quinolone-resistant bacteria in the quinolone arm, than colonizations by trimethoprim/sulfamethoxazole-resistant bacteria in the trimethoprim/sulfamethoxazole arm at the end of the study (RR 0.49; 95% CI 0.37–0.66, 3 trials, Figure 4). There were also fewer infections caused by quinolone-resistant bacteria in the quinolone arm than infections caused by trimethoprim/sulfamethoxazole-resistant bacteria in the trimethoprim/sulfamethoxazole arm (RR 0.45; 95% CI 0.27–0.74, 6 trials, Figure 5).
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Table 2 presents results comparing quinolones to quinolones with additional antibiotics for coverage against Gram-positive infections and to oral non-absorbable antibiotics.
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Secondary outcomes. Of 34 trials comparing quinolones with other antibiotics, 9 trials reported colonization by resistant organisms at baseline and 3 during the trial. Compared with trimethoprim/sulfamethoxazole, baseline resistance to trimethoprim/sulfamethoxazole was significantly lower than baseline resistance to quinolones (RR 0.21; 95% CI 0.06–0.79, Table 2). As in the trials comparing quinolones with control, there were no data regarding infections resistant to antibiotics other than quinolones.
Ten trials of 34 (29%) reported baseline stool and pharynx colonization profiles of bacteria and 18 trials (52%) reported end stool and pharynx colonization profiles of bacteria.
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Discussion |
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We sought to systematically quantify antibiotic resistance development following quinolone prophylaxis for afebrile neutropenia in randomized controlled trials.
We assessed colonization with quinolone-resistant bacteria following prophylaxis. This outcome quantifies the effect of prophylaxis on patients' microflora. Compared with no treatment, quinolone prophylaxis resulted in a non-significantly higher rate of resistant colonization. Compared with trimethoprim/sulfamethoxazole, fewer quinolone-resistant bacteria were observed in the quinolone arm than trimethoprim/sulfamethoxazole-resistant bacteria in the trimethoprim/sulfamethoxazole arm. However, this is probably accounted for by baseline differences in the susceptibility to these antibiotics.
We then compared the rate of infections caused by quinolone-resistant bacteria. This is the clinically significant effect of resistance development. Compared with no treatment, quinolone prophylaxis did not result in a higher rate of quinolone-resistant infections; 4% (54/1358) of quinolone-treated patients developed microbiologically documented infection caused by quinolone-resistant bacteria. However, among infections developing in the two groups, quinolone-resistant infections were significantly more prevalent in the quinolone arm; 30% (54/154) of all microbiologically documented infections were resistant to quinolones. Compared with trimethoprim/sulfamethoxazole, significantly fewer quinolone-resistant infections were observed in the quinolone arm than trimethoprim/sulfamethoxazole-resistant infections in the trimethoprim/sulfamethoxazole arm. None of the trials reported data regarding resistance to other antibiotics following prophylaxis.
We sought to assess baseline resistance levels, which may affect the efficacy of prophylaxis. However, only few data were available and none in studies comparing quinolones with placebo/no treatment. Baseline resistance levels in a specific centre may be influenced by previous routine administration of prophylaxis, and by the period of time it was practised. Included trials did not report whether antibiotic prophylaxis was practised in the units participating in the trial before the trial.
The clinical implications of colonization by resistant bacteria are unclear. Observational studies have shown that routine prophylactic use of antibiotics in neutropenic patients causes colonization of individual patients with resistant organisms, but colonization did not necessarily lead to development of infection.3–6 Oethinger et al.64 observed that in 16 cancer patients on quinolone prophylaxis, faecal colonization with quinolone-resistant Escherichia coli probably preceded infection with identical E. coli strains in 11 patients. This was confirmed according to molecular typing PFGE of chromosomal DNA digests or by random amplified polymorphic DNA fingerprinting.
The clinical implications of resistant infections are clearer. While quinolone prophylaxis reduces the overall number of infections,1 the number of resistant infections remains unchanged. Quinolone prophylaxis does not increase the rate of infections resistant to quinolones. When infections do develop, 1/3 of infections are resistant to the administered quinolone; thus, quinolones should not be given as empirical treatment to patients following quinolone prophylaxis.
The results of our analysis are limited by the paucity of data. While it is generally acknowledged that resistance development is the major drawback of antibiotic prophylaxis, randomized controlled trials assessing quinolone prophylaxis have infrequently addressed this outcome. Less than half of the trials in our study conducted microbiological surveillance and reported data regarding colonization with resistant organisms. Less than a third reported data on quinolone-resistance among infections developing during the trial. None of the trials reported the effect of quinolone prophylaxis on resistance to ß-lactam antibiotics used for the treatment of febrile neutropenia. One of the problems in trying to demonstrate a difference in colonization with resistant organisms in patients in the same unit administered different antibiotics is that of cross-resistance, which may tend to minimize the effect. The use of common empirical antibiotics for the treatment of neutropenic fever in these patients may also tend to dilute any difference, if there is cross-resistance between antibiotics.
These trials were designed to assess the efficacy of antibiotic prophylaxis and the length of follow-up may have been too short to assess resistance development. One of the randomized controlled trials included61 conducted long-term surveillance for development of ciprofloxacin resistance, after implementing routine antibiotic prophylaxis following the trial. After 10 years of prophylaxis with ciprofloxacin, there were 66 episodes of microbiologically documented infection in 47 patients out of approximately 700 neutropenic episodes. Of these, there were only five ciprofloxacin-resistant Gram-negative organisms, and none of these infections were fatal.
The data from our analysis do not allow definitive conclusions to be drawn regarding the threshold of resistance above which prophylaxis will no longer be effective. We did not find significant associations between the RR for mortality and trial years, baseline or end quinolone resistance. Several observational studies examined the outcomes of neutropenic patients in settings with a high prevalence of resistance to fluoroquinolones when fluoroquinolone prophylaxis was stopped.65–67 At a university hospital in Germany two attempts to discontinue prophylaxis were stopped since there were more bacteraemias, Gram-negative bacteraemias and deaths during the periods when prophylaxis was not given.65,66 Discontinuation of prophylaxis in a Swiss hospital67 led to an increase in febrile episodes, Gram-negative bacteraemia, and a non-significant increase in mortality. Thus, data from our analysis and from observational studies suggest the potential for efficacy of prophylaxis despite high levels of quinolone resistance.
Implications for practice and research
Patients given quinolone prophylaxis should not be treated empirically with quinolones for suspected infections. Administration of quinolones may be associated with increased carriage of quinolone-resistant bacteria. Quinolone prophylaxis has been shown to reduce all-cause mortality by 48%.1,2 All-cause mortality encompasses the potential harms to the individual patient, including resistance development. The findings of this review do not support withholding quinolone prophylaxis from patients, for fear of resistance induction.
Future trials of antibiotic prophylaxis should monitor resistance development more rigorously and focus on better documentation of infections caused by organisms resistant to the antibiotic drug administered, namely quinolones. Infection by resistant organisms should be regarded as an outcome. In addition, efforts should be made to document cross-resistance to other antibiotics given as empirical treatment for febrile neutropenia.
The clinical implication of colonization by resistant organisms and the relation of colonization to infection remain uncertain.3–6 Although randomized controlled trials are not equipped to provide these data, observational cohort studies with years of follow-up may help answer the question of whether colonization predicts infection by resistant organisms.
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Transparency declarations |
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None to declare.
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REFERENCES |
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