Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematic review and meta-analysis of randomized trials

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1 Journal of Antimicrobial Chemotherapy (2004) 54, DOI: /jac/dkh303 Advance Access publication 16 June 2004 Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematic review and meta-analysis of randomized trials Liat Vidal 1 *, Mical Paul 1,2, Itsik Ben dor 1, Karla Soares-Weiser 1 and Leonard Leibovici 1,2 1 Department of Medicine E, Beilinson Campus, Rabin Medical Center, Petah Tiqva 49100; 2 Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel JAC Context: Neutropenia is one of the grave consequences of cancer chemotherapy, and the treatment of neutropenic febrile patients with intravenous (iv) antibiotics has been shown to reduce mortality. Oral therapy could be an alternative approach for selected patients. Objectives: To compare the efficacy of oral antibiotics versus iv antibiotic therapy in febrile neutropenic cancer patients. Data sources: The Cochrane Library, the Cochrane Cancer Network Register of trials, EMBASE, LILACS and MEDLINE, databases for ongoing trials and the conference proceedings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Study selection: Randomized controlled trials comparing oral antibiotic/s and iv antibiotic/s for the treatment of neutropenic cancer patients with fever. Data collection: Two reviewers independently assessed trial eligibility, methodological quality and extracted all data. Data concerning mortality, treatment failures and adverse events were drawn from included studies assuming an intention-to-treat and per-protocol basis for the outcome measures whenever possible. Relative risks (RR) with their 95% confidence intervals (CI) for dichotomous data were estimated. Main results: Fifteen trials (median mortality 0, range 0% 8.8%) were included in the analyses. The mortality rate was similar comparing oral and iv antibiotic treatment (RR 0.83, 95% CI , 2224 patients). Treatment failure rates were also similar (RR 0.94, 95% CI , 15 trials). No significant heterogeneity was shown for the primary outcomes. This effect was stable in a wide range of patients. Quinolones alone or combined with other antibiotics were used with comparable results. Adverse reactions, mostly gastrointestinal, were more common with oral antibiotics. Conclusions: Oral antibiotics may be safely offered to neutropenic patients with fever who are at low risk for mortality. Keywords: neutropenic patients, antimicrobial drugs, fever Introduction Neutropenic patients often harbour serious infections 1 4 and therefore are traditionally treated with intravenous (iv) broad-spectrum antibiotics, at the emergence of fever. 5 Observational studies during the last decade have revealed the heterogeneous nature of febrile neutropenia. 6 Several clinical prediction rules have been developed and validated to define patients at low risk for mortality and complications. 7 9 Oral treatment avoids the inconvenience of an iv line and its complications, is less costly than the standard treatment and therefore might be considered beneficial for low risk patients. Clinical trials explored the feasibility of oral antibiotic treatment for low risk febrile neutropenia. 10,11 Most of these trials were small and single centre. Thus, although reporting similar rates of success for oral and iv therapy, the superiority of an iv regimen could not be ruled out. We performed a systematic review and meta-analysis in an attempt to provide better evidence regarding the safety and efficacy of oral treatment as opposed to iv treatment.... *Corresponding author. Tel: ; Fax: ; liatvidal@hotmail.com JAC vol.54 no.1 q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

2 Methods The full protocol is available at We have compared the efficacy of oral antibiotic/s versus iv antibiotic therapy in febrile neutropenic cancer patients. We also compared the efficacy of these treatment modalities in the following subgroups: patients with unexplained fever at presentation versus documented infection; absolute neutrophil count (ANC) of > cells/l versus below; solid tumour versus haematological malignancy and children versus adults. Eligible studies were randomized trials, comparing any oral antibiotics with any iv antibiotics for the treatment of febrile neutropenia induced by chemotherapy in cancer patients, irrespective of language and publication status. The primary outcomes were all-cause mortality at 30 days and treatment failure. Whenever all-cause mortality could not be obtained, infectious-related mortality was used. For the purpose of this review, treatment failure was defined as a composite end-point comprising one or more of the following: death; persistence, recurrence or worsening of clinical signs or symptoms of presenting infection; any addition to or modification of the assigned intervention. 12,13 Secondary outcomes were: treatment failure other than modification of the primary intervention, lost to follow-up before end of study (dropouts). Adverse effects were defined as life-threatening or associated with permanent disability and those requiring discontinuation of therapy. Search strategy Relevant trials were identified by searching CENTRAL (Cochrane Library, issue 2, 2002), the Cochrane Cancer Network Register of trials (November 2002), EMBASE (January ), LILACS (1982 to 2002) and MEDLINE ( ) with the terms: ((fever*:me OR febrile OR infection*:me OR infect* OR sepsis*:me) AND (neutropenia*:me OR neutropen* OR neutropaen* OR granolucytopen* OR granolucytopaen* OR leukopen* OR leukopaen*) AND (oral OR per os) AND (intravenous OR parenteral) AND ((antibiotics*:me OR antibiot* OR antimicrob* OR anti-microb* OR antibact* OR anti-infective agents*:me) NOT decontamination*:me)) References of all identified studies as well as major reviews were inspected to track down further studies. We searched conference proceedings and trial databases for ongoing and unpublished trials. Additionally, the first or corresponding author of each included study was contacted, as were pharmaceutical companies, for complementary information or information regarding unpublished trials. Retrieval of studies and data One reviewer inspected the abstract of each reference identified by the search and applied the inclusion criteria. For possibly relevant articles, the full article was obtained and inspected by two reviewers independently. They assessed the relevant articles for methodological quality and extracted data from included trials. This was conducted using the criteria described in the Cochrane handbook, which are based on the evidence of a strong association between poor allocation concealment and overestimation of effect. 14,15 Data extractions were discussed, decisions documented and all authors of included studies were contacted for clarification. In case of disagreement between the two reviewers, a third reviewer extracted the data. All data were collected on an intention-to-treat basis whenever possible. Statistical analysis Relative risks with 95% confidence intervals for dichotomous data were calculated. Exclusions after randomization were reported. Heterogeneity in the results of the trials was initially graphically inspected and assessed by calculating tests of heterogeneity (x 2 and I 2 ). Heterogeneity was explored through stratifying by the above-defined patient subgroups ( objectives ), separating patients by different low risk criteria. A fixed effect model was used unless significant heterogeneity (P<0.10) was detected, in which case the random effect model was used. A funnel plot, estimating the precision of trials, was examined in order to estimate potential asymmetry that may indicate selection Figure 1. Inclusion and exclusion of trials. 30

3 Table 1. Characteristics of trials. Presented are variations in the design of the studies Characteristics of trials Study ID design unit of randomization type of oral/sequential antibiotics type of iv antibiotics setting Flaherty randomization at presen tation; switch iv to oral after 72 h if stable Freifeld episodes iv ciprofloxacin+azlocillin or iv ceftazidime+amikacin switch to oral ciprofloxacin amoxicillin-clavulanate initially oral episodes oral ciprofloxacin+ Giamarellou randomization at presen patients iv ciprofloxacin switch tation; switch iv to oral to oral ciprofloxacin after 72 h if stable ceftazidime+amikacin ceftazidime ceftazidime+amikacin Hidalgo initially oral episodes oral ofloxacin ceftazidime+amikacin oral as outpatients iv Innes initially oral episodes oral ciprofloxacin amoxicillin-clavulanate gentamicin+tazocin Kern ceftriaxone+amikacin initially oral patients oral ciprofloxacin+ amoxicillin-clavulanate Malik initially oral patients oral ofloxacin amikacin+(carbenicillin or cloxacillin or piperacillin) Mullen sequential oral to iv episodes, a single dose of iv ceftazidime patients in ceftazidime switch mortality to oral ciprofloxacin analysis Paganini sequential oral to iv episodes iv ceftriaxone+ ceftriaxone+amikacin amikacin switch oral to oral as outpatients iv no information;? outpatients cefixime Petrilli initially oral episodes oral ciprofloxacin ceftriaxone outpatients Rolston initially oral episodes oral ciprofloxacin+ aztreonam+clindamycin outpatients amoxicillin-clavulanate Rubenstein initially oral episodes oral ciprofloxacin clindamycin Samomis initially oral patients oral ampicillinsulbactam+ciprofloxacin Shenep sequential oral to iv episodes iv tobramycin/ amikacin +ticarcillin+vancomycin or ceftazidime+vancomycin switch to oral cefixime aztreonam+clindamycin ceftazidime+amikacin tobramycin/ amikacin+ ticarcillin+vancomycin or ceftazidime+vancomycin Velasco initially oral episodes oral ciprofloxacin+penicillin v amikacin+carbenicillin or ceftazidime outpatients oral as outpatients iv bias or methodological flaw in small studies. Publication bias was estimated also by the formal Begg Mazumdar rank correlation test. 16 Results Description of studies The process used to identify eligible trials is described in Figure 1. Fifteen randomized controlled trials were included in the review: 13 published studies 10,11,47 57 and two conference proceedings, identified through ICAAC search 58,59 (further information was provided by Dr Anaissie 59 ). The studies were performed during the years , and included 2511 randomized patients or episodes. Oral antibiotics were compared with intravenous, both given empirically and as the initial treatment ( initial oral ) in 10 trials. In the other five trials, all patients received iv antibiotics prior to oral therapy ( sequential ). 47,49,52,53,55 In two sequential trials, patients were randomized at presentation, but switched to oral therapy if clinically stable 72 h later. 47,49 The setting of therapy also varied. All patients were treated as outpatients in four trials. 11,52,54,58 In three trials, patients randomized to oral therapy were treated as outpatients, whereas the control group was treated (Table 1). 50,57,59 Some exclusion criteria were common to all trials: haemodynamic instability, hypotension, altered mental status, 31

4 Table 2. Case definitions of patients. Shown are inclusion criteria that varied between the trials Criteria Study ID Age, year range Pneumonia Perirectal or severe cellulitis Infected intravascular catheter Expected long duration of neutropenia Haematological malignancy (except acute leukaemia) Flaherty included included included included included acute leukaemia Freifeld excluded included excluded excluded included acute leukaemia Giamarellou >18 included included included included included acute leukaemia Hidalgo excluded excluded included included excluded Innes excluded excluded excluded excluded included Kern excluded excluded included Malik >16 included included included included included acute leukaemia Mullen excluded excluded excluded included included Paganini included excluded excluded included included Petrilli included included included included included Rolston No data No data no data no data included included Rubenstein included included included included included acute leukaemia Samomis excluded included included excluded excluded Shenep excluded excluded excluded included included Velasco >16 included included included included included respiratory failure, poor clinical condition, renal failure, abnormal liver function tests, inability to swallow or take oral medication, allergy to study drugs, pregnancy and lactation. Additional case definitions (e.g. background malignancy, expected duration of neutropenia, documented source of infection) had varied between the trials despite the attempt of all trials to identify patients at low risk for mortality and complications (Table 2). Few studies had remarkably high mortality rates with both regimens (5% 8.8%). 10,47,49,51 This can be explained by the design of the trials: randomization of patients not episodes, 10,47,49 longer follow-up period, 51 and not applying most low risk criteria for inclusion. 10,47,49 Methodological quality of included studies Adequate allocation concealment was employed in six trials. One trial was double-blinded 48 and in another the outcomes assessors were blinded to the treatment arm. 51 Duration of follow-up was pre-defined only in two trials. 51,53 In the other trials, it had varied according to the length of neutropenic febrile episode. In two trials, the patients were followed for a predefined time after resolution fever. In the other trials, patients were followed until the end of the febrile neutropenic episode or the end of antibiotic treatment. The unit of randomization was the patient in four trials 10,49,51,59 and the episode of febrile neutropenia in the other trials. The later trials included 1430 episodes in 1017 patients. Efficacy of oral antibiotics Mortality (15 trials, 2224 patients). No difference in mortality between oral and iv treatment was demonstrated (all-cause mortality: RR 0.83, 95% CI 0.49 to 1.40; Figure 2). Treatment failure (15 trials, 2295 patients). There was no significant difference in failure rate between the two interventions (per protocol analysis: RR 0.96, 95% CI Intention-to-treat analysis: RR 0.94, 95% CI , n = 2511, 15 trials; Figure 3). A comparable relative risk was calculated for failure that was not due to modification of the initial regimen. Subgroup analysis. Oral treatment was not inferior when compared with iv treatment in any of the evaluated subgroups (Table 3). Patients with ANC > cells/l had better outcome with oral treatment. This subgroup is expected to be at a lower risk for mortality and complications, and therefore it may be that the advantages of oral treatment are more pronounced. Comparison of mortality in subgroups could not be performed due to the low fatal outcome rate. Dropouts before end of study (12 trials, 2180 patients). Twelve of the 15 included trials reported the number of patients who 10,11,48 51,53 57,59 were lost to follow-up before the end of the study. No significant difference in the number of dropouts was found between the oral and iv treatment (RR 0.87, 95% CI ). Adverse events. No trial reported death or permanent damage due to the study drug. Adverse effects that required discontinuation of the assigned antibiotic therapy were reported in 11 10,11,47 50,52,55,57 trials (RR 1.79, 95% CI ; n = 1536). Separate analysis of the initial oral studies revealed significantly more adverse events requiring discontinuation among orally treated patients (RR 6.65, ). This finding is explained by the high rates of gastrointestinal adverse events with oral antibiotics and with the fact that these events hamper oral but not iv treatment (post-protocol analysis: RR 3.01, 95% CI ; n = 607). Resistance. Only three trials reported resistance by the microbial isolates to both antibiotic regimens. Four trials reported failure due to resistance; 49 51,57 there was no difference between oral and iv treatment. Sensitivity analyses. Sensitivity analyses of studies with adequate and inadequate quality showed no significant impact on mortality or treatment failure. Sensitivity analyses on different case definitions showed similar relative risks: in the six trials that included patients with any source of infection, patients who 32

5 Figure 2. Mortality with oral versus iv antibiotics treatment for neutropenic febrile patients. Presented are relative risk (RR) and their confidence interval (CI). Whenever all-cause mortality could not be obtained infectious related mortality was used. were treated orally had RR 0.96, 95% CI for treatment failure. 10,11,47,49,54,56 Most of the trials included patients with haematological malignancy (but not acute leukaemia). The RR for treatment failure with oral therapy in those trials was 0.9, 95% CI Treatment setting had no significant effect on failure. When analyses were performed according to oral antibiotic regimen, we observed no significant impact of quinolone treatment alone versus quinolones in combination with other antibiotics (Figure 4). A near symmetry was demonstrated on the funnel plot (Figure 5). The Begg Mazumdar test demonstrated no significant association between the study effects and size (P = 0.488). Discussion The rates of treatment failures and death were similar in neutropenic patients given oral and iv antibiotic treatment. Intentionto-treat analysis might favour equivalence; however, the results of the per-protocol analysis were similar to those of the primary analysis. This effect was stable in a wide range of patients. One limitation of the analysis is its inability to define the patients who may have been offered oral antibiotics. This is due to the variations in the inclusion and exclusion criteria. The difference in low risk criteria is not surprising: the concept of low risk neutropenic fever and its definition developed during the years in which the studies were performed. Different prognostic criteria evolved based on observational studies. 6,7,9,60 62 International collaboration had led to the development of a weighted scoring system identifying low risk patients, 8 adopted by IDSA. 5 Favourable factors are: the development of fever out of hospital, age below 60 years, no to moderate symptoms, no hypotension, no chronic bronchitis, no dehydration and either solid tumour or no history of fungal infection. While receiving conventional therapy this group had 1% mortality. Low mortality rate led to wide confidence intervals in the absolute risk reduction. To confirm equivalence of two treatments, we should ideally be able to show that any estimate of risk included within the confidence interval lay within a predefined range of equivalence and had no clinical significance. 63 In a population with an expected mortality of <1%, this uncertainty may have no real consequences. For treatment failure, the confidence interval is narrower and probably has no clinical importance since failure means mainly a change in the antibiotic regimen. According to the available data, oral antibiotic therapy can be safely offered to febrile children and adults with neutropenia who are haemodynamically stable, have no organ failure, can take oral medications, and do not have pneumonia, infection of a central line or a severe soft-tissue infection. These criteria stand in close relationship to those used in the guidelines of IDSA for 33

6 Figure 3. Failure rates (per-protocol analysis) with oral versus iv antibiotics treatment for neutropenic febrile patients. Intention-to-treat analysis gave similar results. the treatment of neutropenic patients. Oral treatment may improve the quality of life of cancer patients, reduce the complication associated with iv therapy and lower the costs of the treatment. The analysis offered no data in support of a specific oral regimen, but in light of the preponderance of Gram-positive infections, 5,62 the combination of a quinolone and a second drug active against Gram-positive bacteria (e.g., ampicillin/clavulanate) seems prudent. A future trial of oral versus iv antibiotic treatment should include febrile neutropenic patients with mild and stable sepsis, regardless of their underlying disorder, source of infection or neutrophil count. Its sample size should be based on considerations of equivalence. 63 The definitions of response and failure Table 3. Failure rates in different subgroups Number of trials Number of patients or episodes RR 95% CI References ANC a > ANC a < FUO b Documented infection Adults Children Haematological malignancy Solid tumour ,51,55 11,51,55 10,11,48 51,58,59 10,11,48 51,58,59 10,11,47,49 51,56,57, ,49,58 11,50,54,58,59 a Absolute neutrophil count. b Fever of unknown origin. 34

7 Figure 4. Subgroup analysis for failure rates according to the type of antibiotics with oral versus iv antibiotics treatment for neutropenic febrile patients. Paganini, Shenep, Velasco, Freifeld and Paesmans, Dr Marshall who supplied the full unpublished manuscript and Dr Anaissie for providing unpublished data. We also thank Mr Ochan Kilama from Bayer Italia for clarifying the details from a trial not included in the analysis. We thank Mrs Mandy Collingwood and Mrs Vivien Garner of the Cochrane Gynaecological Cancer Review Group, for their helpful advice and assistance in obtaining articles. Supported in part by an EU 5th Framework Grant (TREAT, IST ) and by a grant from the Steering Committee for Research Promotion at Rabin Medical Center, Israel. References Figure 5. Funnel plot illustrating the treatment effect against the precision of trials. The near symmetry in the funnel plot does not support selection bias. and the reported outcomes should be based on guidelines on methodology for clinical trials involving patients with fever and neutropenia. 13,64,65 Acknowledgements We would like to thank all the authors who responded to our letters and supplied information on their studies: Drs Hidalgo, 1. Bodey, G. P. (1966). Infectious complications of acute leukemia. Medical Times 94, Bodey, G. P., Buckley, M., Sathe, Y. S. et al. (1966). Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Annals of Internal Medicine 64, Pizzo, P. A., Robichaud, K. J., Wesley, R. et al. (1982). Fever in the pediatric and young adult patient with cancer. A prospective study of 1001 episodes. Medicine (Baltimore) 61, Schimpff, S. C. (1986). Empiric antibiotic therapy for granulocytopenic cancer patients. American Journal of Medicine 80, Hughes, W. T., Armstrong, D., Bodey, G. P. et al. (2002) guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clinical Infectious Disease 34,

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