Journal of Infection (2014) xx, 1e13
www.elsevierhealth.com/journals/jinf
REVIEW
Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials. Shun-ichi Kimura, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Hideki Nakasone, Misato Kikuchi, Rie Yamazaki, Shinichi Kako, Junya Kanda, Aki Tanihara, Junji Nishida, Yoshinobu Kanda* Division of Hematology, Saitama Medical Center, Jichi Medical University, Japan Accepted 18 February 2014 Available online - - -
KEYWORDS Meta-analysis; Antibiotic prophylaxis; Hematopoietic stem cell transplantation; Fluoroquinolones
Summary Objectives: We performed a meta-analysis to evaluate the impact of systemic antibiotic prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients. Methods: We collected reports from PubMed, the Cochrane Library, EMBASE, CINAHL, and Web of Science, along with references cited therein. We included prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients. Results: Seventeen trials with 1453 autologous and allogeneic HSCT recipients were included. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotics in two trials. Systemic antibiotics other than fluoroquinolones were evaluated in five of these 12 trials. Four trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones. One trial compared two different systemic antibiotic regimens: fluoroquinolones versus trimethoprim-sulfamethoxazole. As a result, systemic antibiotic prophylaxis reduced the incidence of febrile episodes (OR 0.16; 95%CI 0.09e0.30), clinically or microbiologically documented infection (OR 0.38; 95%CI 0.22e0.63) and bacteremia (OR 0.31; 95%CI 0.16e0.59) without significantly affecting allcause mortality or infection-related mortality.
* Corresponding author. Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya-ku, Saitamacity, Saitama 330-8503, Japan. Tel.: þ81 48 647 2111x5416; fax: þ81 48 644 5166. E-mail address: [email protected] (Y. Kanda). 0163-4453/$36 ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2014.02.013 Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
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S.-i. Kimura et al. Conclusions: Systemic antibiotic prophylaxis successfully reduced the incidence of infection. However, there was no significant impact on mortality. The clinical benefits of prophylaxis with fluoroquinolones were inconclusive because of the small number of clinical trials evaluated. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Bacterial infection remains the major cause of morbidity and mortality in the early period after hematopoietic stem cell transplantation (HSCT).1,2 Fever during neutropenia occurs in >90% and 80% of allogeneic and autologous HSCT recipients, respectively.3,4 During the neutropenic period before engraftment, HSCT recipients have two critical risk factors for infection: prolonged severe neutropenia and breaks in the mucocutaneous barrier resulting from conditioning regimens.5 Based on evidence that antibiotic prophylaxis improves the clinical outcome, including the incidences of documented infections and all-cause mortality in patients with chemotherapyinduced neutropenia,6 current guidelines recommend prophylaxis with fluoroquinolones in high-risk patients who are expected to show prolonged and profound neutropenia, such as acute leukemia patients undergoing chemotherapy and HSCT recipients.5,7 However, prophylactic antibiotic therapy has not been thoroughly evaluated in HSCT recipients. Therefore, we performed a metaanalysis to evaluate the impact of systemic antibiotic prophylaxis in HSCT recipients.
Materials and methods Data sources Studies were collected from PubMed, the Cochrane Library, EMBASE, CINAHL, and Web of Science, and included references cited therein. The last search was performed in November 2013. The identified studies were not restricted to those written in English or to published trials. The search terms #1 (antibiotic OR anti-bacterial OR antibacterial agent OR antibacterial OR antibacterial agent OR antibacterial drug OR antibacterials OR antibiotics OR antimicrobial OR antimicrobial agent OR antimicrobials OR antimicrobic OR antimicrobics), #2 (prophylaxis OR prevention OR protection OR pre-emptive), #3 (neutropenia OR neutropaenia OR granulocytopenia OR granulocytopaenia OR agranulocytosis), #4 (stem cell transplantation OR hematopoietic stem cell transplantation OR bone marrow transplantation OR peripheral blood stem cell transplantation) and #5 (autologous OR allogeneic) were crossed as #1 AND #2 AND (#3 OR #4 OR #5).
Study selection A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.8 We included all prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients, which compared either
systemic antibiotic prophylaxis with placebo, no intervention or non-absorbable antibiotics, or two different systemic antibiotic regimens.
Outcome measures Seven outcome measures were used. The primary outcome measure was all-cause mortality at the end of follow-up in each study. The secondary outcome measures were infection-related mortality, febrile episodes, incidence of clinically or microbiologically documented infection, bacteremia, related adverse events and emergence of resistant bacteria. Clinically documented infection was defined as the presence of symptoms or signs of inflammation at an anatomic site irrespective of whether pathogens were recovered from the affected site or not.9 Microbiologically documented infection was defined as the presence of symptoms or signs of inflammation at an anatomic site where pathogens were recovered from the affected site. Bacteremia was also included in microbiologically documented infection.
Data extraction and assessment of quality Two reviewers independently extracted data from each report. Any discrepancies were resolved between the two reviewers by discussion. We assessed the included clinical trials for methodological quality using the Cochrane Collaboration’s risk of bias assessment tool.10 The assessed components included random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), incomplete outcome data (attrition bias) and selective reporting (reporting bias).
Statistical analyses The summarized odds ratios (ORs) were calculated using the ManteleHaenszel (fixed-effect) method and the DerSimonianeLaird (random-effect) method. We used a fixed-effect model for pooling trial results throughout the review because it works well in analyses with a low number of events. However, we chose a random-effect model when heterogeneity was found. We assessed publication bias using a funnel plot. We assessed heterogeneity by a Chi square test of homogeneity and I2 measure of inconsistency. Sensitivity was determined by recalculating the results after dropping a subset of the studies. We assessed the effect of the difference between allogeneic and autologous HSCT on each outcome measure by meta-regression with the percentage of allogeneic HSCT recipients in each study. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Accessed 1 March 2013, at http://www.
Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Meta-analysis of antibiotic prophylaxis in HSCT jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html), which is a graphical user interface for R (The R Foundation for Statistical Computing, version 2.13.0).11 More precisely, it is a modified version of R commander (version 1.6e3) that was designed to add statistical functions that are frequently used in biostatistics. It uses a “meta” package for meta-analysis and “metatest” package for meta-regression analysis.12
Results Clinical trials Fig. 1 shows a flow diagram of the publications identified for the study and exclusions. Seventeen trials with 1453 patients (842 autologous and 407 allogeneic HSCT recipients) were included.4,13e28 The numbers of autologous and allogeneic HSCT recipients were not specified in two trials.16,17 One clinical trial was published in French.22 Since two clinical trials were unpublished, we extracted data from meeting abstracts.16,18 Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials4,13e21 and with nonabsorbable antibiotic in 2 trials22,23 (Tables 1and 2). There were four randomized placebo-controlled clinical trials.15,16,18,21 Systemic antibiotics other than fluoroquinolones were evaluated in five of these 12 trials.4,13,14,17,19 In the study reported by Petersen et al., the effect of systemic antibiotic prophylaxis was investigated in the setting
3 that all patients also received non-absorbable antibiotics.13 Prophylaxis with intravenous vancomycin monotherapy was evaluated in two trials.14,17 In two clinical trials, prophylactic antibiotics were started at the onset of neutropenia.13,19 Since 25 of 26 enrolled patients in the study reported by Lew et al. received HSCT, we considered it to be a clinical trial for HSCT recipients and included it in this meta-analysis.15 A significant publication bias was detected in clinical trials for the evaluation of infectionrelated mortality (P Z 0.042). At least borderline heterogeneity was found in clinical trials for the evaluation for clinically or microbiologically documented infection and bacteremia (P Z 0.051, P Z 0.015, respectively). When we excluded clinical trials on prophylaxis with intravenous vancomycin monotherapy, heterogeneity was not found (P Z 0.61, P Z 0.42, respectively). Four clinical trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones (Table 2).24e27 The additional antibiotics for gram-positive bacteria were rifampicin in two trials,25,27 penicillin G in one trial24 and oral vancomycin in one trial.26 One clinical trial compared two different systemic antibiotic regimens: fluoroquinolones versus trimethoprim-sulfamethoxazole (Table 2).28 Table 3 shows an assessment of the quality of the included clinical trials. The random sequence generation and the allocation concealment were low risk of bias in seven (41%) clinical trials.14,19e21,26e28 The blinding of participants and personnel was low risk of bias in five (29%) clinical
Figure 1 Flow diagram of the publications identified for study and exclusions. Seventeen trials were included. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotic in two trials. Four trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones (FQs). One trial compared FQs to trimethoprim-sulfamethoxazole (TMP-SMZ). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
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Included trials that compared prophylactic systemic antibiotics to no prophylaxis or placebo.
Study name (Year)
No. of pts (SCT pts)
Auto SCT
Allo SCT
Age, year (Range)
Underlying diseases
Intervention (No. of pts)
Control (No. of pts)
Beginning of prophylaxis
End of prophylaxis
Outcome measures
Petersen et al. (1986)1
122 (122)
0
122
Hematological malignancies
ANC 500
60 (60)
23
37
iv VCM, iv TOB, ticarcillin, oral non-absorbable antibiotics (54) iv VCM (30)
Oral nonabsorbable antibiotics (68)
Attal et al. (1991)2
Median intervention 20 control 23 (3e49) Mean 33 (1e65)
No prophylaxis (30)
2 days before BMT
ANC >500 or fever
Lew et al. (1991)3
18 (17)
14
3
Median intervention 41 control 39 (26e54)
Hematological or solid tumors
CPFX (7)
Placebo (11)
Conditioning
ANC >500
Avril et al. (1994)4
60 (60)
59
1
Solid tumors
CAZ, TEIC (30)
No prophylaxis (30)
Day 4 of the conditioning
Neutropenia resolution
Patric et al. (1995)5
48 (48)
NA
NA
Mean intervention 6.9 Control 5.7 (2e16) Median 11
All-cause mortality, infection-related mortality, fever, DI, bacteremia All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E, resistant bacteria Fever, DI, bacteremia, A/E
Leukemia or solid tumors
CPFX (23)
Placebo (25)
10 days before BMT
ANC >500 or fever
Teinturier et al. (1995)6 Ruiz et al. (2001)7
155 (155) 50 (50)
NA
NA 0
Hematological or solid tumors Oncohematological patients
iv VCM (75)
50
No prophylaxis (80) Placebo (50)
5 days before BMT 5 days before SCT
Slavin et al. (2007)8
151 (151)
72
79
73 children & 82 adults Mean intervention 45.7 control 44 NA
Hematological or solid tumors
CFPM (75)
No prophylaxis (76)
ANC ＜1000
1 day after BMT Neutropenia resolution or empirical antibiotics Neutropenia resolution
Papaiakovou et al. (2010)9
157 (157)
157
0
NA
Hematological or solid tumors
CPFX, VCM (61)
No prophylaxis (65)
Day 0 of PBSCT
Neutropenia resolution or fever
Vehreschild et al. (2012)10
66 (66)
66
0
Median intervention 54 control 50 (18e75)
Hematological or solid tumors
MOFX (34)
Placebo (32)
Conditioning
ANC >500 or fever
Hematological malignancies
OFLX (50)
Infection-related mortality, fever, DI, bacteremia Fever, DI, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E
No., number; Pts, patients; SCT, stem cell transplantation; Auto, autologous; Allo, allogeneic; iv, intravenous; VCM, vancomycin; TOB, tobramycin; ANC, absolute neutrophil count; DI, documented infection; BMT, bone marrow transplantation; A/E, adverse event; CPFX, ciprofloxacin; CAZ, ceftazidime; TEIC, teicoplanin; NA, not assessed; OFLX, ofloxacin; CFPM, cefepime; PBSCT, peripheral blood stem cell transplantation; MOFX, moxifloxacin.
S.-i. Kimura et al.
Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Table 1
Included trials that compared two antibiotic regimens.
Study name (Year)
No.of pts (SCT pts)
Auto
Allo
Age
Systemic antibiotics versus non-absorbable antibiotics 65 (65) 0 65 Mean 20 Gluckman (6e38) et al. (1988)11
Gluckman et al. (1991)12
44 (44)
0
44
Mean 33.2 (11e54)
Underlying diseases
Intervention (No. of pts)
Control (No. of pts)
Beginning of prophylaxis
End of prophylaxis
Outcome measures
Hematological diseases
Pefloxacin, penicillin (32)
Oral cephalotin, oral GM (33)
8 days before BMT
15 days after BMT
Hematological diseases
OFLX, AMPC, (22)
Oral VCM, oral TOB, oral colistin (22)
10 days before BMT
15 days after BMT
All-cause mortality, infection-related mortality, DI, resistant bacteria All-cause mortality, infection-related mortality, DI, A/E
NOFX (21)
7 days before BMT
ANC >500
CPFX (20)
2 days before BMT
ANC >500 or fever
Fluoroquinolones plus antibiotics for gram-positive bacteria versus only fluoroquinolones 43 (43) 43 0 Median Hematological NOFX, PCG Broun intervention or solid tumors (22) et al. (1994)13 36 control 37 (20e52) 40 (40) 40 0 Mean Lymphoma or CPFX, RFP Hidalgo intervention solid tumors (20) et al. (1997)14 36 control 40.2 Ford et al. (1998)15
84 (84)
52
32
123 (123)
123
0
NA
Mean intervention 42.9 control 40.8 Fluoroquinolone versus trimethoprim-sulfametoxazole 167 (167) 143 24 Median 41 Lew et al. (18e64) (1995)17 Gomez-Martin et al. (2000)16
Hematological or solid tumors
CPFX, oral VCM (43)
CPFX (41)
Admission
ANC >500 or use of systemic antibiotics
Lymphoma or solid tumors
CPFX, RFP (61)
CPFX (62)
2 days before BMT
ANC >500 or fever
Hematological or solid tumors
CPFX (82)
TMP-SMZ (85)
More than 3 days before conditioning
ANC >400 or fever
All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E, resistant bacteria All-cause mortality, infection-related mortality, DI, bacteremia Infection-related mortality, fever, DI, bacteremia, A/E
Meta-analysis of antibiotic prophylaxis in HSCT
All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E, resistant bacteria
No., number; Pts, patients; SCT, stem cell transplantation; Auto, autologous; Allo, allogeneic; GM, gentamicin; BMT, bone marrow transplantation; DI, documented infection; OFLX, ofloxacin; AMPC, amoxicillin; VCM, vancomycin; TOB, tobramycin; A/E, adverse event; NOFX, norfloxacin; PCG, penicillin G; ANC, absolute neutrophil count; CPFX, ciprofloxacin; RFP, rifampicin, NA, not assessed; TMP-SMZ, trimethoprim-sulphamethoxazole.
5
Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Table 2
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S.-i. Kimura et al. Table 3
Assessment of the quality of included trials.
Study name (Year)
Random sequence generation (Selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Petersen et al. (1986)1 Attal et al. (1991)2 Lew et al. (1991)3 Avril et al. (1994)4 Patric et al. (1995)5 Teinturier et al. (1995)6 Ruiz et al. (2001)7 Slavin et al. (2007)8 Papaiakovou et al. (2010)9 Vehreschild et al. (2012)10 Gluckman et al. (1988)11 Gluckman et al. (1991)12 Broun et al. (1994)13 Hidalgo et al. (1997)14 Ford et al. (1998)15 Gomez-Martin et al. (2000)16 Lew et al. (1995)17
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk
Unclear risk Unclear risk Low risk Unclear risk Low risk Unclear risk Low risk Unclear risk Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Low risk Low risk Unclear risk Unclear risk Low risk Unclear risk Unclear risk
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Low risk Unclear risk Unclear risk Low risk Unclear risk Unclear risk
trials.15,16,18,21,28 Incomplete outcome data was low risk of bias in seven (41%) clinical trials.14,19e23,26 Selective reporting was low risk of bias in six (35%) clinical trials.14,20e23,26 Since only four clinical trials fully evaluated the emergence of resistant bacteria,15,22,25,28 we could not perform a meta-analysis on this issue. In a clinical trial which compared ciprofloxacin and placebo, colonization of ciprofloxacin-resistant organisms was observed five of seven patients in ciprofloxacin group and one of 11 patients in placebo group, respectively.15 Most of the organisms in the former group were yeasts including Candida albicans, C.
tropicalis, Saccharomyces cerevisiae, and not identified yeast recovered from stool, while only one patient acquired bacteria colonization of Streptococcus viridans recovered from the orophyarynx. One placebo recipients acquired colonization of Geotrichum capitatum, recovered from orophyarynx and diphtheroides in the stool. In another clinical trial of 65 allogeneic stem cell transplantation recipients which compared pefloxacin plus penicillin with nonabsorbable antibiotics, five of 32 pefloxacin plus penicillin patients and eight of 33 non-absorbable antibiotic patients developed microbiologically documented infection.22
Figure 2 All-cause mortality: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. The odds ratio (OR) is presented with a 95 percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Meta-analysis of antibiotic prophylaxis in HSCT
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Figure 3 Infection-related mortality: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. All three fluoroquinolone-based trials were excluded from the analysis, since there were no events in either group in these trials. The odds ratio (OR) is presented with a 95percent confidence interval (95%CI).
Among these episodes, one Pseudomonas bacteremia resistant to pefloxacin was observed in pefloxacin plus penicillin group. In the other clinical trial which compared ciprofloxacin alone with ciprofloxacin and rifampicin in 40 autologous stem cell transplantation recipients,25 five episodes of bacteremia in the former group (four infections with coagulase-negative staphylococci and one with viridans streptococcus) were observed. All these strains were susceptible to rifampicin, and all but one were resistant to ciprofloxacin. Two patients in the latter group developed
bacteremia due to Enterobacter cloacae and Pseudomonas aerginosa. Both of the patients were complaint with the prophylactic regimen and the isolates were susceptible to ciprofloxacin. In the fourth clinical trial which compared ciprofloxacin and trimethoprim-sulphamethoxazole, 51 of 80 ciprofloxacin patients and 43 of 83 trimethoprimsulphamethoxazole patients acquired colonization of ciprofloxacin-resistant organisms.28 The leading organism was streptococci, especially viridans streptococcus, followed by yeasts, mostly Candida.
Figure 4 Febrile episodes: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and the other trials is shown. The odds ratio (OR) is presented with a 95percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
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Systemic antibiotic prophylaxis versus no prophylaxis or placebo Systemic antibiotic prophylaxis significantly reduced the incidence of febrile episodes (OR 0.16; 95 percent confidence interval [CI], 0.09e0.30), clinically or microbiologically documented infection (OR 0.38; 95%CI 0.22e0.63) and bacteremia (OR 0.31; 95%CI 0.16e0.59), but had no significant effect on all-cause mortality or infection-related mortality (OR 0.89; 95%CI 0.48e1.66, OR 1.37; 95%CI 0.50e3.76, respectively) (Figs. 1e6). When we only considered clinical trials with fluoroquinolones, prophylactic antibiotics also significantly reduced febrile episodes (OR 0.14; 95%CI 0.07e0.32), clinically or microbiologically documented infection (OR 0.31; 95%CI 0.17e0.56) and bacteremia (OR 0.18; 95%CI 0.09e0.36) (Figs. 4e6). The impact of prophylaxis with fluoroquinolones on mortality was inconclusive because of the small number of clinical trials evaluated (Figs. 2 and 3). Patients with systemic antibiotic prophylaxis had a greater incidence of adverse events compared to controls (OR 3.32; 95%CI 1.45e7.63) (Fig. 7). Adverse events included rash, gastrointestinal complications, elevation of liver enzyme, renal toxicity, Clostridium difficile-associated diarrhea, QT prolongation, fever, abnormal prothrombin time, insomnia, and joint pain. Renal toxicity was observed in the clinical trial with prophylactic intravenous vancomycin monotherapy.14 We could not perform subgroup analysis in allogeneic and autologous HSCT separately, because one third of clinical trials included both allogeneic and autologous HSCT recipients together. Therefore, we used meta-
S.-i. Kimura et al. regression to evaluate the difference in the impact of allogeneic and autologous HSCT. In a meta-regression, the percentage of allogeneic HSCT recipients was not associated with outcome measures (data not shown). Sensitivity was determined by recalculating the results after dropping specific clinical trials. We recalculated each outcome measure after excluding clinical trials on prophylaxis with intravenous vancomycin monotherapy,14,17 a clinical trial in which prophylactic non-absorbable antibiotics were administered in both groups,13 a clinical trial that included one non-HSCT patient,15 clinical trials in which prophylactic antibiotics were started at the onset of neutropenia,13,19 non-blinded clinical trials,4,13,14,17,19,20 and unpublished clinical trials.16,18 When we excluded two clinical trials in which prophylactic antibiotics were started at the onset of neutropenia,13,19 the OR of all-cause mortality for systemic antibiotic prophylaxis changed from 0.89 (95%CI 0.48e1.66) to 0.29 (95%CI 0.05e1.88), which, while not statistically significant, showed a tendency toward less mortality with systemic antibiotic prophylaxis, although there was no change in the OR of infection-related mortality; OR 1.37 (95%CI 0.50e3.76) to 1.66 (95%CI 0.43e6.48). Otherwise, there was no dramatic change in the OR in a sensitivity analysis.
Systemic antibiotics versus non-absorbable antibiotics Only two clinical trials compared systemic antibiotics to non-absorbable antibiotics in this analysis (Table 2).22,23 Systemic antibiotics decreased clinically or microbiologically documented infection and bacteremia (OR 0.28; 95%
Figure 5 Clinically or microbiologically documented infection: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. Borderline heterogeneity was found (P Z 0.051). When we excluded clinical trials on prophylaxis with intravenous vancomycin monotherapy, heterogeneity was not found (P Z 0.61). The odds ratio (OR) is presented with a 95percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Meta-analysis of antibiotic prophylaxis in HSCT
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Figure 6 Bacteremia: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. Heterogeneity was found (P Z 0.015). When we excluded clinical trials on prophylaxis with intravenous vancomycin monotherapy, heterogeneity was not found (P Z 0.42). The odds ratio (OR) is presented with a 95percent confidence interval (95%CI).
CI 0.11e0.71 and OR 0.38; 95%CI 0.16e0.94, respectively) without significantly affecting all-cause mortality (OR 0.61; 95%CI 0.11e3.50) (Table 4). Due to the small number of clinical trials evaluated, it was difficult to draw definitive conclusions from this comparison.
Addition of antibiotics for gram-positive bacteria Four clinical trials were included in this analysis (Table 2).24e27 The addition of antibiotics for grampositive bacteria to fluoroquinolones decreased the
Figure 7 Adverse events: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. The odds ratio (OR) is presented with a 95percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
0.69 (0.34; 1.39) 3 (206) 1.59 (0.71; 3.56) 1 (145) 0.30 (0.01; 7.88) 4 (290) 7.00 (0.36; 137.99) 1 (145)
OR, odds ratio; 95%CI, 95percent confidence interval; No., number; Pts, patients; NA, not assessed; FQs, fluoroquinolones; GPB, gram-positive bacteria; TMP-SMZ, trimethoprimsulfamethoxazole.
NA
0.38 (0.16; 0.94) 2 (109) 0.44 (0.24; 0.80) 4 (290) 0.61 (0.29; 1.30) 1 (145) NA
Systemic vs. non-absorbable FQs plus antibiotics for GPB vs. FQs FQs vs. TMP-SMZ
0.61(0.11; 3.50) 2 (109) 1.38 (0.41; 4.58) 4 (290) 2.00 (0.48; 8.31) 1 (145)
Not estimable
0.28 (0.11; 0.71) 2(109) 0.55 (0.30; 1.01) 4 (290) 0.88 (0.45; 1.75) 1 (145)
6.65 (2.15; 20.54) 4 (290) 1.62 (0.85; 3.1) 1 (163)
No. of studies (Pts) No. of studies (Pts) No. of studies (Pts) No. of studies (Pts)
No. of studies (Pts)
No. of studies (Pts)
OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)
Febrile episodes Infection-related mortality All-cause mortality Comparison
Table 4
Results of a meta-analysis of the comparison of two antibiotic regimens.
Clinically or microbiologically documented infection
Adverse events
S.-i. Kimura et al.
Bacteremia
10
incidence of bacteremia (OR 0.44; 95%CI 0.24e0.80) without affecting all-cause mortality, infection-related death or febrile episodes (OR 1.38; 95%CI 0.41e4.58 and OR 0.69; 95%CI 0.34e1.39, respectively) (Table 4). Clinically or microbiologically documented infections were reduced with a borderline significance (OR 0.55; 95%CI 0.30e1.01). There was a significant increase in adverse events in patients who received antibiotics for grampositive bacteria in addition to fluoroquinolones (OR 6.65; 95%CI 2.15e20.54). Adverse events included gastrointestinal complications, elevation of liver enzyme, C. difficile-associated diarrhea and rash.
Comparison of two different systemic antibiotic regimens Only one trial compared fluoroquinolones and trimethoprim-sulfamethoxazole (Table 2).28 Therefore, it was difficult to draw a conclusion from this analysis.
Discussion A 2005 meta-analysis of 95 clinical trials by Gafter-Gvili et al. showed that antibiotic prophylaxis significantly reduced not only febrile patients, clinically documented infection and microbiologically documented infection, but also all-cause mortality and infection-related mortality in chemotherapy-induced neutropenic patients.6 The strongest evidence was for oral fluoroquinolones.6,29 Among 17 clinical trials in their meta-analysis that compared fluoroquinolones with no prophylaxis,6 four included HSCT recipients.15,30e32 Most of the patients consisted of HSCT recipients in a trial reported by Lew et al.,15 which was also included in our study. However, the percentage of HSCT recipients was at most 10% in three other clinical trials.30e32 They updated their meta-analysis6 with two subsequent large randomized controlled trials33,34 and divided the trials according to the type of patient.35 In a subanalysis with 10 clinical trials that only included patients with acute leukemia and those who underwent HSCT, allcause mortality was decreased by 33% (95%CI 2e54%) by prophylaxis with fluoroquinolones. However, six of the 10 clinical trials did not include HSCT recipients.36e41 Two studies included only a few HSCT recipients.30,31 In two other clinical trials, the percentages of HSCT recipients among study patients were approximately 50%, in the study reported by Bucaneve et al.,33 and 10%, in that reported by Thomas et al.32 Overall, their updated meta-analysis also included a small number of HSCT recipients. In general, HSCT recipients experience not only neutropenia but also severe mucositis caused by conditioning regimens, which are considered to be major risk factors for infection during the early period after transplantation.5 Since the risk of bacterial infection is high, HSCT recipients are closely monitored and should receive empiric antibiotic therapy immediately after they develop fever during neutropenia. In addition, current guidelines recommend prophylaxis with fluoroquinolones, especially in allogeneic HSCT.5,7 However, prophylactic antibiotic therapy in HSCT has not been thoroughly evaluated, as we noted earlier. For the management of bacterial infection in HSCT,
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Meta-analysis of antibiotic prophylaxis in HSCT pre-emptive antibiotic therapy, in which prophylactic intravenous antibiotic therapy would be started at the onset of neutropenia, has also been investigated, and has shown variable results.19,42,43 Therefore, the effect of this strategy has not been clarified. The results of this study showed that systemic antibiotic prophylaxis successfully reduced the incidence of febrile episodes, clinically or microbiologically documented infection and bacteremia, without significantly affecting allcause mortality or infection-related mortality compared with no prophylaxis in HSCT patients. One possible reason for this lack of impact on mortality is that the number of studies was not sufficient to address this question. The incidence of mortality was not high even without prophylaxis, and therefore a large number of studies will be required to show that prophylaxis offers a clinical benefit on mortality. In addition, the prophylactic antibiotics used and the timing for the initiation of prophylaxis varied in each clinical trial. Since the mortality analysis included only three clinical trials with fluoroquinolone prophylaxis,15,20,21 the impact of prophylaxis with fluoroquinolones on mortality was inconclusive. However, no significant effect of fluoroquinolone prophylaxis on allcause mortality might suggest that there was actually no true effect on mortality in autologous HSCT recipients, who were less immunosuppressed than allogeneic HSCT recipients, since data regarding all-cause mortality were derived from two clinical trials, both of which were autologous HSCT recipients.20,21 In another point of view, when we excluded two clinical trials in which prophylactic antibiotics were started at the onset of neutropenia,13,19 systemic antibiotic prophylaxis tended to reduce all-cause mortality (OR 0.29, 95%CI 0.05e1.88). This might suggest that antibiotic prophylaxis should be started earlier, before neutropenia develops. Another possible explanation is that immediate empiric antibiotic treatment would cancel out the effect of an increase in bacterial infection on mortality. A delay in empiric antibiotic therapy could increase mortality.44 However, in the patients in this study, empiric antibiotics were considered to have been started immediately because all of the clinical trials in this meta-analysis were performed in an in-patient setting, with the exception of two trials in which the clinical setting was not mentioned.16,18 With regard to the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones, a metaanalysis that included nine clinical trials in patients with chemotherapy-induced neutropenia has been performed.45 According to this report, gram-positive prophylaxis reduced the incidences of bacteremia, streptococcal infections, coagulase-negative staphylococcal infections and febrile episodes. There was no significant effect on clinically documented infections and infection-related mortality. In addition, gram-positive prophylaxis significantly increased side effects. All four of the clinical trials in this meta-analysis on the use of additional antibiotics for gram-positive bacteria24e27 were also included in the previous metaanalysis. Although the included patients were restricted to HSCT recipients in this study, the results were similar. The addition of antibiotics for gram-positive bacteria to fluoroquinolones decreased the incidence of clinically or microbiologically documented infection, and bacteremia,
11 without affecting all-cause mortality, infection-related mortality or febrile episodes. There was a significant increase in adverse events in patients who received additional antibiotics for gram-positive bacteria. Therefore, since it offers no clear benefit with regard to morbidity and mortality, the routine use of gram-positive prophylaxis is not advisable even in HSCT recipients. It is difficult to discuss the comparison of systemic antibiotic prophylaxis and non-absorbable antibiotics because only two clinical trials were included in this meta-analysis.22,23 In addition, it was also difficult to compare different prophylactic regimens because only one clinical trial compared fluoroquinolones and trimethoprim-sulfamethoxazole.28 Another important issue when we consider prophylactic strategy is antibiotic resistance. Some experts have raised an alarm over the emergence of resistant bacteria46e48 or C. difficile infection49,50 as a result of the expansive use of fluoroquinolones. However, this subject is beyond the scope of this study because it included only a small number of clinical trials that evaluated antibiotic resistance. In conclusion, systemic antibiotic prophylaxis successfully reduced the incidence of infection in HSCT recipients. However, it did not have a significant impact on mortality in this study. This lack of an effect on mortality should be interpreted with caution because the statistical power of the study might be insufficient and the prophylactic antibiotics used and the timing at which prophylaxis was started varied in each clinical trial. In addition, the clinical benefits of prophylaxis with fluoroquinolones in HSCT recipients were inconclusive because of the small number of trials evaluated.
Funding No specific funding was received for this study.
Conflict of interest We have no conflict of interest for this study.
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12 5. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transpl 2009;15(10): 1143e238. 6. Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142(12 Pt 1):979e95. 7. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52(4):e56e93. 8. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. 9. Gafter-Gvili A, Fraser A, Paul M, Vidal L, Lawrie TA, van de Wetering MD, et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev 2012;1:CD004386. 10. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. 11. Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transpl 2013; 48(3):452e8. 12. Huizenga HM, Visser I, Dolan CV. Testing overall and moderator effects in random effects meta-regression. Br J Math Stat Psychol 2011;64(Pt 1):1e19. 13. Petersen FB, Buckner CD, Clift RA, Lee S, Nelson N, Counts GW, et al. Laminar air flow isolation and decontamination: a prospective randomized study of the effects of prophylactic systemic antibiotics in bone marrow transplant patients. Infection 1986;14(3):115e21. 14. Attal M, Schlaifer D, Rubie H, Huguet F, Charlet JP, Bloom E, et al. Prevention of gram-positive infections after bone marrow transplantation by systemic vancomycin: a prospective, randomized trial. J Clin Oncol 1991;9(5):865e70. 15. Lew MA, Kehoe K, Ritz J, Antman KH, Nadler L, Takvorian T, et al. Prophylaxis of bacterial infections with ciprofloxacin in patients undergoing bone marrow transplantation. Transplantation 1991;51(3):630e6. 16. Patric CC, Adair JR, Warner Jr WC, Church DA, Sanders RH, Krance R, et al. Safety of ciprofloxacin as a prophylactic agent for prevention of bacterial infection in pediatric bone marrow transplant (BMT) patients. In: 35th Interscience Conference on antimicrobial agents and chemotherapy; 1995. San Francisco.LM17. 17. Teinturier C, Hartmann O, Lemerle J, Benhamou E, Maraninchi D. Prevention of gram-positive infections in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomized controlled trial of vancomycin. Pediatr Hematol Oncol 1995;12(1):73e7. 18. Ruiz I, Fuentes I, Capdevila JA, Juli A, Carreras J, Pahissa A, et al. Ofloxacin prophylaxis in preventing bacterial infection after autologous peripheral blood stem cell transplantation (A-PBSC). In: 41st Interscience Conference on antimicrobial agents and chemotherapy; 2001. Chicago.L-781. 19. Slavin MA, Grigg AP, Schwarer AP, Szer J, Spencer A, Sainani A, et al. A randomized comparison of empiric or pre-emptive antibiotic therapy after hematopoietic stem cell transplantation. Bone Marrow Transpl 2007;40(2):157e63. 20. Eleutherakis-Papaiakovou E, Kostis E, Migkou M, Christoulas D, Terpos E, Gavriatopoulou M, et al. Prophylactic antibiotics for the prevention of neutropenic fever in patients undergoing autologous stem-cell transplantation: results of a single institution, randomized phase 2 trial. Am J Hematol 2010;85(11): 863e7.
S.-i. Kimura et al. 21. Vehreschild JJ, Moritz G, Vehreschild MJ, Arenz D, Mahne M, Bredenfeld H, et al. Efficacy and safety of moxifloxacin as antibacterial prophylaxis for patients receiving autologous haematopoietic stem cell transplantation: a randomised trial. Int J Antimicrob Agents 2012;39(2):130e4. 22. Gluckman E, Cavazzana M, Devergie A, Meletis J, Arlet G, Perol Y, et al. Prevention of bacterial infections after bone marrow graft by broad-spectrum oral antibiotics, absorbable (pefloxacin, penicillin) and non absorbable (cephalosporin, gentamycin, bacitracin). Pathol Biol Paris 1988;36(7): 902e6. 23. Gluckman E, Roudet C, Hirsch I, Devergie A, Bourdeau H, Arlet C, et al. Prophylaxis of bacterial infections after bone marrow transplantation. A randomized prospective study comparing oral broad-spectrum nonabsorbable antibiotics (vancomycin-tobramycin-colistin) to absorbable antibiotics (ofloxacin-amoxicillin). Chemotherapy 1991;37(Suppl. 1): 33e8. 24. Broun ER, Wheat JL, Kneebone PH, Sundblad K, Hromas RA, Tricot G. Randomized trial of the addition of gram-positive prophylaxis to standard antimicrobial prophylaxis for patients undergoing autologous bone marrow transplantation. Antimicrob Agents Chemother 1994;38(3):576e9. 25. Hidalgo M, Hornedo J, Lumbreras C, Trigo JM, Gomez C, Perea S, et al. Lack of ability of ciprofloxacin-rifampin prophylaxis to decrease infection-related morbidity in neutropenic patients given cytotoxic therapy and peripheral blood stem cell transplants. Antimicrob Agents Chemother 1997; 41(5):1175e7. 26. Ford CD, Reilly W, Wood J, Classen DC, Burke JP. Oral antimicrobial prophylaxis in bone marrow transplant recipients: randomized trial of ciprofloxacin versus ciprofloxacin-vancomycin. Antimicrob Agents Chemother 1998;42(6):1402e5. 27. Gomez-Martin C, Sola C, Hornedo J, Perea S, Lumbreras C, Valenti V, et al. Rifampin does not improve the efficacy of quinolone antibacterial prophylaxis in neutropenic cancer patients: results of a randomized clinical trial. J Clin Oncol 2000;18(10):2126e34. 28. Lew MA, Kehoe K, Ritz J, Antman KH, Nadler L, Kalish LA, et al. Ciprofloxacin versus trimethoprim/sulfamethoxazole for prophylaxis of bacterial infections in bone marrow transplant recipients: a randomized, controlled trial. J Clin Oncol 1995;13(1):239e50. 29. Imran H, Tleyjeh IM, Arndt CA, Baddour LM, Erwin PJ, Tsigrelis C, et al. Fluoroquinolone prophylaxis in patients with neutropenia: a meta-analysis of randomized placebocontrolled trials. Eur J Clin Microbiol Infect Dis 2008;27(1): 53e63. 30. Karp JE, Merz WG, Hendricksen C, Laughon B, Redden T, Bamberger BJ, et al. Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1987;106(1):1e7. 31. Sampi K, Maseki N, Hattori M. A comparison of nystatin with norfloxacin for prevention of infection after consolidation therapy in patients with acute leukemia or autologous bone marrow transplantation: a randomized study. Gan To Kagaku Ryoho 1992;19(6):823e6. 32. Thomas X, Troncy J, Belhabri A, Thiebaut A, Bouheddou N, Michallet M, et al. Effectiveness of combined vancomycin and pefloxacine in gastrointestinal decontamination for preventing infections after chemotherapy-induced bone marrow aplasia. A randomized double-blind study. Presse Med 2000; 29(32):1745e51. 33. Bucaneve G, Micozzi A, Menichetti F, Martino P, Dionisi MS, Martinelli G, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2005; 353(10):977e87.
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Meta-analysis of antibiotic prophylaxis in HSCT 34. Cullen M, Steven N, Billingham L, Gaunt C, Hastings M, Simmonds P, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353(10):988e98. 35. Leibovici L, Paul M, Cullen M, Bucaneve G, Gafter-Gvili A, Fraser A, et al. Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions. Cancer 2006;107(8): 1743e51. 36. Brodsky AL, Minissale CJ, Melero MJ, Sanchez Avalos JC. Prophylaxis with fluoroquinolones in patients with neutropenia. Medicina (B Aires) 1993;53(5):401e7. 37. Talbot GH, Cassileth PA, Paradiso L, Correa-Coronas R, Bond L. Oral enoxacin for infection prevention in adults with acute nonlymphocytic leukemia. The Enoxacin Prophylaxis Study Group. Antimicrob Agents Chemother 1993; 37(3):474e82. 38. Yamada T, Dan K, Nomura T. Prevention of bacterial and fungal infections in acute leukemia patients: a new and potent combination of oral norfloxacin and amphotericin B. Intern Med 1993;32(9):710e5. 39. Moreau P, Milplied N, Richard P, Bulbois CE, Richet H, Harousseau JL. Prospective randomized study comparing prophylactic ciprofloxacine(C) and amoxicillinþclavulanic acid (A-CA) vs prophylactic vancomycin (V) vs non prophylactic conventional empiric antimicrobial therapy in neutropenic patients. Bone Marrow Transpl 1995;15:S129 [Abstract]. 40. Nenova IS, Ananostev NH, Goranov SE, Mateva NG, Haidushka IA. Fluoroquinolone prophylaxis for bacterial infections in neutropenic patients with hematologic malignancies. Folia Med Plovdiv 2001;43(4):40e5. 41. Lee DG, Choi SM, Choi JH, Yoo JH, Park YH, Kim YJ, et al. Selective bowel decontamination for the prevention of infection in acute myelogenous leukemia: a prospective randomized trial. Korean J Intern Med 2002; 17(1):38e44. 42. Perez-Simon JA, Garcia-Escobar I, Martinez J, Vazquez L, Caballero D, Canizo C, et al. Antibiotic prophylaxis with
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meropenem after allogeneic stem cell transplantation. Bone Marrow Transpl 2004;33(2):183e7. Hamadah A, Schreiber Y, Toye B, McDiarmid S, Huebsch L, Bredeson C, et al. The use of intravenous antibiotics at the onset of neutropenia in patients receiving outpatient-based hematopoietic stem cell transplants. PLoS One 2012;7(9): e46220. Bodey GP, Jadeja L, Elting L. Pseudomonas bacteremia. Retrospective analysis of 410 episodes. Arch Intern Med 1985;145(9):1621e9. Cruciani M, Rampazzo R, Malena M, Lazzarini L, Todeschini G, Messori A, et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996;23(4):795e805. Kern WV, Klose K, Jellen-Ritter AS, Oethinger M, Bohnert J, Kern P, et al. Fluoroquinolone resistance of Escherichia coli at a cancer center: epidemiologic evolution and effects of discontinuing prophylactic fluoroquinolone use in neutropenic patients with leukemia. Eur J Clin Microbiol Infect Dis 2005; 24(2):111e8. Rangaraj G, Granwehr BP, Jiang Y, Hachem R, Raad I. Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug-resistant organisms. Cancer 2010; 116(4):967e73. Bow EJ. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis 2011;24(6): 545e53. Pepin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41(9):1254e60. Muto CA, Pokrywka M, Shutt K, Mendelsohn AB, Nouri K, Posey K, et al. A large outbreak of Clostridium difficileassociated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 2005; 26(3):273e80.
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www.elsevierhealth.com/journals/jinf
REVIEW
Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials. Shun-ichi Kimura, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Hideki Nakasone, Misato Kikuchi, Rie Yamazaki, Shinichi Kako, Junya Kanda, Aki Tanihara, Junji Nishida, Yoshinobu Kanda* Division of Hematology, Saitama Medical Center, Jichi Medical University, Japan Accepted 18 February 2014 Available online - - -
KEYWORDS Meta-analysis; Antibiotic prophylaxis; Hematopoietic stem cell transplantation; Fluoroquinolones
Summary Objectives: We performed a meta-analysis to evaluate the impact of systemic antibiotic prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients. Methods: We collected reports from PubMed, the Cochrane Library, EMBASE, CINAHL, and Web of Science, along with references cited therein. We included prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients. Results: Seventeen trials with 1453 autologous and allogeneic HSCT recipients were included. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotics in two trials. Systemic antibiotics other than fluoroquinolones were evaluated in five of these 12 trials. Four trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones. One trial compared two different systemic antibiotic regimens: fluoroquinolones versus trimethoprim-sulfamethoxazole. As a result, systemic antibiotic prophylaxis reduced the incidence of febrile episodes (OR 0.16; 95%CI 0.09e0.30), clinically or microbiologically documented infection (OR 0.38; 95%CI 0.22e0.63) and bacteremia (OR 0.31; 95%CI 0.16e0.59) without significantly affecting allcause mortality or infection-related mortality.
* Corresponding author. Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya-ku, Saitamacity, Saitama 330-8503, Japan. Tel.: þ81 48 647 2111x5416; fax: þ81 48 644 5166. E-mail address: [email protected] (Y. Kanda). 0163-4453/$36 ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2014.02.013 Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
2
S.-i. Kimura et al. Conclusions: Systemic antibiotic prophylaxis successfully reduced the incidence of infection. However, there was no significant impact on mortality. The clinical benefits of prophylaxis with fluoroquinolones were inconclusive because of the small number of clinical trials evaluated. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Bacterial infection remains the major cause of morbidity and mortality in the early period after hematopoietic stem cell transplantation (HSCT).1,2 Fever during neutropenia occurs in >90% and 80% of allogeneic and autologous HSCT recipients, respectively.3,4 During the neutropenic period before engraftment, HSCT recipients have two critical risk factors for infection: prolonged severe neutropenia and breaks in the mucocutaneous barrier resulting from conditioning regimens.5 Based on evidence that antibiotic prophylaxis improves the clinical outcome, including the incidences of documented infections and all-cause mortality in patients with chemotherapyinduced neutropenia,6 current guidelines recommend prophylaxis with fluoroquinolones in high-risk patients who are expected to show prolonged and profound neutropenia, such as acute leukemia patients undergoing chemotherapy and HSCT recipients.5,7 However, prophylactic antibiotic therapy has not been thoroughly evaluated in HSCT recipients. Therefore, we performed a metaanalysis to evaluate the impact of systemic antibiotic prophylaxis in HSCT recipients.
Materials and methods Data sources Studies were collected from PubMed, the Cochrane Library, EMBASE, CINAHL, and Web of Science, and included references cited therein. The last search was performed in November 2013. The identified studies were not restricted to those written in English or to published trials. The search terms #1 (antibiotic OR anti-bacterial OR antibacterial agent OR antibacterial OR antibacterial agent OR antibacterial drug OR antibacterials OR antibiotics OR antimicrobial OR antimicrobial agent OR antimicrobials OR antimicrobic OR antimicrobics), #2 (prophylaxis OR prevention OR protection OR pre-emptive), #3 (neutropenia OR neutropaenia OR granulocytopenia OR granulocytopaenia OR agranulocytosis), #4 (stem cell transplantation OR hematopoietic stem cell transplantation OR bone marrow transplantation OR peripheral blood stem cell transplantation) and #5 (autologous OR allogeneic) were crossed as #1 AND #2 AND (#3 OR #4 OR #5).
Study selection A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.8 We included all prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients, which compared either
systemic antibiotic prophylaxis with placebo, no intervention or non-absorbable antibiotics, or two different systemic antibiotic regimens.
Outcome measures Seven outcome measures were used. The primary outcome measure was all-cause mortality at the end of follow-up in each study. The secondary outcome measures were infection-related mortality, febrile episodes, incidence of clinically or microbiologically documented infection, bacteremia, related adverse events and emergence of resistant bacteria. Clinically documented infection was defined as the presence of symptoms or signs of inflammation at an anatomic site irrespective of whether pathogens were recovered from the affected site or not.9 Microbiologically documented infection was defined as the presence of symptoms or signs of inflammation at an anatomic site where pathogens were recovered from the affected site. Bacteremia was also included in microbiologically documented infection.
Data extraction and assessment of quality Two reviewers independently extracted data from each report. Any discrepancies were resolved between the two reviewers by discussion. We assessed the included clinical trials for methodological quality using the Cochrane Collaboration’s risk of bias assessment tool.10 The assessed components included random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), incomplete outcome data (attrition bias) and selective reporting (reporting bias).
Statistical analyses The summarized odds ratios (ORs) were calculated using the ManteleHaenszel (fixed-effect) method and the DerSimonianeLaird (random-effect) method. We used a fixed-effect model for pooling trial results throughout the review because it works well in analyses with a low number of events. However, we chose a random-effect model when heterogeneity was found. We assessed publication bias using a funnel plot. We assessed heterogeneity by a Chi square test of homogeneity and I2 measure of inconsistency. Sensitivity was determined by recalculating the results after dropping a subset of the studies. We assessed the effect of the difference between allogeneic and autologous HSCT on each outcome measure by meta-regression with the percentage of allogeneic HSCT recipients in each study. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Accessed 1 March 2013, at http://www.
Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Meta-analysis of antibiotic prophylaxis in HSCT jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html), which is a graphical user interface for R (The R Foundation for Statistical Computing, version 2.13.0).11 More precisely, it is a modified version of R commander (version 1.6e3) that was designed to add statistical functions that are frequently used in biostatistics. It uses a “meta” package for meta-analysis and “metatest” package for meta-regression analysis.12
Results Clinical trials Fig. 1 shows a flow diagram of the publications identified for the study and exclusions. Seventeen trials with 1453 patients (842 autologous and 407 allogeneic HSCT recipients) were included.4,13e28 The numbers of autologous and allogeneic HSCT recipients were not specified in two trials.16,17 One clinical trial was published in French.22 Since two clinical trials were unpublished, we extracted data from meeting abstracts.16,18 Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials4,13e21 and with nonabsorbable antibiotic in 2 trials22,23 (Tables 1and 2). There were four randomized placebo-controlled clinical trials.15,16,18,21 Systemic antibiotics other than fluoroquinolones were evaluated in five of these 12 trials.4,13,14,17,19 In the study reported by Petersen et al., the effect of systemic antibiotic prophylaxis was investigated in the setting
3 that all patients also received non-absorbable antibiotics.13 Prophylaxis with intravenous vancomycin monotherapy was evaluated in two trials.14,17 In two clinical trials, prophylactic antibiotics were started at the onset of neutropenia.13,19 Since 25 of 26 enrolled patients in the study reported by Lew et al. received HSCT, we considered it to be a clinical trial for HSCT recipients and included it in this meta-analysis.15 A significant publication bias was detected in clinical trials for the evaluation of infectionrelated mortality (P Z 0.042). At least borderline heterogeneity was found in clinical trials for the evaluation for clinically or microbiologically documented infection and bacteremia (P Z 0.051, P Z 0.015, respectively). When we excluded clinical trials on prophylaxis with intravenous vancomycin monotherapy, heterogeneity was not found (P Z 0.61, P Z 0.42, respectively). Four clinical trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones (Table 2).24e27 The additional antibiotics for gram-positive bacteria were rifampicin in two trials,25,27 penicillin G in one trial24 and oral vancomycin in one trial.26 One clinical trial compared two different systemic antibiotic regimens: fluoroquinolones versus trimethoprim-sulfamethoxazole (Table 2).28 Table 3 shows an assessment of the quality of the included clinical trials. The random sequence generation and the allocation concealment were low risk of bias in seven (41%) clinical trials.14,19e21,26e28 The blinding of participants and personnel was low risk of bias in five (29%) clinical
Figure 1 Flow diagram of the publications identified for study and exclusions. Seventeen trials were included. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotic in two trials. Four trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones (FQs). One trial compared FQs to trimethoprim-sulfamethoxazole (TMP-SMZ). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
4
Included trials that compared prophylactic systemic antibiotics to no prophylaxis or placebo.
Study name (Year)
No. of pts (SCT pts)
Auto SCT
Allo SCT
Age, year (Range)
Underlying diseases
Intervention (No. of pts)
Control (No. of pts)
Beginning of prophylaxis
End of prophylaxis
Outcome measures
Petersen et al. (1986)1
122 (122)
0
122
Hematological malignancies
ANC 500
60 (60)
23
37
iv VCM, iv TOB, ticarcillin, oral non-absorbable antibiotics (54) iv VCM (30)
Oral nonabsorbable antibiotics (68)
Attal et al. (1991)2
Median intervention 20 control 23 (3e49) Mean 33 (1e65)
No prophylaxis (30)
2 days before BMT
ANC >500 or fever
Lew et al. (1991)3
18 (17)
14
3
Median intervention 41 control 39 (26e54)
Hematological or solid tumors
CPFX (7)
Placebo (11)
Conditioning
ANC >500
Avril et al. (1994)4
60 (60)
59
1
Solid tumors
CAZ, TEIC (30)
No prophylaxis (30)
Day 4 of the conditioning
Neutropenia resolution
Patric et al. (1995)5
48 (48)
NA
NA
Mean intervention 6.9 Control 5.7 (2e16) Median 11
All-cause mortality, infection-related mortality, fever, DI, bacteremia All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E, resistant bacteria Fever, DI, bacteremia, A/E
Leukemia or solid tumors
CPFX (23)
Placebo (25)
10 days before BMT
ANC >500 or fever
Teinturier et al. (1995)6 Ruiz et al. (2001)7
155 (155) 50 (50)
NA
NA 0
Hematological or solid tumors Oncohematological patients
iv VCM (75)
50
No prophylaxis (80) Placebo (50)
5 days before BMT 5 days before SCT
Slavin et al. (2007)8
151 (151)
72
79
73 children & 82 adults Mean intervention 45.7 control 44 NA
Hematological or solid tumors
CFPM (75)
No prophylaxis (76)
ANC ＜1000
1 day after BMT Neutropenia resolution or empirical antibiotics Neutropenia resolution
Papaiakovou et al. (2010)9
157 (157)
157
0
NA
Hematological or solid tumors
CPFX, VCM (61)
No prophylaxis (65)
Day 0 of PBSCT
Neutropenia resolution or fever
Vehreschild et al. (2012)10
66 (66)
66
0
Median intervention 54 control 50 (18e75)
Hematological or solid tumors
MOFX (34)
Placebo (32)
Conditioning
ANC >500 or fever
Hematological malignancies
OFLX (50)
Infection-related mortality, fever, DI, bacteremia Fever, DI, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E
No., number; Pts, patients; SCT, stem cell transplantation; Auto, autologous; Allo, allogeneic; iv, intravenous; VCM, vancomycin; TOB, tobramycin; ANC, absolute neutrophil count; DI, documented infection; BMT, bone marrow transplantation; A/E, adverse event; CPFX, ciprofloxacin; CAZ, ceftazidime; TEIC, teicoplanin; NA, not assessed; OFLX, ofloxacin; CFPM, cefepime; PBSCT, peripheral blood stem cell transplantation; MOFX, moxifloxacin.
S.-i. Kimura et al.
Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Table 1
Included trials that compared two antibiotic regimens.
Study name (Year)
No.of pts (SCT pts)
Auto
Allo
Age
Systemic antibiotics versus non-absorbable antibiotics 65 (65) 0 65 Mean 20 Gluckman (6e38) et al. (1988)11
Gluckman et al. (1991)12
44 (44)
0
44
Mean 33.2 (11e54)
Underlying diseases
Intervention (No. of pts)
Control (No. of pts)
Beginning of prophylaxis
End of prophylaxis
Outcome measures
Hematological diseases
Pefloxacin, penicillin (32)
Oral cephalotin, oral GM (33)
8 days before BMT
15 days after BMT
Hematological diseases
OFLX, AMPC, (22)
Oral VCM, oral TOB, oral colistin (22)
10 days before BMT
15 days after BMT
All-cause mortality, infection-related mortality, DI, resistant bacteria All-cause mortality, infection-related mortality, DI, A/E
NOFX (21)
7 days before BMT
ANC >500
CPFX (20)
2 days before BMT
ANC >500 or fever
Fluoroquinolones plus antibiotics for gram-positive bacteria versus only fluoroquinolones 43 (43) 43 0 Median Hematological NOFX, PCG Broun intervention or solid tumors (22) et al. (1994)13 36 control 37 (20e52) 40 (40) 40 0 Mean Lymphoma or CPFX, RFP Hidalgo intervention solid tumors (20) et al. (1997)14 36 control 40.2 Ford et al. (1998)15
84 (84)
52
32
123 (123)
123
0
NA
Mean intervention 42.9 control 40.8 Fluoroquinolone versus trimethoprim-sulfametoxazole 167 (167) 143 24 Median 41 Lew et al. (18e64) (1995)17 Gomez-Martin et al. (2000)16
Hematological or solid tumors
CPFX, oral VCM (43)
CPFX (41)
Admission
ANC >500 or use of systemic antibiotics
Lymphoma or solid tumors
CPFX, RFP (61)
CPFX (62)
2 days before BMT
ANC >500 or fever
Hematological or solid tumors
CPFX (82)
TMP-SMZ (85)
More than 3 days before conditioning
ANC >400 or fever
All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E, resistant bacteria All-cause mortality, infection-related mortality, DI, bacteremia Infection-related mortality, fever, DI, bacteremia, A/E
Meta-analysis of antibiotic prophylaxis in HSCT
All-cause mortality, infection-related mortality, fever, DI, bacteremia, A/E, resistant bacteria
No., number; Pts, patients; SCT, stem cell transplantation; Auto, autologous; Allo, allogeneic; GM, gentamicin; BMT, bone marrow transplantation; DI, documented infection; OFLX, ofloxacin; AMPC, amoxicillin; VCM, vancomycin; TOB, tobramycin; A/E, adverse event; NOFX, norfloxacin; PCG, penicillin G; ANC, absolute neutrophil count; CPFX, ciprofloxacin; RFP, rifampicin, NA, not assessed; TMP-SMZ, trimethoprim-sulphamethoxazole.
5
Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Table 2
6
S.-i. Kimura et al. Table 3
Assessment of the quality of included trials.
Study name (Year)
Random sequence generation (Selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Petersen et al. (1986)1 Attal et al. (1991)2 Lew et al. (1991)3 Avril et al. (1994)4 Patric et al. (1995)5 Teinturier et al. (1995)6 Ruiz et al. (2001)7 Slavin et al. (2007)8 Papaiakovou et al. (2010)9 Vehreschild et al. (2012)10 Gluckman et al. (1988)11 Gluckman et al. (1991)12 Broun et al. (1994)13 Hidalgo et al. (1997)14 Ford et al. (1998)15 Gomez-Martin et al. (2000)16 Lew et al. (1995)17
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk
Unclear risk Unclear risk Low risk Unclear risk Low risk Unclear risk Low risk Unclear risk Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Low risk Low risk Unclear risk Unclear risk Low risk Unclear risk Unclear risk
Unclear risk Low risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk Low risk Unclear risk Unclear risk Low risk Unclear risk Unclear risk
trials.15,16,18,21,28 Incomplete outcome data was low risk of bias in seven (41%) clinical trials.14,19e23,26 Selective reporting was low risk of bias in six (35%) clinical trials.14,20e23,26 Since only four clinical trials fully evaluated the emergence of resistant bacteria,15,22,25,28 we could not perform a meta-analysis on this issue. In a clinical trial which compared ciprofloxacin and placebo, colonization of ciprofloxacin-resistant organisms was observed five of seven patients in ciprofloxacin group and one of 11 patients in placebo group, respectively.15 Most of the organisms in the former group were yeasts including Candida albicans, C.
tropicalis, Saccharomyces cerevisiae, and not identified yeast recovered from stool, while only one patient acquired bacteria colonization of Streptococcus viridans recovered from the orophyarynx. One placebo recipients acquired colonization of Geotrichum capitatum, recovered from orophyarynx and diphtheroides in the stool. In another clinical trial of 65 allogeneic stem cell transplantation recipients which compared pefloxacin plus penicillin with nonabsorbable antibiotics, five of 32 pefloxacin plus penicillin patients and eight of 33 non-absorbable antibiotic patients developed microbiologically documented infection.22
Figure 2 All-cause mortality: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. The odds ratio (OR) is presented with a 95 percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Meta-analysis of antibiotic prophylaxis in HSCT
7
Figure 3 Infection-related mortality: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. All three fluoroquinolone-based trials were excluded from the analysis, since there were no events in either group in these trials. The odds ratio (OR) is presented with a 95percent confidence interval (95%CI).
Among these episodes, one Pseudomonas bacteremia resistant to pefloxacin was observed in pefloxacin plus penicillin group. In the other clinical trial which compared ciprofloxacin alone with ciprofloxacin and rifampicin in 40 autologous stem cell transplantation recipients,25 five episodes of bacteremia in the former group (four infections with coagulase-negative staphylococci and one with viridans streptococcus) were observed. All these strains were susceptible to rifampicin, and all but one were resistant to ciprofloxacin. Two patients in the latter group developed
bacteremia due to Enterobacter cloacae and Pseudomonas aerginosa. Both of the patients were complaint with the prophylactic regimen and the isolates were susceptible to ciprofloxacin. In the fourth clinical trial which compared ciprofloxacin and trimethoprim-sulphamethoxazole, 51 of 80 ciprofloxacin patients and 43 of 83 trimethoprimsulphamethoxazole patients acquired colonization of ciprofloxacin-resistant organisms.28 The leading organism was streptococci, especially viridans streptococcus, followed by yeasts, mostly Candida.
Figure 4 Febrile episodes: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and the other trials is shown. The odds ratio (OR) is presented with a 95percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
8
Systemic antibiotic prophylaxis versus no prophylaxis or placebo Systemic antibiotic prophylaxis significantly reduced the incidence of febrile episodes (OR 0.16; 95 percent confidence interval [CI], 0.09e0.30), clinically or microbiologically documented infection (OR 0.38; 95%CI 0.22e0.63) and bacteremia (OR 0.31; 95%CI 0.16e0.59), but had no significant effect on all-cause mortality or infection-related mortality (OR 0.89; 95%CI 0.48e1.66, OR 1.37; 95%CI 0.50e3.76, respectively) (Figs. 1e6). When we only considered clinical trials with fluoroquinolones, prophylactic antibiotics also significantly reduced febrile episodes (OR 0.14; 95%CI 0.07e0.32), clinically or microbiologically documented infection (OR 0.31; 95%CI 0.17e0.56) and bacteremia (OR 0.18; 95%CI 0.09e0.36) (Figs. 4e6). The impact of prophylaxis with fluoroquinolones on mortality was inconclusive because of the small number of clinical trials evaluated (Figs. 2 and 3). Patients with systemic antibiotic prophylaxis had a greater incidence of adverse events compared to controls (OR 3.32; 95%CI 1.45e7.63) (Fig. 7). Adverse events included rash, gastrointestinal complications, elevation of liver enzyme, renal toxicity, Clostridium difficile-associated diarrhea, QT prolongation, fever, abnormal prothrombin time, insomnia, and joint pain. Renal toxicity was observed in the clinical trial with prophylactic intravenous vancomycin monotherapy.14 We could not perform subgroup analysis in allogeneic and autologous HSCT separately, because one third of clinical trials included both allogeneic and autologous HSCT recipients together. Therefore, we used meta-
S.-i. Kimura et al. regression to evaluate the difference in the impact of allogeneic and autologous HSCT. In a meta-regression, the percentage of allogeneic HSCT recipients was not associated with outcome measures (data not shown). Sensitivity was determined by recalculating the results after dropping specific clinical trials. We recalculated each outcome measure after excluding clinical trials on prophylaxis with intravenous vancomycin monotherapy,14,17 a clinical trial in which prophylactic non-absorbable antibiotics were administered in both groups,13 a clinical trial that included one non-HSCT patient,15 clinical trials in which prophylactic antibiotics were started at the onset of neutropenia,13,19 non-blinded clinical trials,4,13,14,17,19,20 and unpublished clinical trials.16,18 When we excluded two clinical trials in which prophylactic antibiotics were started at the onset of neutropenia,13,19 the OR of all-cause mortality for systemic antibiotic prophylaxis changed from 0.89 (95%CI 0.48e1.66) to 0.29 (95%CI 0.05e1.88), which, while not statistically significant, showed a tendency toward less mortality with systemic antibiotic prophylaxis, although there was no change in the OR of infection-related mortality; OR 1.37 (95%CI 0.50e3.76) to 1.66 (95%CI 0.43e6.48). Otherwise, there was no dramatic change in the OR in a sensitivity analysis.
Systemic antibiotics versus non-absorbable antibiotics Only two clinical trials compared systemic antibiotics to non-absorbable antibiotics in this analysis (Table 2).22,23 Systemic antibiotics decreased clinically or microbiologically documented infection and bacteremia (OR 0.28; 95%
Figure 5 Clinically or microbiologically documented infection: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. Borderline heterogeneity was found (P Z 0.051). When we excluded clinical trials on prophylaxis with intravenous vancomycin monotherapy, heterogeneity was not found (P Z 0.61). The odds ratio (OR) is presented with a 95percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Meta-analysis of antibiotic prophylaxis in HSCT
9
Figure 6 Bacteremia: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. Heterogeneity was found (P Z 0.015). When we excluded clinical trials on prophylaxis with intravenous vancomycin monotherapy, heterogeneity was not found (P Z 0.42). The odds ratio (OR) is presented with a 95percent confidence interval (95%CI).
CI 0.11e0.71 and OR 0.38; 95%CI 0.16e0.94, respectively) without significantly affecting all-cause mortality (OR 0.61; 95%CI 0.11e3.50) (Table 4). Due to the small number of clinical trials evaluated, it was difficult to draw definitive conclusions from this comparison.
Addition of antibiotics for gram-positive bacteria Four clinical trials were included in this analysis (Table 2).24e27 The addition of antibiotics for grampositive bacteria to fluoroquinolones decreased the
Figure 7 Adverse events: systemic antibiotic prophylaxis versus no prophylaxis or placebo. A forest plot grouped into fluoroquinolone-based trials and other trials is shown. The odds ratio (OR) is presented with a 95percent confidence interval (95%CI). Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
0.69 (0.34; 1.39) 3 (206) 1.59 (0.71; 3.56) 1 (145) 0.30 (0.01; 7.88) 4 (290) 7.00 (0.36; 137.99) 1 (145)
OR, odds ratio; 95%CI, 95percent confidence interval; No., number; Pts, patients; NA, not assessed; FQs, fluoroquinolones; GPB, gram-positive bacteria; TMP-SMZ, trimethoprimsulfamethoxazole.
NA
0.38 (0.16; 0.94) 2 (109) 0.44 (0.24; 0.80) 4 (290) 0.61 (0.29; 1.30) 1 (145) NA
Systemic vs. non-absorbable FQs plus antibiotics for GPB vs. FQs FQs vs. TMP-SMZ
0.61(0.11; 3.50) 2 (109) 1.38 (0.41; 4.58) 4 (290) 2.00 (0.48; 8.31) 1 (145)
Not estimable
0.28 (0.11; 0.71) 2(109) 0.55 (0.30; 1.01) 4 (290) 0.88 (0.45; 1.75) 1 (145)
6.65 (2.15; 20.54) 4 (290) 1.62 (0.85; 3.1) 1 (163)
No. of studies (Pts) No. of studies (Pts) No. of studies (Pts) No. of studies (Pts)
No. of studies (Pts)
No. of studies (Pts)
OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)
Febrile episodes Infection-related mortality All-cause mortality Comparison
Table 4
Results of a meta-analysis of the comparison of two antibiotic regimens.
Clinically or microbiologically documented infection
Adverse events
S.-i. Kimura et al.
Bacteremia
10
incidence of bacteremia (OR 0.44; 95%CI 0.24e0.80) without affecting all-cause mortality, infection-related death or febrile episodes (OR 1.38; 95%CI 0.41e4.58 and OR 0.69; 95%CI 0.34e1.39, respectively) (Table 4). Clinically or microbiologically documented infections were reduced with a borderline significance (OR 0.55; 95%CI 0.30e1.01). There was a significant increase in adverse events in patients who received antibiotics for grampositive bacteria in addition to fluoroquinolones (OR 6.65; 95%CI 2.15e20.54). Adverse events included gastrointestinal complications, elevation of liver enzyme, C. difficile-associated diarrhea and rash.
Comparison of two different systemic antibiotic regimens Only one trial compared fluoroquinolones and trimethoprim-sulfamethoxazole (Table 2).28 Therefore, it was difficult to draw a conclusion from this analysis.
Discussion A 2005 meta-analysis of 95 clinical trials by Gafter-Gvili et al. showed that antibiotic prophylaxis significantly reduced not only febrile patients, clinically documented infection and microbiologically documented infection, but also all-cause mortality and infection-related mortality in chemotherapy-induced neutropenic patients.6 The strongest evidence was for oral fluoroquinolones.6,29 Among 17 clinical trials in their meta-analysis that compared fluoroquinolones with no prophylaxis,6 four included HSCT recipients.15,30e32 Most of the patients consisted of HSCT recipients in a trial reported by Lew et al.,15 which was also included in our study. However, the percentage of HSCT recipients was at most 10% in three other clinical trials.30e32 They updated their meta-analysis6 with two subsequent large randomized controlled trials33,34 and divided the trials according to the type of patient.35 In a subanalysis with 10 clinical trials that only included patients with acute leukemia and those who underwent HSCT, allcause mortality was decreased by 33% (95%CI 2e54%) by prophylaxis with fluoroquinolones. However, six of the 10 clinical trials did not include HSCT recipients.36e41 Two studies included only a few HSCT recipients.30,31 In two other clinical trials, the percentages of HSCT recipients among study patients were approximately 50%, in the study reported by Bucaneve et al.,33 and 10%, in that reported by Thomas et al.32 Overall, their updated meta-analysis also included a small number of HSCT recipients. In general, HSCT recipients experience not only neutropenia but also severe mucositis caused by conditioning regimens, which are considered to be major risk factors for infection during the early period after transplantation.5 Since the risk of bacterial infection is high, HSCT recipients are closely monitored and should receive empiric antibiotic therapy immediately after they develop fever during neutropenia. In addition, current guidelines recommend prophylaxis with fluoroquinolones, especially in allogeneic HSCT.5,7 However, prophylactic antibiotic therapy in HSCT has not been thoroughly evaluated, as we noted earlier. For the management of bacterial infection in HSCT,
Please cite this article in press as: Kimura S-i, et al., Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials., J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.02.013
Meta-analysis of antibiotic prophylaxis in HSCT pre-emptive antibiotic therapy, in which prophylactic intravenous antibiotic therapy would be started at the onset of neutropenia, has also been investigated, and has shown variable results.19,42,43 Therefore, the effect of this strategy has not been clarified. The results of this study showed that systemic antibiotic prophylaxis successfully reduced the incidence of febrile episodes, clinically or microbiologically documented infection and bacteremia, without significantly affecting allcause mortality or infection-related mortality compared with no prophylaxis in HSCT patients. One possible reason for this lack of impact on mortality is that the number of studies was not sufficient to address this question. The incidence of mortality was not high even without prophylaxis, and therefore a large number of studies will be required to show that prophylaxis offers a clinical benefit on mortality. In addition, the prophylactic antibiotics used and the timing for the initiation of prophylaxis varied in each clinical trial. Since the mortality analysis included only three clinical trials with fluoroquinolone prophylaxis,15,20,21 the impact of prophylaxis with fluoroquinolones on mortality was inconclusive. However, no significant effect of fluoroquinolone prophylaxis on allcause mortality might suggest that there was actually no true effect on mortality in autologous HSCT recipients, who were less immunosuppressed than allogeneic HSCT recipients, since data regarding all-cause mortality were derived from two clinical trials, both of which were autologous HSCT recipients.20,21 In another point of view, when we excluded two clinical trials in which prophylactic antibiotics were started at the onset of neutropenia,13,19 systemic antibiotic prophylaxis tended to reduce all-cause mortality (OR 0.29, 95%CI 0.05e1.88). This might suggest that antibiotic prophylaxis should be started earlier, before neutropenia develops. Another possible explanation is that immediate empiric antibiotic treatment would cancel out the effect of an increase in bacterial infection on mortality. A delay in empiric antibiotic therapy could increase mortality.44 However, in the patients in this study, empiric antibiotics were considered to have been started immediately because all of the clinical trials in this meta-analysis were performed in an in-patient setting, with the exception of two trials in which the clinical setting was not mentioned.16,18 With regard to the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones, a metaanalysis that included nine clinical trials in patients with chemotherapy-induced neutropenia has been performed.45 According to this report, gram-positive prophylaxis reduced the incidences of bacteremia, streptococcal infections, coagulase-negative staphylococcal infections and febrile episodes. There was no significant effect on clinically documented infections and infection-related mortality. In addition, gram-positive prophylaxis significantly increased side effects. All four of the clinical trials in this meta-analysis on the use of additional antibiotics for gram-positive bacteria24e27 were also included in the previous metaanalysis. Although the included patients were restricted to HSCT recipients in this study, the results were similar. The addition of antibiotics for gram-positive bacteria to fluoroquinolones decreased the incidence of clinically or microbiologically documented infection, and bacteremia,
11 without affecting all-cause mortality, infection-related mortality or febrile episodes. There was a significant increase in adverse events in patients who received additional antibiotics for gram-positive bacteria. Therefore, since it offers no clear benefit with regard to morbidity and mortality, the routine use of gram-positive prophylaxis is not advisable even in HSCT recipients. It is difficult to discuss the comparison of systemic antibiotic prophylaxis and non-absorbable antibiotics because only two clinical trials were included in this meta-analysis.22,23 In addition, it was also difficult to compare different prophylactic regimens because only one clinical trial compared fluoroquinolones and trimethoprim-sulfamethoxazole.28 Another important issue when we consider prophylactic strategy is antibiotic resistance. Some experts have raised an alarm over the emergence of resistant bacteria46e48 or C. difficile infection49,50 as a result of the expansive use of fluoroquinolones. However, this subject is beyond the scope of this study because it included only a small number of clinical trials that evaluated antibiotic resistance. In conclusion, systemic antibiotic prophylaxis successfully reduced the incidence of infection in HSCT recipients. However, it did not have a significant impact on mortality in this study. This lack of an effect on mortality should be interpreted with caution because the statistical power of the study might be insufficient and the prophylactic antibiotics used and the timing at which prophylaxis was started varied in each clinical trial. In addition, the clinical benefits of prophylaxis with fluoroquinolones in HSCT recipients were inconclusive because of the small number of trials evaluated.
Funding No specific funding was received for this study.
Conflict of interest We have no conflict of interest for this study.
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