Pneumonia Prevention to Decrease Mortality in Intensive Care ...

M A J O R A R T I C L E

Pneumonia Prevention to Decrease Mortality inIntensive Care Unit: A Systematic Review andMeta-analysis

Antoine Roquilly,1 Emmanuel Marret,3 Edward Abraham,4 and Karim Asehnoune1,2

1Service d’Anesthésie Réanimation Hôtel-Dieu, Nantes University Hospital, 2UPRES EA3826, Faculty of Médecine of Nantes, and 3Department ofAnesthesiology and Critical Care, Tenon University Hospital, University Pierre et Marie Curie, Paris, France; and 4Wake Forest School of Medicine,Winston-Salem, North Carolina

(See the Editorial Commentary by Klompas on pages 76–8.)

Background. To determine the strategies of prevention of hospital-acquired pneumonia that reduce mortality inintensive care unit (ICU).

Methods. We followed PRISMA (Preferred Reported Items for Systemic Reviews and Meta-Analyses) guide-lines. We searched MEDLINE and the Cochrane Controlled Trials Register (through 10 June 2014) as well as refer-ence lists of articles. We included all randomized controlled trials conducted in critically ill adult patientshospitalized in ICUs and evaluating digestive prophylactic methods (selective digestive decontamination [SDD],acidification of gastric content, early enteral feeding, prevention of microinhalation); circuit prophylactic methods(closed suctioning systems, early tracheotomy, aerosolized antibiotics, humidification, lung secretion drainage, sil-ver-coated endotracheal tubes) or oropharyngeal prophylactic methods (selective oropharyngeal decontamination,patient position, sinusitis prophylaxis, subglottic secretion drainage, tracheal cuff monitoring). One reviewer extract-ed data that were checked by 3 others. The primary outcome was the mortality rate in the ICU.

Results. We identified 157 randomized trials to pool in a meta-analysis. The primary outcome was available in145 studies (n = 37 156). The risk ratio (RR) for death was 0.95 (95% confidence interval [CI], .92–.99; P = .02) in theintervention groups. In subgroup analysis, only SDD significantly decreased mortality compared with control(n = 10 227; RR, 0.84 [95% CI, .76–.92; P < .001]). The RR for in-ICU death was 0.78 (95% CI, .69–.89; P < .001;I2 = 33%) in trials investigating SDD with systemic antimicrobial therapy and 1.00 (.84–1.21; P = .96; I2 = 0%) with-out systemic antimicrobial therapy.

Conclusions. Selective digestive decontamination with systemic antimicrobial therapy reduced mortality andshould be considered in critically ill patients at high risk for death.

Keywords. hospital-acquired pneumonia/prevention; mortality; selective digestive decontamination; mechanicalventilation.

Hospital-acquired pneumonia (HAP), and notably ven-tilator-associated pneumonia, developing as a conse-quence of lung bacterial colonization, alters clinically

important outcomes, including duration of mechanicalventilation, length of stay in the intensive care unit(ICU), and mortality rates [1–3]. HAP is associatedwith use of antibiotics that may increase the risk of mul-tiple-drug-resistant bacteria in ICUs, and the increase inmedical costs is estimated to be to $20 000 per episode ofHAP [4]. Given HAP-associated morbidity, the preven-tion of HAP has been the focus of numerous studies incritically ill patients and remains a controversial issue.

Bacterial colonization of the oropharynx and subse-quent microaspirations are initial events that lead toHAP [5–7]. The prevention of such events was therefore

Received 22 January 2014; accepted 4 August 2014; electronically published 24September 2014.

Correspondence: Karim Asehnoune, MD, PhD, CHU de Nantes, Service d’Anes-thésie Réanimation, 1 Pl Alexis Ricordeau, 44093 Nantes Cedex 1, France ([email protected]).

Clinical Infectious Diseases® 2015;60(1):64–75© The Author 2014. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]: 10.1093/cid/ciu740

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proposed as a method for reducing the rate of HAP and presum-ably for reducing associated morbidity and mortality. Three mainapproaches have been evaluated: (1) diminishing the microaspi-ration of digestive flora; (2) reducing the volume of oropharyn-geal secretions aspirated into the lungs; and (3) inhibitingovergrowth or alterations in the microbiome in the oropharynxor larynx. Several meta-analyses of approaches to reducing the in-cidence of HAP conclude to a reduction in the risk of infection ofsuch strategies. However, international recommendations for theprevention of HAP provide different conclusions [8–11] and donot state which intervention is mandatory or superior to the oth-ers. The combination of several strategies for preventing HAPfailed to improve mortality rates [12], and nonadherence to inter-national guidelines for HAP prevention is common [13].

We have hypothesized that all the preventive strategies do notequally alter the risk of death. Because many interventions areoften poorly applied in clinical practice, it is important to deter-mine the most effective interventions that should be implementedin critically ill patients. We thus performed a systematic review todetermine which method is the most effective for decreasingmor-tality rates. The rates of HAP, duration of mechanical ventilation,and ICU length of stay were also evaluated as secondary criteria.

MATERIALS AND METHODS

Data Source and SearchesWe followed PRISMA (Preferred Reported Items for SystemicReviews and Meta-Analyses) guidelines were followed duringthe design and implementation of this meta-analysis (Supple-mentary Table 1). We attempted to identify all relevant studiespublished in English regardless of publication status (publishedor in press). We considered abstracts presented at scientificmeetings <3 years earlier (Society Of Critical Care Medicine,European Society of Intensive Care Medicine, Societé Françaised’Anesthesie Reanimation, Societé de Reanimation de LangueFrançaise). PubMed (MEDLINE/Index Medicus) and theCochrane Controlled Trials Register were searched for studiespublished from January 1969 through 10 June 2014. The Med-ical Subject Heading terms used for the search were pneumoniaand intensive care units with the limit “adult 19+ years.” The“related articles” hyperlinks in MEDLINE were explored for ad-ditional references. The reference lists of all selected trials andprevious published meta-analysis were checked for additionalreferences. We contacted authors to identify unpublished data.

Study SelectionThe authors selected all randomized trials that evaluated any ofthe following strategies in adult patients (aged ≥18 years) hos-pitalized in ICUs: acidified enteral feeding, selective digestivedecontamination (SDD), early enteral feeding, postpyloricenteral feeding, decreased gastric retention, probiotic/symbiotic

therapies, ulcer prophylaxis, aerosolized antibiotics, closed suc-tioning systems, early tracheotomy, humidification, phytotherapy(ginger extract), physiotherapy, positive end-expiratory pressure(PEEP), tracheal saline instillation, silver-coated endotrachealtubes), selective oropharyngeal decontamination (SOD), patientposition, sinusitis prophylaxis, subglottic secretion drainage, andtracheal cuff monitoring. Studies using a cluster-randomizationprocedure were included in the main analysis, but a sensitiveanalysis with exclusion of such studies was planned a priori.Pediatric patients were excluded from the study.

Data Extraction and Quality AssessmentOne author (A. R.) checked all titles and abstracts of the articlesidentified from the database research and examined in full allrandomized trials potentially eligible for the review. Quality as-sessment for each study was performed by 2 unblinded investi-gators (A. R. and K. A.). Any disagreement among the 2 authorswas resolved by discussion. Persistent disagreement was settledby discussion with other authors (E. M. and E. A.) after separatereview of the report.

One author (A. R.) designed a standard data extraction form,and other authors (E. M., E. A., and K. A.) amended and vali-dated the design of the form before abstraction of data. One au-thor (A. R.) extracted the following data from each eligiblestudy: first author, year of publication, quality assessment bythe Cochrane Collaboration’s risk of bias tool, type of interven-tion, inclusion criteria, criteria used for HAP diagnosis, numberof patients, number of HAP cases, duration of mechanical ven-tilation and of ICU stay, and ICU mortality rate. Data were ex-tracted from the tables, figures, text of the manuscript, and/orfrom previous meta-analysis that included the selected trial.

Data Synthesis and AnalysisThe primary evaluation criterion was the rate of in-ICU deaths, thatis, the ICU mortality rate. When no information was available onin-ICU deaths, the rate of in-hospital death was considered if pro-vided.When trials had 2 control arms, the numbers of deaths in thecontrol arms were pooled. The other end points analyzed includedthe incidence of HAP, the duration of mechanical ventilation, andthe ICU length of stay (or duration of hospitalization, as provided).

Statistical AnalysesAll statistical analyses were performed using Review Managersoftware (version 5.1.6; Cochrane Collaboration; NordicCochrane Centre) or Stata software (version 10.1; StataCorp).For dichotomous data (mortality and HAP), we calculated therisk ratio (RR) with 95% confidence intervals (CIs). To estimatethe clinical relevance of a beneficial effect on mortality, we cal-culated the number needed to treat with 95% CIs, using RR andcontrol event rates if the RR was significant. For continuousdata, weighted mean differences with 95% CIs were calculated.

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Heterogeneity was determined using the I2 statistics. All pooledestimates used the randomeffectsmodel. A sensitivity analysis wasachieved with the exclusion of cluster-randomized trial [14].

In exploratory analyses, we compared the effects of SDD onmortality rates, based on the administration of systemic antimi-crobial therapy (or not), population (trauma and surgical vsmedical or mixed population), sample size (>200 or <200 pa-tients), and risk of bias (double blinding and randomization).To evaluate publication bias for trials that studied SDD, we con-structed a funnel plot and carried out Egger regression interceptand Begg rank correlation tests to assess asymmetry. The preci-sion of each trial was evaluated according to the standard errorof logarithm RR. Egger test and Begg rank test results were con-sidered significant at P < .10 because these tests have low power.We finally performed a meta-regression analysis to explore thepossible interaction between the mortality rate (baseline risk) in

the control group and the effect of SDD. Differences were con-sidered statistically significant at P < .05.

Role of the Funding SourceNone of the institutions/sponsors of individual author had anyrole in thedesignandconduct of the study; collection,management,analysis, and interpretation of the data; or preparation, review, orapproval of the manuscript. The corresponding author had full ac-cess to all the data in the study and had final responsibility for thedecision to submit the manuscript for publication.

RESULTS

Identification of the TrialsFigure 1 presents the overall search approach. Our initialsearches identified 1113 studies in MEDLINE and 465 studies

Figure 1. Literature search and study selection. Asterisks indicate studies providing the primary outcome, intensive care unit (ICU) mortality rate. Ab-breviations: PEEP, positive end-expiratory pressure; SDD, selective digestive decontamination; SOD, selective oropharyngeal decontamination. aTotal 146studies because one study comparing 1 control group to 2 intervention groups (1 digestive method and 1 oro-pharyngeal method) was counted twice.


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in the Cochrane Controlled Trials Register. After duplicate titlesand abstracts were removed, 1220 citations were excluded (1041nonrandomized trials and 179 irrelevant citations). The remain-ing 278 studies were considered potentially eligible and wereaccessed for full-text review. After exclusion of 117 trials (103nonrandomized, 8 without outcomes of interest, 6 with ab-stracts >3 years old), we included 157 evaluable trials, ofwhich 145 provided the mortality rate.

Description of Recorded Outcomes and Tested InterventionsSupplementary Table 2 summarizes the characteristics of theincluded clinical trials. Fifteen trials (9.6%) had >2 arms: 7(5%) compared 1 control group with 2 interventional groupscombined for analysis, 1 (1%) compared 1 control group with2 interventional groups considered separately for the analysis;5 (3.2%) compared 1 interventional group with 2 control

groups combined for analysis. For 2 trials with a 2 × 2 design,the 3 intervention groups (two groups with one of the inter-ventions and one group with the association of the twointerventions) were combined and compared with the double-dummy (none of the intervention) group. One trial with a2 × 2 design compared patients who received continuous sub-glottic secretion drainage or control and ulcer prophylaxiswith either H2-receptor antagonist or aluminate, no placebowas used for ulcer prophylaxis, and only 2 arms were thus con-sidered for the analyses (subglottic secretion drainage vscontrol).

Description of ParticipantsFifteen studies (9.6%) included medical ICU patients, 46(29.2%) included surgical or trauma ICU patients, and 96(61.1%) included mixed ICU populations.

Figure 2. Hospital mortality rates in critically ill patients receiving a strategy for preventing hospital-acquired pneumonia. All pooled estimates used the randomeffects model. Boldface P values indicate significant differences (P < .05). Abbreviations: CI, confidence interval; ET, endotracheal tube; NA, not applicable; PEEP,positive end-expiratory pressure; RCT, randomized controlled trial; SDD, selective digestive decontamination; SOD, selective oropharyngeal decontamination.


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Risk of Bias in the Included StudiesThe risks for bias are presented in Supplementary Table 3. All stu-dies were randomized; the risk of bias for allocation concealmentwas low in 98 studies (62%). The risks of performance (double-blind study) and detection bias (blinding of outcome assessment)were low in 52 (33.1%) and 89 (56.7%) of the studies, respectively.

Effect of InterventionsPrimary Outcome: In-ICU DeathsWe computed data from 145 randomized trials (37 156 pa-tients). The in-ICU mortality rate was 4079 of 18 838 (21.6%)in the experimental groups versus 4160 of 18 318 (22.7%) incontrols (RR, 0.95 [95% CI, .92–.99; P = .02; I2 = 4%]; numberneeded to treat, 89 [95% CI, 50–443]). The results for each in-tervention analyzed separately are provided in Figure 2 (andSupplementary Figure 1 for forest plots of each interventionseparately). Except SDD, no tested strategy significantly de-creased ICU mortality rates.

In the 30 trials (10 227 patients) investigating SDD versusstandard care or placebo, the in-ICU mortality rate for treatedvs control patients was 1051 of 5326 (19.7%) versus 1143 of4901 (23.3%) (RR, 0.84 [95% CI, .76–.92]; number needed totreat, 27 [95% CI, 18–54]) (Figure 3A) [14–43]. The benefit ofSDD for in-ICU mortality rates remains significant after exclu-sion of the cluster-randomized trial (603 of 3209 [18.8%] vs 686of 2880 [23.8%]; RR, 0.82 [95% CI, .68–.95, P < .001]) (Supple-mentary Table 4). The funnel plot showed no evidence forasymmetry and does not suggest publication bias or otherbias (Egger test, P = .17; Begg test, P = .69) (Figure 3B). In sub-group analyses, the RR for in-ICU death was 0.78 (95% CI,.69–.90; P < .001; I2 = 40%) in trials investigating SDD with sys-temic antimicrobial therapy and 1.01 (95% CI, .85–1.21; P = .91;I2 = 0%) in trials without systemic antimicrobial therapy (Sup-plementary Tables 4 and 5). Given the risk of selection of resis-tant bacteria with antimicrobial therapies [44], defining thepopulation in which SDD is more effective is an important inassessing the use of such therapy. We thus investigated the as-sociation between the effects of SDD and mortality rate in thecontrol group (a proxy for baseline risk). In meta-regressionanalysis, there was a trend toward a positive interaction betweenthe rate of death in the control groups and benefit from SDD(P = .07; Figure 3C).

Secondary OutcomesThe HAP rate was reported in 148 trials (28 856 patients); HAPwas diagnosed in 2156 of 14 457 patients (14.9%) assigned totreatment versus 2994 of 13 799 (21.7%) who received controltherapy (RR, 0.69 [95% CI, .63–.75; P < .001]; χ2 = 391[P < .001; I2 = 63%]). When each intervention is analyzed sepa-rately (Figure 4), the RR for HAP was reduced in trials evaluat-ing SDD versus placebo (P < .001), postpyloric versus gastric

enteral feeding (P = .02), PEEP versus no PEEP (P = .02), tra-cheal saline instillation versus standard secretion drainage(P = .009), aerosolized antibiotic versus placebo (P = .04), sil-ver-coated versus classic endotracheal tube (P = .002), SOD ver-sus standard oral care (P < .001), and subglottic versus routinesecretion drainage (P < .001).

The duration of mechanical ventilation was reported in 85studies (23 691 patients) and showed high heterogeneity acrossstudies (I2 = 84%). The duration of mechanical ventilation wasreduced in the intervention groups compared with the controlgroups (weighted mean difference, −0.75 days (95 CI%, −1.16to −.35; P < .001). When each intervention is analyzed sepa-rately (Figure 5), the duration of mechanical ventilation was re-duced in trials evaluating SDD versus standard care or placebo(P = .003) and physiotherapy versus standard care (P = .03).

The duration of the ICU stay was reported in 82 studies(22 718 patients). It was reduced in the intervention groupscompared with the control groups (weighted mean difference,−1.13 days [95 CI%, −1.70, −.57; P < .001; I2 = 89%]). Wheneach intervention is analyzed separately (Figure 6), the durationof ICU stay was reduced in trials evaluating phytotherapy (gin-ger extract) versus placebo (P < .001) or SOD versus standardoral care (P = .03).

DISCUSSION

For this systematic review, we performed an extensive literaturesearch with few limits regarding publication status, therebyminimizing the risk of missing important studies. This meta-analysis shows that SDD is the main intervention decreasingthe mortality rate in critically ill patients.

It is widely accepted that HAP increases morbidity and mor-tality rates in critically ill patients [45, 46]. In the current results,there is a paradox between the sharp reduction in the rate ofHAP and the small reductions in death rates and time on ven-tilators [47]. This paradox may be attributable to the systemicdiffusion of prophylactic antibiotics used for the SDD [48,49], which can alter the accuracy of the bacteriological samplesand thus increase the rate of false-negatives in the diagnosis ofHAP. Moreover, the diagnosis of HAP has a low specificity andhigh interobserver variability [50], and there are major discrep-ancies between the clinical diagnoses of HAP and the autopsyfindings in critically ill patients [51, 52]. We thus used mortalityrate as the primary outcome in this meta-analysis, because it al-lows us to control the risk of detection bias associated with thediagnosis of HAP, notably in open-label trials.

Previous reviews and meta-analyses have already reported areduction in the risk of death with SDD [53]. In clinical practice,however, SDD is rarely used in ICUs [54] and was not even con-sidered in a recent European survey that evaluated the approach-es for HAP prevention in ICUs [55].The most likely explanation


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Figure 3. Intensive care unit (ICU) mortality rates in trials evaluating selective digestive decontamination. A, Forest plot for mortality in randomizedclinical trials evaluating the effects of digestive decontamination in critically ill patients [14–43]. B, Funnel plot for mortality rates in randomized controlledtrials depicts the effects of digestive decontamination on mortality. The x-axis represents the effect; the y-axis, precision. C, Meta-regression analysisexploring the interaction between survival benefit with digestive decontamination and the incidence of mortality in the control group (y =−0.83x + 1.107;P = .07). Abbreviations: CI, confidence interval; M-H, Mantel-Haenszel; RR, risk ratio; SE (Log RR), standard error of the logarithm of the risk ratio.


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Figure 4. Hospital-acquired pneumonia in critically ill patients receiving a strategy for preventing hospital acquired pneumonia. All pooled estimates used the random effects model. Boldface P values indicatesignificant differences (P < .05). Abbreviations: CI, confidence interval; ET, endotracheal tube; NA, not applicable; PEEP, positive end-expiratory pressure; RCT, randomized controlled trials; SDD, selective digestivedecontamination; SOD, selective oropharyngeal decontamination.

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for the infrequent use of SDD is concern about the risk foremerging antimicrobial resistance during treatment [44, 56,57]. However, in the largest trial of SDD [14], the percentagesof resistant bacteria causing ICU-acquired bacteremia were notsignificantly altered in patients treated with SDD, compared withcontrols. Moreover, in a recent meta-analysis including microbi-ological data issue from 35 studies, no relationship was foundbetween the use of SDD and development of antimicrobial-resistance in pathogens [58]. In the subgroup of patients with in-fection due to gram-negative bacteria, SDD was associated with adecreased risk of resistance to cephalosporins and quinolones[58]. This surprising result may be explained by the reductionin the total daily doses of antibiotics that has been reportedwith SDD [14]. The lack of a proof for increased antimicrobialresistance in numerous studies suggests that the perceived riskof selection of resistant bacteria does not justify the low rate ofSDD use in clinical practice. However, the long-term risk of

emergence of resistance needs to be better investigated beforewe can rule out this potential side effect of SDD.

Given concerns regarding acquisition of bacterial resistance,it has been suggested that SDD may be used in selected popu-lations, but little information is available regarding the popula-tions that could be eligible for SDD. In particular, medicalversus surgical reasons for ICU admission are not reliable crite-ria in selecting patients for SDD [59]. The result of the meta-regression (Figure 2C) suggests that SDD is more effective inpatients with a high risk of death. In 2 systematic reviews,SDD seemed particularly effective in patients with multipleorgan dysfunction syndrome or with a high risk for bacteremia[60]. Taken together, these data suggest that the use of SDDcould be limited to patients with a high risk of death, such asthose presenting with acute organ failure on admission.

Several regimens of SDD have been proposed, and the use ofa systemic antimicrobial therapy is one of the main differences

Figure 5. Duration of mechanical ventilation in critically ill patients receiving a strategy for preventing hospital-acquired pneumonia. All pooled estimatesused the random effects model. Boldface P values indicate significant differences (P < .05). Abbreviations: CI, confidence interval; ET, endotracheal tube; NA,not applicable; PEEP, positive end-expiratory pressure; RCT, randomized controlled trial; SDD, selective digestive decontamination; SOD, selective oropha-ryngeal decontamination; WMD, weighted mean difference.


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between them. We found that systemic antimicrobial therapy isessential to a decrease in the risk of mortality. The recent dem-onstration that the distal respiratory flora is not distinct fromthe upper airway microbiome in healthy lungs [61, 62] suggeststhat HAP results from an increased population of distal lungbacteria rather than colonization from the digestive tract.This hypothesis can explain why the application of an oralpaste of nonabsorbable antibiotics, which has no effect onthe lung microbiome, is not sufficient to prevent HAP and re-duce the risk of death. Finally, the current results argue thatprotocols of SDD should always include a short course of sys-temic antimicrobial therapy and question the importance ofthe oral paste.

This meta-analysis has some limitations. First, our studycombined different types of interventions. This strategy of anal-ysis has already been used to estimate the attributable mortalityof HAP [46, 63], and it will enable intensivists to prioritize strat-egies for implementation in clinical practice. Second, the num-ber of patients in the SDD analyses is greater than the numberfor any other intervention, which results in a higher power forSDD than for other strategies. Thus, the current meta-analysescannot rule out the efficiency of strategies with fewer includedpatients. Third, the prevention of ventilator-associated pneu-monia was analyzed together with that of HAP. However, path-ogens involved in HAP are similar regardless of whether or notHAP is acquired during mechanical ventilation, thereby

Figure 6. Duration of ICU stay for critically ill patients receiving a strategy for preventing hospital-acquired pneumonia. All pooled estimates used therandom effects model. Boldface P values indicate significant differences (P < .05). Abbreviations: CI, confidence interval; ET, endotracheal tube; ICU, inten-sive care unit; NA, not applicable; PEEP, positive end-expiratory pressure; RCT, randomized controlled trial; SDD, selective digestive decontamination; SOD,selective oropharyngeal decontamination; WMD, weighted mean difference.


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suggesting that preventive strategies should be efficient withboth HAP and ventilator-acquired pneumonia [64]. Finally,the existing literature on SDD has mainly considered short-term impacts on morbidity and mortality rates. If SDD eventu-ally leads to increased prevalence of resistant bacteria, then theshort-term benefits could be reversed by increases in failure ofcurative antimicrobial therapy.

In conclusion, the current meta-analysis, which includes 157randomized studies, highlights the benefits preventing HAP indecreasing death rates in critically ill patients. When specific in-terventions are considered separately, SDD with systemic anti-microbial therapy should be considered first in critically illpatients, mainly in those with acute organ failure and at highrisk for death. Ongoing trials should (1) enhance the selectionof patients who may benefit from SDD and determine the min-imal efficient duration of systemic antimicrobial therapy;(2) compare systemic antimicrobial therapy, with or withoutdigestive decontamination; (3) determine the optimal antimi-crobial therapy in patients treated with SDD who develop asubsequent infection; and (4) assess the long-term risk foremergence of multiple-drug-resistant bacteria.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online(http://cid.oxfordjournals.org). Supplementary materials consist of dataprovided by the author that are published to benefit the reader. The postedmaterials are not copyedited. The contents of all supplementary data are thesole responsibility of the authors. Questions or messages regarding errorsshould be addressed to the author.

Notes

Author contributions. A. R., E. M., and K. A. designed and organizedresearch; acquired, analyzed and interpreted data; and wrote the manuscript.Emmanuel Marret performed the statistical analysis. E. A. provided criticalrevision of the manuscript for intellectual content. E. A. and K. A. supervisedthe study. K. A. had full access to all the data in the study and takes respon-sibility for the integrity of the data and the accuracy of the data analysis. Allauthors have agreed to submit data for publication.Disclaimer. The funders had no role in study design, data collection

and analysis, decision to publish, or preparation of the manuscript.Financial support. This work was supported by institutional and

departmental funds.Potential conflicts of interest. E. M. has been a consultant for Bayer.

K. A. has been on the speakers’ bureau for Fresenius and B. Braun Medicaland has been a consultant to Astellas Pharma. All other authors report nopotential conflicts.All authors have submitted the ICMJE Form for Disclosure of Potential

Conflicts of Interest. Conflicts that the editors consider relevant to the con-tent of the manuscript have been disclosed.

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