Introduction
A recent global point prevalence survey of infections in 1,265 intensive care units (ICUs) documented bloodstream infection (BSI) among 15% of patients [
1], and this rate may be increasing over time because of increased use of immunosuppressive drugs, invasive procedures, and older patients who have concomitant medical conditions and who are admitted to intensive care [
2,
3]. These infections are a major contributor to patient morbidity [
1] and are associated with a doubling or even tripling of mortality [
4,
5]. Mortality rates may be higher if delayed [
6] or ineffective [
7] initial antimicrobial therapy is prescribed, and so it is difficult to reduce broad-spectrum antibiotic use in the initial empiric phase of treatment in this vulnerable patient population [
8]. In contrast, it may be more feasible to reduce antibiotic use at the back end of treatment courses. Up to half of the antibiotic use in hospital wards and critical care units is unnecessary or inappropriate, and excessive durations of treatment are the greatest contributor to inappropriate use [
9‐
11]. A reduction in the length of antibiotic courses is, therefore, a potentially viable strategy to minimize the consequences of antibiotic overuse in critical care, including antibiotic resistance, adverse effects,
Clostridium difficile colitis, and costs [
12].
The optimal duration of therapy for primary BSI and BSI secondary to major organ system infections has been poorly defined. A review of the Infectious Diseases Society of America (IDSA) guidelines for the treatment of infections most commonly encountered in the critical care setting - including guidelines for community- and hospital-acquired pneumonia [
13,
14], intra-abdominal infection [
15], catheter-related bloodstream infection (CRBSI) [
16], pyelonephritis [
17], and skin and soft tissue infection (SSTI) [
18] - provides no guidance about the optimal duration of therapy for the subset of patients with bacteremia. In the absence of high-grade evidence, there is wide variability in antibiotic treatment duration recommendations from infectious disease and critical care specialists, and the presence of bacteremia is often used as a justification for extended courses of antibiotic therapy regardless of the observed clinical response to treatment [
19,
20]. Randomized controlled trials (RCTs) examining duration of therapy in several organ system infections have demonstrated that treatment can be shortened to 1 week or less without worsening patient outcomes [
11,
21‐
23], so it is plausible that treatment duration could potentially be shortened for BSIs as well.
The objective of this study was to determine whether the therapeutic equivalence of shorter- and longer-course antibiotic therapy extends to patients with bacteremia. We conducted a systematic review and meta-analysis of RCTs explicitly examining the efficacy of shorter-course versus longer-course antibiotic therapy for patients with bacteremia as well as comparable trials examining the organ system infections most commonly causing bacteremia in critically ill patients.
Materials and methods
Search strategy
We searched the Cochrane Central Register of Controlled Trials, Ovid Medline (1948 to 2010), and Ovid Embase (1947 to 2010) to find relevant RCTs comparing shorter versus longer durations of treatment for bacteremia or the five most common organ system infections causing bacteremia in critically ill patients [
1]. Filters for RCTs specified by the Scottish Intercollegiate Guidelines Network [
24] were combined individually with the following keywords: 'bacteremia', 'bacteraemia', 'pneumonia', 'pyelonephritis', 'cellulitis', 'soft tissue infection', 'skin disease, bacterial', 'peritonitis', 'intra-abdominal infection', 'catheter-related infections', and 'catheterization, central venous AND bacteremia OR bacteraemia OR bloodstream infection'. Results were restricted to trials performed on humans. We manually reviewed the reference lists of retrieved studies, editorials, systematic reviews, and meta-analyses to identify additional relevant trials.
Eligibility criteria
Clinical trials were included if they used random allocation of patients to treatment groups comparing differing durations of oral, intramuscular, or intravenous antimicrobial treatment of bacteremia, CRBSIs, pneumonia, pyelonephritis, SSTI, or intra-abdominal infections. Eligible trials randomly assigned subjects to one of two different durations of treatment with the same antibiotic regimen and evaluated one or more of the following outcomes: clinical cure, microbiologic cure, or survival. We excluded trials that determined duration of treatment on the basis of physician discretion, clinical improvement, or biomarker measurements. Observational studies were not included, because a large volume of studies was anticipated and because the association of treatment duration and patient outcomes would be impossible to interpret in light of survivor bias and bias-by-indication. A sample of 200 citations from each of the six searches (1,200 total citations) was independently reviewed by a second author to assess agreement via calculation of a kappa statistic. Disagreements were resolved through consensus.
Study quality
The quality of included trials was appraised by using the Cochrane Risk of Bias tool, which assesses sequence generation, allocation concealment, blinding, data completeness, and outcome reporting, and, on the basis of these domains, summarizes studies as exhibiting a low, high, or unclear risk of bias.
Data collection
Data were collected via a prespecified data extraction spreadsheet with criteria agreed upon by all authors. The information extracted from each trial consisted of the following: (1) infectious syndrome; (2) number of eligible patients screened and randomly assigned; (3) patient characteristics; (4) antibiotic regimen; (5) shorter- and longer-arm treatment duration; (6) day of randomization; (7) allocation sequence method, method of concealment, and presence or absence of blinding strategy; (8) inclusion and exclusion criteria; (9) extent of loss to follow-up; (10) primary outcome measure (including clinical cure, microbiologic cure, and survival); and (11) results of primary outcome in shorter- and longer-arm treatment groups and bacteremic subgroups (CRBSI, pneumonia, intra-abdominal infection, pyelonephritis, and SSTI).
Outcomes
From all trials, we extracted available data on outcomes of clinical cure, microbiologic cure, and survival for the overall groups of patients receiving shorter- and longer-duration antibiotic therapy. In our primary analysis, though, we examined these three outcomes (clinical cure, microbiologic cure, and survival) among the subgroup of patients with bacteremia in each treatment arm. Therefore, individual studies were closely examined for any information relating to the collection of blood cultures and stated inclusion/exclusion of patients with bacteremia. In studies that included patients with bacteremia, data regarding the proportion with bacteremia in each intervention arm (if available) and outcomes for this bacteremic subgroup (if available) were extracted.
Statistical analysis
Outcomes with shorter versus longer antibiotic therapy were reported as risk differences and relative risks with 95% confidence intervals (CIs). In primary analyses, these measures of effect were calculated for the bacteremic subgroups. In secondary analyses, these measures of effect were calculated for the overall study populations. Heterogeneity was assessed across all studies (and for studies within each individual syndrome) via graphical inspection of forest plots as well as calculation of I
2 and chi-squared statistics.
P values of less than 0.1 were deemed to suggest statistically significant between-study heterogeneity [
25]. Pooled relative risks were calculated by using the Mantel-Haenszel fixed effects model. These statistical analyses were performed by using Review Manager version 5 software (The Cochrane Collaboration, Copenhagen, Denmark).
Discussion
This systematic review and meta-analysis identified only one RCT examining shorter versus longer duration of antibiotic therapy exclusively for patients with bacteremia and a further 23 trials among patients with the infectious syndromes that are most commonly associated with bacteremia in the ICU. No significant difference in cure or survival was detected for bacteremic patients receiving shorter- versus longer-duration therapy. These data indicate that shorter-duration therapy may be effective for BSIs but also highlight the need for a larger, high-quality trial dedicated to this question.
The only trial randomly assigning exclusively patients with bacteremia, rather than an identified infectious syndrome, was conducted in a severely ill neonatal population [
26]. The main finding of this trial was that overall outcomes were not significantly different for neonates receiving shorter- versus longer-duration antibiotics. A high rate of failure was seen among the small number of patients receiving short-duration treatment for
S. aureus bacteremia, and this is consistent with the findings of some prior retrospective studies and current treatment guidelines for this pathogen [
50,
51]; yet other studies support short-course therapy for catheter-associated
S. aureus bacteremia [
52]. This review highlights the potential importance of considering
S. aureus bacteremia separately from other pathogens in the context of adequately powered trials in the future.
Although bacteremia caused by intravascular catheters is often cited as the commonest cause of BSI in the critical care setting, we were unable to identify any prospective, randomized investigations examining the duration of antibiotic therapy for CRBSI. Recommendations for length of treatment from the current IDSA guidelines are based only on expert opinion and retrospective case series and call for 5 to 7 days for infections caused by coagulase-negative staphylococci, 7 to 14 days for
Enterococci and Gram-negative organisms, and 2 to 6 weeks for
S. aureus[
16]. Trials are urgently needed, as this may be the syndrome most appropriate for shorter-course therapy given that the focus of infection is removable and thereby leaves no persisting infectious nidus for most patients.
The available trials randomly assigning patients with intra-abdominal infections to shorter versus longer durations of antibiotic therapy were conducted in non-ICU settings and populations and explicitly excluded those with generalized secondary peritonitis or nosocomial infections. Equivalent outcomes for shorter- versus longer-duration therapy for SBP and localized intra-abdominal infection are in keeping with similar findings in a retrospective analysis of 929 patients with intra-abdominal infections, in which less than 7 days of therapy was not associated with higher complications or mortality [
53]. We have not uncovered evidence, though, of whether the effectiveness of short-duration therapy extends to patients with severe infections complicated by bacteremia or in those for whom source control cannot readily be achieved.
Several narrative reviews [
54,
55] and meta-analyses [
22,
23] of RCTs have provided evidence of the efficacy and safety of treating mild to moderate CAP with short-duration antibiotic therapy (5 to 7 days). The 13 studies of pneumonia identified for this review included 5 studies of CAP that provided the prevalence of bacteremia; in total, 80 patients with bacteremia were randomly assigned in equal numbers to short (3 to 7 days) and long (7 to 10 days) durations of therapy. Only three studies provided outcome data for bacteremic subgroups, and clinical cure was reported in 19 out of 21 patients (89.4%) receiving short-duration therapy (5 to 7 days) and in 17 out of 19 patients (90.4%) receiving extended therapy (7 to 10 days). These results provide a modicum of support for the growing consensus that CAP may be safely treated with shorter durations of therapy irrespective of the presence of bacteremia [
11,
12]. Although a large VAP trial documented equivalent survival with shorter (8 days) versus longer (15 days) treatment [
42], very few of these patients were bacteremic, and it is unclear whether shorter-duration treatment can be extended to this subgroup.
The eligible trials of treatment duration in pyelonephritis involved diverse patient populations, durations of treatment, and outcome measures, and this explains the heterogeneity of outcomes with shorter durations of therapy. Recently, the results of several RCTs have demonstrated short-course (5 or 7 days) fluoroquinolone therapy to be equally as efficacious as 10 to 14 days of treatment with comparator medications [
56‐
58]. IDSA guidelines were accordingly amended to recommend therapy for 7 days [
17], but the issue of bacteremia was not explicitly addressed. Our data suggest that patients with bacteremia secondary to uncomplicated pyelonephritis can be successfully treated with shorter-duration therapy.
The sole trial of treatment duration in SSTI demonstrated that, in a carefully selected healthy adult population, a short duration of therapy was associated with a cure rate equal to that of a long duration of therapy [
49]. However, the explicit exclusion of patients with more serious infections, argues that it is unlikely that these data can be directly extrapolated to critically ill patients with bacteremic soft tissue infections.
The present review has several important limitations. The prespecified search strategy excluded unpublished data and non-English language trials. Of eligible trials, bias may have been introduced by low rates of blinding and use of placebo controls. Some studies included only patients with early clinical improvement for randomization to short- or long-course therapy; consequently, the effect size and findings may not be generalizable to sicker patient populations. Other trials excluded patients post-randomization or presented only per-protocol analyses and so may have excluded bacteremic patients failing therapy. Treatment outcomes for patients with bacteremia in individual studies were derived from small post hoc subgroup analyses. Finally, within individual infectious syndromes, significant variability was encountered both in study design and in the durations of therapy employed (with 14 days even considered shorter-course therapy in one study). However, the lack of outcome heterogeneity between syndromes suggests that it is valid to pool BSI data from multiple infectious foci into a single meta-analysis or enroll such patients within a single RCT.
Conclusions
The ICU is the epicenter of bacteremia, antibiotic use, and antibiotic resistance in most hospitals. Reductions in the length of antibiotic treatment courses could potentially limit antibiotic use, adverse effects, and resistance pressure, but antibiotic stewardship efforts to shorten therapy are hampered by the lack of research regarding minimally acceptable durations of treatment for BSIs. Our systematic review and meta-analysis indicate that both inpatients and outpatients with non-S. aureus bacteremia secondary to mild to moderate intra-abdominal infection, CAP, or pyelonephritis may be successfully treated with shorter (5 to 7 days) courses of therapy. However, this finding must be interpreted with caution, as only very small numbers of patients and subgroup analyses are currently available for interpretation. A large dedicated trial of treatment duration for bacteremia in severely ill patients is urgently needed to determine the optimal duration of therapy.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All authors contributed to the inception of the research question and study design. TCH executed the main database searches and helped to extract data from individual studies by using prespecified methods determined by all study authors. ND independently reviewed a subset of 1,200 citations and helped to extract data from individual studies by using prespecified methods determined by all study authors. All authors contributed to drafting the manuscript and read and approved the final manuscript.