Shorter Versus Longer Courses of Antibiotics for Infection in Hospitalized Patients: A Systematic Review and Meta-Analysis

Study Outcomes and Statistical Analysis

Our primary outcomes were clinical cure, microbiologic cure, mortality, and infection recurrence. Secondary outcomes were secondary MDR infection, cost, and length of stay (LOS). We conducted all analyses with Stata MP version 14 (StataCorp, College Station, TX). For each outcome, we reported the difference (95% confidence interval [CI]) between treatment arms as the rate in the short course arm minus the rate in the long course arm, consistent with the typical presentation of noninferiority data. When not reported in a study, we calculated risk difference and 95% CI using reported patient-level data. Positive values for risk difference favor the short course arm for favorable outcomes (ie, clinical and microbiologic cure) and the long course arm for adverse outcomes (ie, mortality and recurrence). A meta-analysis was used to pool risk differences across all studies for primary outcomes and for clinical cure in the community-acquired pneumonia (CAP) subgroup. We also present results as odds ratios and risk ratios in the online supplement. All meta-analyses used random effects models, as described by DerSimonian and Laird,^27,28 with variance estimates of heterogeneity taken from the Mantel-Haenszel fixed effects model. We investigated heterogeneity between studies using the χ2 I² statistic. We considered a P < .1 to indicate statistically significant heterogeneity and classified heterogeneity as low, moderate, or high on the basis of an I2 of 25%, 50%, or 75%, respectively. We used funnel plots to assess for publication bias.

RESULTS

Search Results

We identified 5187 unique citations, of which 110 underwent full-text review (Figure 1). Reviewer agreement for selection of title and/or abstracts for full evaluation was 99.1% (kappa = 0.71). Nineteen RCTs with a total of 2867 patients met inclusion criteria and were included in the analysis.^29-47

Characteristics of Included Studies

Publication years ranged from 1991 to 2015 (Table). Study populations were primarily from Europe (n = 9) or the United States (n = 5). Pneumonia was the most common infection studied, with 3 studies evaluating VAP and 9 studies evaluating CAP. There were also 3 studies of intra-abdominal infections, 2 studies of urinary tract infections (UTIs), 1 study of typhoid fever, and 1 study of hospital-acquired infection of unknown origin. No studies of bacteremia or soft tissue infections met inclusion criteria. Short courses of antibiotics ranged from 1 to 8 days, while long courses ranged from 3 to 15 days.

Common study outcomes included clinical cure or efficacy (composite of symptom cure and improvement; n = 13), infection recurrence (n = 10), mortality (n = 9), microbiologic cure (n = 8), and LOS (n = 7; supplementary Table 1).

Nine studies were pilot studies, 1 was a traditional superiority design study, and 9 were noninferiority studies with a prespecified limit of equivalence of either 10% (n = 7) or 15% (n = 2).

Clinical Cure and Efficacy

Thirteen studies of 1727 patients evaluated clinical cure and efficacy (Figure 2).^{29,30,33,35-40,44-47} The overall risk difference was d = 1.6% (95% CI, −1.0%-4.2%), and the pooled odds ratio was 1.11 (95% CI, 0.85-1.45; supplementary Table 2). There was no heterogeneity between studies (I² = 0%, P = .55). Five of 6 studies with a noninferiority design met their prespecified margin, while 1 study of VAP failed to meet the 15% noninferiority margin (d = −11.2% [95% CI, −26.3%-3.8%]).³⁷

Nine studies of 1225 patients evaluated clinical cure and efficacy in CAP (supplementary Figure 1).^{29,35,38-40,44-47} The overall risk difference was d = 2.4% (95% CI, −0.7%-5.5%). There was no heterogeneity between studies (I² = 0%, P = .45).

Microbiologic Cure

Eight studies of 366 patients evaluated microbiologic cure (supplementary Figure 2).^{32-34,36,38,40,41,47} The overall risk difference was d = 1.2% (95% CI, −4.1%-6.4%). There was no statistically significant heterogeneity between studies (I² = 13.3%, P = .33).

Mortality

Eight studies of 1740 patients evaluated short-term mortality (in hospital to 45 days; Figure 2),^{30-32,37,39,41,43} while 3 studies of 654 patients evaluated longer-term mortality (60 to 180 days; supplementary Figure 3).^30,31,33 The overall risk difference was d = 0.3% (95% CI, −1.2%-1.8%) for short-term mortality and d = −0.4% (95% CI, −6.3%-5.5%) for longer-term mortality. There was no heterogeneity between studies for either short-term (I² = 0.0%, P = .66) or longer-term mortality (I² = 0.0%, P = .69).

Infection Recurrence

Ten studies of 1554 patients evaluated infection recurrence (Figure 2).^{30-34,40-42,45,46} The overall risk difference was d = 2.1% (95% CI, −1.2%-5.3%). There was no statistically significant heterogeneity between studies (I² = 21.0%, P = .25). Two of the 3 studies with noninferiority design (both evaluating intra-abdominal infections) met their prespecified margins.^41,42 In Chastre et al.,³¹ the overall population (d = 3.0%; 95% CI, −5.8%-11.7%) and the subgroup with VAP due to nonfermenting gram-negative bacilli (NF-GNB; d = 15.2%; 95% CI, −0.9%-31.4%) failed to meet the 10% noninferiority margin.