Antimicrobial Stewardship Programs: Effects on Clinical and Economic Outcomes and Future Directions

Results

Antimicrobial Usage

The most widely studied aspect of ASPs in the current review was the effect of ASP interventions on antimicrobial consumption and use. Three systematic reviews [22–24] showed improved antibiotic prescribing practices and reduced consumption rates overall, as did several studies inside and outside the intensive care unit (ICU) [25–31].One study found an insignificant declining usage trend [32]. An important underlying facet of this observation is that even as total antibiotic consumption decreases, certain antibiotic and antibiotic class consumption may increase. This is evident in several studies, which showed that as aminoglycoside, carbapenem, and β-lactam-β-lactamase inhibitor use increased, clindamycin (1 case), glycopeptide, fluoroquinolone, and macrolide use decreased [27,28,30]. A potential confounding factor relating to decreased glycopeptide use in Bevilacqua et al [30] was that there was an epidemic of glycopeptide-resistant enterococci during the study period, potentially causing prescribers to naturally avoid it. In any case, since the aim of ASPs is to encourage a more judicious usage of antimicrobials, the observed decreases in consumption of those restricted medications is intuitive. These observations about antimicrobial consumption related to ASPs are relevant because they putatively drive improvements in clinical outcomes, especially those related to reduced adverse events associated with these agents, such as the risk of C. difficile infection with certain drugs (eg, fluoroquinolones, clindamycin, and broad-spectrum antibiotics) and prolonged antibiotic usage [33–35]. There is evidence that these benefits are not limited to antibiotics but extend to antifungal agents and possibly antivirals [22,27,36].

Utilization, Mortality, and Infection Rates

ASPs typically intend to improve patient-focused clinical parameters such as hospital LOS, hospital readmissions, mortality, and incidence of infections acquired secondary to antibiotic usage during a hospital stay, especially C. difficile infection. Most of the reviewed evidence indicates that there has been no significant LOS benefit due to stewardship interventions [24–26,32,37], and one meta-analysis noted that when overall hospital LOS was significantly reduced, ICU-specific LOS was not [22]. Generally, there was also not a significant change in hospital readmission rates [24,26,32]. However, 2 retrospective observational studies found mixed results for both LOS and readmission rates relative to ASP interventions; while both noted a significantly reduced LOS, one study [38] showed an all-cause readmission benefit in a fairly healthy patient population (but no benefit for readmissions due to the specific infections of interest), and the another [29] showed a benefit for readmissions due to infections but an increased rate of readmissions in the intervention group overall. In this latter study, hospitalizations within the previous 3 months were significantly higher at baseline for the intervention group (55% vs. 46%, P = 0.042), suggesting sicker patients and possibly providing an explanation for this unique observation. Even so, a meta-analysis of 5 studies found a significantly elevated risk of readmission associated with ASP interventions (RR 1.26, 95% CI 1.02–1.57; P = 0.03); the authors noted that non–infection-related readmissions accounted for 61% of readmissions, but this was not significantly different between intervention and non-intervention arms [37].

With regard to mortality, most studies found no significant reductions related to stewardship interventions [22,24,26,29,32]. In a prospective randomized controlled trial, all reported deaths (7/160, 4.4%) were in the ASP intervention arm, but these were attributed to the severities of infection or an underlying, chronic disease [25]. One meta-analysis, however, found that there were significant mortality reductions related to stewardship guidelines for empirical antibiotic treatment (OR 0.65, 95% CI 0.54–0.80, P < 0.001; I ² = 65%) and to de-escalation of therapy based on culture results (RR 0.44, 95% CI 0.30–0.66, P < 0.001; I ² = 59%), based on 40 and 25 studies, respectively [39]; but both results exhibited substantial heterogeneity (defined as I ² = 50%–90% [40]) among the relevant studies. Another meta-analysis found that there was no significant change in mortality related to stewardship interventions intending to improve antibiotic appropriateness (RR 0.92, 95% CI 0.69–1.2, P = 0.56; I ² = 72%) or intending to reduce excessive prescribing (RR 0.92, 95% CI 0.81–1.06, P = 0.25; I ² = 0%), but that there was a significant mortality benefit associated with interventions aimed at increasing guideline compliance for pneumonia diagnoses (RR 0.89, 95% CI 0.82–0.97, P = 0.005; I ² = 0%) [37]. In the case of Schuts et al [39], search criteria specifically sought studies that assessed clinical outcomes (eg, mortality), whereas the search of Davey et al [37] focused on studies whose aim was to improve antibiotic prescribing, with a main comparison being between restrictive and persuasive interventions; while the difference may seem subtle, the body of data compiled from these searches may characterize the ASP effect of mortality differently. No significant evidence was found to suggest that reduced antimicrobial consumption increases mortality.