Cycling Empirical Antibiotic Therapy in Hospitals: Meta-Analysis and Models

Abstract

The rise of resistance together with the shortage of new broad-spectrum antibiotics underlines the urgency of optimizing the use of available drugs to minimize disease burden. Theoretical studies suggest that coordinating empirical usage of antibiotics in a hospital ward can contain the spread of resistance. However, theoretical and clinical studies came to different conclusions regarding the usefulness of rotating first-line therapy (cycling). Here, we performed a quantitative pathogen-specific meta-analysis of clinical studies comparing cycling to standard practice. We searched PubMed and Google Scholar and identified 46 clinical studies addressing the effect of cycling on nosocomial infections, of which 11 met our selection criteria. We employed a method for multivariate meta-analysis using incidence rates as endpoints and find that cycling reduced the incidence rate/1000 patient days of both total infections by 4.95 [9.43–0.48] and resistant infections by 7.2 [14.00–0.44]. This positive effect was observed in most pathogens despite a large variance between individual species. Our findings remain robust in uni- and multivariate metaregressions. We used theoretical models that reflect various infections and hospital settings to compare cycling to random assignment to different drugs (mixing). We make the realistic assumption that therapy is changed when first line treatment is ineffective, which we call “adjustable cycling/mixing”. In concordance with earlier theoretical studies, we find that in strict regimens, cycling is detrimental. However, in adjustable regimens single resistance is suppressed and cycling is successful in most settings. Both a meta-regression and our theoretical model indicate that “adjustable cycling” is especially useful to suppress emergence of multiple resistance. While our model predicts that cycling periods of one month perform well, we expect that too long cycling periods are detrimental. Our results suggest that “adjustable cycling” suppresses multiple resistance and warrants further investigations that allow comparing various diseases and hospital settings.

Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance

“…For example, starting patients on a single drug before adding a second drug promotes the evolution of multidrug resistance (8)(9)(10)(11). A similar effect is seen for studies that rotate antibiotics (12)(13)(14). Even if drugs are given simultaneously but have different in vivo half-lives (15)(16)(17) or postantibiotic effects (18), periods of "effective monotherapy" with the longer-lived drug can occur, which may favor resistance evolution.…”

Role of cephalosporins in the era ofClostridium difficileinfection

“…65 A meta-analysis showed that increased heterogeneity of prescribing was beneficial in reducing the incidence of all hospital-acquired infections and resistant infections. 66 Positive effects were also observed for most pathogens, and effects were particularly pronounced when baseline levels of resistance were low. 66 Therefore, selective use of cephalosporins, as part of a stewardship programme that delivers antibiotic diversity, could be an effective and well-tolerated therapeutic option.…”

“…66 Positive effects were also observed for most pathogens, and effects were particularly pronounced when baseline levels of resistance were low. 66 Therefore, selective use of cephalosporins, as part of a stewardship programme that delivers antibiotic diversity, could be an effective and well-tolerated therapeutic option.…”

“…Moreover, increasing the heterogeneity of antibiotic prescribing is associated with reduced selection pressure and the emergence of resistance. 65,66 A study conducted in a single intensive care unit showed that antibiotic prescribing protocols for ventilator-associated pneumonia that led to highly homogeneous prescribing were associated with marked increases in carbapenem-resistant Acinetobacter baumannii and extended-spectrum β-lactamase-producing Enterobacteriaceae. 65 A meta-analysis showed that increased heterogeneity of prescribing was beneficial in reducing the incidence of all hospital-acquired infections and resistant infections.…”

Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

“…However, theoretical studies of one such approach, known as antimicrobial cycling, have shown that cycling reduces such contacts only under restricted conditions (34); in practice, cycling strategies are difficult to implement and to study (35). Recently, an alternative strategy, "adjustable cycling," in which treatment is changed when not effective in patients, has been proposed and shown in a theoretical model to suppress the emergence of MDR in most settings (36). The clinical impact of these linked determinants depends on their persistence as a linked group.…”