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

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.Author Summary: The rise of antibiotic resistance is a major concern for public health. In hospitals, frequent usage of antibiotics leads to high resistance levels; at the same time the patients are especially vulnerable. We therefore urgently need treatment strategies that limit resistance without compromising patient care. Here, we investigate two strategies that coordinate the usage of different antibiotics in a hospital ward: “cycling”, i.e. scheduled changes in antibiotic treatment for all patients, and “mixing”, i.e. random assignment of patients to antibiotics. Previously, theoretical and clinical studies came to different conclusions regarding the usefulness of these strategies. We combine meta-analyses of clinical studies and epidemiological modeling to address this question. Our meta-analyses suggest that cycling is beneficial in reducing the total incidence rate of hospital-acquired infections as well as the incidence rate of resistant infections, and that this is most pronounced at low baseline levels of resistance. We corroborate our findings with theoretical epidemiological models. When incorporating treatment adjustment upon deterioration of a patient's condition (“adjustable cycling”), we find that our theoretical model is in excellent accordance with the clinical data. With this combined approach we present substantial evidence that adjustable cycling can be beneficial for suppressing the emergence of multiple resistance.