Implications of reducing antibiotic treatment duration for antimicrobial resistance in hospital settings: A modelling study and meta-analysis

BackgroundReducing antibiotic treatment duration is a key component of hospital antibiotic stewardship interventions. However, its effectiveness in reducing antimicrobial resistance is uncertain and a clear theoretical rationale for the approach is lacking. In this study, we sought to gain a mechanistic understanding of the relation between antibiotic treatment duration and the prevalence of colonisation with antibiotic-resistant bacteria in hospitalised patients. Methods and findingsWe constructed 3 stochastic mechanistic models that considered both between- and within-host dynamics of susceptible and resistant gram-negative bacteria, to identify circumstances under which shortening antibiotic duration would lead to reduced resistance carriage. In addition, we performed a meta-analysis of antibiotic treatment duration trials, which monitored resistant gram-negative bacteria carriage as an outcome. We searched MEDLINE and EMBASE for randomised controlled trials published from 1 January 2000 to 4 October 2022, which allocated participants to varying durations of systemic antibiotic treatments. Quality assessment was performed using the Cochrane risk-of-bias tool for randomised trials. The meta-analysis was performed using logistic regression. Duration of antibiotic treatment and time from administration of antibiotics to surveillance culture were included as independent variables. Both the mathematical modelling and meta-analysis suggested modest reductions in resistance carriage could be achieved by reducing antibiotic treatment duration. The models showed that shortening duration is most effective at reducing resistance carriage in high compared to low transmission settings. For treated individuals, shortening duration is most effective when resistant bacteria grow rapidly under antibiotic selection pressure and decline rapidly when stopping treatment. Importantly, under circumstances whereby administered antibiotics can suppress colonising bacteria, shortening antibiotic treatment may increase the carriage of a particular resistance phenotype. We identified 206 randomised trials, which investigated antibiotic duration. Of these, 5 reported resistant gram-negative bacteria carriage as an outcome and were included in the meta-analysis. The meta-analysis determined that a single additional antibiotic treatment day is associated with a 7% absolute increase in risk of resistance carriage (80% credible interval 3% to 11%). Interpretation of these estimates is limited by the low number of antibiotic duration trials that monitored carriage of resistant gram-negative bacteria, as an outcome, contributing to a large credible interval. ConclusionsIn this study, we found both theoretical and empirical evidence that reducing antibiotic treatment duration can reduce resistance carriage, though the mechanistic models also highlighted circumstances under which reducing treatment duration can, perversely, increase resistance. Future antibiotic duration trials should monitor antibiotic-resistant bacteria colonisation as an outcome to better inform antibiotic stewardship policies. Author summary Why was this study done? Shortening antibiotic treatment duration is a commonly adopted antibiotic stewardship strategy, with the expectation that it will reduce antimicrobial resistance in treated individuals and in the overall population.Antibiotic selective pressure acts predominantly on "bystander" colonising bacteria for resistance, and this depends on the spectrum of coverage, pharmacokinetic and pharmacodynamic properties of individual antibiotics.Empirical evidence and an understanding of the mechanisms by which antibiotic treatment duration effects the emergence and spread of antimicrobial resistance are lacking. Understanding the key factors driving the effect of antibiotic treatment duration on resistance carriage will help to inform future research study designs, antimicrobial stewardship interventions, and resource allocation in multimodal control strategies. What did the researchers do and find? We modelled within- and between-host dynamics of colonising "bystander" susceptible and resistant bacteria in response to systemic antibiotic treatment and compared the model findings with a systematic review and meta-analysis.The meta-analysis found one additional antibiotic treatment day is associated with a 7% absolute increase in risk of resistance carriage when antibiotics administered were not effective against the resistance phenotype in the colonising bacteria.For treated individuals, the models showed that shortening antibiotic treatment duration is most effective at reducing resistance carriage when resistant bacteria grow rapidly under antibiotic selection pressure and decline rapidly when stopping treatment.At a population level, shortening antibiotic treatment duration is most effective at reducing resistance carriage in high transmission settings.Shortening antibiotic treatment duration may increase resistance carriage when the antibiotics administered are effective at eliminating colonising bacteria with a particular resistance phenotype. What do these findings mean? Shortening antibiotic treatment duration may increase or decrease colonisation by resistant bacteria, dependent upon individual and combined bacterial and antibiotic characteristics.The effect of shortening antibiotic treatment duration on colonisation by resistant bacteria colonisation is potentially modest due to short hospitalisation periods and slow decolonisation of resistant bacteria.These findings can inform antibiotic stewardship programmes to shorten antibiotic treatment and infection prevention and control policies to reduce transmission of resistant bacteria.