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

BACKGROUND: Reducing 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 FINDINGS: We 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. CONCLUSIONS: In 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.

Using machine learning to guide targeted and locally-tailored empiric antibiotic prescribing in a children's hospital in Cambodia.

Background: Early and appropriate empiric antibiotic treatment of patients suspected of having sepsis is associated with reduced mortality. The increasing prevalence of antimicrobial resistance reduces the efficacy of empiric therapy guidelines derived from population data. This problem is particularly severe for children in developing country settings. We hypothesized that by applying machine learning approaches to readily collect patient data, it would be possible to obtain individualized predictions for targeted empiric antibiotic choices. Methods and Findings: We analysed blood culture data collected from a 100-bed children's hospital in North-West Cambodia between February 2013 and January 2016. Clinical, demographic and living condition information was captured with 35 independent variables. Using these variables, we used a suite of machine learning algorithms to predict Gram stains and whether bacterial pathogens could be treated with common empiric antibiotic regimens: i) ampicillin and gentamicin; ii) ceftriaxone; iii) none of the above. 243 patients with bloodstream infections were available for analysis. We found that the random forest method had the best predictive performance overall as assessed by the area under the receiver operating characteristic curve (AUC). The random forest method gave an AUC of 0.80 (95%CI 0.66-0.94) for predicting susceptibility to ceftriaxone, 0.74 (0.59-0.89) for susceptibility to ampicillin and gentamicin, 0.85 (0.70-1.00) for susceptibility to neither, and 0.71 (0.57-0.86) for Gram stain result. Most important variables for predicting susceptibility were time from admission to blood culture, patient age, hospital versus community-acquired infection, and age-adjusted weight score. Conclusions: Applying machine learning algorithms to patient data that are readily available even in resource-limited hospital settings can provide highly informative predictions on antibiotic susceptibilities to guide appropriate empiric antibiotic therapy. When used as a decision support tool, such approaches have the potential to improve targeting of empiric therapy, patient outcomes and reduce the burden of antimicrobial resistance.

Transmission Dynamics of Hyper-Endemic Multi-Drug Resistant Klebsiella pneumoniae in a Southeast Asian Neonatal Unit: A Longitudinal Study With Whole Genome Sequencing.

Background:Klebsiella pneumoniae is an important and increasing cause of life-threatening disease in hospitalized neonates. Third generation cephalosporin resistance (3GC-R) is frequently a marker of multi-drug resistance, and can complicate management of infections. 3GC-R K. pneumoniae is hyper-endemic in many developing country settings, but its epidemiology is poorly understood and prospective studies of endemic transmission are lacking. We aimed to determine the transmission dynamics of 3GC-R K. pneumoniae in a newly opened neonatal unit (NU) in Cambodia and to address the following questions: what is the diversity of 3GC-R K. pneumoniae both within- and between-host; to what extent is high carriage prevalence driven by ward-based transmission; and to what extent can environmental contamination explain patterns of patient acquisition. Methods: We performed a prospective longitudinal study between September and November 2013. Rectal swabs from consented patients were collected upon NU admission and every 3 days thereafter. Morphologically different colonies from swabs growing cefpodoxime-resistant K. pneumoniae were selected for whole-genome sequencing (WGS). Results: One hundred and fifty-eight samples from 37 patients and 7 environmental sites were collected. 32/37 (86%) patients screened positive for 3GC-R K. pneumoniae and 93 colonies from 119 swabs were successfully sequenced. Isolates were resistant to a median of six (range 3-9) antimicrobials. WGS revealed high diversity; pairwise distances between isolates from the same patient were either 0-1 SNV or >1,000 SNVs; 19/32 colonized patients harbored K. pneumoniae colonies differing by >1000 SNVs. Diverse lineages accounted for 18 probable importations to the NU and nine probable transmission clusters involving 19/37 (51%) of screened patients. Median cluster size was five patients (range 3-9). Seven out of 46 environmental swabs (15%) were positive for 3GC-R K. pneumoniae. Environmental sources were plausible sources for acquisitions in 2/9 transmission clusters, though in both cases other patients were also plausible sources. Conclusion: The epidemiology of 3GC-R K. pneumoniae was characterized by multiple introductions, high within- and between host diversity and a dense network of cross-infection, with half of screened neonates part of a transmission cluster. We found no evidence to suggest that environmental contamination was playing a dominant role in transmission.