Colonization Amplification despite Limited In-Hospital Transmission: Modeling the Epidemiological Paradox of C. difficile and the Impact of Control Strategies in Healthcare Settings.

Background: Although healthcare-associated transmission of C. difficile is a recognized public health concern, healthcare-onset infections (CDI) remain comparable in number to community-onset cases. This paradox likely reflects the underappreciated interplay between these settings. We aimed to quantify in-hospital transmission and the hospital's contribution to community colonization by estimating the intrinsic reproduction number (Ri) and introducing the colonization amplification index (Ai), defined as the ratio of colonized patients at discharge to those at admission. Given the potential contribution of external cases, we also evaluated interventions targeting asymptomatic carriers at admission to reduce disease burden. Methods and Findings: We developed a compartmental model informed by data from UCSF Medical Center to capture C. difficile transmission dynamics among symptomatic and asymptomatic patients. Across simulations, the median Ri was 0.58 (Q1-Q3: 0.50-0.65), consistently indicating limited sustained in-hospital transmission (Ri<1). In contrast, Ai was 1.9 (Q1-Q3: 1.7-2.1), suggesting substantial amplification of colonization during hospital stay. Sensitivity analyses showed that estimates were mainly influenced by discharge rates, antibiotic exposure, transmission rate, and case classification thresholds. Redefining hospital-onset CDI using thresholds from ≥1 to ≥5 days post-admission increased Ai and Ri by 13% and 17%, and reduced them by 5% and 9%, respectively. Interventions targeting asymptomatic carriers through contact precautions and/or prophylactic treatment reduced both Ai and CDI incidence, with combined interventions yielding the greatest reductions, followed by contact precautions alone. Conclusions: Our findings indicate that in-hospital transmission of C. difficile is limited (Ri<1) and likely sustained by continuous importation of cases from the community. Nevertheless, hospitalization amplifies colonization (Ai>1), further contributing to community transmission. These results underscore the importance of interventions addressing asymptomatic carriers, a currently overlooked source of spread. Our study highlights the need to broaden metrics beyond Ri to capture hospitals' contribution to the C. difficile burden. Future infection control strategies should address colonization dynamics at admission and potentially at discharge to mitigate transmission and reduce the overall burden of C. difficile.