Transmission dynamics and between-species interactions of multidrug-resistant Enterobacteriaceae

Widespread resistance to antibiotics is among the gravest threats to modern medicine, and controlling the spread of multi-drug resistant Enterobacteriaceae has been given priority status by the World Health Organization. Interventions to reduce transmission within hospital wards may be informed by modifiable patient-level risk factors for becoming colonised, however understanding of factors that influence a patient’s risk of acquisition is limited. We analyse data from a one year prospective carriage study in a neonatal intensive care unit in Cambodia using Bayesian hierarchical models to estimate the daily probability of acquiring multi-drug resistant organisms, while accounting for patient-level time-varying covariates, including interactions between species, and interval-censoring of transmission events. We estimate the baseline daily probability for becoming colonised with third generation cephalosporin resistant (3GC-R) Klebsiella pneumoniae as 0.142 (95% credible interval [CrI] 0.066, 0.27), nearly ten times higher than the daily probability of acquiring 3GC-R Escherichia coli (0.016 [95% CrI 0.0038, 0.049]). Prior colonization with 3GC-R K. pneumoniae was associated with a greatly increased risk of a patient acquiring 3GC-R E. coli (odds ratio [OR] 6.4 [95% CrI 2.8, 20.9]). Breast feeding was associated with a reduced risk of colonization with both 3GC-R K. pneumoniae (OR 0.73 [95% CrI 0.38, 1.5]) and E. coli (OR 0.62 [95% CrI 0.28, 1.6]). The use of an oral probiotic (Lactobacillus acidophilus) did not show clear evidence of protection against colonization with either 3GC-R K. pneumoniae (OR 0.83 [95% CrI 0.51, 1.3]) or 3GC-R E. coli (OR 1.3 [95% CrI 0.77, 2.1]). Antibiotic consumption within the past 48 hours did not strongly influence the risk of acquiring 3GC-R K. pneumoniae. For 3GC-R E. coli, ceftriaxone showed the strongest effect for increasing the risk of acquisition (OR 2.2 [95% CrI 0.66, 6.2]) and imipenem was associated with a decreased risk (OR 0.31 [95% CrI 0.099, 0.76). Using 317 whole-genome assemblies of K. pneumoniae, we determined putatively related clusters and used a range of models to infer transmission rates. Model comparison strongly favored models with a time-varying force of infection term that increased in proportion with the number of colonized patients, providing evidence of patient-to-patient transmission, including among a cluster of Klebsiella quasipneumoniae. Our findings provide support for the hypothesis that K. pneumoniae can be spread person-to-person within ward settings. Subsequent horizontal gene transfer within patients from K. pneumoniae provides the most parsimonious explanation for the strong association between colonization with 3GC-R K. pneumoniae and acquisition of 3GC-R E. coli.