Reply to Mills and Linkin.

TO THE EDITOR—In their letter [1], Mills and Linkin question the conclusion of our recent study that patient-to-patient transmission of Staphylococcus aureus rarely occurs on an intensive care unit [2]. Over 14 months, we detected only 7 patient-to-patient transmissions using whole-genome sequencing, a finding that strongly supports our conclusions. Furthermore, patient-to-patient transmission accounted for only a minority of the observed acquisitions. It is important to emphasize that we conducted our study in the context of enhanced infection prevention measures including scrupulous hand hygiene, environmental decontamination, and washing of patients with chlorhexidine. Our results suggest that these measures are highly effective in preventing transmission. Mills and Linkin base their criticism on calculation of confidence intervals (CIs) around proportions; in fact our observed 18.9% (7/37) of S. aureus acquisitions that could plausibly represent patient-to-patient transmissions, based on whole-genome sequencing, has an exact binomial 95% CI [3] of 8.0%–35.1% (this method better allows for the small number of acquisitions than the Wald/ normal approximation used in [1]). Mills and Linkin pay particular attention to methicillin-resistant S. aureus (MRSA) acquisitions (actually 5/15 [33%; 95% CI, 11.8%–61.6%] patient-to-patient transmissions from Figure 2 in our article; patient 35 acquired 2 MRSA strains of differing spa types). Approaches that focus on effects within small subgroups that have not been predefined are widely recognized as flawed [4, 5].We did not predefine subgroups as we knew the number of S. aureus acquisitions to be limited before we performed sequencing to identify transmissions. The 95% CI within any subgroup will widen substantially because of the even smaller size, making inference on the basis of 95% CI alone problematic. If, as recommended [4, 5], we consider heterogeneity across subgroups (albeit in exploratory/post-hoc analyses), comparing the 33% of MRSA acquisitions that are plausible transmissions with the corresponding 9% (2/22; 95% CI, 1.1%–29.2%) of methicillin-sensitive S. aureus (MSSA) acquisitions, we find weak evidence for such an effect (two-sided P = .10 by Fisher’s exact test). In our study context of enhanced infection prevention practice, larger numbers would be needed to confirm whether or not MRSA could be responsible for greater patient-to-patient transmission than MSSA, and to estimate the proportion of acquisitions that could be due to patient-to-patient transmission more precisely.