Reply to Scheper and de Boer's comment on “Duration of rifampin therapy is a key determinant of improved outcomes in early-onset acute prosthetic joint infection due to Staphylococcus treated with a debridement, antibiotics and implant retention (DAIR): a retrospective multicenter study in France” by Becker et al. (2020)
Dear editor,
We thank Henk Scheper and Mark G. J. de Boer for their valuable comments on our recent
paper published in the journal (Becker et al., 2020). The authors raise concerns about several biases that could distort the association between prolonged rifampin therapy
and improved outcomes in patients with acute staphylococcal prosthetic joint
infection treated with debridement, antibiotics and implant retention (DAIR). We totally agree with their comments, and we have tried to address them. First of all, the impact of rifampin is complex
to evaluate, as a delay could be observed between DAIR and the rifampin
initiation, the population who receives it could differ from the population
who does not, and finally among patients who receive it, its duration could
be variable. Concerning the different potential biases, survival bias might
arise because patients with early failures are more likely not to
“survive” enough to be started on rifampin, thus inflating the proportion
of “non-rifampin” patients in the “failure” group. As the median time from
DAIR surgery to failure was 16 d, we compared patients receiving rifampin
among those with early (<16 d, n=11) and late (≥16 d,
n=14) failure and found respectively that (64 %) and 10/14 (71 %)
had received rifampin (p>0.99 by Fisher's exact test). Then, to address confounding by indication, we compared variables potentially associated with “failure” according to treatment. We found that patients
with rifampin (n=58) were younger (71 [61–80] vs. 75 [66–86] years,
p=0.046), but the majority of them are >70 years in both
groups, and no differences were noticed concerning the prevalence of
comorbidities. Even though we used multivariate modelling to control for this bias, we acknowledge that interaction could be searched between treatment
and patient characteristics related to practice guidelines. Then, we agree
that excluding patients with failure while still on rifampin underestimates
the proportion of “rifampin” patients in the “failure” group. However, our
aim was to compare the duration of rifampin treatment between patients with
failure and success of DAIR, among the patients receiving rifampin
(n=58). As suggested by a reviewer, removing patients failing while on
rifampin (n=7) limits the bias whereby the proportion of patients with a
short duration of rifampin is inflated in the “failure” group (because in
those cases rifampin is stopped because failure occurs, and not the
opposite). In fact, when considering the whole population (n=79), we still
found by multivariate logistic regression that duration of rifampin was
independently associated with DAIR failure (OR =0.948,
IC95 % =0.893–0.985, p=0.027 for each day of treatment). To limit
potential biases evaluating the impact of rifampin, the use of a propensity score could be proposed, but the sample size was here too limited for this
approach (D'Agostino, 1998). Finally, the analysis could be treated as a multi-state
question where a patient goes from an initial state and could transit to a failure state directly or not, and on which rifampin treatment could
influence the transition rate (Putter et al., 2007). Indeed, an event-specific model including rifampin as a time-dependent variable would be a valuable approach to estimate
rifampin treatment duration on failure rate.