TY - JOUR
AU - Regev-Yochay, Gili
AB - to the editor—Mical Paul and Leonard Leibovici raised concern that our recently published study [1] may be harmful to antibiotic stewardship attempts. As they have noted, current guidelines recommend adding macrolide or fluoroquinolone, therapy for atypical pathogens, to beta-lactam in all patients with severe community-acquired pneumonia (CAP) [2]. Their assumption is that all patients who did not receive macrolides were likely to be elderly or critically ill patients from nursing homes, and thus at higher risk for mortality. Notably, in our study, more than 30% of the patients who did not receive macrolides received quinolones (Supplementary Table 1). Although quinolones are given for the same indication to patients with similar characteristics, we did not detect an association of quinolones with survival as observed with the macrolides [1], thereby highlighting the macrolide-specific effect in this patient population. They have also questioned the validity of the study results due to lack of a dose effect of macrolide use. However, the macrolide effect in our cohort was most likely immunomodulatory and such effect may not be related to conventional expected dose effects—that is, longer treatment duration may not be necessarily better. To further accommodate their concerns, we added a table comparing patients who were or were not given a macrolide (Supplementary Table 1) and repeated the logistic regression analysis and now included nursing home residence as a potential confounder for mortality in the debilitated patient population (Supplementary Table 1 and Table 2). We also performed 2 different propensity-score analyses (Supplementary Figure 1, detailed Supplementary Methods). All 3 models found a significant association between macrolide therapy and survival (Table 1). Table 1. Association Between Macrolide Use of Patients Who Survived the First 72 Hours at the Hospital and Outcome of In-Hospital Mortality Model . OR . 95% CI . P . Univariate logistic regression .429 .307–.589 <.001 Multivariate logistic regression .539 .380–.755 <.001 Inverse probability weighting .588 .420–.822 .002 Matched analysis (full matching) .368 .249–.543 <.001 Model . OR . 95% CI . P . Univariate logistic regression .429 .307–.589 <.001 Multivariate logistic regression .539 .380–.755 <.001 Inverse probability weighting .588 .420–.822 .002 Matched analysis (full matching) .368 .249–.543 <.001 Abbreviations: CI, confidence interval; OR, odds ratio. Open in new tab Table 1. Association Between Macrolide Use of Patients Who Survived the First 72 Hours at the Hospital and Outcome of In-Hospital Mortality Model . OR . 95% CI . P . Univariate logistic regression .429 .307–.589 <.001 Multivariate logistic regression .539 .380–.755 <.001 Inverse probability weighting .588 .420–.822 .002 Matched analysis (full matching) .368 .249–.543 <.001 Model . OR . 95% CI . P . Univariate logistic regression .429 .307–.589 <.001 Multivariate logistic regression .539 .380–.755 <.001 Inverse probability weighting .588 .420–.822 .002 Matched analysis (full matching) .368 .249–.543 <.001 Abbreviations: CI, confidence interval; OR, odds ratio. Open in new tab Sepsis severity was not included in the analysis, since, as explicitly mentioned in the limitation section of our paper, these data were not available for this cohort. Nevertheless, all the patients included in the study had pneumococcal bacteremia, which is known to correlate with severity. This was reflected in the high mortality rate compared with outcome in other randomized controlled trial (RCT) CAP studies [3]. Moreover, our study is in line with other cohort studies of patients with severe pneumonia, including patients with more detailed disease severity scores [4–6]. As suggested by Paul and Leibovici, RCT studies are indeed the gold-standard methodology for drug effect assessment. However, these studies often suffer from an inherent disadvantage of underrepresentation of the sickest patients, frequently due to specific exclusion criteria. Thus, the important role of observational studies in determining real-world effects cannot be overlooked. Therefore, an effect that is prominent in severe cases may be absent or difficult to discover in an RCT. We are as concerned about antibiotic stewardship as the authors but believe that our study should actually lead to better stewardship, with less use of quinolones and more, but shorter, use of macrolides. In nonsevere cases, the current recommendation is beta-lactam as a sole agent [2], with which we agree. Moreover, our results suggest that, once culture results are available, within 24–48 hours, macrolide therapy can be safely discontinued. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Notes Financial support. This work was supported in part by a grant from Pfizer (grant number 0887X1-4603). Potential conflicts of interest. G. R.-Y. has received a research grant from Pfizer and has been a scientific consultant for Teva and Merck; has received payment or honoraria from MSD regarding the COVID pandemic, unrelated to the topic of the study; and has participated on Data Safety Monitoring Boards or Advisory Boards for Moderna and AstraZeneca. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1 Chowers M , Gerassy-Vainberg S, Cohen-Poradosu R, et al. The effect of macrolides on mortality in bacteremic pneumococcal pneumonia: a retrospective, nationwide cohort study, Israel, 2009-2017 . Clin Infect Dis 2022 ; ciac317 . doi:10.1093/cid/ciac317 Google Scholar OpenURL Placeholder Text WorldCat 2 Metlay JP , Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America . Am J Respir Crit Care Med 2019 ; 200 : e45 – e67 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Postma DF , Van Werkhoven CH, Van Elden LJ, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults . N Engl J Med 2015 ; 372 : 1312 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Baddour LM , Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia . Am J Respir Crit Care Med 2004 ; 170 : 440 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Martin-Loeches I , Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia . Intensive Care Med 2010 ; 36 : 612 – 20 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Shumilak G , Sligl WI. Moving past the routine use of macrolides—reviewing the role of combination therapy in community-acquired pneumonia . Curr Infect Dis Rep 2018 ; 20 : 1 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
TI - Reply to Paul and Leibovici 
JF - Clinical Infectious Diseases
DO - 10.1093/cid/ciac415
DA - 2022-07-12
UR - https://www.deepdyve.com/lp/oxford-university-press/reply-to-paul-and-leibovici-4rDTeikhb9
SP - 1485
EP - 1485
VL - 75
IS - 8
DP - DeepDyve
ER -