Choosing Wisely: Effectiveness and Safety of Antibiotic Prophylaxis in Close Contacts of Invasive Group A Streptococci Infection

Abstract

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Infection by Streptococcus pyogenes (group A streptococci [GAS]) causes a wide range of syndromes including invasive GAS (iGAS), such as bacteremia, pneumonia, necrotizing fasciitis, and streptococcal toxic shock syndrome [1]. iGAS causes significant morbidity and mortality in both children and adults [2], with increasing incidence being reported by multiple countries across the globe [3]. In 2005–2012, the United States had an estimated 9557 cases (3.8 cases/100 000 persons per year) with 1116 deaths (case-fatality rate, 11.7%) [4].

Based on biological plausibility and expert opinion, public health guidelines, such as those in the United States, recommend the use of antibiotic prophylaxis among all close contacts of people with iGAS, mainly confirmed severe cases (eg, necrotizing fasciitis, meningitis, or other conditions resulting in death) [5,6]. However, there is a lack of evidence demonstrating the effectiveness of antibiotic prophylactics in preventing GAS in people closely exposed to someone with iGAS [6]. Given increasing concerns about antibiotic overuse and the development of antibiotic resistance, this is a key knowledge gap that we aimed to study.

Merative™ MarketScan® Commercial and Medicare (2010–2019) claims from the United States (Supplementary Material A) were used to evaluate the effectiveness and unintended harm of antibiotic prophylaxis in preventing infection in families within 30 days of an initial (index) iGAS case. We identified index iGAS infections using International Classification of Diseases Ninth and Tenth Revision, Clinical Modification (ICD-9-CM and ICD-10-CM) diagnostic codes recorded in physician billing and hospitalization records, as well as laboratory testing (including GAS bacterial growth) in a subset of cases (Supplementary Material—Table 1). We assumed that family members enrolled under a single health plan are close contacts of the index case. We determined whether family members received antibiotic prophylaxis within 7 days of index infection, in keeping with guidelines for prophylactic use of antibiotics, defined as the dispensation of cephalosporins, macrolides, penicillin, and clindamycin in the drug claims database. To characterize antibiotic use as prophylaxis, we further required that the antibiotic was not initiated within 7 days after a diagnosis of any infection (ICD-9-CM codes 001–139 and ICD-10-CM codes A00–B99). We evaluated if antibiotic use was associated with a lower incidence of GAS infection in family members within 30 days from the index case day (effectiveness) and unintended harm was the occurrence of an adverse reaction within the same 30 days (Supplementary Material—Table 2).

Table 1 summarizes baseline characteristics of close contacts (n = 21 032) of index cases (n = 17 078). Crude GAS infection rates per 1000 person-years were similar in those who used antibiotics (13.2, 95% confidence interval [CI]: 1.9–93.7; n = 1/935) versus non-users (14.8, 95% CI: 9.9–22.1; n = 24/20 097). In multivariate logistic regression (adjusted for sex, age, comorbidity, steroid use, and recent infection), we did not observe a clear difference in GAS infection among those who used antibiotics as prophylaxis compared to those non-users (odds ratio of 0.88, 95% CI: .12–6.51). On the other hand, we observed a 3-fold increase in potential unintended harm. The incidence of potential adverse drug events was 39.6/100 person-years (95% CI: 27.7–56.6) in those receiving antibiotic prophylaxis and 10.6/100 person-years (95% CI: 9.1–12.3) in those not receiving prophylaxis (Supplementary Material—Table 2).

A systematic review showed that there is still scant evidence to confidently confirm the benefit-risk of antibiotics use in preventing subsequent GAS [6]. Antibiotic prophylaxis may be warranted in some high-risk groups, such as older adults (≥65), during pregnancy, and those with cancer, chronic lung disease, diabetes, heart disease, human immunodeficiency virus (HIV) infection, skin trauma, varicella infection, alcohol use disorder, injection drug use, or using high-dose steroids [7, 8]. However, the relatively high rate of subsequent infections in family members seen in our data suggests the importance of education and maintenance of heightened suspicion for family member infections after the diagnosis of the index case. In addition to avoiding adverse drug effects and cost savings, avoiding the use of antibiotics when unnecessary may help slow the emergence of resistant GAS strains, an increasing concern [9–12]. For all of these reasons, tailoring guidelines for antibiotic prophylaxis in close contacts of GAS infections may be beneficial.

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

Acknowledgments. M. G. B., C. S. M., M. A. A. M., and S. B. contributed to the study design. C. S. M., A. N., and S. B. contributed to data collection. All authors helped with the interpretation of results, preparation and editing of the brief report, and final approval. The authors thank Alexandra Nunn, Public Health Agency of Canada, and Katie Rutledge-Taylor, formerly Public Health Agency of Canada, for their contributions during various stages of the research and paper preparation.

Data availability. Data not publicly available.

Financial support. This work was supported by the Canadian Institutes of Health Research (grant number DMC-166262).

References

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