Abstract
Streptococcus pyogenes, also known as group A Streptococcus (GAS), is one of the top 10 infectious causes of death worldwide. Macrolide and tetracycline resistant GAS has emerged as a major health concern in China coinciding with an ongoing scarlet fever epidemic. Furthermore, increasing rates of fluoroquinolone (FQ) non-susceptibility within GAS from geographical regions outside of China has also been reported. Fluoroquinolones are the third most commonly prescribed antibiotic in China and is an therapeutic alternative for multi-drug resistant GAS. The purpose of this study was to investigate the epidemiological and molecular features of GAS fluoroquinolone (FQ) non-susceptibility in Shanghai, China. GAS (n = 2,258) recovered between 2011 and 2016 from children and adults were tested for FQ-non-susceptibility. Efflux phenotype and mutations in parC, parE, gyrA, and gyrB were investigated and genetic relationships were determined by emm typing, pulsed-field gel electrophoresis and phylogenetic analysis. The frequency of GAS FQ-non-susceptibility was 1.3% (30/2,258), with the phenotype more prevalent in GAS isolated from adults (14.3%) than from children (1.2%). Eighty percent (24/30) of FQ-non-susceptible isolates were also resistant to both macrolides (ermB) and tetracycline (tetM) including the GAS sequence types emm12, emm6, emm11, and emm1. Genomic fingerprinting analysis of the 30 isolates revealed that non-susceptibility may arise in various genetic backgrounds even within a single emm type. No efflux phenotype was observed in FQ non-susceptible isolates, and molecular analysis of the quinolone resistance-determining regions (QRDRs) identified several sequence polymorphisms in ParC and ParE, and none in GyrA and GyrB. Expansion of this analysis to 152 publically available GAS whole genome sequences from Hong Kong predicted 7.9% (12/152) of Hong Kong isolates harbored a S79F ParC mutation, of which 66.7% (8/12) were macrolide and tetracycline resistant. Phylogenetic analysis of the parC QRDR sequences suggested the possibility that FQ resistance may be acquired through inter-species lateral gene transfer. This study reports the emergence of macrolide, tetracycline, and fluoroquinolone multidrug-resistant clones across several GAS emm types including emm1 and emm12, warranting continual surveillance given the extensive use of fluoroquinolones in clinical use.
Highlights
Streptococcus pyogenes, ranked as one of the top 10 infectious causes of death worldwide, is responsible for more than 517,000 deaths annually (Carapetis et al, 2005)
We identified FQ nonsusceptibility to be 1.3% in 2,258 group A Streptococcus (GAS) isolates from Shanghai, China, including within emm12 and emm1 scarlet fever clones resistant to macrolides and tetracycline
We observed a significant difference in FQ resistance frequencies in GAS isolated from adults (14.3%) compared to children (1.2%)
Summary
Streptococcus pyogenes, ranked as one of the top 10 infectious causes of death worldwide, is responsible for more than 517,000 deaths annually (Carapetis et al, 2005). S. pyogenes remains susceptible to penicillin, resistance to macrolides is increasing and a major cause for concern in China, with a frequency >93% (Chen et al, 2012; Yang et al, 2013). Increasing frequencies of S. pyogenes isolates with reduced susceptibility to FQs have been observed in many countries (Reinert et al, 2004; Malhotra-Kumar et al, 2005; Smeesters et al, 2009; Montes et al, 2010; Pires et al, 2010; Van Heirstraeten et al, 2012; Petrelli et al, 2014), yet data on FQ-nonsusceptible S. pyogenes in China remain scarce despite extremely high resistance to primary interventions such as macrolides
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