Antimicrobial Drug Use and Macrolide-Resistant Streptococcus pyogenes, Belgium

Liesbet Van Heirstraeten, Samuel Coenen, Christine Lammens, Niel Hens, Herman Goossens, and Surbhi Malhotra-Kumar

Author affiliations: University of Antwerp, Antwerp, Belgium (L. Van Heirstraeten, S. Coenen, C. Lammens, N. Hens, H. Goossens, S. Malhotra-Kumar); and University of Hasselt, Hasselt, Belgium (N. Hens)

Abstract

In Belgium, decreasing macrolide, lincosamide, streptogramins B, and tetracycline use during 1997–2007 correlated significantly with decreasing macrolide-resistant Streptococcus pyogenes during 1999–2009. Maintaining drug use below a critical threshold corresponded with low-level macrolide-resistant S. pyogenes and an increased number of erm(A)-harboring emm77 S. pyogenes with low fitness costs.

Macrolide resistance in Streptococcus pyogenes results primarily from modification of the drug target site by methyltransferases encoded by erm genes, erm(A) and erm(B) or by active efflux mediated by a mef-encoded efflux pump. Of these, erm(A) is inducibly expressed (1) and generally confers low-level resistance to macrolides, whereas lincosamides and streptogramins B (MLS_B), which share overlapping binding sites, remain active against erm(A)-harboring S. pyogenes (2). Conversely, erm(B) can be constitutively or inducibly expressed and confers high-level resistance to MLS_B (2). mef(A) also is constitutively expressed but confers low to moderate resistance to 14- and 15-membered macrolides and susceptibility to 16-membered MLS_B (2).
That macrolide use is the main driver of macrolide resistance in streptococci has been well demonstrated at the population and individual levels (3,4). Because erm and mef are cocarried with tet genes on mobile elements, tetracycline use also affects macrolide resistance (4). In addition, acquisition of resistance often confers a cost to bacteria, the magnitude of which is the main parameter influencing the rate of development and stability of the resistance mechanisms and, conversely, the rate at which resistance would decrease under decreasing use of antimicrobial drugs (5). We investigated temporal changes in the molecular epidemiology of macrolide-resistant S. pyogenes during 1999–2009 in relation to strain fitness (i.e., ability of bacteria to survive and reproduce) and to outpatient use of MLS_B and tetracycline in Belgium.