Antibiotic Treatment, Mechanisms for Failure, and Adjunctive Therapies for Infections by Group A Streptococcus

Abstract

Group A Streptococcus (GAS; Streptococcus pyogenes) is a nearly ubiquitous human pathogen responsible for a significant global disease burden. No vaccine exists, so antibiotics are essential for effective treatment. Despite a lower incidence of antimicrobial resistance than many pathogens, GAS is still a top 10 cause of death due to infections worldwide. The morbidity and mortality are primarily a consequence of the immune sequelae and invasive infections that are difficult to treat with antibiotics. GAS has remained susceptible to penicillin and other β-lactams, despite their widespread use for 80 years. However, the failure of treatment for invasive infections with penicillin has been consistently reported since the introduction of antibiotics, and strains with reduced susceptibility to β-lactams have emerged. Furthermore, isolates responsible for outbreaks of severe infections are increasingly resistant to other antibiotics of choice, such as clindamycin and macrolides. This review focuses on the challenges in the treatment of GAS infection, the mechanisms that contribute to antibiotic failure, and adjunctive therapeutics. Further understanding of these processes will be necessary for improving the treatment of high-risk GAS infections and surveillance for non-susceptible or resistant isolates. These insights will also help guide treatments against other leading pathogens for which conventional antibiotic strategies are increasingly failing.

Keywords: Streptococcus pyogenes; antibiotic resistance; experimental therapeutics; group A Streptococcus; treatment failure.

FIGURE 1

Summary of the treatment methods discussed in this review. Bactericidal β-lactams such as penicillin target the peptidoglycan of the cell wall, leading to cell lysis. This can lead to an efflux of virulence factors and other cellular proteins, resulting in inflammation. Macrolides and lincosamides are bacteriostatic, blocking protein synthesis by targeting the bacterial ribosome. Preventing toxin synthesis works to reduce inflammation. Intravenous immunoglobulin (IVIG) is an infusion of pooled antibodies from human donors, which works to induce opsonization and neutralize toxins, reducing inflammation. Figure made in biorender.

FIGURE 2

Model of mechanisms contributing to antibiotic failure during Group A Streptococcus (GAS) infections. Community-mediated resistance mediated by protection by endogenous microbiota is likely most prevalent during pharyngitis and not invasive infections, where GAS most often exists as a monoculture. Persisters, resistant through altered growth rates or other epigenetic states, can contribute to treatment failure of any infection. The formation of biofilms, invasion of epithelial cells, and survival within phagocytes can similarly occur during any infection and serve to shield single bacterium from antibiotic action. During invasive infections in particular, inflammation- and toxin-mediated necrosis of tissue and thrombosis of dermal vasculature can limit antibiotic perfusion, necessitating surgical removal of the infected tissue.