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.

Case Report: Therapeutic Strategy With Delayed Debridement for Culture-Negative Invasive Group A Streptococcal Infections Diagnosed by Metagenomic Next-Generation Sequencing

“…Other potential advantages of clindamycin for the treatment of iGAS include: (a) clindamycin is associated with a longer postantibiotic effect than beta-lactam agents, and (b) clindamycin suppresses the synthesis of penicillin binding proteins, which are involved in cell wall synthesis and degradation ( 34 ). Clindamycin also has non-antimicrobial antibiotic effects such as the inhibition of M-protein synthesis, superantigens and other toxins ( 35 ). Clindamycin, together with β-lactams, is considered to be effective in the treatment of necrotizing fasciitis or STSS ( 35 , 36 ).…”

“…Clindamycin also has non-antimicrobial antibiotic effects such as the inhibition of M-protein synthesis, superantigens and other toxins ( 35 ). Clindamycin, together with β-lactams, is considered to be effective in the treatment of necrotizing fasciitis or STSS ( 35 , 36 ). An Australian prospective study suggested that adding clindamycin could reduce mortality ( 37 ).…”

Purinergic Signalling in Group A Streptococcus Pathogenesis

“…GAS expresses various virulence factors to subvert the host innate immune system, which is central to controlling GAS infection ( 3 ). Since current treatment strategies are failing ( 4 ), there is a need to further examine the (dys)regulation of host immune networks underlying GAS pathophysiology and identify novel therapeutic targets to arrest disease progression.…”

Group AStreptococcusInduces Lysosomal Dysfunction in THP-1 Macrophages

“…However, GAS has been shown to survive intracellularly in macrophages during both acute invasive soft tissue infection and asymptomatic carriage (3)(4)(5). Although GAS remains highly sensitive to beta-lactam antibiotics, the gold standard of treatment (6), the ability of bacteria to persist in macrophages and re-emerge after antibiotic treatment poses a therapeutic challenge (4).…”