Therapeutic Failures of Antibiotics Used To Treat Macrolide-Susceptible Streptococcus pyogenes Infections May Be Due to Biofilm Formation

Abstract

Streptococcus pyogenes infections often fail to respond to antibiotic therapy, leading to persistent throat carriage and recurrent infections. Such failures cannot always be explained by the occurrence of antibiotic resistance determinants, and it has been suggested that S. pyogenes may enter epithelial cells to escape antibiotic treatment. We investigated 289 S. pyogenes strains isolated from different clinical sources to evaluate their ability to form biofilm as an alternative method to escape antibiotic treatment and host defenses. Up to 90% of S. pyogenes isolates, from both invasive and noninvasive infections, were able to form biofilm. Specific emm types, such as emm6, appeared to be more likely to produce biofilm, although variations within strains belonging to the same type might suggest biofilm formation to be a trait of individual strains rather than a general attribute of a serotype. Interestingly, erythromycin-susceptible isolates formed a significantly thicker biofilm than resistant isolates (P < 0.05). Among resistant strains, those carrying the erm class determinants formed a less organized biofilm than the mef(A)-positive strains. Also, prtF1 appeared to be negatively associated with the ability to form biofilm (P < 0.01). Preliminary data on a selection of strains indicated that biofilm-forming isolates entered epithelial cells with significantly lower efficiency than biofilm-negative strains. We suggest that prtF1-negative macrolide-susceptible or mef(A)-carrying isolates, which are poorly equipped to enter cells, may use biofilm to escape antimicrobial treatments and survive within the host. In this view, biofilm formation by S. pyogenes could be responsible for unexplained treatment failures and recurrences due to susceptible microorganisms.Biofilm formation is recognized as an important virulence factor for both opportunistic pathogens (such as coagulase-negative staphylococci or enterococci) and "true" pathogens (such as Staphylococcus aureus or Pseudomonas aeruginosa) (32).Streptococcus pyogenes (group A streptococcus [GAS]) is an important human pathogen that causes a variety of clinical manifestations ranging from noninvasive diseases, such as pharyngitis and impetigo, to more-severe, invasive infections, including necrotizing fasciitis, sepsis, and toxic shock-like syndrome (14). A large number of secreted or cell-attached virulence factors expressed by this microorganism have been investigated so far (5, 14). As far as biofilm is concerned, streptococcal species such as Streptococcus gordonii and Streptococcus mutans are well-known biofilm formers (17, 26), and recent observations suggesting that biofilm may also have a role in S. pyogenes infections have been reported. HidalgoGrass and colleagues (24) have observed that structured communities appear to be present in necrotizing fasciitis lesions, and Neely et al. (30) found similar characteristics in a model of S. pyogenes myositis in zebrafish. Akiyama et al. (1) reported that S. pyogenes from a murine model of impetigo was embedded ...

Adherence and Biofilm Production of Streptococcus pyogenes

“…Several authors have noticed better biofilm production in non-invasive streptococcal strains compared to invasive strains [33,34], and also in erythromycin-sensitive isolates compared to erythromycin-resistant isolates of S. pyogenes [35]. These results strongly indicate that biofilm production is protective mechanism enabling bacterial survival of antibiotic treatment and immune system reaction.…”

“…Although Baldassari et al [35] have proven biofilm production in 90% of tested invasive and non-invasive isolates, still most researchers agreed that biofilm formation is a trait of individual strains rather than a general serotype attribute. GAS biofilm production is complex process influenced not only by environmental conditions such as ECM proteins, incubation temperature and medium, but also by many bacterial virulence factors such as capsule, SpeB, M protein, pili, etc.…”

emm Types, Virulence Factors, and Antibiotic Resistance of Invasive Streptococcus pyogenes Isolates from Italy: What Has Changed in 11 Years?

“…The nonrandom and M phenotype-type-specific distributions of streptococcal exotoxins (in this study of speA) are already known, as is the lack of compelling evidence for the specific factors associated with the more severe spectrum of GAS disease (3,4,23,31).…”

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

“…Despite universal sensitivity to penicillin, GAS infections may fail to respond to penicillin therapy, leading to persistent throat carriage and recurrent infections (473,474). It has been suggested that GAS may escape penicillin treatment by entering epithelial cells, which are poorly penetrated by penicillin (475)(476)(477), or by forming a biofilm (478,479), or alternatively, failure of penicillin treatment may possibly be due to the protection of GAS by other ␤-lactamase-producing bacterial species; however, this has not been proven (480,481).…”