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| 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.
Source publication
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 wor...
Contexts in source publication
Context 1
... β-lactam penicillin remains the gold standard of antibiotic treatment for many GAS infections ( Stevens et al., 2014). β-lactams target penicillin-binding proteins (PBPs) to block peptidoglycan cross-linking in metabolically active bacteria, leading to bacterial death (Figure 1; Wilke et al., 2005). Despite extensive use for decades, there has been minimal change in the susceptibility of GAS to penicillin (Macris et al., 1998). ...
Context 2
... occurs through blocking of the peptidyl transferase reaction, preventing protein synthesis in susceptible pathogens, commonly Gram-positive cocci of Streptococcus, Staphylococcus, and Clostridium species ( Stevens et al., 1987). Clindamycin is bacteriostatic and can limit the production of toxic proteins and virulence factors independent of its effects on growth (Figure 1; Schlievert and Kelly, 1984). This is also true for GAS ( Mascini et al., 2001), where clindamycin inhibition of M protein synthesis promotes phagocytic killing (Gemmell et al., 1981) and inhibition of superantigens and other toxins ( Sriskandan et al., 1997;Mascini et al., 2001) can mitigate septic shock (Schlievert and Kelly, 1984). ...
Context 3
... and macrolides are the drugs of choice for GAS and therefore have the highest concern for the development of resistance. Along with rapid increases in erythromycin and clindamycin resistance, tetracycline resistance is widespread and levofloxacin resistance is observed (Fay et al., 2021). However, the challenges with GAS treatment are still typically antibiotic failure, not intrinsic drug resistance. ...
Context 4
... likely include major toxins and surface-anchored virulence factors ( Wilde et al., 2021a). Through their neutralization ( Parks et al., 2018) and increased opsonization of the bacterium, IVIG antibodies can decrease the bacterial burden and limit pro-inflammatory cytokine storms (Figure 1; Kaul et al., 1999). The repertoire of virulence factors produced by GAS is variable, as is the repertoire of specific antibodies between donors used for IVIG (Dhainaut et al., 2013), so the ability to neutralize toxins will vary between treatments and requires optimization (Norrby-Teglund et al., 1998;Schrage et al., 2006). ...
Similar publications
Background:
This work reports on antimicrobial resistance data for invasive Streptococcus pyogenes in Spain, collected by the 'Surveillance Program for Invasive Group A Streptococcus', in 2007-2020.
Methods:
emm typing was determined by sequencing. Susceptibility to penicillin, tetracycline, erythromycin, and clindamycin was determined via the E...
Citations
... Prompt antibiotic treatment of GAS in children, after microbiologic confirmation, is necessary to prevent complications, further disease transmission, and deaths. Invasive GAS infections can rapidly worsen if left untreated, often necessitating surgical intervention to be fully controlled [13]. A recent multicenter cohort study including 320 children with iGAS infections reported an overall mortality rate of 2%, with 12% experiencing survival with neurodisability, amputation, skin grafts, hearing loss, and the need for surgery [14]. ...
Group A Streptococcus (GAS) presents a significant global health burden due to its diverse clinical manifestations ranging from mild infections to life-threatening invasive diseases. While historically stable, the incidence of GAS infections declined during the COVID-19 pandemic but resurged following the relaxation of preventive measures. Despite general responsiveness to β-lactam antibiotics, there remains an urgent need for a GAS vaccine due to its substantial global disease burden, particularly in low-resource settings. Vaccine development faces numerous challenges, including the extensive strain diversity, the lack of suitable animal models for testing, potential autoimmune complications, and the need for global distribution, while addressing socioeconomic disparities in vaccine access. Several vaccine candidates are in various stages of development, offering hope for effective prevention strategies in the future.
... Target-protection proteins, like some ATP-binding cassette (ABC) proteins, can remove the antibiotic from the ribosome to restore translation [115,116]. Lastly, multidrug efflux pumps, including mefA and msrA, may provide another mechanism of resistance to lincosamides like clindamycin, albeit they are more effective in contributing to macrolide rather than lincosamide resistance [117,118]. and macrolide resistance [123]. Importantly, a fine-tuned balance must exist between species like S. epidermidis and C. acnes in order to maintain a healthy, homeostatic state in the skin [10] and prevent dysbiosis and ward off inflammation. ...
Clindamycin is a highly effective antibiotic of the lincosamide class. It has been widely used for decades to treat a range of skin and soft tissue infections in dermatology and medicine. Clindamycin is commonly prescribed for acne vulgaris, with current practice standards utilizing fixed-combination topicals containing clindamycin that prevent Cutibacterium acnes growth and reduce inflammation associated with acne lesion formation. Certain clinical presentations of folliculitis, rosacea, staphylococcal infections, and hidradenitis suppurativa are also responsive to clindamycin, demonstrating its suitability and versatility as a treatment option. This review describes the use of clindamycin in dermatological practice, the mechanism of protein synthesis inhibition by clindamycin at the level of the bacterial ribosome, and clindamycin’s anti-inflammatory properties with a focus on its ability to ameliorate inflammation in acne. A comparison of the dermatologic indications for similarly utilized antibiotics, like the tetracycline class antibiotics, is also presented. Finally, this review addresses both the trends and mechanisms for clindamycin and antibiotic resistance, as well as the current clinical evidence in support of the continued, targeted use of clindamycin in dermatology.
... An overall antibiotic failure rate of 20 to 40% has been reported for GAS (28), although GAS antibiotic susceptibility studies have reported no resistance to penicillin so far and the mechanism for this resistance remains elusive (29). In addition, antibiotic resistance to macrolides, tetracycline and fluoroquinolones has been reported (30). ...
The human pathobiont Streptococcus pyogenes forms biofilms and causes invasive infections, such as pharyngotonsillitis and necrotizing fasciitis. Bacterial biofilms are more resilient to antibiotic treatment and new therapeutic strategies are needed to control biofilm-associated infections, such as recurrent pharyngotonsillitis. Lactiplantibacillus plantarum and Lacticaseibacillus rhamnosus are two bacterial commensals used for their probiotic properties. This study aimed to elucidate the anti-biofilm properties of L. plantarum and L. rhamnosus cell-free supernatants (LPSN and LRSN, respectively) on S. pyogenes biofilms grown in vitro in supplemented minimal medium. When planktonic or biofilm S. pyogenes were exposed to LPSN or LRSN, S. pyogenes survival was reduced significantly in a concentration-dependent manner and the effect was more pronounced on preformed biofilms. Enzymatic digestion of LPSN and LRSN suggested that glycolipid compounds might cause the antimicrobial effect. In conclusion, this study indicates that L. plantarum and L. rhamnosus produce glycolipid bioactive compounds that reduce S. pyogenes viability in planktonic and biofilm cultures.
... The majority of therapeutic methods for the treatment of non-invasive GAS infections include the use of antibiotics (e.g., penicillin), however, antibiotic resistance confers to poor therapeutic results in first-in-line adjunctive, penicillin alternate treatments, and subclinical β-lactam treatment, leading to recurrent GAS infections with treatment failure. Therefore, the difficulty of antibiotic-treating post-infection sequelae GAS infections necessitates elimination through the development of an effective GAS vaccine [3,91]. Furthermore, geographic distribution and various GAS emm genes cause a wide spectrum of GAS isolates, capable of reducing the susceptibility of penicillin and increasing macrolide resistance, threatening both frontline and penicillin-adjunctive antibiotic treatment [3]. ...
Group A Streptococcus (GAS), or Streptococcus pyogenes, is a gram-positive bacterium that extensively colonises within the human host. GAS is responsible for causing a range of human infections, such as pharyngitis, impetigo, scarlet fever, septicemia, and necrotising fasciitis. GAS pathogens have the potential to elicit fatal autoimmune sequelae diseases (including rheumatic fever and rheumatic heart diseases) due to recurrent GAS infections, leading to high morbidity and mortality of young children and the elderly worldwide. Antibiotic drugs are the primary method of controlling and treating the early stages of GAS infection; however, the recent identification of clinical GAS isolates with reduced sensitivity to penicillin-adjunctive antibiotics and increasing macrolide resistance is an increasing threat. Vaccination is credited as the most successful medical intervention against infectious diseases since it was discovered by Edward Jenner in 1796. Immunisation with an inactive/live-attenuated whole pathogen or selective pathogen-derived antigens induces a potent adaptive immunity and protection against infectious diseases. Although no GAS vaccines have been approved for the market following more than 100 years of GAS vaccine development, the understanding of GAS pathogenesis and transmission has significantly increased, providing detailed insight into the primary pathogenic proteins, and enhancing GAS vaccine design. This review highlights recent advances in GAS vaccine development, providing detailed data from preclinical and clinical studies across the globe for potential GAS vaccine candidates. Furthermore, the challenges and future perspectives on the development of GAS vaccines are also described
... Primary infection sites are usually upper airways and skin, where non-invasive GAS infections occur and from where the pathogen can be transmitted to a new host or can disseminate causing invasive disease (iGAS) such as empyema (infection of the pleural cavity), streptococcal toxic shock syndrome (STSS) or necrotising fasciitis (Efstratiou and Lamagni, 2022;Stevens and Bryant, 2022a,b;. iGAS infections can rapidly progress and often require prompt surgical treatment to obtain rapid and adequate source control (Stevens et al., 2014;Johnson and LaRock, 2021). They are also characterized by high morbidity and mortality rates, with ∼8-23% of deaths within 7 days from infection (Walker et al., 2014). ...
Background
Group A Streptococcus (GAS) causes multiple clinical manifestations, including invasive (iGAS) or even life-threatening (severe-iGAS) infections. After the drop in cases during COVID-19 pandemic, in 2022 a sharp increase of GAS was reported globally.
Methods
GAS strains collected in 09/2022–03/2023 in two university hospitals in Milan, Italy were retrospectively analyzed. Clinical/epidemiological data were combined with whole-genome sequencing to: (i) define resistome/virulome, (ii) identify putative transmission chains, (iii) explore associations between emm-types and clinical severity.
Results
Twenty-eight isolates were available, 19/28 (67.9%) from adults and 9/28 (32.1%) from pediatric population. The criteria for iGAS were met by 19/28 cases (67.9%), of which 11/19 (39.3%) met the further criteria for severe-iGAS. Pediatric cases were mainly non-invasive infections (8/9, 88.9%), adult cases were iGAS and severe-iGAS in 18/19 (94.7%) and 10/19 (52.6%), respectively. Thirteen emm-types were detected, the most prevalent being emm1 and emm12 (6/28 strains each, 21.4%). Single nucleotide polymorphism (SNP) analysis of emm1.0 and emm12.0 strains revealed pairwise SNP distance always >10, inconsistent with unique transmission chains. Emm12.0-type, found to almost exclusively carry virulence factors speH and speI, was mainly detected in children and in no-iGAS infections (55.6 vs. 5.3%, p = 0.007 and 66.7 vs. 0.0%, p < 0.001, respectively), while emm1.0-type was mainly detected in severe-iGAS (0.0 vs. 45.5%, p = 0.045).
Conclusions
This study showed that multiple emm-types contributed to a 2022/2023 GAS infection increase in two hospitals in Milan, with no evidence of direct transmission chains. Specific emm-types could be associated with disease severity or invasiveness. Overall, these results support the integration of classical epidemiological studies with genomic investigation to appropriately manage severe infections and improve surveillance.
... Antibiotics have been the primary method of treating bacterial infections, including S. pyogenes infections. For decades, the gold standard of treatment of S. pyogenes infections has been penicillin 12 . Due to irresponsible, widespread use of antibiotics 10 , and the last new class of antibiotics being introduced in 2003 13 , bacteria have developed antibiotic resistance since they are exposed to low levels of antibiotics over long periods, allowing the bacteria to adapt and build survival mechanisms in the presence of antibiotics. ...
Streptococcus pyogenes is a causative agent for strep throat, impetigo, and more invasive diseases. The leading cause of treatment failure of streptococcal infections is increased antibiotic resistance. In recent years,...
... Since tissue damage impacts the efficiency of antibiotics to kill S. pyogenes, treatment strategies for necrotizing disease often include an antibiotic that inhibits expression of tissue-damaging toxins in combination with an antibiotic that targets bacterial growth. The latter typically includes a β-lactam (e.g., piperacillin/tazobactam), while the former includes clindamycin (13,17,18), which at . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
... However, the use of clindamycin is now threatened by increasing rates of resistance in healthcare settings (17)(18)(19). ...
We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that have antimicrobial activities against a broad-spectrum of Gram-positive pathogens. Here we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes . Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes . Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens and accelerated rates of wound-healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.
... 4,6,9,17,19,30,37,68 La amigdalectomía no se recomienda únicamente con el fin de reducir la faringitis por SGA, ya que no previene de su colonización. 12,69 Dependiendo de la cepa y su capacidad de producir toxinas con destrucción tisular local, puede producirse una infección invasiva local, como los abscesos periamigdalinos, las otitis medias agudas con mastoiditis, linfadenitis y abscesos, celulitis, erisipela, y otras infecciones de piel y partes blandas. 4,7,9,30 Una vez rotas las barreras epiteliales, SGA tiene la capacidad de causar gran variedad de enfermedades invasivas (EISGA), definidas como el aislamiento del microorganismo en zonas que normalmente son estériles. ...
... Posteriormente cursa con hipotensión, erupción cutánea eritrodérmica, destrucción de tejidos de partes blandas, aumento de enzimas hepáticas, coagulopatía, trombocitopenia, fallo renal, choque y finalmente fallo multiorgánico. 4,19,29,[69][70][71][72]74,79,80 Sobre la asociación con influenza, se ha observado que la gravedad de las infecciones respiratorias en caso de infección bacteriana simultánea (coinfección) o posterior (sobreinfección), suelen ser más graves (especialmente las infecciones por neumococo y SGA), con aumento de la carga bacteriana, mayor inflamación pulmonar y aumento de mortalidad. 19 En el diagnóstico diferencial se incluyen el choque séptico, enfermedad de Kawasaki con choque, el síndrome de reacción farmacológica con eosinofilia y síntomas sistémicos (DRESS), infecciones tropicales (tifus de los matorrales, dengue, malaria, leptospirosis y fiebre entérica) y SIMS-C posterior a SARS-CoV-2. ...
... Las manifestaciones menos comunes de la piel incluyen eritema marginado (2%) y nódulos subcutáneos. 37,69 El diagnóstico se basa en los clásicos criterios de Jones, revisados en 1992 84 y Rev Latin Infect Pediatr. 2024; 37 (1): [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] revalorados en 2015, con diagnóstico ecocardiográfico de carditis (Tabla 4). ...
... However, the overall selective pressure of penicillin on Streptococcus species has been relatively low compared to other bacteria. 38,39 This reduced selective pressure is due to the shorter duration of treatment required to effectively eliminate Streptococcus infections and the generally low levels of penicillin resistance in these bacteria. ...
... Furthermore, mild GAS infections can trigger immune complications such as rheumatic heart disease or develop into more severe diseases such as scarlet fever, sepsis, puerperal fever, toxic shock syndrome, or necrotizing fasciitis, collectively responsible for an estimated 500,000 annual deaths (1). There is currently no vaccine, and while GAS remains sensitive to several antibiotics, treatment failure remains a challenge (2). ...
The pro-inflammatory cytokine IL-6 regulates antimicrobial responses that are broadly crucial in the defense against infection. Our prior work shows that IL-6 promotes the killing of the M4 serotype group A Streptococcus (GAS) but does not impact the globally disseminated M1T1 serotype associated with invasive infections. Using in vitro and in vivo infection models, we show that IL-6 induces phagocyte reactive oxygen species (ROS) that are responsible for the differential susceptibility of M4 and M1T1 GAS to IL-6-mediated defenses. Clinical isolates naturally deficient in capsule, or M1T1 strains deficient in capsule production, are sensitive to this ROS killing. The GAS capsule is made of hyaluronic acid, an antioxidant that detoxifies ROS and can protect acapsular M4 GAS when added exogenously. During in vitro interactions with macrophages and neutrophils, acapsular GAS can also be rescued with the antioxidant N-acetylcysteine, suggesting this is a major virulence contribution of the capsule. In an intradermal infection model with gp91 phox -/- (chronic granulomatous disease [CGD]) mice, phagocyte ROS production had a modest effect on bacterial proliferation and the cytokine response but significantly limited the size of the bacterial lesion in the skin. These data suggest that the capsule broadly provides enhanced resistance to phagocyte ROS but is not essential for invasive infection. Since capsule-deficient strains are observed across several GAS serotypes and are competent for transmission and both mild and invasive infections, additional host or microbe factors may contribute to ROS detoxification during GAS infections.
