Macrolide-resistant Group A Streptococci Research Articles

A global snapshot on the prevalent macrolide-resistant emm types of Group A Streptococcus worldwide, their phenotypes and their resistance marker genotypes during the last two decades: A systematic review.

Watchful epidemiological surveillance of macrolide-resistant Group A Streptococcus (MRGAS) clones is important owing to the evolutionary and epidemiological dynamic of GAS. Meanwhile, data on the global distribution of MRGAS emm types according to macrolide resistance phenotypes and genotypes are scant and need to be updated. For this, the present systematic review analyses a global set of extensively characterized MRGAS isolates from patients of diverse ages and clinical presentations over approximately two decades (2000 to 2020) and recaps the peculiar epidemiological features of the dominant MRGAS clones. Based on the inclusion and exclusion criteria, 53 articles (3593 macrolide-resistant and 15,951 susceptible isolates) distributed over 23 countries were dissected with a predominance of high-income countries over low-income ones. Although macrolide resistance in GAS is highly variable in different countries, its within-GAS distribution seems not to be random. emm pattern E, 13 major emm types (emm12, 4, 28, 77, 75, 11, 22, 92, 58, 60, 94, 63, 114) and 4 emm clusters (A-C4, E1, E6, and E2) were significantly associated with macrolide resistance. emm patterns A-C and D, 14 major emm types (emm89, 3, 6, 2, 44, 82, 87, 118, 5, 49, 81, 59, 227, 78) and 3 well-defined emm clusters (A-C5, E3, and D4) were significantly associated with macrolide susceptibility. Scrutinizing the tendency of each MRGAS emm type to be significantly associated with specific macrolide resistance phenotype or genotype, interesting vignettes are also unveiled. The 30-valent vaccine covers ~95% of MRGAS isolates. The presented data urge the importance of comprehensive nationwide sustained surveillance of MRGAS circulating clones particularly in Low and Middle income countries where sampling bias is high and GAS epidemiology is obfuscated and needs to be demystified.

Emergence of macrolide-resistant Streptococcus pyogenes emm12 in southern Taiwan from 2000 to 2019

Group A Streptococcus (GAS) is an important pathogen causing morbidity and mortality worldwide. Surveillance of resistance and emm type has important implication to provide helpful information on the changing GAS epidemiology and empirical treatment. To study the emergence of resistant GAS in children with upper respiratory tract infection (URTI), a retrospective study was conducted from 2000 to 2019 in southern Taiwan. Microbiological studies, including antibiotic susceptibility, were performed. GAS emm types and sequences were determined by molecular methods. The population was divided into two separate decades to analyze potential changes over time. The 1st decade was 2000-2009; the 2nd decade was 2010-2019. Multivariate analyses were performed to identify independent risk factors associated with macrolide resistance between these periods. A total of 320 GAS from 339 children were enrolled. Most of the children (75%) were under 9 years of age. The most common diagnosis was scarlet fever (225, 66.4%), and the frequency increased from 54.8% in the 1st to 77.9% in the 2nd decade (p<0.0001). There was a significant increase in resistance to erythromycin and azithromycin from 18.1%, 19.3% in the 1st to 58.4%, 61.0% in the 2nd decade (p<0.0001). This was associated with clonal expansion of the GAS emm12-ST36 which carrying erm(B) and tet(M) from 3.0% in the 1st to 53.2% in the 2nd decade (p<0.0001). Significant emergence of macrolide-resistant GAS emm12-ST36 in children supports the need for continuing surveillance and investigation for the clonal virulence.

Emm Types and clusters and macrolide resistance of pediatric group A streptococcal isolates in Central Greece during 2011-2017.

BackgroundThe surveillance of emm types and macrolide susceptibility of group A streptococcus (GAS) in various areas and time periods enhances the understanding of the epidemiology of GAS infections and may guide treatment strategies and the formulation of type-specific vaccines. Greece has emerged as a country with high macrolide use. However, studies suggest a gradual reduction in macrolide consumption after 2007.MethodsDuring a 7-year period (2011–2017), 604 GAS isolates were recovered from consecutive children presenting with pharyngeal or nonpharyngeal infections in Central Greece; 517 viable isolates underwent molecular analysis, including emm typing.ResultsIsolates belonged to 20 different emm types (in decreasing order of prevalence: 1, 89, 4, 12, 28, 3, 75 and 6, accounting for 88.2% of total isolates). The emm types comprised 10 emm clusters (five most common clusters: E4, A-C3, E1, A-C4 and A-C5). The emm89 isolates were acapsular (‘new clade‘). Overall macrolide resistance rate was 15.4%, and cMLSB emerged as the predominant resistance phenotype (56.4%). The lowest annual resistance rates occurred in 2014 (13.1%), 2016 (5.5%) and 2017(8.0%) (P for trend = 0.002). Consumption of macrolide/lincosamide/streptogramin B declined by 22.6% during 2011–2017. Macrolide resistance and emm28 and emm77 types were associated (both P<0.001). The most frequently identified genetic lineages of macrolide-resistant GAS included emm28/ST52, emm77/ST63, emm12/ST36, emm89/ST101 and emm4/ST39. We estimated that 98.8% of the isolates belonged to emm types incorporated into a novel 30-valent M protein vaccine.ConclusionsIn Central Greece during 2011–2017, the acapsular emm89 isolates comprised the second most prevalent type. Susceptibility testing and molecular analyses revealed decreasing GAS macrolide resistance rates, which may be attributed to the reduction in the consumption of macrolides and/or the reduced circulation of macrolide-resistant clones in recent years. Such data may provide valuable baseline information in targeting therapeutic intervention and the formulation of type-specific GAS vaccines.

Molecular emm typing of Bulgarian macrolide-resistant Streptococcus pyogenes isolates.

Group A streptococcus (GAS) is a human pathogen causing a broad range of infections, linked with global morbidity and mortality. Macrolide resistance rates vary significantly in different parts of the world. Driving factors of the emergence and spread of resistant clones are not clearly understood. We investigated 102 macrolide-resistant GAS strains collected during the period 2014-2018 from various clinical specimens from Bulgarian patients. Strains were characterized by the presence of mefA/mefE, ermA, and ermB using polymerase chain reaction and sequencing for mefA/mefE. Resistant strains were studied by emm sequence typing and emm-cluster system. Most prevalent emm types among the macrolide-resistant GAS strains were emm28 (22.55%), emm12 (17.65%), and emm4 (16.66%). Almost all (87.25%) of the macrolide-resistant isolates harboring ermB were emm28. The isolates that carried ermA were predominantly emm12 (38.24%) and emm77 (38.24%), with fewer emm89 (23.53%). The isolates harbored predominantly mefE (49 isolates) and only 9 strains carried mefA. The most prevalent emm clusters among the GAS isolates were E4 (40.20%), A-C4 (17.65%), and E1 (16.66%). The study's results suggest that dissemination of specific clones in GAS population may also be the reason for the increasing macrolide-resistance rate in our country.

Changes in Macrolide Resistance Among Group A Streptococci in Serbia and Clonal Evolution of Resistant Isolates.

In Serbia, the frequency of macrolide-resistant group A streptococci (MRGASs) increased significantly from 2006 to 2009. MRGAS analysis in 2008 revealed the presence of three major clonal lineages: emm75/mefA, emm12/mefA, and emm77/ermTR. The aim of the present study was to determine the prevalence of macrolide resistance and to evaluate variations in the clonal composition of MRGASs. The study included 1,040 pharyngeal group A streptococci collected throughout Serbia, which were tested for antimicrobial susceptibility. MRGAS isolates were further characterized by the presence of resistance determinants, emm typing, and pulsed-field gel electrophoresis analysis. The prevalence of macrolide resistance was 9.6%, showing a slight decrease compared with the rate of 12.5% (2008). Tetracycline resistance was present in 6% of isolates, while norfloxacin nonsusceptibility detected for the first time in Serbia was 9.8%. The M phenotype dominated (84%), followed by the constitutive macrolides, lincosamides, and streptogramin B phenotype (12%). Five emm types were detected: emm75, emm12, emm1, emm28, and emm89. The emm75/mefA (62%), emm12/mefA (14%), and emm12/ermB/tetM (6%) were predominant clones and were found in both the present and the previous study periods at different frequencies. The major change was the loss of emm77/ermTR/tetO, which contributed to 15% of MRGASs in 2008.

Declining macrolide resistance in Streptococcus pyogenes in Portugal (2007-13) was accompanied by continuous clonal changes.

Macrolide resistance among Streptococcus pyogenes [group A streptococci (GAS)] in Portugal decreased between 1999 and 2006 and this decrease was accompanied by alterations in the prevalence of macrolide resistance phenotypes and clonal composition of the population. The aims of this study were to determine the macrolide resistance rate, resistance phenotypes and clones of GAS recovered from pharyngitis in 2007-13 in Portugal. Antimicrobial susceptibility was tested by disc diffusion. Macrolide-resistant isolates were characterized by emm typing, T typing, PFGE profiling and MLST, and the presence of macrolide resistance determinants was determined by PCR. We found continuing changes in macrolide resistance phenotypes and a persistent decline in overall erythromycin resistance, from 10% in 2007 to 1% in 2013. During this period there was a marked increase in emm11-ST403 cMLSB isolates, the disappearance of the emm3-ST315 M lineage and changes in the prevalence of previously identified GAS clones. Unexpectedly, the decline in erythromycin resistance and the decreasing prevalence of the MLSB phenotype were accompanied by a high consumption of long-acting and intermediate-acting macrolides, known to select for resistance and particularly for the erm(B) gene. The continuous decline in macrolide resistance detected since 2000, accompanied by a high clonal instability, emphasizes the importance of considering factors other than antibiotic consumption in explaining the prevalence of macrolide-resistant GAS.

Distribution of macrolide-resistant genes among isolates of macrolideresistant Streptococcus pyogenes and Streptococcus pneumoniae in Serbia

Macrolide resistance in Streptococcus pneumoniae and in group A streptococci (GAS) is a significant problem worldwide. In Serbia, data on the mechanisms of resistance and the corresponding resistance genes in streptococci are largely lacking. Therefore, we analyzed the distribution of macrolide resistance phenotypes and genotypes in 44 macrolideresistant GAS (MRGAS) and 50 macrolide-resistant S. pneumoniae (MRSP) isolates collected in the same period. The double disk diffusion test and PCR were used to analyze resistance phenotypes and resistance genes, respectively. Among MRSP, the MLSB phenotype dominated, whereas the M phenotype was the most prevalent among MRGAS isolates. Consequently, in MRSP, the ermB gene was the most common (n=40, 80%), followed by the mefA gene (n=7,14%). In MRGAS strains, mefA dominated (n=27,61%), followed by ermA (n=15, 33%) and ermB (n=3, 7%). In 3 MRSP isolates no resistance genes were detected, while one MRGAS strain with iMLSB phenotype harbored both ermA and mefA genes.

Multicentre surveillance of the prevalence and molecular epidemiology of macrolide resistance among pharyngeal isolates of group A streptococci in the USA

Rates of macrolide resistance in group A streptococci (GAS) were reported to be low in the US in the 1990s. However, we documented an unexpectedly high rate of macrolide resistance among GAS in Pittsburgh, PA, in 2001 and 2002. In an effort to define the current prevalence of macrolide-resistant GAS in the US, a multicentre surveillance project was initiated. Between October 2002 and May 2003, 50 pharyngeal GAS isolates per month were requested from each of the nine participating sites representing a wide geographical distribution. Standard susceptibility testing was performed and the macrolide resistance phenotype was assessed using double-disc diffusion testing. Monthly and annual rates of macrolide resistance were calculated for each site. An adjusted overall rate of macrolide resistance was determined to account for differences in the numbers of GAS isolates sent from each centre. Overall, 171 of the 2797 collected isolates of GAS (6.1%) were resistant to erythromycin. The adjusted overall resistance rate was 5.2%. Rates of macrolide resistance varied by site (range 3.0-8.7%) and also by month (<2% to >10%). The M phenotype of macrolide resistance accounted for >60% of all macrolide-resistant isolates recovered in this study. These data suggest an increasing prevalence and broad geographical distribution of macrolide-resistant GAS in the US, indicating the need for ongoing local and national longitudinal surveillance to define the extent of this problem.

In Vitro Activity of Telithromycin against Macrolide-Susceptible and Macrolide-Resistant Pharyngeal Isolates of Group A Streptococci in the United States

In vitro susceptibility testing of 2,797 group A streptococcus (GAS) isolates demonstrated that telithromycin was fully active against all macrolide-susceptible strains and among 80 of 115 macrolide-resistant GAS expressing the M phenotype. Telithromycin resistance was identified in 2 of 45 strains expressing the inducible macrolide-lincosamide-streptogramin B phenotype and four of nine isolates expressing the constitutive macrolide-lincosamide-streptogramin B resistance phenotype.

Community-Based Surveillance in the United States of Macrolide-Resistant Pediatric Pharyngeal Group A Streptococci during 3 Respiratory Disease Seasons

In 2001, a total of 48% of pharyngeal group A streptococci (GAS) from Pittsburgh children were macrolide resistant. We assessed macrolide resistance, resistance genes, and emm types among GAS in the United States. In prospective, multicenter, community-based surveillance of pharyngeal GAS recovered from children 3-18 years old during 3 respiratory seasons (the 2000-2001 season, the 2001-2002 season, and the 2002-2003 season), GAS were tested for macrolide resistance and underwent emm gene sequencing. Macrolide-resistant GAS were tested for resistance to clindamycin, and resistance genes were determined. Erythromycin resistance was observed in 4.4% of isolates from the 2000-2001 season, 4.3% from the 2001-2002 season, and 3.8% from the 2002-2003 season (P=.80). Clindamycin resistance was found in 1.04% of isolates; annual rates of clindamycin resistance were stable (P=.75). The predominant resistance genotype each year was mef A (65%-76.9%; overall, 70.3%). Resistant isolates included strains representing 8-11 different emm types each year. Heterogeneity of emm subtypes, resistance genes, and clindamycin resistance was evident among resistant isolates within some emm types. Geographic variability in resistance rates was present each year. The macrolide resistance rate among pharyngeal GAS was <5% and was stable over the 3 seasons. However, rates varied among sites each year. There was no evidence of spread of a specific resistant clone, increasing clindamycin resistance, or escalation in median erythromycin MICs.