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Molecular evolution of beta-lactam-resistant Haemophilus influenzae: 9-year surveillance of penicillin-binding protein 3 mutations in isolates from Japan.

ABSTRACT: A total of 621 clinical isolates of Haemophilus influenzae collected in Japan between 1995 and 2003 were studied for their susceptibilities to several antimicrobial agents, beta-lactamase production, and amino acid substitutions in penicillin-binding protein 3 (PBP 3). Over the four study periods (first period, 1995 to 1996; second period, 1997 to 1998; third period, 2000 to 2001; fourth period, 2002 to 2003), the susceptibilities to beta-lactam agents decreased and the incidence of isolates with substitutions at positions 377, 385, 389, 517, and/or 526 in PBP 3 increased from 28.8% to 52.0%. Five hundred seventy-one beta-lactamase-nonproducing isolates were grouped into 18 classes, based on the pattern of the five mutations in PBP 3. The Asp526Lys substitution led to 6.0-, 4.3-, 2.4-, and 5.4-fold increases in amoxicillin-clavulanic acid, cefdinir, cefditoren, and faropenem resistance, respectively. PBP 3 with multiple substitutions (Met377Ile, Ser385Thr, and/or Leu389Phe) together with Asp526Lys resulted in increased resistance compared to that for PBP 3 with the Asp526Lys substitution alone. These results indicate that mutations at these five positions increased resistance to most beta-lactams. Although a significant change in the prevalence of beta-lactamase-producing strains was not observed, the proportions of those possessing both PBP 3 alterations and beta-lactamase production have slightly increased (from 1.4% to 5.0%). The ROB-1 beta-lactamase was rare, but this is the first report of this beta-lactamase in Japan.

SUBMITTER: Sanbongi Y

PROVIDER: S-EPMC1489784 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Molecular evolution of beta-lactam-resistant Haemophilus influenzae: 9-year surveillance of penicillin-binding protein 3 mutations in isolates from Japan.

Sanbongi Yumiko Y Suzuki Takahisa T Osaki Yumi Y Senju Nami N Ida Takashi T Ubukata Kimiko K

Antimicrobial agents and chemotherapy 20060701 7

A total of 621 clinical isolates of Haemophilus influenzae collected in Japan between 1995 and 2003 were studied for their susceptibilities to several antimicrobial agents, beta-lactamase production, and amino acid substitutions in penicillin-binding protein 3 (PBP 3). Over the four study periods (first period, 1995 to 1996; second period, 1997 to 1998; third period, 2000 to 2001; fourth period, 2002 to 2003), the susceptibilities to beta-lactam agents decreased and the incidence of isolates wit ...[more]

PMID: 16801430

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Project description:BACKGROUND: Beta-lactam resistance in Haemophilus influenzae due to ftsI mutations causing altered penicillin-binding protein 3 (PBP3) is increasing worldwide. Low-level resistant isolates with the N526K substitution (group II low-rPBP3) predominate in most geographical regions, while high-level resistant isolates with the additional S385T substitution (group III high-rPBP3) are common in Japan and South Korea.Knowledge about the molecular epidemiology of rPBP3 strains is limited. We combined multilocus sequence typing (MLST) and ftsI/PBP3 typing to study the emergence and spread of rPBP3 in nontypeable H. influenzae (NTHi) in Norway. RESULTS: The prevalence of rPBP3 in a population of 795 eye, ear and respiratory isolates (99% NTHi) from 2007 was 15%. The prevalence of clinical PBP3-mediated resistance to ampicillin was 9%, compared to 2.5% three years earlier. Group II low-rPBP3 predominated (96%), with significant proportions of isolates non-susceptible to cefotaxime (6%) and meropenem (20%). Group III high-rPBP3 was identified for the first time in Northern Europe.Four MLST sequence types (ST) with characteristic, highly diverging ftsI alleles accounted for 61% of the rPBP3 isolates. The most prevalent substitution pattern (PBP3 type A) was present in 41% of rPBP3 isolates, mainly carried by ST367 and ST14. Several unrelated STs possessed identical copies of the ftsI allele encoding PBP3 type A.Infection sites, age groups, hospitalization rates and rPBP3 frequencies differed between STs and phylogenetic groups. CONCLUSIONS: This study is the first to link ftsI alleles to STs in H. influenzae. The results indicate that horizontal gene transfer contributes to the emergence of rPBP3 by phylogeny restricted transformation.Clonally related virulent rPBP3 strains are widely disseminated and high-level resistant isolates emerge in new geographical regions, threatening current empiric antibiotic treatment. The need of continuous monitoring of beta-lactam susceptibility and a global system for molecular surveillance of rPBP3 strains is underlined. Combining MLST and ftsI/PBP3 typing is a powerful tool for this purpose.

Project description:The sequences of the ftsI gene, encoding the transpeptidase domain of penicillin binding protein (PBP) 3A and/or PBP 3B, which are involved in septal peptidoglycan synthesis, were determined for 108 clinical strains of Haemophilus influenzae with reduced susceptibility to beta-lactam antibiotics with or without beta-lactamase production and were compared to those of the ampicillin-susceptible Rd strain and ampicillin-susceptible clinical isolates. The sequences have 18 different mutation patterns and were classified into two groups on the basis of amino acid substitutions deduced from the nucleotide sequences located between bp 960 and 1618 of the ftsI gene. In group I strains (n = 7), His-517 was substituted for Arg-517. In group II strains (n = 101), Lys-526 was substituted for Asn-526. In subgroup IIa (n = 5; H. influenzae ATCC 49247), the only observed substitution was Lys-526 for Asn-526; in subgroup IIb (n = 56), Val-502 was substituted for Ala-502 (n = 13), along with several other substitutions: Asn-350 for Asp-350 (n = 15), Asn-350 for Asp-350 and Glu-490 for Gly-490 (n = 14), and Asn-350 for Asp-350 and Ser-437 for Ala-437 (n = 5). In subgroup IIc (n = 25), Thr-502 was substituted for Ala-502. In subgroup IId, Val-449 was substituted for Ile-449 (n = 15). The MICs of beta-lactam antibiotics for the 108 strains were to 8 to 16 times the MICs for susceptible strains. The strains, isolated from both adults and children, were analyzed for genetic relationship by pulsed-field gel electrophoresis and by determination of ftsI sequence phylogeny. Both analyses revealed the lack of clonality and the heterogeneity of the strains, but some clusters suggest the spread and/or persistence of a limited number of strains of the same pulsotype and pattern of amino acid substitutions. Reduced susceptibility to beta-lactam, brought about by mutations of the ftsI gene, is becoming a frequent phenomenon, affecting both strains that produce beta-lactamase and those that do not. The level of resistance remains low but opens the way to greater resistance in the future.

Project description:Neisseria meningitidis causes a life-threatening invasive meningococcal disease (IMD). Isolates resistant to antibiotics, such as penicillin, ceftriaxone, and ciprofloxacin that are recommended for the treatment of IMD patients and their close contacts have been serious public health concerns globally. However, susceptibility profiles to critically important antibiotics and the genetic characteristics of isolates possessing antibiotic resistance are extremely limited as IMD incidence is low in Japan. We assessed the susceptibility profiles of 87 randomly selected, sterile site-derived N. meningitidis strains isolated from hospitals nationwide, recovered between April 1998 and March 2018 in Japan, to seven antibiotics. As a result, we demonstrated, for the first time, that the isolates remained highly susceptible to ceftriaxone, meropenem, azithromycin, ciprofloxacin, chloramphenicol, and rifampin, but not to penicillin. We then characterized the genetic relatedness of six penicillin- and/or ciprofloxacin-resistant isolates obtained in this study with global 112 genomes using core-genome phylogenetic analysis. These results provide the first evidence that invasive lineages such as a penicillin-resistant serogroup W, sequence type (ST)-11 clonal complex (CC), and a ciprofloxacin-resistant serogroup B/C, ST-4821 CC that is considered as a global threat, have been sporadically identified in Japan. Our findings highlight the need to monitor antibiotic resistance in clinical isolates of N. meningitidis, thereby preventing the spread of antibiotic-resistant invasive lineages and maintaining effective treatment for IMD patients and their close contacts. IMPORTANCE Although antibiotics such as penicillin and ceftriaxone can treat invasive meningococcal disease (IMD), the emergence and spread of antibiotic-resistant Neisseria meningitidis have become a global concern. To provide effective treatment, including chemoprophylaxis to IMD patients and their close contacts, we highlighted the importance of recognizing the antibiotic resistance and genetic features of N. meningitidis isolates.

Project description:IntroductionThis study aimed to investigate the epidemiology, serotype distribution, phenotypical antibiogram, and molecular resistance gene characteristics of invasive Haemophilus influenzae infections in Denmark from 2014 to 2022. Additionally, the potential impact of outdoor temperature and COVID-19 restrictions on the epidemiology of H. influenzae was assessed.Materials and methodsInvasive H. influenzae isolates were received from patients with positive culture results from cerebrospinal fluid, blood, or other sterile sites. Sample data were obtained from the Danish laboratory surveillance system/MiBa database, and whole-genome sequencing (WGS) was performed on the isolates. The incidence rates and distribution of H. influenzae cases were analyzed, and antibiotic susceptibility were assessed.ResultsA total of 1,007 invasive H. influenzae cases were identified, with serotyping conducted for 752 (74.7%) isolates. The median incidence per year of H. influenzae was 2.0 cases per 100,000, with the highest incidence in 2014 and the lowest in 2020. The majority of H. influenzae isolates were non-typeable H. influenzae (NTHi), while the most prominent serotypes were serotype f followed by serotype b. Bacteremia cases accounted for the majority (88.6%) of occurrences, although meningitis cases showed an increasing trend during the time period. The age group 85+ exhibited the highest incidence. The implementation of COVID-19 preventive interventions in 2020 resulted in a significant reduction in H. influenzae incidence, which returned to pre-COVID levels in 2021. A negative correlation was observed between monthly H. influenzae cases and outdoor temperature. An overall level of genetic beta-lactamase resistance of 26.3% was observed divided into 10.6% beta-lactamase-positive ampicillin-resistant (gBLPAR), 13.6% beta-lactamase-negative ampicillin-resistant (gBLNAR) and 2.1% beta-lactamase-positive amoxicillin clavulanate-resistant (gBLPACR). Other non-beta-lactam resistance traits were detected in 7.6% of isolates (primarily aminoglycoside-modifying enzymes).ConclusionThe overall incidence of H. influenzae in Denmark returned to stable levels after the COVID-19 epidemic, with NTHi strains dominating. The COVID-19 preventive interventions led to a major reduction in incidence. A significant negative correlation between the incidence of H. influenzae and temperature was observed. The study revealed an overall genetic beta-lactam resistance rate of 26.3%, and the concordance between genotypic and phenotypic beta-lactam resistance was high (98.2%).

Dataset Information

Molecular evolution of beta-lactam-resistant Haemophilus influenzae: 9-year surveillance of penicillin-binding protein 3 mutations in isolates from Japan.

Publications

Molecular evolution of beta-lactam-resistant Haemophilus influenzae: 9-year surveillance of penicillin-binding protein 3 mutations in isolates from Japan.

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