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Genomic identification of a novel co-trimoxazole resistance genotype and its prevalence amongst Streptococcus pneumoniae in Malawi.

ABSTRACT: OBJECTIVES:This study aimed to define the molecular basis of co-trimoxazole resistance in Malawian pneumococci under the dual selective pressure of widespread co-trimoxazole and sulfadoxine/pyrimethamine use. METHODS:We measured the trimethoprim and sulfamethoxazole MICs and analysed folA and folP nucleotide and translated amino acid sequences for 143 pneumococci isolated from carriage and invasive disease in Malawi (2002-08). RESULTS:Pneumococci were highly resistant to both trimethoprim and sulfamethoxazole (96%, 137/143). Sulfamethoxazole-resistant isolates showed a 3 or 6 bp insertion in the sulphonamide-binding site of folP. The trimethoprim-resistant isolates fell into three genotypic groups based on dihydrofolate reductase (encoded by folA) mutations: Ile-100-Leu (10%), the Ile-100-Leu substitution together with a residue 92 substitution (56%) and those with a novel uncharacterized resistance genotype (34%). The nucleotide sequence divergence and dN/dS of folA and folP remained stable from 2004 onwards. CONCLUSIONS:S. pneumoniae exhibit almost universal co-trimoxazole resistance in vitro and in silico that we believe is driven by extensive co-trimoxazole and sulfadoxine/pyrimethamine use. More than one-third of pneumococci employ a novel mechanism of co-trimoxazole resistance. Resistance has now reached a point of stabilizing evolution. The use of co-trimoxazole to prevent pneumococcal infection in HIV/AIDS patients in sub-Saharan Africa should be re-evaluated.

SUBMITTER: Cornick JE

PROVIDER: S-EPMC3886935 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Genomic identification of a novel co-trimoxazole resistance genotype and its prevalence amongst Streptococcus pneumoniae in Malawi.

Cornick Jennifer E JE Harris Simon R SR Parry Christopher M CM Moore Michael J MJ Jassi Chikondi C Kamng'ona Arox A Kulohoma Benard B Heyderman Robert S RS Bentley Stephen D SD Everett Dean B DB

The Journal of antimicrobial chemotherapy 20130929 2

<h4>Objectives</h4>This study aimed to define the molecular basis of co-trimoxazole resistance in Malawian pneumococci under the dual selective pressure of widespread co-trimoxazole and sulfadoxine/pyrimethamine use.<h4>Methods</h4>We measured the trimethoprim and sulfamethoxazole MICs and analysed folA and folP nucleotide and translated amino acid sequences for 143 pneumococci isolated from carriage and invasive disease in Malawi (2002-08).<h4>Results</h4>Pneumococci were highly resistant to bo ...[more]

PMID: 24080503

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Project description:BackgroundAzithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study.MethodsIn the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture Streptococcus pneumoniae. The primary outcome was the proportion of S pneumoniae isolates exhibiting macrolide resistance at 12 months and 24 months, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02048007.FindingsAt baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage of S pneumoniae was greater than 85% and the proportion of strains resistant to macrolides was 28%. At the 12-month follow-up, macrolide resistance was higher in the azithromycin group (36·9%, 95% CI 32·5-41·2) than in the placebo group (21·6%, 17·7-25·4; OR 2·26, 95% CI 1·46-3·49; p=0·0002). At 24 months, macrolide resistance remained higher in the azithromycin group (43·9%, 39·2-48·5) compared with placebo (32·8%, 28·5-37·1; OR 1·66, 1·15-2·40; p=0·0069).InterpretationThese findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality.FundingBill & Melinda Gates Foundation.

Dataset Information

Genomic identification of a novel co-trimoxazole resistance genotype and its prevalence amongst Streptococcus pneumoniae in Malawi.

Publications

Genomic identification of a novel co-trimoxazole resistance genotype and its prevalence amongst Streptococcus pneumoniae in Malawi.

Similar Datasets

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