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Novel Soil-Derived Beta-Lactam, Chloramphenicol, Fosfomycin and Trimethoprim Resistance Genes Revealed by Functional Metagenomics.

ABSTRACT: Antibiotic resistance genes (ARGs) in soil are considered to represent one of the largest environmental resistomes on our planet. As these genes can potentially be disseminated among microorganisms via horizontal gene transfer (HGT) and in some cases are acquired by clinical pathogens, knowledge about their diversity, mobility and encoded resistance spectra gained increasing public attention. This knowledge offers opportunities with respect to improved risk prediction and development of strategies to tackle antibiotic resistance, and might help to direct the design of novel antibiotics, before further resistances reach hospital settings or the animal sector. Here, metagenomic libraries, which comprise genes of cultivated microorganisms, but, importantly, also those carried by the uncultured microbial majority, were screened for novel ARGs from forest and grassland soils. We detected three new beta-lactam, a so far unknown chloramphenicol, a novel fosfomycin, as well as three previously undiscovered trimethoprim resistance genes. These ARGs were derived from phylogenetically diverse soil bacteria and predicted to encode antibiotic inactivation, antibiotic efflux, or alternative variants of target enzymes. Moreover, deduced gene products show a minimum identity of ~21% to reference database entries and confer high-level resistance. This highlights the vast potential of functional metagenomics for the discovery of novel ARGs from soil ecosystems.

SUBMITTER: Willms IM

PROVIDER: S-EPMC8066302 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceOral β-lactam antibiotics are traditionally not recommended to treat Enterobacterales bacteremia because of concerns over subtherapeutic serum concentrations, but there is a lack of outcomes data, specifically after initial treatment with parenteral antibiotics. Given the limited data and increasing limitations of fluoroquinolones or trimethoprim-sulfamethoxazole (TMP-SMX), oral β-lactam antibiotics may be a valuable additional treatment option.ObjectiveTo compare definitive therapy with oral β-lactam antibiotics vs fluoroquinolones or TMP-SMX for Enterobacterales bacteremia from a suspected urine source.Design, setting, and participantsA retrospective cohort study was conducted from January 1, 2007, to September 30, 2015, at 114 Veterans Affairs hospitals among 4089 adults with Escherichia coli, Klebsiella spp, or Proteus spp bacteremia and matching urine culture results. Additional inclusion criteria were receipt of active parenteral antibiotic(s) followed by conversion to an oral antibiotic. Exclusion criteria were previous Enterobacterales bacteremia, urologic abscess, or chronic prostatitis. Data were analyzed from April 15, 2019, to July 26, 2020.ExposuresConversion of therapy to an oral β-lactam antibiotic vs fluoroquinolones or TMP-SMX after 1 to 5 days of parenteral antibiotics.Main outcomes and measuresThe main outcome was a composite of either 30-day all-cause mortality or 30-day recurrent bacteremia. Propensity-based overlap weights were used to adjust for differences between groups. Log binomial regression models were used to estimate adjusted relative risks (aRRs) and adjusted risk differences (aRDs).ResultsOf the 4089 eligible patients (3731 men [91.2%]; median age, 71 years [interquartile range, 63-81 years]), 955 received an oral β-lactam antibiotic, and 3134 received fluoroquinolones or TMP-SMX. The primary outcome occurred for 42 patients (4.4%) who received β-lactam antibiotics and 94 patients (3.0%) who received fluoroquinolones or TMP-SMX (aRD, 0.99% [95% CI, -0.42% to 2.40%]; aRR, 1.31 [95% CI, 0.87-1.95]). Mortality rates were 3.0% (n = 29) for patients receiving β-lactam antibiotics vs 2.6% (n = 82) for those receiving fluoroquinolones or TMP-SMX (aRD, 0.06% [95% CI, -1.13% to 1.26%]; aRR, 1.02 [95% CI, 0.67-1.56]). Recurrent bacteremia rates were 1.5% (n = 14) among those receiving β-lactam antibiotics vs 0.4% (n = 12) among those receiving fluoroquinolones or TMP-SMX (aRD, 1.03% [95% CI, 0.24%-1.82%]; aRR, 3.43 [95% CI, 0.42-27.90]).Conclusions and relevanceIn this cohort study of adults with E coli, Klebsiella spp, or Proteus spp bacteremia from a suspected urine source, the relative risk of recurrent bacteremia was not significantly higher with β-lactam antibiotics compared with fluoroquinolones or TMP-SMX, and the absolute risk and risk difference were small (ie, <3%). No significant difference in mortality was observed. Oral β-lactam antibiotics may be a reasonable step-down treatment option, primarily when alternative options are limited by resistance or adverse effects. Further study is needed because statistical power was limited owing to a low number of recurrent bacteremia events.

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Novel Soil-Derived Beta-Lactam, Chloramphenicol, Fosfomycin and Trimethoprim Resistance Genes Revealed by Functional Metagenomics.

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