Hypermutable and Fluoroquinolone-Resistant Clinical Isolates of
            <i>Staphylococcus aureus</i>

Trong, Hiep N′Guyen; Prunier, Anne-Laure; Leclercq, Roland

doi:10.1128/aac.49.5.2098-2101.2005

Cited by 46 publications

(30 citation statements)

References 20 publications

(20 reference statements)

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“…The TD-SCVs, in turn, showed a significantly higher prevalence of strong mutators than all NCV isolates analyzed in this study, both CF and non-CF derived. In accordance with previous studies on P. aeruginosa and S. aureus CF NCVs (7,31,44), antibiotic resistance was more prevalent among isolates with elevated mutation frequencies. Thus, TD-SCVs with a mutation frequency of Ն10 Ϫ8 had acquired antibiotic resistance.…”

Section: Vol 52 2008 Thymidine-dependent S Aureus Scvs Are Hypermusupporting

confidence: 78%

The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates

Besier

Zander

Kahl

et al. 2008

Antimicrob Agents Chemother

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Thymidine-dependent small-colony variants (TD-SCVs) of Staphylococcus aureus can be isolated from the airway secretions of patients suffering from cystic fibrosis (CF) and are implicated in persistent and treatmentresistant infections. These characteristics, as well as the variety of mutations in the thymidylate synthaseencoding thyA gene which are responsible for thymidine dependency, suggest that these morphological variants are hypermutable. To prove this hypothesis, we analyzed the mutator phenotype of different S. aureus phenotypes, in particular CF-derived TD-SCVs, CF-derived isolates with a normal phenotype (NCVs), and non-CF NCVs. The comparative analysis revealed that the CF isolates had significantly higher mutation rates than the non-CF isolates. The TD-SCVs, in turn, harbored significantly more strong hypermutators (mutation rate > 10 ؊7 ) than the CF and non-CF NCVs. In addition, antimicrobial resistance to non-beta-lactam antibiotics, including gentamicin, ciprofloxacin, erythromycin, fosfomycin, and rifampin, was significantly more prevalent in TD-SCVs than in CF and non-CF NCVs. Interestingly, macrolide resistance, which is usually mediated by mobile genetic elements, was conferred in half of the macrolide-resistant TD-SCVs by the point mutation A2058G or A2058T in the genes encoding the 23S rRNA. Sequence analysis of mutS and mutL, which are involved in DNA mismatch repair in gram-positive bacteria, revealed that in hypermutable CF isolates and especially in TD-SCVs, mutL was often truncated due to frameshift mutations. In conclusion, these data provide direct evidence that TD-SCVs are hypermutators. This hypermutability apparently favors the acquisition of antibiotic resistance and facilitates bacterial adaptation during long-term persistence.

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Section: Vol 52 2008 Thymidine-dependent S Aureus Scvs Are Hypermusupporting

confidence: 78%

The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates

Besier

Zander

Kahl

et al. 2008

Antimicrob Agents Chemother

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“…Of note, the type II SCCmec element has been demonstrated to reduce the toxicity of MRSA CC30 strains in comparison with methicillinsensitive CC30 strains, by preventing normal stationary phase induction of the agr system, leading to decreased expression of cytolytic toxins (35,36). It is speculated that this reduction in energy requirement could compensate for the metabolically costly maintenance of a large SCCmec element and its associated methicillin resistance, but which would be likely to lead to reduced fitness outside of the hospital setting (37). In addition to SCCmecII, we identified a number of nonsynonymous mutations specific to EMRSA-16 in loci previously demonstrated to influence antibiotic resistance, which are likely to have been the result of selective pressures prevalent in hospitals.…”

Section: Identification Of Mutations That Correlate With the Hospitalmentioning

confidence: 99%

Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus

McAdam

Templeton

Edwards

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

169

139

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Hospital-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health burden dominated by a small number of bacterial clones. The pandemic EMRSA-16 clone (ST36-II) has been widespread in UK hospitals for 20 y, but its evolutionary origin and the molecular basis for its hospital association are unclear. We carried out a Bayesian phylogenetic reconstruction on the basis of the genome sequences of 87 S. aureus isolates including 60 EMRSA-16 and 27 additional clonal complex 30 (CC30) isolates, collected from patients in three continents over a 53-y period. The three major pandemic clones to originate from the CC30 lineage, including phage type 80/81, Southwest Pacific, and EMRSA-16, shared a most recent common ancestor that existed over 100 y ago, whereas the hospital-associated EMRSA-16 clone is estimated to have emerged about 35 y ago. Our CC30 genome-wide analysis revealed striking molecular correlates of hospital-or community-associated pandemics represented by mobile genetic elements and nonsynonymous mutations affecting antibiotic resistance and virulence. Importantly, phylogeographic analysis indicates that EMRSA-16 spread within the United Kingdom by transmission from hospitals in large population centers in London and Glasgow to regional health-care settings, implicating patient referrals as an important cause of nationwide transmission. Taken together, the high-resolution phylogenomic approach used resulted in a unique understanding of the emergence and transmission of a major MRSA clone and provided molecular correlates of its hospital adaptation. Similar approaches for hospitalassociated clones of other bacterial pathogens may inform appropriate measures for controlling their intra-and interhospital spread.nosocomial | epidemiology

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“…Both hypermutability and any SCV phenotype contribute to resistance to macrolides, aminoglycosides, rifampin, fosfomycin, and ciprofloxacin (18,23,266,267). Furthermore, growth of S. aureus in CF lungs is associated with hypermutability (22,266), in vitro exposure of hypermutators to gentamicin resulted in an increased emergence of SCVs (268), and antibacterials other than gentamicin have not been studied.…”

Section: Emergence Of Resistance In Pk/pd Studies and In Cf Patientsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

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Hypermutable and Fluoroquinolone-Resistant Clinical Isolates of Staphylococcus aureus

Cited by 46 publications

References 20 publications

The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates

The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates

Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

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