Bactericidal activity of quinupristin-dalfopristin against strains of Staphylococcus aureus with the MLS(B) phenotype of resistance according to the erm gene type.
ABSTRACT The bactericidal activity of quinupristin-dalfopristin was assessed by time-kill experiments against Staphylococcus aureus strains with characterized phenotypes and genotypes of MLS(B) resistance. A set of laboratory strains composed of isogenic pairs of S. aureus RN4220 derivatives containing or not the erm(A), erm(B) or erm(C) genes constitutively expressed and of 13 clinical isolates containing these genes inducibly or constitutively expressed were studied. Three of the clinical isolates with erm(B) or erm(A) genes had an unusual inducible MLS(B) cross resistance. The early bactericidal activity of quinupristin-dalfopristin was altered against strains expressing constitutive quinupristin resistance regardless of the erm(A), erm(B) or erm(C) type of gene. We conclude that the bactericidal activity of quinupristin-dalfopristin against staphylococci was dependent on the activity of quinupristin rather than on the erm genotype of the strain.
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ABSTRACT: Decreased susceptibility of Staphylococcus aureus to antistaphylococcal agents may be associated with inability to eradicate intracellular forms, which could explain therapeutic failures. This hypothesis was tested using clinical isolates obtained from a patient with persistent staphylococcal bacteraemia under therapy. Four isogenic isolates (three from tissue, one from blood) with increased MICs for vancomycin (1-4 mg/L) and for daptomycin (1-4 mg/L) were collected after an initial 16-day treatment with vancomycin-rifampicin-gentamicin, followed by 13-20 days of treatment with daptomycin-rifampicin-gentamicin. Isolates were tested for MICs and for: (i) vancomycin (BODIPY-FL-vancomycin) and daptomycin binding; (ii) cell wall turnover (loss of N-acetyl-d-[1-(14)C]glucosamine in 30 min after 1 h of labelling); and (iii) Triton X-100-induced autolysis. Extracellular (broth) and intracellular (THP-1 macrophages) activities of rifampicin, linezolid and fusidic acid at C(max), and of vancomycin, daptomycin, quinupristin-dalfopristin and oritavancin over a wide range of extracellular concentrations (with pharmacological modelling to determine E(max)), were measured at 24 h. Increases in vancomycin MICs correlated with increased drug binding, and decreased cell wall turnover and detergent-induced autolysis. Increases in daptomycin MICs correlated with decreased daptomycin binding. Intracellular activity was weak (E(max) <1 log(10) CFU decrease) for vancomycin against all isolates, and for daptomycin against isolates with MICs >1 mg/L. Among all antibiotics tested, only quinupristin-dalfopristin and oritavancin provided close to bactericidal intracellular activities (1.6-2.5 log(10) CFU decreases at C(max)). Determination of the intracellular susceptibility of S. aureus, combined with improved methods of diagnosis, could be useful when dealing with persistent staphylococcal infections and could improve therapy.Clinical Microbiology and Infection 08/2008; 14(8):766-77. · 4.58 Impact Factor
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ABSTRACT: The prevalence of macrolide-lincosamide-streptogramin B (MLSB) resistance as well as the MLSB resistance phenotypes were investigated by the double-disk diffusion test among 532 clinical staphylococci isolates in a Turkish university hospital. The activity of other antimicrobials, including trimethoprim/sulfamethoxazole, telithromycin, quinupristin/dalfopristin, linezolid, gentamicin, chloramphenicol, ciprofloxacin and vancomycin, was also evaluated. Of 532 isolates, 38.5% were resistant to MLSB antibiotics; 63.9% of the resistant isolates exhibited a constitutive phenotype (cMLSB) whereas 36.1% expressed an inducible resistance phenotype (iMLSB). MLSB resistance was more prevalent among coagulase-negative staphylococci (CoNS) strains. Oxacillin-resistant strains exhibited significantly higher MLSB resistance rates compared with oxacillin-susceptible strains (P<0.0001). The most frequently detected resistance phenotype among the total staphylococcal isolates was the constitutive type and this phenotype was more frequently encountered among oxacillin-resistant strains. With the exception of the fully active agents such as vancomycin, linezolid and quinupristin/dalfopristin, the most effective antibiotics were telithromycin and chloramphenicol among all isolates. Susceptibility rates to other antibiotics tested were higher among isolates without MLS(B) resistance than isolates with MLSB resistance. The detection of a considerable rate (43.5%) of iMLSB resistance among erythromycin-resistant/clindamycin-susceptible strains suggests that the true percentage of clindamycin resistance may be underestimated if testing for inducible resistance is not performed.International Journal of Antimicrobial Agents 05/2008; 31(4):364-8. · 4.42 Impact Factor
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ABSTRACT: Treatment of chronic or recurrent Staphylococcus aureus infections may require using antibiotics with activity against intracellular multiresistant organisms. Quinupristin/dalfopristin (3:7) has been examined in this context. Quinupristin and dalfopristin were used separately or mixed. Strains used were: (i) methicillin-susceptible and -resistant S. aureus (MSSA and MRSA); (ii) one vat(B) MSSA and msr(A/B) MRSA; (iii) erm(A)+ [MSSA, MRSA, vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA)]; and (iv) one erm(A/B)+ cfr+ MRSA resistant to quinupristin, dalfopristin and their combination. Assessment of activity was determined by: (i) MICs (CLSI method); and (ii) concentration-response curves in broth and after phagocytosis by THP-1 macrophages, with descriptors of the model (Emin) and the pharmacodynamic response [maximal relative efficacy (Emax), relative potency (EC50) and apparent static concentration (Cstatic)]. erm(A)-positive strains were all susceptible to quinupristin/dalfopristin (except strain CM05), with MICs not adversely influenced by acid pH or by the MRSA, VISA or VRSA character of the strain. In concentration-response experiments, quinupristin/dalfopristin showed similar patterns for all strains (except strain CM05), with a >3 log10 cfu decrease in broth and a 1.3 [erm(A) strain] to 2.6 [fully susceptible, vat(B) and msr(A/B) strains] log10 cfu decrease for intracellular bacteria at the maximal extracellular concentration tested (25 mg/L). Maximal extracellular and intracellular activity was obtained for a quinupristin/dalfopristin ratio of 3:7. For strain CM05, quinupristin/dalfopristin was static in all conditions. Based on historical comparisons with rifampicin, fluoroquinolones, lipoglycopeptides and other antistaphylococcal drugs with a large accumulation in eukaryotic cells, quinupristin/dalfopristin appears to be one of the most active antibiotics against intracellular S. aureus studied in this model so far, largely irrespective of its resistance phenotype.Journal of Antimicrobial Chemotherapy 04/2010; 65(6):1228-36. · 5.34 Impact Factor