Exposure of Staphylococcus aureus to subinhibitory concentrations of β-lactam antibiotics induces heterogeneous vancomycin-intermediate Staphylococcus aureus

International audienceGlycopeptides are known to select for heterogeneous vancomycin-intermediate Staphylococcus aureus (h-VISA) from susceptible strains. In certain clinical situations, h-VISA strains have been isolated from patients without previous exposure to glycopeptides, such as cystic fibrosis patients, who frequently receive repeated treatments with beta-lactam antibiotics. Our objective was to determine whether prolonged exposure to beta-lactam antibiotics can induce h-VISA. We exposed 3 clinical vancomycin-susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains to ceftazidime, ceftriaxone, imipenem, and vancomycin (as a control) at subinhibitory concentrations for 18 days in vitro. Population analyses showed progressive increases in vancomycin resistance; seven of the 12 derived strains obtained after induction were classified as h-VISA according to the following criteria: area under the curve (AUC) on day 18/AUC of Mu3 of >=90% and/or growth on brain heart infusion (BHI) agar with 4 mg/liter vancomycin. The derived isolates had thickened cell walls proportional to the level of glycopeptide resistance. Genes known to be associated with glycopeptide resistance (vraSR, yvqF, SA1703, graRS, walKR, and rpoB) were PCR sequenced; no de novo mutations were observed upon beta-lactam exposure. To determine whether trfA, a gene encoding a glycopeptide resistance factor, was essential in the selection of h-VISA upon beta-lactam pressure, a trfA-knockout strain was generated by allelic replacement. Indeed, beta-lactam exposure of this mutated strain showed no capacity to induce vancomycin resistance. In conclusion, these results showed that beta-lactam antibiotics at subinhibitory concentrations can induce intermediate vancomycin resistance in vitro. This induction required an intact trfA locus. Our results suggest that prior use of beta-lactam antibiotics can compromise vancomycin efficacy in the treatment of MRSA infections

Discrepancy Between European Association of Urology Guidelines and Daily Practice in the Management of Non-muscle-invasive Bladder Cancer: Results of a European Survey.

BACKGROUND The European Association of Urology (EAU) non-muscle-invasive bladder cancer (NMIBC) guidelines are meant to help minimise morbidity and improve the care of patients with NMIBC. However, there may be underuse of guideline-recommended care in this potentially curable cohort. OBJECTIVE To assess European physicians' current practice in the management of NMIBC and evaluate its concordance with the EAU 2013 guidelines. DESIGN, SETTING, AND PARTICIPANTS Initial 45-min telephone interviews were conducted with 20 urologists to develop a 26-item questionnaire for a 30-min online quantitative interview. A total of 498 physicians with predefined experience in treatment of NMIBC patients, from nine European countries, completed the online interviews. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Descriptive statistics of absolute numbers and percentages of the use of diagnostic tools, risk group stratification, treatment options chosen, and follow-up regimens were used. RESULTS AND LIMITATIONS Guidelines are used by ≥87% of physicians, with the EAU guidelines being the most used ones (71-100%). Cystoscopy (60-97%) and ultrasonography (42-95%) are the most used diagnostic techniques. Using EAU risk classification, 40-69% and 88-100% of physicians correctly identify all the prognostic factors for low- and high-risk tumours, respectively. Re-transurethral resection of the bladder tumour (re-TURB) is performed in 25-75% of low-risk and 55-98% of high-risk patients. Between 21% and 88% of patients received a single instillation of chemotherapy within 24h after TURB. Adjuvant intravesical treatment is not given to 6-62%, 2-33%, and 1-20% of the patients with low-, intermediate-, and high-risk NMIBC, respectively. Patients with low-risk NMIBC are likely to be overmonitored and those with high-risk NMIBC undermonitored. Our study is limited by the possible recall bias of the selected physicians. CONCLUSIONS Although most European physicians claim to apply the EAU guidelines, adherence to them is low in daily practice. PATIENT SUMMARY Our survey among European physicians investigated discrepancies between guidelines and daily practice in the management of non-muscle-invasive bladder cancer (NMIBC). We conclude that the use of the recommended diagnostic tools, risk-stratification of NMIBC, and performance of re-TURB have been adopted, but adjuvant intravesical treatment and follow-up are not uniformly applied