South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study.

BACKGROUND: Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei. METHODS AND FINDINGS: We performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei. CONCLUSIONS: This study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally.

Simulation model to predict the fate of ciprofloxacin in the environment after wastewater treatment.

The extent hospital effluent contributes to antimicrobial presence in the environment and its impact on resistance dissemination remains unknown. To investigate the fate of the antimicrobial ciprofloxacin in hospital effluent a Monte Carlo simulation model was developed to model levels from hospital use to wastewater treatment plant (WWTP) effluent release, in addition to modeling resistance formation potential, hazard quotient (HQ) and swimmer exposure. The mean predicted concentration (PC) of ciprofloxacin in hospital effluent, urban effluent, WWTP effluent, sludge, soil and sea water was 579, 6.06, 2.59, 3.48, 0.006 and 0.15 mg/m(3), respectively. A parallel surveillance study confirmed levels of ciprofloxacin above or below the limit of detection. The model predicted levels would never exceed the ECOSAR toxicity value. The model predicted a 98% probability of ciprofloxacin exhibiting a HQ > 1 (low toxicity concern). The mean ciprofloxacin PC in WWTP effluent was less than the minimum inhibitory concentration (MIC). The probability of conditions in WWTP effluent being favorable for resistance at 20% and 80% of the MIC was 3% and 72%, respectively. In all instances, when the MIC was bound, the probability for resistance formation within soil and sea water was < 1%. The probability of a swimmer being exposed to a level of ciprofloxacin greater than the acceptable daily intake was negligible. The study concluded that release of hospital effluent into the environment may lead to concentrations of ciprofloxacin which are of low toxicity concern but may be conducive to resistance formation and allow for the dissemination of resistance.

A multilevel analysis of trimethoprim and ciprofloxacin prescribing and resistance of uropathogenic Escherichia coli in general practice.

OBJECTIVES: A retrospective analysis of databases was performed to describe trimethoprim and ciprofloxacin prescribing and resistance in Escherichia coli within general practices in the West of Ireland from 2004 to 2008. METHODS: Antimicrobial susceptibility testing was performed by disc diffusion methods according to the CLSI methods and criteria on significant E. coli isolates (colony count >10(5) cfu/mL) from urine samples submitted from general practice. Data were collected over a 4.5 year period and aggregated at practice level. Data on antimicrobial prescribing of practices were obtained from the national Irish prescribing database, which accounts for approximately 70% of all medicines prescribed in primary care. A multilevel model (MLwiN) was fitted with trimethoprim/ciprofloxacin resistance rates as outcome and practice prescribing as predictor. Practice and individual routinely collected variables were controlled for in the model. RESULTS: Seventy-two general practices sent between 13 and 720 (median 155) samples that turned out to be E. coli positive. Prescribing at practice level was significantly correlated with the probability of antimicrobial-resistant E. coli with an odds ratio of 1.02 [95% confidence interval (CI) 1.01-1.04] for every additional prescription of trimethoprim per 1000 patients per month in the practice and 1.08 (1.04-1.11) for ciprofloxacin. Age was a significant risk factor in both models. Higher variation between practices was found for ciprofloxacin as well as a yearly increase in resistance. Comparing a 'mean' practice with 1 prescription per month with one with 10 prescriptions per month showed an increase in predicted probability of a resistant E. coli for the 'mean' patient from 23.9% to 27.5% for trimethoprim and from 3.0% to 5.5% for ciprofloxacin. CONCLUSIONS: A higher level of antimicrobial prescribing in a practice is associated with a higher probability of a resistant E. coli for the patient. The variation in antimicrobial resistance levels between practices was relatively higher for ciprofloxacin than for trimethoprim.

Linezolid compared with eperezolid, vancomycin, and gentamicin in an in vitro model of antimicrobial lock therapy for Staphylococcus epidermidis central venous catheter-related biofilm infections.

Central venous catheter (CVC)-related infection (CVC-RI) is a common complication of CVC use. The most common etiological agents of CVC-RI are gram-positive organisms, in particular, staphylococci. An in vitro model for the formation of biofilms by Staphylococcus epidermidis ATCC 35984 on polyurethane coupons in a modified Robbins device was established. Biofilm formation was confirmed by electron microscopy and was quantified by determination of viable counts. Mueller-Hinton broth was replaced with sterile physiological saline (control) or a solution of vancomycin (10 mg/ml), gentamicin (10 mg/ml), linezolid (2 mg/ml), or eperezolid (4 mg/ml). Viable counts were performed with the coupons after exposure to antimicrobials for periods of 24, 72, 168, and 240 h. The mean viable count per coupon following establishment of the biofilm was 4.6 x 10(8) CFU/coupon, and that after 14 days of exposure to physiological saline was 2.5 x 10(7) CFU/coupon. On exposure to vancomycin (10 mg/ml), the mean counts were 2.5 x 10(7) CFU/coupon at 24 h, 4.3 x 10(6) CFU/coupon at 72 h, 1.4 x 10(5) CFU/coupon at 168 h, and undetectable at 240 h. With gentamicin (10 mg/ml) the mean counts were 2.7 x 10(7) CFU/coupon at 24 h, 3.7 x 10(6) CFU/coupon at 72 h, 8.4 x 10(6) CFU/coupon at 168 h, and 6.5 x 10(6) CFU/coupon at 240 h. With linezolid at 2 mg/ml the mean counts were 7.1 x 10(5) CFU/coupon at 24 h and not detectable at 72, 168, and 240 h. With eperezolid (4 mg/ml) no viable cells were recovered after 168 h. These data suggest that linezolid (2 mg/ml) and eperezolid (4 mg/ml) achieve eradication of S. epidermidis biofilms more rapidly than vancomycin (10 mg/ml) and gentamicin (10 mg/ml).