Archive for July 24, 2016

Editor’s Choice: Transferable resistance to colistin: a new but old threat

Journal of Antimicrobial Chemotherapy August 2016 V.71 N.8  P.2066-2070

Stefan Schwarz and Alan P. Johnson

1Institute of Farm Animal Genetics, Friedrich-Loeffler-Institut (FLI), Neustadt-Mariensee, Germany

2Department of Healthcare-Associated Infection and Antimicrobial Resistance, National Infection Service, Public Health England, London NW9 5EQ, UK

In this Leading article, we summarize current knowledge of the occurrence of the first and so far only transferable colistin resistance gene, mcr-1. Its location on a conjugative plasmid is likely to have driven its spread into a range of enteric bacteria in humans and animals. Screening studies have identified mcr-1 in five of the seven continents and retrospective studies in China have identified this gene in Escherichia coli originally isolated in the 1980s, while the first European isolate dates back to 2005. Based on the widespread use of colistin in pigs and poultry in several countries and the higher number of mcr-1-carrying isolates of animal origin than of human origin, it is tempting to assume that this resistance may have emerged in the animal sector. Whatever its origin, interventions to reduce its further spread will require an integrated global one-health approach, comprising robust antibiotic stewardship to reduce unnecessary colistin use, improved infection prevention, and control and surveillance of colistin usage and resistance in both veterinary and human medicine.

The mcr-1 gene encoding colistin resistance in Escherichia coli has been around since the 1980s, appears to be ubiquitous and may have emerged in the animal sector, but interventions to reduce its further spread will require an integrated global one-health approach.


July 24, 2016 at 12:30 pm

Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases

Antimicrob. Agents Chemother. August 2016 V.60 N.8 P.4652-4658

Devyani Deshpande, Shashikant Srivastava, Sandirai Musuka, and Tawanda Gumbo

aCenter for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA

bDepartment of Medicine, University of Cape Town, Observatory, South Africa

Mycobacterium avium-intracellulare complex (MAC) causes an intractable intracellular infection that presents as chronic pulmonary disease. Currently, therapy consists of ethambutol and macrolides and takes several years to complete. The neuroleptic phenothiazine thioridazine kills mycobacteria by inhibiting the electron transport chain. In several experiments with bacterial populations of up to 1012 CFU/ml, we failed to isolate any bacteria resistant to 3 times the MIC of thioridazine, suggesting the absence of resistant mutants at bacterial burdens severalfold higher than those encountered in patients. In the hollow-fiber model of intracellular MAC (HFS-MAC), thioridazine achieved an extracellular half-life of 16.8 h and an intracellular half-life of 19.7 h. Thioridazine concentrations were >28,000-fold higher inside infected macrophages than in the HFS-MAC central compartment (equivalent to plasma). Thioridazine maximal kill was 5.20 ± 0.75 log10 CFU/ml on day 7 (r2 = 0.96) and 7.19 ± 0.31 log10 CFU/ml on day 14 (r2 = 0.99), the highest seen with any drug in the system. Dose fractionation studies revealed that thioridazine efficacy and acquired drug resistance were driven by the peak concentation-to-MIC ratio, with a 50% effective concentration (EC50) of 2.78 ± 0.44 for microbial killing. Acquired drug resistance was encountered by day 21 with suboptimal doses, demonstrating that fluctuating drug concentrations drive evolution faster than static concentrations in mutation frequency studies. However, the thioridazine EC50 changed 16.14-fold when the concentration of fetal bovine serum was changed from 0% to 50%, suggesting that intracellular potency could be heavily curtailed by protein binding. Efficacy in patients will depend on the balance between trapping of the drug in the pulmonary system and the massive intracellular concentrations versus very high protein binding of thioridazine.



July 24, 2016 at 12:29 pm

Clostridium difficile Infection: Is It Finally Time to Give Mom Vancomycin?

Infectious Diseases in Clinical Practice July 2016 V.24 N.4 P.193–194

Editorial Comment

Gallagher, Jason C.

From the Department of Pharmacy Practice, School of Pharmacy, Temple University, Philadelphia, PA.

Despite the long-term availability of 2 primary and familiar options, the pharmacotherapy for Clostridium difficile infections (CDI) has evolved along an interesting path. Vancomycin enjoyed a time at the top of the armamentarium, though it was initially used due to the thought that Staphylococcus aureus was the cause of pseudomembranous colitis.1 When C. difficile was determined to be the true cause of disease in 1978, vancomycin was known to be active and had already demonstrated efficacy in the treatment of CDI.2 However, 2 primary factors prompted the search for a substitute therapy: the cost of commercially available oral vancomycin, and concerns that oral vancomycin use is associated with infection from vancomycin-resistant enterococci (VRE).3–5 From a microbiological, tolerance, and cost perspective, metronidazole was a logical choice……



July 24, 2016 at 12:27 pm


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