A Once-Weekly R207910-containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis

Rationale: R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis. Objectives: To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide). Methods: The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs. Measurements and Main Results: Eight weeksofmonotherapy reduced the bacillary load by 3 to 4 log10 for rifapentine and by 5 to 6 log10 for R207910 (P , 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P , 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week. Conclusions: The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen

Efficiency of different control measures for preventing carbapenemase-producing enterobacteria and glycopeptide-resistant Enterococcus faecium outbreaks: a 6-year prospective study in a French multihospital institution, January 2010 to December 2015

An infection control programme was implemented in a 21,000-bed multihospital institution for controlling the spread of carbapenemase-producing Enterobacteriaceae (CPE) and glycopeptide-resistant Enterococcus faecium (GRE), classified as ‘emergent extensively drug-resistant bacteria’ (eXDR) in France. We evaluated factors associated with outbreaks occurrence (n = 103), which followed 901 eXDR introductions (index case followed or not by secondary cases) from 2010 to 2015. In univariate analysis, knowing that patients had been hospitalised abroad, bacterial species (GRE vs CPE, as well as the CPE Klebsiella pneumoniae compared with the other Enterobacteriaceae species) and type of measures implemented within the first 2 days of hospitalisation were associated with outbreaks occurrence, but not the type of wards where carriers were hospitalised, nor the eXDR colonisation or infection status. In multivariate analysis, occurrence of outbreaks was significantly lower when contact precautions (odds ratio (OR): 0.34; 95% confidence interval (CI): 0.22–0.54) and even more when dedicated nursing staff (OR: 0.09; 95% CI: 0.02–0.39) were implemented around eXDR index cases within the first 2 days of hospitalisation (p <  10 − 3). GRE introductions were more frequently associated with occurrence of outbreaks than CPE (OR: 3.58; 95% CI: 2.32–5.51, p < 10 − 3). A sustained and coordinated strategy is efficient to limit the spread of eXDR at the scale of a large health institution

Antibacterial Resistance, Wayampis Amerindians, French Guyana

Drug resistance in fecal bacteria was high in Wayampis Amerindians who did not take antibacterial agents and were not hospitalized for 1 year. In the Wayampis Amerindians, an isolated traditional community in French Guyana, antibacterial use was 0.64 treatments per person per year. Hospitalization rate was 6.1% per year. Antibacterial drug–resistant bacteria can spread in persons who are not taking antibacterial agents

Extended-spectrum β-lactamase-producing Escherichia coli in human-derived and foodchain-derived samples from England, Wales, and Scotland: an epidemiological surveillance and typing study

Background: Escherichia coli isolates producing extended-spectrum βlactamases (‘ESBL-E. coli’) cause >5000 bacteraemias annually in the UK. The contribution of the food chain to this challenge is debated. Methods: Selective media were used to seek ESBL-E. coli in routinely-submitted human faeces, sewage, farm slurry, and retail foodstuffs in London, East Anglia, Northwest England, Scotland and Wales. Recovered isolates were sequenced and compared with 293 bloodstream and 83 veterinary surveillance ESBL-E. coli isolates from the same regions. Findings: 10.7% (2157/20243) of human faeces contained ESBL-E. coli, rising to 17.0% (678/3995) in London. ESBL-E. coli also were frequent in sewage and present in 65.4% (104/159) of retail chicken, but rare in other meats and absent from plant-based foods. Sequence Type (ST) 131 dominated among ESBL-E. coli from human blood (188/293, 64.2%), faeces (128/360, 35.6%) and sewage (14/65, 21.5%) with STs 38 and 648 also widespread; CTX-M-15 was the predominant ESBL in these lineages. By contrast, STs 602, 23, 117 - mostly with CTX-M-1 ESBL - dominated among food and veterinary isolates, with only two ST131 organisms recovered. ST10 occurred in both animals and humans: being frequent in surveillance bovines and representing 4.2% (15/360) of human faecal isolates (but only 1% [3/293] from bacteraemias); however both human and animal ST10 isolates were diverse in serotype. Interpretation: Most human bacteraemias with ESBL-E. coli in the UK involve successful human-associated STs, particularly ST131; non-human reservoirs made little contribution to invasive human disease. Funding: NIHR Policy Research

High prevalence of fecal carriage of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in a pediatric unit in Madagascar

<p>Abstract</p> <p>Background</p> <p>Extended-spectrum β-lactamase (ESBL)-producing <it>Enterobacteriaceae </it>have spread worldwide but there are few reports on carriage in hospitals in low-income countries. ESBL-producing <it>Enterobacteriaceae </it>(ESBL-PE) have been increasingly isolated from nosocomial infections in Antananarivo, Madagascar.</p> <p>Methods</p> <p>we conducted a prevalence survey in a pediatric unit from March to April 2008 Patient rectal swabs were sampled on the first and the last day of hospitalization. Medical staff and environment were also sampled. Rectal and environmental swabs were immediately plated onto Drigalski agar supplemented with 3 mg/liter of ceftriaxon.</p> <p>Results</p> <p>Fecal carriage was detected in 21.2% of 244 infants on admission and 57.1% of 154 on discharge, after more than 48 hours of hospitalization (p < 0.001). The species most frequently detected on admission were <it>Escherichia coli and Klebsiella pneumoniae </it>(36.9%), whereas, on discharge, <it>K. pneumoniae </it>was the species most frequently detected (52.7%). ESBL-associated resistances were related to trimethoprim-sulfamethoxazole (91.3%), gentamicin (76.1%), ciprofloxacin (50.0%), but not to amikacin and imipenem. The increased prevalence of carriage during hospitalization was related to standard antimicrobial therapy.</p> <p>Conclusion</p> <p>The significant emergence of multidrug-resistant enteric pathogens in Malagasy hospitals poses a serious health threat requiring the implementation of surveillance and control measures for nosocomial infections.</p

Sterilizing Activity of Second-Line Regimens Containing TMC207 in a Murine Model of Tuberculosis

The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model. (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model).Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment.The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207, moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide.In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18–24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside

Targeting the Mycobacterium ulcerans cytochrome bc1:aa3 for the treatment of Buruli ulcer

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a neglected tropical skin disease that is most commonly found in children from West and Central Africa. Despite the severity of the infection, therapeutic options are limited to antibiotics with severe side effects. Here, we show that M. ulcerans is susceptible to the anti-tubercular drug Q203 and related compounds targeting the respiratory cytochrome bc; 1; :aa; 3; . While the cytochrome bc; 1; :aa; 3; is the primary terminal oxidase in Mycobacterium tuberculosis, the presence of an alternate bd-type terminal oxidase limits the bactericidal and sterilizing potency of Q203 against this bacterium. M. ulcerans strains found in Buruli ulcer patients from Africa and Australia lost all alternate terminal electron acceptors and rely exclusively on the cytochrome bc; 1; :aa; 3; to respire. As a result, Q203 is bactericidal at low dose against M. ulcerans replicating in vitro and in mice, making the drug a promising candidate for Buruli ulcer treatment