Archive for October 23, 2016

Virological efficacy of PI monotherapy for HIV-1 in clinical practice

Antimicrob. Chemother. November 2016 V.71 N.11 P. 3228-3234

Kate El Bouzidi, Dami Collier, Eleni Nastouli, Andrew J. Copas, Robert F. Miller, and Ravindra K. Gupta

1Research Department of Infection, Division of Infection and Immunity, University College London, London, UK

2Research Department of Infection and Population Health, University College London, London, UK

3Department of Clinical Virology, University College London Hospitals NHS Trust, London, UK

4NIHR University College London Hospitals Biomedical Research Centre, London, UK

5Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

Background

Clinical trials of PI monotherapy indicate that most participants maintain viral suppression and emergent protease resistance is rare. However, outcomes among patients receiving PI monotherapy for clinical reasons, such as toxicity or adherence issues, are less well studied.

Methods

An observational study of patients attending an HIV treatment centre in London, UK, who had received PI monotherapy between 2004 and 2013, was conducted using prospectively collected clinical data and genotypic resistance reports. Survival analysis techniques were used to examine the times to virological failure and treatment discontinuation.

Results

Ninety-five patients had PI monotherapy treatment for a median duration of 126 weeks. Virological failure occurred during 64% of episodes and 8% of patients developed emergent protease mutations. We estimate failure occurs in half of episodes within 2 years following initiation. Where PI monotherapy was continued following virological failure, 68% of patients achieved viral re-suppression. Despite a high incidence of virological failure, many patients continued PI monotherapy and 79% of episodes were ongoing at the end of the study. The type of PI used, the presence of baseline protease mutations and the plasma HIV RNA at initiation did not have a significant impact on treatment outcomes.

Conclusions

There was a higher incidence of virological failure and emerging resistance in our UK clinical setting than described in PI monotherapy clinical trials and other European observational studies. Despite this, many patients continued PI monotherapy and regained viral suppression, indicating this strategy remains a viable option in certain individuals following careful clinical evaluation.

PDF

http://jac.oxfordjournals.org/content/71/11/3228.full.pdf+html

 

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October 23, 2016 at 6:25 pm

Interaction of Avibactam with Class B Metallo-β-Lactamases

Antimicrobial Agents and Chemotherapy October 2016 V.60 N.10 P.5655-5662

Martine I. Abboud, Christian Damblon, Jürgen Brem, Nicolas Smargiasso, Paola Mercuri, Bernard Gilbert, Anna M. Rydzik, Timothy D. W. Claridge, Christopher J. Schofield, and Jean-Marie Frère

aDepartment of Chemistry, University of Oxford, Oxford, United Kingdom

bLaboratoire de Chimie Biologique Structurale (CBS), Département de Chimie, Université de Liège, Liège, Belgium

cLaboratory of Mass Spectrometry, GIGA-R-CART, Université de Liège, Liège, Belgium

dCentre d’Ingénierie des Protéines, Université de Liège, Liège, Belgium

eChimie Analytique Inorganique, Département de Chimie, Université de Liège, Liège, Belgium

β-Lactamases are the most important mechanisms of resistance to the β-lactam antibacterials.

There are two mechanistic classes of β-lactamases: the serine β-lactamases (SBLs) and the zinc-dependent metallo-β-lactamases (MBLs). Avibactam, the first clinically useful non-β-lactam β-lactamase inhibitor, is a broad-spectrum SBL inhibitor, which is used in combination with a cephalosporin antibiotic (ceftazidime).

There are multiple reports on the interaction of avibactam with SBLs but few such studies with MBLs.

We report biochemical and biophysical studies on the binding and reactivity of avibactam with representatives from all 3 MBL subfamilies (B1, B2, and B3).

Avibactam has only limited or no activity versus MBL-mediated resistance in pathogens.

Avibactam does not inhibit MBLs and binds only weakly to most of the MBLs tested; in some cases, avibactam undergoes slow hydrolysis of one of its urea N-CO bonds followed by loss of CO2, in a process different from that observed with the SBLs studied.

The results suggest that while the evolution of MBLs that more efficiently catalyze avibactam hydrolysis should be anticipated, pursuing the development of dual-action SBL and MBL inhibitors based on the diazabicyclooctane core of avibactam may be productive.

PDF

http://aac.asm.org/content/60/10/5655.full.pdf+html

October 23, 2016 at 6:23 pm

Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia

Antimicrob. Agents Chemother. November 1, 2016 V.60 N.11 P.6609-6618

George Sakoulas, Joshua Olson, Juwon Yim, Niedita B. Singh, Monika Kumaraswamy, Diana T. Quach, Michael J. Rybak, Joseph Pogliano, and Victor Nizet

aUniversity of California San Diego School of Medicine, La Jolla, California, USA

bSharp Healthcare System, San Diego, California, USA

cEugene Appelbaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA

dDepartment of Biological Sciences, University of California San Diego, La Jolla, California, USA

eSkaggs School of Pharmacy, University of California San Diego, La Jolla, California, USA

Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.

In addition, recent work has demonstrated activity of combination therapy with beta-lactams from different classes against methicillin-resistant S. aureus (MRSA).

The ertapenem-plus-cefazolin combination was evaluated for synergy in vitro and in vivo in a murine skin infection model using an index MSSA bloodstream isolate from a patient in whom persistent bacteremia was cleared with this combination and against a cadre of well-described research strains and clinical strains of MSSA and MRSA.

Against the index MSSA bloodstream isolate, ertapenem and cefazolin showed synergy using both checkerboard (fractional inhibitory concentration [FIC] index = 0.375) and time-kill assays.

Using a disk diffusion ertapenem potentiation assay, the MSSA isolate showed a cefazolin disk zone increased from 34 to 40 mm. In vitro pharmacokinetic/pharmacodynamic modeling at clinically relevant drug concentrations demonstrated bactericidal activity (>3 log10-CFU/ml reduction) of the combination but bacteriostatic activity of ether drug alone at 48 h.

A disk diffusion potentiation assay showed that ertapenem increased the cefazolin zone of inhibition by >3 mm for 34/35 (97%) MSSA and 10/15 (67%) MRSA strains.

A murine skin infection model of MSSA showed enhanced activity of cefazolin plus ertapenem compared to monotherapy with these agents. After successful use in clearance of MSSA bacteremia, the combination of ertapenem and cefazolin showed synergy against MSSA in vitro and in vivo.

This combination may warrant consideration for future clinical study in MSSA bacteremia.

PDF

http://aac.asm.org/content/60/11/6609.full.pdf+html

October 23, 2016 at 6:22 pm

Results from the Canadian Nosocomial Infection Surveillance Program on Carbapenemase-Producing Enterobacteriaceae, 2010 to 2014

Antimicrob. Agents Chemother. November 1, 2016  V.60 N.11 P.6787-6794

Laura F. Mataseje, Kahina Abdesselam, Julie Vachon, Robyn Mitchel, Elizabeth Bryce, Diane Roscoe, David A. Boyd, Joanne Embree, Kevin Katz, Pamela Kibsey, Andrew E. Simor, Geoffrey Taylor, Nathalie Turgeon, Joanne Langley, Denise Gravel, Kanchana Amaratunga, and Michael R. Mulvey , on behalf of the Canadian Nosocomial Infection Surveillance Program

aAntimicrobial Resistance and Nosocomial Infections, Public Health Agency of Canada, Winnipeg, MB, Canada

bCenter for Communicable Diseases and Infection Control, Public Health Agency of Canada, Ottawa, ON, Canada

cDepartment of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada

dDepartment of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada

eDepartment of Infection Prevention and Control, North York General Hospital, Toronto, ON, Canada

fDepartment of Laboratory Medicine, Victoria General Hospital, Victoria, BC, Canada

gDepartment of Infectious Diseases, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

hDepartment of Infectious Diseases, University of Alberta Hospital, Edmonton, AB, Canada

iDepartment of Medical Microbiology, Hotel-Dieu de Quebec du CHUQ, QC, Canada

jDepartment of Pediatrics, IWK Health Centre, Halifax, NS, Canada

Carbapenemase-producing Enterobacteriaceae (CPE) are increasing globally; here we report on the investigation of CPE in Canada over a 5-year period. Participating acute care facilities across Canada submitted carbapenem-nonsusceptible Enterobacteriaceae from 1 January 2010 to 31 December 2014 to the National Microbiology Laboratory.

All CPE were characterized by antimicrobial susceptibilities, pulsed-field gel electrophoresis, multilocus sequence typing, and plasmid restriction fragment length polymorphism analysis and had patient data collected using a standard questionnaire. The 5-year incidence rate of CPE was 0.09 per 10,000 patient days and 0.07 per 1,000 admissions.

There were a total of 261 CPE isolated from 238 patients in 58 hospitals during the study period. blaKPC-3 (64.8%) and blaNDM-1 (17.6%) represented the highest proportion of carbapenemase genes detected in Canadian isolates. Patients who had a history of medical attention during international travel accounted for 21% of CPE cases.

The hospital 30-day all-cause mortality rate for the 5-year surveillance period was 17.1 per 100 CPE cases. No significant increase in the occurrence of CPE was observed from 2010 to 2014. Nosocomial transmission of CPE, as well as international health care, is driving its persistence within Canada.

PDF

http://aac.asm.org/content/60/11/6787.full.pdf+html

 

October 23, 2016 at 6:20 pm


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