Archive for November 19, 2016

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

Antimicrob. Agents Chemother. November 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.



November 19, 2016 at 8:03 am

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

Antimicrob. Agents Chemother. November 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.


November 19, 2016 at 8:01 am

Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery

Antimicrob. Agents Chemother. November 2016 V.60 N.11 P.6619-6625

Cheng Lu, Yuyi Zhang, Mingyu Chen, Ping Zhong, Yuancheng Chen, Jicheng Yu, Xiaojie Wu, Jufang Wu, and Jing Zhang

aInstitute of Antibiotics, Huashan Hospital Affiliated to Fudan University, Shanghai, China

bKey Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China

cDepartment of Neurosurgery, Huashan Hospital Affiliated to Fudan University, Shanghai, China

Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known.

Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients.

Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling.

Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF.

A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively.

Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount.

The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases.

A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at under identifier NCT02506686.)


November 19, 2016 at 7:59 am

Mechanisms of Resistance – Interaction of Avibactam with Class B Metallo-β-Lactamases

Antimicrob. Agents Chemother. 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.


November 19, 2016 at 7:29 am


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