George G Zhanel

Diagnostic Services of Manitoba, Inc., Winnipeg, Manitoba, Canada

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Publications (291)1056.3 Total impact

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    ABSTRACT: Plazomicin is a next generation aminoglycoside that is not affected by most clinically relevant aminoglycoside modifying enzymes. The in vitro activities of plazomicin and comparator antimicrobials were evaluated against a collection of 5015 bacterial isolates obtained from patients in Canadian hospitals between January 2011 and October 2012. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, with minimum inhibitory concentrations interpreted according to CLSI breakpoints when available. Plazomicin demonstrated potent in vitro activity against members of the family Enterobacteriaceae, with all species except Proteus mirabilis having an MIC90 of ≤1 μg/mL. Plazomicin was active against aminoglycoside non-susceptible Escherichia coli, with MIC50 and MIC90 values identical to those for aminoglycoside susceptible isolates. Further, plazomicin demonstrated equivalent activity versus extended-spectrum beta-lactamase (ESBL)-producing and non-ESBL-producing E. coli and Klebsiella pneumoniae, with 90% of isolates inhibited by an MIC of ≤1 μg/mL. MIC50 and MIC90 values for plazomicin against Pseudomonas aeruginosa were 4 μg/mL and 16 μg/mL, in comparison with 4 μg/mL and 8 μg/mL for amikacin. Plazomicin had an MIC50 of 8 μg/mL and an MIC90 of 32 μg/mL versus 64 multidrug-resistant P. aeruginosa. Plazomicin was active against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, with both having an MIC50 and MIC90 of 0.5 μg/mL and 1 μg/mL, respectively. In summary, plazomicin demonstrated potent in vitro activity against a diverse collection of gram-negative bacilli and gram-positive cocci, obtained over a large geographic area. These data support further evaluation of plazomicin in the clinical setting.
    Antimicrobial Agents and Chemotherapy 02/2014; · 4.57 Impact Factor
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    ABSTRACT: Ceftolozane is a novel cephalosporin currently being developed with the β-lactamase inhibitor tazobactam for the treatment of complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), and ventilator-associated bacterial pneumonia (VABP). The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity. As a β-lactam, its mechanism of action is the inhibition of penicillin-binding proteins (PBPs). Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases (e.g., TEM-1 and SHV-1), but, similar to other oxyimino-cephalosporins such as ceftazidime and ceftriaxone, it is compromised by extended-spectrum β-lactamases (ESBLs) and carbapenemases. The addition of tazobactam extends the activity of ceftolozane to include most ESBL producers as well as some anaerobic species. Ceftolozane is distinguished from other cephalosporins by its potent activity versus Pseudomonas aeruginosa, including various drug-resistant phenotypes such as carbapenem, piperacillin/tazobactam, and ceftazidime-resistant isolates, as well as those strains that are multidrug-resistant (MDR). Its antipseudomonal activity is attributed to its ability to evade the multitude of resistance mechanisms employed by P. aeruginosa, including efflux pumps, reduced uptake through porins and modification of PBPs. Ceftolozane demonstrates linear pharmacokinetics unaffected by the coadministration of tazobactam; specifically, it follows a two-compartmental model with linear elimination. Following single doses, ranging from 250 to 2,000 mg, over a 1-h intravenous infusion, ceftolozane displays a mean plasma half-life of 2.3 h (range 1.9-2.6 h), a steady-state volume of distribution that ranges from 13.1 to 17.6 L, and a mean clearance of 102.4 mL/min. It demonstrates low plasma protein binding (20 %), is primarily eliminated via urinary excretion (≥92 %), and may require dose adjustments in patients with a creatinine clearance <50 mL/min. Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic-pharmacodynamic index that is best correlated with ceftolozane's in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen (%fT >MIC), as expected of β-lactams. Two phase II clinical trials have been conducted to evaluate ceftolozane ± tazobactam in the settings of cUTIs and cIAIs. One trial compared ceftolozane 1,000 mg every 8 h (q8h) versus ceftazidime 1,000 mg q8h in the treatment of cUTI, including pyelonephritis, and demonstrated similar microbiologic and clinical outcomes, as well as a similar incidence of adverse effects after 7-10 days of treatment, respectively. A second trial has been conducted comparing ceftolozane/tazobactam 1,000/500 mg and metronidazole 500 mg q8h versus meropenem 1,000 mg q8h in the treatment of cIAI. A number of phase I and phase II studies have reported ceftolozane to possess a good safety and tolerability profile, one that is consistent with that of other cephalosporins. In conclusion, ceftolozane is a new cephalosporin with activity versus MDR organisms including P. aeruginosa. Tazobactam allows the broadening of the spectrum of ceftolozane versus β-lactamase-producing Gram-negative bacilli including ESBLs. Potential roles for ceftolozane/tazobactam include empiric therapy where infection by a resistant Gram-negative organism (e.g., ESBL) is suspected, or as part of combination therapy (e.g., with metronidazole) where a polymicrobial infection is suspected. In addition, ceftolozane/tazobactam may represent alternative therapy to the third-generation cephalosporins after treatment failure or for documented infections due to Gram-negative bacilli producing ESBLs. Finally, the increased activity of ceftolozane/tazobactam versus P. aeruginosa, including MDR strains, may lead to the treatment of suspected and documented P. aeruginosa infections with this agent. Currently, ceftolozane/tazobactam is being evaluated in three phase III trials for the treatment of cUTI, cIAI, and VABP.
    Drugs 12/2013; · 4.63 Impact Factor
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    ABSTRACT: The aim of this study was to compare the potential of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) targets against MRSA isolates collected from ICU settings. Monte Carlo Simulations were performed to simulate the PK/PD indices of the investigated antimicrobials. Probability of target attainment (PTA) was estimated at MIC values ranging from 0.03-32 μg/ml to define the PK/PD susceptibility breakpoints. Cumulative fraction of response (CFR) was computed using MIC data from the Canadian National Intensive Care Unit (CAN-ICU) study. Analysis of the simulation results suggested the breakpoints of 4 μg/ml for ceftobiprole (500 mg /2hrs TID), 0.25 μg/ml for dalbavancin (1000 mg), 0.12 μg/ml for daptomycin (4 mg/kg QD and 6 mg/kg QD) and tigecycline (50 mg BID), and 2 μg/ml for linezolid (600 mg BID) and vancomycin (1 gm BID and 1.5 gm BID). The estimated CFR were 100, 100, 70.6, 88.8, 96.5, 82.4, 89.4 and 98.3% for ceftobiprole, dalbavancin, daptomycin (4mg/kg/day), daptomycin (6mg/kg/day), linezolid, tigecycline, vancomycin (1gm BID) and vancomycin (1.5gm BID), respectively. In conclusion, ceftobiprole and dalbavancin have the highest probability of achieving their requisite PK/PD targets against MRSA isolated from the ICU settings. The susceptibility predictions suggested a reduction of the vancomycin breakpoint to 1 μg/ml. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Pharmacology and Physiology 12/2013; · 2.16 Impact Factor
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    ABSTRACT: Alterations in penicillin-binding proteins, the target enzymes for ß-lactam antibiotics, are recognized as primary penicillin resistance mechanisms in Streptococcus pneumoniae. Few studies analyzed penicillin resistance at the genome scale, however, and we report the sequencing of S. pneumoniae R6 transformants generated while reconstructing the penicillin resistance phenotype from three penicillin resistant clinical isolates by serial genome transformation. The genome sequence of the three last-level transformants T2-18209, T5-1983 and T3-55938 revealed that 16.2 kb, 82.7kb and 137.2 kb of their genomes had been replaced with 5, 20 and 37 recombinant sequence segment derived from their respective parental clinical isolates, documenting the extent of DNA transformation between strains. A role in penicillin resistance was confirmed for some of the mutations identified in the transformants. Several multiple recombination events were also found to happen at single loci coding for penicillin-binding proteins to increase resistance. Sequencing of the transformants with similar minimal inhibitory concentrations for penicillin as the parent clinical strains confirmed the importance of mosaic PBP2x, 2b and 1a as a driving force in penicillin resistance. A role in resistance for mosaic PBP2a was also observed for two of the clinical resistant isolates.
    Antimicrobial Agents and Chemotherapy 12/2013; · 4.57 Impact Factor
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    ABSTRACT: We tested 868 urine isolates of E. coli collected from 2010 to 2013, as part of the Canadian national surveillance study, CANWARD, against fosfomycin using the Clinical and Laboratory Standards Institute (CLSI) agar dilution method with MICs interpreted using CLSI M100-S23 (2013) criteria. The concentrations of fosfomycin inhibiting 50% (MIC50) and 90% (MIC90) of isolates were ≤1 and 4 μg/ml; 99.4% of isolates were susceptible to fosfomycin.
    Antimicrobial Agents and Chemotherapy 12/2013; · 4.57 Impact Factor
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    ABSTRACT: The in vitro activities of ceftaroline-avibactam, ceftaroline and comparative agents were determined for a collection of frequent bacterial pathogens isolated from patients seeking care at 15 Canadian hospitals from January 2010 to December 2012. In total, 9758 isolates were tested using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (M07-A9, 2012) with MICs interpreted using CLSI breakpoints (M100-S23, 2013). Ceftaroline-avibactam demonstrated potent activity (MIC90, ≤0.5 μg/ml) against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Morganella morganii, Citrobacter freundii and Haemophilus influenzae; >99% of isolates of E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, M. morganii, C. freundii and H. influenzae were susceptible to ceftaroline-avibactam using CLSI MIC interpretative criteria for ceftaroline. Ceftaroline was less active than ceftaroline-avibactam against all species of Enterobacteriaceae tested with rates of susceptibility ranging from 93.9% (P. mirabilis) to 54.0% (S. marcescens). All isolates of methicillin-susceptible Staphylococcus aureus (MIC90, 0.25 μg/ml) and 99.6% of methicillin-resistant S. aureus (MIC90, 1 μg/ml) were susceptible to ceftaroline; the addition of avibactam to ceftaroline did not alter its activity against staphylococci or streptococci. All isolates of Streptococcus pneumoniae (MIC90, 0.03 μg/ml), Streptococcus pyogenes (MIC90, ≤0.03 μg/ml), and Streptococcus agalactiae (MIC90, 0.015 μg/ml) tested were susceptible to ceftaroline. We conclude that combining avibactam with ceftaroline expanded its spectrum of activity to include most isolates of Enterobacteriaceae resistant to third-generation cephalosporins, including extended-spectrum β-lactamase (ESBL)- and AmpC-producing E. coli and ESBL-producing K. pneumoniae, while maintaining potent activity against staphylococci and streptococci.
    Antimicrobial Agents and Chemotherapy 08/2013; · 4.57 Impact Factor
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    ABSTRACT: The in vitro activity of ceftolozane in combination with tazobactam (fixed concentration of 4 μg/mL) was evaluated against 2435 Pseudomonas aeruginosa clinical isolates obtained from across Canada using Clinical and Laboratory Standards Institute broth microdilution methods. The MIC50 and MIC90 values for ceftolozane/tazobactam were 0.5 μg/mL and 1 μg/mL, respectively (32 fold lower MIC90 than for ceftazidime). Eighty-nine percent (141/158) of multidrug-resistant isolates were inhibited by ≤8 μg/mL of ceftolozane/tazobactam.
    Antimicrobial Agents and Chemotherapy 08/2013; · 4.57 Impact Factor
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    ABSTRACT: The second-generation fluoroquinolone ciprofloxacin is a bactericidal antibiotic targeting DNA topoisomerase IV and DNA gyrase encoded by the parC and gyrA genes. Resistance to ciprofloxacin in Streptococcus pneumoniae mainly occurs through the acquisition of mutations in the quinolone-resistance-determining-region (QRDR) of the ParC and GyrA targets. A role in low-level ciprofloxacin resistance has also been attributed to efflux systems. To look into ciprofloxacin resistance at a genome wide scale and to discover additional mutations implicated in resistance, we performed whole genome sequencing of a S. pneumoniae isolate selected for resistance to ciprofloxacin in vitro (128 μg/mL) and of a clinical isolate displaying low-level ciprofloxacin resistance (2 μg/mL). Gene disruption and DNA transformation experiments with PCR fragments harboring the mutations identified in the in vitro S. pneumoniae mutant revealed that resistance is mainly due to QRDR mutations in parC and gyrA and by the overexpression of the ABC transporters PatA and PatB. In contrast, no QRDR mutations were identified in the genome of the S. pneumoniae clinical isolate with low level resistance to ciprofloxacin. Assays performed in the presence of the efflux pump inhibitor reserpine suggested that resistance is likely mediated by efflux. Interestingly, the genome sequence of this clinical isolate also revealed mutations in the coding region of patA and patB that we implicated in resistance. Finally, a mutation in the NAD(P)H-dependent glycerol-3-phosphate dehydrogenase identified in the S. pneumoniae clinical strain was shown to protect against ciprofloxacin-mediated reactive oxygen species.
    Antimicrobial Agents and Chemotherapy 07/2013; · 4.57 Impact Factor
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    ABSTRACT: Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections.
    Drugs 02/2013; · 4.63 Impact Factor
  • Joseph P Lynch, Nina M Clark, George G Zhanel
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    ABSTRACT: Introduction: Bacteria within the family Enterobacteriaceae are important pathogens in nosocomial and community settings. Over the past two decades, antimicrobial resistance among Enterobacteriaceae dramatically escalated worldwide. The authors review the mechanisms of antimicrobial resistance among Enterobacteriaceae, epidemiology and global spread of resistance elements and discuss therapeutic options. Areas covered: An exhaustive search for literature relating to Enterobacteriaceae was performed using PubMed, using the following key words: Enterobacteriaceae; Klebsiella pneumoniae; Escherichia coli; antimicrobial resistance; plasmids; global epidemiology; carbapenemases (CPEs); extended spectrum β-lactamases (ESBLs) and multidrug resistance (MDR). Expert opinion: Enterobacteriaceae are inhabitants of intestinal flora and spread easily among humans (via hand carriage, contaminated food or water or environmental sources). Antimicrobial resistance may develop via plasmids, transposons or other mobile resistance elements. Mutations conferring resistance typically increase over time; the rate of increase is amplified by selection pressure from antibiotic use. Factors that enhance spread of antimicrobial resistance include: crowding; lack of hygiene; overuse and over-the-counter use of antibiotics; tourism; refugees and international travel. Clonal spread of resistant organisms among hospitals, geographic regions and continents has globally fueled the explosive rise in resistance. The emergence and widespread dissemination of MDR clones containing novel resistance elements (particularly ESBLs and CPEs) has greatly limited therapeutic options. In some cases, infections due to MDR Enterobacteriaceae are untreatable with existing antimicrobial agents. The authors discuss current and future therapeutic options for difficult-to-treat infections due to these organisms.
    Expert Opinion on Pharmacotherapy 01/2013; · 2.86 Impact Factor
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    ABSTRACT: Background. Fluoroquinolone-resistant Escherichia coli are increasingly prevalent. Their clonal origins-potentially critical for control efforts-remain undefined.Methods. Antimicrobial resistance profiles and fine clonal structure were determined for 236 diverse-source historical (1967-2009) E. coli isolates representing sequence type ST131 and 853 recent (2010-2011) consecutive E. coli isolates from five clinical laboratories in Seattle, WA, and Minneapolis, MN. Clonal structure was resolved based on fimH sequence (fimbrial adhesin gene: H sub-clone assignments), multi-locus sequence typing, gyrA and parC sequence (fluoroquinolone resistance-determining loci), and pulsed-field gel electrophoresis.Results. Of the recent fluoroquinolone-resistant clinical isolates, 52% represented a single ST131 sub-clonal lineage, H30, which expanded abruptly after 2000. This sub-clone had a unique and conserved gyrA/parC allele combination, supporting its tight clonality. Unlike other ST131 sub-clones, H30 was significantly associated with fluoroquinolone resistance and was the most prevalent sub-clone among current E. coli clinical isolates, overall (10.4%) and within every resistance category (11-52%).Conclusions. Most current fluoroquinolone-resistant E. coli clinical isolates, and the largest share of multidrug-resistant isolates, represent a highly clonal sub-group that likely originated from a single rapidly expanded and disseminated ST131 strain. Focused attention to this strain will be required to control the fluoroquinolone and multidrug-resistant E. coli epidemic.
    The Journal of Infectious Diseases 01/2013; · 5.85 Impact Factor
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    ABSTRACT: Considering the rise of antibiotic resistance, the development of new antibacterial agents with improved biocidal functions is urgently required. In this study, ionic 5,5-dimethylhydantoin (DMH) analogues containing either a quaternary ammonium moiety (2)-4) or a phosphonate functional group (5),-6), were designed and synthesized to investigate the possible enhancing effect of quaternary ammonium moieties on the antibacterial performance of N-chloramines. These ionic DMH analogues were converted to their N-chloramine counterparts either in free form or after being covalently immobilized on a polymer surface via the "click" chemistry method. In the subsequent antimicrobial assessment against multi-drug-resistant Escherichia coli (MDR-E. coli) and methicillin-resistant Staphylococcus aureus (MRSA), chlorinated 2 and 3, the cyclic N-chloramines with a structural cation, exhibited distinctly enhanced biocidal functions in solution and after immobilization on surfaces.
    Advanced healthcare materials. 09/2012; 1(5):609-20.
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    ABSTRACT: A baseline serotype distribution was established by age and region for 2058 invasive Streptococcus pneumoniae isolates collected during the implementation period of the 13-valent pneumococcal conjugate vaccine (PCV13) program in many parts of Canada in 2010. Serotypes 19A, 7F, and 3 were the most prevalent in all age groups, accounting for 57% in <2 year olds, 62% in 2-4 year olds, 45% in 5-14 year olds, 44% in 15-49 year olds, 41% in 50-64 year olds, and 36% in ≥65 year olds. Serotype 19A was most predominant in Western and Central Canada representing 15% and 22%, respectively, of the isolates from those regions, whereas 7F was most common in Eastern Canada with 20% of the isolates. Other prevalent serotypes include 15A, 23B, 12F, 22F, and 6C. PCV13 serotypes represented 65% of the pneumococci isolated from <2 year olds, 71% of 2-4 year olds, 61% of 5-14 year olds, 60% of 15-49 year olds, 53% of 50-64 year olds, and 49% of the ≥65 year olds. Continued monitoring of invasive pneumococcal serotypes in Canada is important to identify epidemiological trends and assess the impact of the newly introduced PCV13 vaccine on public health.
    Canadian Journal of Microbiology 08/2012; 58(8):1008-17. · 1.20 Impact Factor
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    ABSTRACT: Amphiphilic aminoglycoside antimicrobials are an emerging class of new antibacterial agents with novel modes of action. Previous studies have shown that amphiphilic neomycin-B and kanamycin-A analogs restore potent antibacterial activity against Gram-positive neomycin-B- and kanamycin-A-resistant organisms. In this paper, we investigated the antibacterial properties of a series of amphiphilic tobramycin analogs. We prepared tobramycin-lipid conjugates, as well as tobramycin-peptide triazole conjugates, and studied their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains, including isolates obtained from Canadian hospitals. Our results demonstrate that the antibacterial activity of amphiphilic tobramycin is greatly affected by the length and nature of the hydrophobic lipid tail, whereas the nature of the polycationic headgroup or the number of cationic charges appear to be less important. Replacement of the hydrophobic tail by a fluorinated lipid confers good activity against two Pseudomonas strains and reduces hemolytic activity. However, susceptibility studies in the presence of bovine serum albumin indicate that all amphiphilic tobramycin analogs are strongly protein-bound, leading to a typical four- to eight-fold increase in MIC.The Journal of Antibiotics advance online publication, 11 July 2012; doi:10.1038/ja.2012.59.
    The Journal of Antibiotics 07/2012; · 2.19 Impact Factor
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    ABSTRACT: Phenotypic tolerances to antibiotics of mature and young Pseudomonas aeruginosa PAO1 biofilms and released planktonic bacteria were compared for four antibiotics. Resistance levels were similar for gentamicin and ciprofloxacin but differed for ceftazidime and meropenem. β-Lactamase mapping showed that, after 5 h of ceftazidime exposure, mature biofilms produced more β-lactamase than young biofilms, facilitating the growth of released planktonic bacteria. This shows the importance of early treatment and choice of antibiotics for P. aeruginosa biofilm infections.
    Antimicrobial Agents and Chemotherapy 07/2012; 56(9):4976-9. · 4.57 Impact Factor
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    ABSTRACT: Broth microdilution (Clinical and Laboratory Standards Institute) was used to evaluate the antimicrobial susceptibility of 1549 Pseudomonas aeruginosa clinical isolates collected in Canada between January 2008 and October 2011. The percentage of isolates susceptible was as follows: amikacin 92.0%, ceftazidime 83.5%, ciprofloxacin 74.3%, colistin 93.4%, gentamicin 76.8%, meropenem 82.7%, and piperacillin-tazobactam 83.6%. Antimicrobial susceptibility did not change significantly between 2008 and 2011, with the exception of increasing susceptibility to gentamicin (P < 0.0001).
    Diagnostic microbiology and infectious disease 06/2012; 73(4):361-4. · 2.45 Impact Factor
  • Brandon Findlay, George G Zhanel, Frank Schweizer
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    ABSTRACT: To probe the effect of carbon-fluorine bonds on antimicrobial peptide-membrane interactions, 24 cationic lipopeptides were created. The collection of lipopeptides was built from two different peptide sequences, KGK and KKK, with a variety of different lipids selected to probe the effectiveness of both hydrocarbon and fluorinated tails. The antimicrobial activity of each peptide was tested against a mixture of pathogenic and reference bacterial strains, with the cationic disinfectant benzalkonium chloride as a positive control. Non-specific interactions with hydrophobic proteins were assessed by repeating antimicrobial testing in the presence of bovine serum albumin (BSA), and the toxicity of the lipopeptides was assessed by measuring lysis of ovine erythrocytes. Peptide sequence had a moderate effect on activity, with the most active peptide (C16-KGK) inhibiting the growth of two Staphylococcus epidermidis strains at ≤ 0.25 μg/mL. Tail composition was less important than the overall hydrophobicity, with the most active fluorinated tails equivalent to moderately active hydrocarbon tails. The activity of all peptides was significantly reduced by the presence of BSA, and haemolysis was closely correlated with antimicrobial activity.
    International journal of antimicrobial agents 05/2012; 40(1):36-42. · 3.03 Impact Factor
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    ABSTRACT: We have recently reported high levels of fluoroquinolone resistance in a single region of Kenya. In this article, we report high prevalence of fluoroquinolone resistance (53.2%) in Neisseria gonorrhoeae isolates from 4 clinics in 3 additional regions of Kenya. These findings highlight the need to change first-line treatment in these settings and the need to evaluate empirical management guidelines for treatment of gonococcal infection in Kenya.
    Sexually transmitted diseases 05/2012; 39(5):332-4. · 2.58 Impact Factor
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    ABSTRACT: Oritavancin is a semisynthetic lipoglycopeptide analogue of vancomycin that contains the heptapeptide core common to all glycopeptides. It differs from vancomycin by the presence of a hydrophobic N-4-(4-chlorophenyl)benzyl (also referred to as 4'-chlorobiphenylmethyl) substituent on the disaccharide sugar, the addition of a 4-epi-vancosamine monosaccharide to the amino acid residue in ring 6, and the replacement of the vancosamine moiety by 4-epi-vancosamine. One mechanism of action of oritavancin is inhibition of transglycosylation (important in peptidoglycan synthesis) by binding to D-alanyl-D-alanine stem termini in Gram-positive bacteria. The inhibition of peptidoglycan synthesis via inhibition of transglycosylation is common to all glycopeptides (vancomycin) and lipoglycopeptides. Secondary binding of oritavancin to the pentaglycyl (Asp/Asn) bridging segment in peptidoglycan also occurs, which distinguishes it from vancomycin and contributes to oritavancin's activity versus vancomycin-resistant organisms. The presence of the hydrophobic 4'-chlorobiphenylmethyl group allows for interaction and disruption of the cell membrane, resulting in depolarization, permeabilization, and concentration-dependent, rapid cell death. This mechanism is shared with telavancin but not vancomycin and results in activity against daptomycin-nonsusceptible organisms. In conclusion, oritavancin's mechanism of action involves at least 3 known mechanisms: inhibition of transglycosylation, inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin's multiple mechanisms of action confer activity against vancomycin-susceptible and -resistant organisms, as well as rapid, concentration-dependent killing versus actively growing, stationary phase, and biofilm-producing Gram-positive bacteria.
    Clinical Infectious Diseases 04/2012; 54 Suppl 3:S214-9. · 9.37 Impact Factor

Publication Stats

4k Citations
929 Downloads
1,056.30 Total Impact Points

Institutions

  • 2006–2013
    • Diagnostic Services of Manitoba, Inc.
      Winnipeg, Manitoba, Canada
    • CSU Mentor
      Long Beach, California, United States
    • Emory University
      • Department of Microbiology and Immunology
      Atlanta, Georgia, United States
  • 2005–2013
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 1990–2013
    • University of Manitoba
      • • Faculty of Medicine
      • • Department of Chemistry
      • • Department of Medical Microbiology and Infectious Diseases
      • • Faculty of Pharmacy
      Winnipeg, Manitoba, Canada
  • 2012
    • Public Health Agency of Canada
      Ottawa, Ontario, Canada
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 1988–2012
    • Health Sciences Centre Winnipeg
      Winnipeg, Manitoba, Canada
  • 2011
    • Hampton University
      • School of Pharmacy
      Hampton, Virginia, United States
  • 1991–2011
    • Hôpital St-Boniface Hospital
      Winnipeg, Manitoba, Canada
  • 2007–2010
    • University of British Columbia - Vancouver
      • • Division of Infectious Diseases
      • • Department of Microbiology and Immunology
      Vancouver, British Columbia, Canada
  • 2009
    • University of Minnesota Twin Cities
      • Division of Pediatric Infectious Diseases
      Minneapolis, MN, United States
  • 2008
    • McMaster University
      • Division of Infectious Diseases
      Hamilton, Ontario, Canada
  • 2005–2008
    • University of Minnesota Duluth
      • • College of Pharmacy
      • • Department of Pharmacy Practice and Pharmaceutical Sciences
      Duluth, Minnesota, United States
  • 2004–2005
    • University of Alberta
      • Faculty of Pharmacy and Pharmaceutical Sciences
      Edmonton, Alberta, Canada
  • 2003–2005
    • The Ottawa Hospital
      • Department of Pharmacy
      Ottawa, Ontario, Canada
  • 2000
    • The University of Winnipeg
      Winnipeg, Manitoba, Canada
  • 1994
    • University of Toronto
      Toronto, Ontario, Canada