George G Zhanel

Health Sciences Centre Winnipeg, Winnipeg, Manitoba, Canada

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Publications (345)1313.24 Total impact

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    ABSTRACT: Aerobic gram-negative bacilli, including the family of Enterobacteriaceae and non-lactose fermenting bacteria such as Pseudomonas and Acinetobacter species, are major causes of hospital-acquired infections. The rate of antibiotic resistance among these pathogens has accelerated dramatically in recent years and has reached pandemic scale. It is no longer uncommon to encounter gram-negative infections that are untreatable using conventional antibiotics in hospitalized patients. In this review, we provide a summary of the major classes of gram-negative bacilli and their key mechanisms of antimicrobial resistance, discuss approaches to the treatment of these difficult infections, and outline methods to slow the further spread of resistance mechanisms.
    Chest 05/2015; 147(5):1413-21. DOI:10.1378/chest.14-2171 · 7.13 Impact Factor
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    ABSTRACT: The goal of this study was to characterize Streptococcus pneumoniae demonstrating MDR (resistant to three or more antimicrobial classes) or XDR (resistant to five or more classes) phenotypes, collected from Canada during the CANWARD 2007-13 study. From 2007 to 2013 inclusive, S. pneumoniae isolates were collected as a part of the CANWARD surveillance study. MDR and XDR isolates were subjected to PFGE, MLST, molecular detection of pneumococcal pili and macrolide resistance determinants mef(A/E) and erm(B), sequencing of PBPs 1A, 2B and 2X and comparison with Pneumococcal Molecular Epidemiology Network (PMEN) clones. Of 2129 S. pneumoniae isolates collected during the CANWARD 2007-13 study, 61 (2.9%) were found to be MDR. Of these MDR isolates, 43 (70.5%) were XDR. The most common serotypes for both MDR and XDR S. pneumoniae were 19A and 19F. Twenty-nine of 61 isolates (48%) demonstrated resistance to clarithromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulfamethoxazole. All isolates possessed at least one macrolide resistance determinant and mutations in PBPs 1A, 2B and 2X. The most common clone was piliated, XDR ST320, an internationally circulating double-locus variant of Taiwan(19F)-14 (ST236). Though the rate of MDR S. pneumoniae has remained relatively stable since 2007, XDR strains have emerged in Canada. These strains are virulent, possess resistance determinants and are related to international clones. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Journal of Antimicrobial Chemotherapy 04/2015; DOI:10.1093/jac/dkv107 · 5.44 Impact Factor
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    ABSTRACT: Of 1927 Enterococcus spp. isolated across Canada from 2007-2013, inclusive, 4.2% (80) were identified as VRE. VRE infections tripled in Canadian hospitals from 1.8% to 6.0% (p=0.03). All VRE were E. faecium, with 90% possessing vanA. The prevalence of vanB decreased from 37.5% in 2007 to 0% in 2013 (p<0.05). VRE were multi-drug resistant but 70.6%, 86.3% and 100% were susceptible to doxycycline, linezolid and daptomycin, respectively. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 04/2015; 59(7). DOI:10.1128/AAC.00384-15 · 4.45 Impact Factor
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    ABSTRACT: This work examined Escherichia coli O157:H7 strain 02-0304 for putative genes responsible for sinigrin hydrolysis. Sinigrin is a glucosinolate present in Oriental mustard (Brassica juncea), and its hydrolysis is mediated in plants by the enzyme myrosinase. Sinigrin hydrolysis by plant or bacterial myrosinase yields allyl isothiocyanate (AITC) which is bactericidal. In silico analysis using public databases found sequence similarity between plant myrosinase and enzymes encoded by genes from β-glucosidase families in E. coli O157:H7. Specifically, 6-phospho-β-glucosidase encoded by the genes bglA and ascB (family 1), and chbF (family 4) present in E. coli O157:H7 showed the highest similarity. Polymerase chain reaction (PCR) confirmed the presence of bglA, ascB, and chbF in the clinical E. coli strain tested. Disruption of these genes in wild-type E. coli O157:H7 strain 02-0304 using lambda-red replacement created single and double mutants. The relative importance of each gene in the hydrolysis of sinigrin by E. coli O157:H7 was also assessed by comparing gene expression and sinigrin degradation rates among the E. coli O157:H7 wild-type strain and its mutants. The results suggested that the genes bglA and ascB play a substantial role in the degradation of sinigrin by E. coli O157:H7 strain 02-0304. Copyright © 2015. Published by Elsevier B.V.
    International journal of food microbiology 04/2015; 205:105-111. DOI:10.1016/j.ijfoodmicro.2015.04.008 · 3.16 Impact Factor
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    ABSTRACT: Amphiphilic aminoglycosides (AAGs) are an emerging source of antibacterials to combat infections caused by antibiotic-resistant bacteria. Mode-of-action studies indicate that AAGs predominately target bacterial membranes, thereby leading to depolarization and increased permeability. To assess whether AAGs also induce host-directed immunomodulatory responses, we determined the AAG-dependent induction of cytokines in macrophages in the absence or presence of lipopolysaccharide (LPS). Our results show for the first time that AAGs can boost the innate immune response, specifically the recruitment of immune cells such as neutrophils required for the resolution of infections. Moreover, AAGs can selectively control inflammatory responses induced in the presence of endotoxins to prevent septic shock. In conclusion, our study demonstrates that AAGs possess multifunctional properties that combine direct antibacterial activity with host-directed clearance effects reminiscent of those of host-defense peptides. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 04/2015; 54(21). DOI:10.1002/anie.201500598 · 11.34 Impact Factor
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    ABSTRACT: Amphiphilic aminoglycosides (AAGs) are an emerging source of antibacterials to combat infections caused by antibiotic-resistant bacteria. Mode-of-action studies indicate that AAGs predominately target bacterial membranes, thereby leading to depolarization and increased permeability. To assess whether AAGs also induce host-directed immunomodulatory responses, we determined the AAG-dependent induction of cytokines in macrophages in the absence or presence of lipopolysaccharide (LPS). Our results show for the first time that AAGs can boost the innate immune response, specifically the recruitment of immune cells such as neutrophils required for the resolution of infections. Moreover, AAGs can selectively control inflammatory responses induced in the presence of endotoxins to prevent septic shock. In conclusion, our study demonstrates that AAGs possess multifunctional properties that combine direct antibacterial activity with host-directed clearance effects reminiscent of those of host-defense peptides.
    Angewandte Chemie 04/2015; DOI:10.1002/ange.201500598
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    ABSTRACT: The mechanism of aminoglycoside resistance among 338 gentamicin non-susceptible gram-negative bacteria (207 Enterobacteriaceae and 131 Pseudomonas aeruginosa) was assessed, and the in vitro activity of ceftazidime-avibactam versus these isolates was determined. Aminoglycoside modifying enzymes (AMEs) were detected in 91.8% of Enterobacteriaceae and 13.7% of P. aeruginosa. A single strain of Klebsiella pneumoniae harbored a 16S rRNA methylase (ArmA). The ceftazidime-avibactam MIC90 was 0.5 μg/ml (MIC, ≤8 μg/ml, for 100% of isolates) and 16 μg/ml (MIC, ≤8 μg/ml, for 87.8% of isolates) versus the gentamicin non-susceptible Enterobacteriaceae and P. aeruginosa isolates, respectively. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 03/2015; 59(6). DOI:10.1128/AAC.00364-15 · 4.45 Impact Factor
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    ABSTRACT: We investigated whether specific sequence types, and their shared virulence gene profiles, may be associated with both human and food animal reservoirs. A total of 600 Escherichia coli isolates were assembled from human (n=265) and food-animal (n=335) sources from overlapping geographic areas and time periods (2005-2010) in Canada. The entire collection was subjected to multilocus sequence typing and a subset of 286 E. coli isolates was subjected to an E. coli-specific virulence gene microarray. The most common sequence type (ST) was E. coli ST10, which was present in all human and food-animal sources, followed by ST69, ST73, ST95, ST117, and ST131. A core group of virulence genes was associated with all 10 common STs including artJ, ycfZ, csgA, csgE, fimA, fimH, gad, hlyE, ibeB, mviM, mviN, and ompA. STs 73, 92, and 95 exhibited the largest number of virulence genes, and all were exclusively identified from human infections. ST117 was found in both human and food-animal sources and shared virulence genes common in extraintestinal pathogenic E. coli lineages. Select groups of E. coli may be found in both human and food-animal reservoirs.
    Foodborne Pathogens and Disease 03/2015; 12(4). DOI:10.1089/fpd.2014.1860 · 2.09 Impact Factor
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    ABSTRACT: Serotype replacement in Streptococcus pneumoniae following the implementation of a new vaccine has been associated with the emergence of non-vaccine serotypes as prominent causes of invasive pneumococcal disease (IPD). The aim of this study was to characterize specific non-PCV-13 serotypes 15A, 22F, 33F and 35B from IPD, isolated in Canada post-PCV-13 introduction in 2010. Of 3802 IPD isolates collected from across Canada in 2011-13, 18.4% were found to be serotypes 15A, 22F, 33F and 35B. These 699 isolates were subjected to antimicrobial susceptibility testing, PFGE, MLST, molecular detection of pneumococcal pili and comparison with Pneumococcal Molecular Epidemiology Network (PMEN) clones. This study demonstrated clonal spread of specific STs, including MDR ST63 and its Sweden(15A)-25-related variants, the increasingly common ST433 and a variant of piliated, penicillin-non-susceptible ST558, related to PMEN clone Utah(35B)-24 (ST377). New STs of serotype 33F were identified. Several potential capsular switching events were identified within these serotypes. Non-PCV-13 serotype 22F is increasing in Canada through the rapid clonal expansion of ST433. Numerous new STs associated with serotype 33F indicate the potential divergence of the serotype. Serotypes 15A and 35B in Canada are related to international clones of S. pneumoniae. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Journal of Antimicrobial Chemotherapy 03/2015; DOI:10.1093/jac/dkv061 · 5.44 Impact Factor
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    ABSTRACT: Tedizolid phosphate is a novel oxazolidinone prodrug (converted to the active form tedizolid by phosphatases in vivo) that has been developed and recently approved (June 2014) by the United States FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Tedizolid is an oxazolidinone, but differs from other oxazolidinones by possessing a modified side chain at the C-5 position of the oxazolidinone nucleus which confers activity against certain linezolid-resistant pathogens and has an optimized C- and D-ring system that improves potency through additional binding site interactions. The mechanism of action of tedizolid is similar to other oxazolidinones and occurs through inhibition of bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA) of the 50S subunit of the ribosome. As with other oxazolidinones, the spontaneous frequency of resistance development to tedizolid is low. Tedizolid is four- to eightfold more potent in vivo than linezolid against all species of staphylococci, enterococci, and streptococci, including drug-resistant phenotypes such as MRSA and vancomycin-resistant enterococci (VRE) and linezolid-resistant phenotypes. Importantly, tedizolid demonstrates activity against linezolid-resistant bacterial strains harboring the horizontally transmissible cfr gene, in the absence of certain ribosomal mutations conferring reduced oxazolidinone susceptibility. With its half-life of approximately 12 h, tedizolid is dosed once daily. It demonstrates linear pharmacokinetics, has a high oral bioavailability of approximately 90 %, and is primarily excreted by the liver as an inactive, non-circulating sulphate conjugate. Tedizolid does not require dosage adjustment in patients with any degree of renal dysfunction or hepatic dysfunction. Studies in animals have demonstrated that the pharmacodynamic parameter most closely associated with the efficacy of tedizolid is fAUC0-24h/MIC. In non-neutropenic animals, a dose-response enhancement was observed with tedizolid and lower exposures were required compared to neutropenic cohorts. Two Phase III clinical trials have demonstrated non-inferiority of a once-daily tedizolid 200 mg dose for 6-10 days versus twice-daily 600 mg linezolid for the treatment of ABSSSIs. Both trials used the primary endpoint of early clinical response at 48-72 h; however, one trial compared oral formulations while the other initiated therapy with the parenteral formulation and allowed oral sequential therapy following initial clinical response. Throughout its development, tedizolid has demonstrated that it is well tolerated and animal studies have shown a lower propensity for neuropathies with long-term use than its predecessor linezolid. Data from the two completed Phase III clinical trials demonstrated that the studied tedizolid regimen (200 mg once daily for 6 days) had significantly less impact on hematologic parameters as well as significantly less gastrointestinal treatment-emergent adverse effects (TEAEs) than its comparator linezolid. As with linezolid, tedizolid is a weak, reversible MAO inhibitor; however, a murine head twitch model validated to assess serotonergic activity reported no increase in the number of head twitches with tedizolid even at doses that exceeded the C max in humans by up to 25-fold. Tyramine and pseudoephedrine challenge studies in humans have also reported no meaningful MAO-related interactions with tedizolid. With its enhanced in vitro activity against a broad-spectrum of Gram-positive aerobic bacteria, convenient once-daily dosing, a short 6-day course of therapy, availability of both oral and intravenous routes of administration, and an adverse effect profile that appears to be more favorable than linezolid, tedizolid is an attractive agent for use in both the hospital and community settings. Tedizolid is currently undergoing additional Phase III clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilated nosocomial pneumonia (VNP).
    Drugs 02/2015; 75(3). DOI:10.1007/s40265-015-0352-7 · 4.13 Impact Factor
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    ABSTRACT: Enterococcus species are part of the normal intestinal flora of a large number of mammals including humans and consequently, they can be used as indicators of faecal contamination in food and water for human consumption. Their presence in large numbers in foods may indicate a lapse in sanitation and their ability to serve as a genetic reservoir of transferable antibiotic resistance is of concern. In the present study, Enterococcus spp., isolated from commercially fermented meat and human clinical specimen were studied to determine genetic relationships. SmaI pulsed-field gel electrophoresis (PFGE) patterns exhibited genomic heterogeneity within and between both groups of isolates. However, in spite of this heterogeneity there were still substantial phenotypic similarities which suggested that food might be a potential vehicle for distribution of resistant bacteria among humans. In vitro conjugation experiments demonstrated transfer of the tetracycline resistant determinant, tet(M), from Enterococcus faecium S27 isolated from fermented sausage to clinical isolates of both E. faecium and Enterococcus faecalis. The streptomycin resistance of E. faecium S27 was also transferred to a clinical strain, E. faecalis 82916, which was confirmed by the presence of the streptomycin resistance gene, aadA, in the donor and transconjugant strains. Since the aadA gene is associated with a class 1 integron, results also suggested that resistance transfer might have occurred via an integron. It appears this is the first identification of a class 1 integron in E. faecium isolated from food. The importance of food enterococci as a reservoir of antibiotic resistance genes and the potential for their genetic transfer to human strains following consumption of uncooked or undercooked contaminated meat is underlined by this work. Copyright © 2015 Elsevier B.V. All rights reserved.
    International Journal of Food Microbiology 01/2015; 199C:78-85. DOI:10.1016/j.ijfoodmicro.2015.01.013 · 3.16 Impact Factor
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    ABSTRACT: Gram-positive pathogens isolated in 15 Canadian hospital laboratories between 2011 and 2013 were tested for susceptibility to oritavancin and comparative antimicrobial agents using the CLSI broth microdilution method. Oritavancin demonstrated in vitro activity equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against the isolates of methicillin-susceptible Staphylococcus aureus (n = 1460; oritavancin MIC90, 0.06 μg/ml; 99.7% oritavancin-susceptible), methicillin-resistant S. aureus (n = 427; oritavancin MIC90, 0.06 μg/ml; 99.5% oritavancin-susceptible), Streptococcus pyogenes (n = 132; oritavancin MIC90, 0.25 μg/ml; 99.2% oritavancin-susceptible), Streptococcus agalactiae (n = 156; oritavancin MIC90, 0.12 μg/ml; 100% oritavancin-susceptible), and Enterococcus faecalis (n = 304; oritavancin MIC90, 0.06 μg/ml; 98.7% oritavancin-susceptible) tested.
    Diagnostic Microbiology and Infectious Disease 09/2014; 80(4). DOI:10.1016/j.diagmicrobio.2014.09.003 · 2.57 Impact Factor
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    ABSTRACT: In order to determine if triclosan can select for mutants of A. baumannii ATCC17978 that display reduced susceptibility to antibiotics, we isolated a triclosan-resistant mutant A. baumannii AB042 by serial passaging of A. baumannii ATCC17978 in growth medium supplemented with triclosan. Antimicrobial susceptibility of AB042 was analyzed by the two-fold serial dilution method. Expression of five different RND pump-encoding genes (adeB, adeG, adeJ, A1S_2818 and A1S_3217), two outer membrane porin-encoding genes (carO and oprD), and the MATE family pump-encoding abeM was analysed using quantitative RT-PCR. A. baumannii AB042 exhibited elevated resistance to multiple antibiotics, including piperacillin/tazobactam, doxycycline, moxifloxacin, ceftriaxone, cefepime, meropenem, doripenem, ertapenem, ciprofloxacin, aztreonam, tigecycline, and trimethoprim/sulfamethoxazole, in addition to triclosan. Genome sequencing of A. baumannii AB042 revealed a (116)G→V mutation in fabI, the gene encoding the target enzyme for triclosan. Expression analysis of efflux pumps showed overexpression of the AdeIJK pump; and sequencing of adeN, the gene that encodes the repressor of the adeIJK operon, revealed a 73-bp deletion which would cause a premature termination of translation resulting in an inactive truncated AdeN protein. This work shows that triclosan can select for mutants of A. baumannii that display reduced susceptibility to multiple antibiotics from chemically distinct classes in addition to triclosan resistance. The multi-drug resistance can be explained by the overexpression of the AdeIJK efflux pump.
    Antimicrobial Agents and Chemotherapy 08/2014; 58(11). DOI:10.1128/AAC.03074-14 · 4.45 Impact Factor
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    ABSTRACT: In light of in vivo/in vitro discordance among beta-lactams against Gram-negatives, we compared in vivo pharmacodynamics of humanized ceftaroline against 9 S. aureus (MIC 0.13-1mg/L) from published in vitro studies using standard and high inocula in the murine thigh infection model. Consistent with in vitro findings, mean reductions of ≥1log10CFU were observed for ceftaroline against all strains using both standard and high inocula. These results suggest in vivo/in vitro concordance with no observed inoculum effect.
    Antimicrobial Agents and Chemotherapy 08/2014; 58(11). DOI:10.1128/AAC.03652-14 · 4.45 Impact Factor
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    ABSTRACT: Taking a minimalistic approach in efforts to lower the cost for the development of new synthetic antimicrobial peptides, ultrashort cationic lipopeptides were designed to mimic the amphiphilic nature crucial for their activity but with only a very short peptide sequence ligated to a lipidic acid. Nine ultrashort cationic lipopeptides were prepared to study the effects of ring constraint in the amino acid side chain of the peptide component. USCL-PCat1, consisting of only four L-4R-aminoproline residues and acylated with palmitic acid at the N-terminus, was found to populate a polyproline II helical secondary conformation that is stable to different pHs and temperatures using circular dichroism. The synthesized lipopeptides were found to have a micellar structure in water using negative staining transmission electron microscopy. We found that constraining the side chain of the amino acid component is not beneficial to the antimicrobial activity. USCL-Dab1, USCL-Dab3 and USCL-K1 showed promising activity against a panel of laboratory reference and clinically isolated Gram-positive and Gram-negative bacterial strains, some of which are multidrug resistant. No appreciable cytotoxicity against human monocytic THP-1 cells was observed up to concentrations of 20-40 µM for all synthesized compounds. Moreover, all USCLs did not induce the production of either pro-inflammatory cytokines or chemokines up to 40 µM.
    Amino Acids 07/2014; 46(11). DOI:10.1007/s00726-014-1806-z · 3.65 Impact Factor
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    ABSTRACT: Background: Community-acquired respiratory tract infections (CARTI) are commonly caused by Streptococcus pneumoniae (SPN) and empirically treated with azithromycin. This study assessed clinical cure rates in azithromycin-treated subjects with CARTI caused by azithromycin-susceptible (Azi-S) or azithromycin-resistant (Azi-R) SPN. Methods: 1127 subjects with CARTI (402 acute otitis media, 309 community-acquired pneumonia, 255 acute bacterial exacerbations of chronic bronchitis and 161 acute bacterial sinusitis) in 13 Phase 3 clinical trials (1993-2007) had a confirmed pathogen, received azithromycin and were assessed for clinical cure/failure. 34.4% of subjects (388/1127) had a positive culture for SPN; 33.4% (376/1127) had Azi-S or Azi-R SPN. Results: 28.9% (112/388) of subjects with SPN had Azi-R SPN: 35.7% (40/112) were low-level Azi-R SPN (LLAR; MIC 2-8 mg/L), while 64.3% (72/112) were high-level Azi-R SPN (HLAR; MIC >= 16 mg/L). Among Azi-S and Azi-R SPN CARTI subjects, clinical cure rates were: 86.2% (324/376) overall; 89.4% (236/264) for subjects with Azi-S SPN; 78.6% (88/112) for subjects with Azi-R SPN (P = 0.003, versus Azi-S); 77.5% (31/40) for subjects with LLAR SPN (P < 0.001); and 79.2% (57/72) for subjects with HLAR SPN (P = 0.122). Conclusions: Clinical cure rates in CARTI subjects treated with azithromycin were higher for Azi-S SPN (89.4%) versus Azi-R SPN (78.6%; P = 0.003). However, cure rates were not different for subjects infected with LLAR-SPN versus HLAR-SPN. At the observed prevalence of Azi-R SPN of 28.9%, an additional 3.1 clinical failures would be predicted, as a consequence of azithromycin resistance (LLAR and HLAR), per 100 subjects treated empirically with azithromycin.
    Journal of Antimicrobial Chemotherapy 06/2014; 69(10). DOI:10.1093/jac/dku207 · 5.44 Impact Factor
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    ABSTRACT: We assessed the pharmacodynamic activity of ertapenem against Escherichia coli with reduced susceptibility (MIC 0.12-0.5 mg/L), intermediate resistance (MIC 1.0 mg/L) or resistance (MIC ≥2 mg/L) to ertapenem using an in vitro model. Fifteen extended-spectrum β-lactamase- or carbapenemase-producing E. coli were studied. The in vitro pharmacodynamic model was inoculated with ∼1 × 10(6) cfu/mL and ertapenem was dosed once daily at 0 and 24 h to simulate free (ƒ) Cmax and t½ obtained after either 1 g or 2 g intravenous once-daily doses in healthy volunteers (1 g: ƒCmax 15 mg/L, t½ 4 h). Sampling was performed over 48 h to assess viable growth and resistance selection. An ertapenem T> MIC ≥75.4% (ertapenem MICs ≤0.5 mg/L) resulted in bactericidal (≥3 log10 killing) activity against all strains. An ertapenem T>MIC of 61% was bactericidal at 6 and 12 h but regrowth at 24 and 48 h occurred in some strains. An ertapenem T>MIC of 13%-43% was bactericidal at 6 h but regrowth (with MIC increases) occurred. No inhibition of an NDM strain with an ertapenem T>MIC of 0% (ertapenem MIC 256 mg/L) occurred at any timepoint. Once-daily dosing with 1 g of ertapenem was bactericidal against ESBL-producing E. coli with ertapenem MICs ≤0.5 mg/L and was bactericidal against strains with MICs of 1.0 mg/L, with regrowth in some strains. Ertapenem MICs of 2-8 mg/L resulted in early bactericidal activity followed by regrowth. Once-daily dosing with 2 g of ertapenem was bactericidal against strains with an MIC of 1.0 mg/L, but regrowth occurred in some strains with an ertapenem MIC of 2 mg/L.
    Journal of Antimicrobial Chemotherapy 05/2014; 69(9). DOI:10.1093/jac/dku149 · 5.44 Impact Factor
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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; 58(5). DOI:10.1128/AAC.02744-13 · 4.45 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; 74(1). DOI:10.1007/s40265-013-0168-2 · 4.13 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; DOI:10.1111/1440-1681.12195 · 2.41 Impact Factor

Publication Stats

7k Citations
1,313.24 Total Impact Points

Institutions

  • 1996–2015
    • Health Sciences Centre Winnipeg
      Winnipeg, Manitoba, Canada
  • 1990–2015
    • University of Manitoba
      • • Faculty of Medicine
      • • Department of Chemistry
      • • Department of Medical Microbiology and Infectious Diseases
      • • Faculty of Pharmacy
      Winnipeg, Manitoba, Canada
  • 2005–2013
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 2012
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Diagnostic Services of Manitoba, Inc.
      Winnipeg, Manitoba, Canada
  • 2010
    • University of British Columbia - Vancouver
      • Division of Infectious Diseases
      Vancouver, British Columbia, Canada
  • 2008
    • McMaster University
      • Division of Infectious Diseases
      Hamilton, Ontario, Canada
  • 2006
    • Emory University
      • Department of Microbiology and Immunology
      Atlanta, Georgia, United States
  • 1994–2002
    • University of Toronto
      Toronto, Ontario, Canada
  • 1992–2000
    • The University of Winnipeg
      Winnipeg, Manitoba, Canada
  • 1991
    • Hôpital St-Boniface Hospital
      Winnipeg, Manitoba, Canada