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[hide abstract]
ABSTRACT: Antimicrobial resistance is a growing problem among upper respiratory tract pathogens. Resistance to β-lactam drugs among
Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes is increasing. As safe and well-tolerated antibiotics, macrolides play a key role in the treatment of community-acquired
upper respiratory tract infections (RTIs). Their broad spectrum of activity against gram-positive cocci, such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, has led to the widespread use of macrolides for empiric treatment
of upper RTIs and as alternatives for patients allergic to β-lactams. Macrolide resistance is increasing among pneumococci
and recently among S. pyogenes, and is associated with increasing use of the newer macrolides, such as azithromycin. Ribosomal target modification mediated
by erm(A) [erm(TR)] and erm(B) genes and active efflux due to mef(A) and mef(E) are the principal mechanisms of resistance in S. pneumoniae and S. pyogenes. Recently, ribosomal protein and RNA mutations have been found responsible for acquired resistance to macrolides in S. pneumoniae, S. pyogenes, and H. influenzae. Although macrolides are only weakly active against macrolide-resistant streptococci species producing an efflux pump (mef) and are inactive against pathogens with ribosomal target modification (erm), treatment failures are uncommon. Therefore, macrolide therapy, for now, remains a good alternative for treatment of upper
RTIs; however, continuous monitoring of the local resistance patterns is essential.
Current Infectious Disease Reports 04/2012; 7(3):175-184.
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ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and vancomycin-resistant enterococci (VRE) are important hospital pathogens in Canada and worldwide.
To genotypically and phenotypically characterize the isolates of MRSA, VRE and ESBL-producing E coli collected from patients in Canadian intensive care units (ICUs) in 2005 and 2006.
Between September 1, 2005, and June 30, 2006, 19 medical centres participating in the Canadian National Intensive Care Unit (CAN-ICU) study collected 4133 unique patient isolates associated with infections in ICUs. Isolates of MRSA underwent mecA polymerase chain reaction (PCR) and Panton-Valentine leukocidin analysis; they were typed using pulsed-field gel electrophoresis. All isolates of E coli with ceftriaxone minimum inhibitory concentrations greater than or equal to 1 mug/mL were tested for the presence of an ESBL using the Clinical Laboratory Standards Institute double-disk diffusion method. Subsequently, PCR and sequence analysis were used to identify bla(SHV), bla(TEM) and bla(CTX-M). Isolates of VRE were tested for the presence of vanA and vanB genes by PCR.
Of the 4133 ICU isolates collected, MRSA accounted for 4.7% (193 of 4133) of all isolates. MRSA represented 21.9% (193 of 880) of all S aureus collected during the study; 90.7% were health care-associated MRSA strains and 9.3% were community-associated MRSA strains. Resistance rates for the isolates of MRSA were 91.8% to levofloxacin, 89.9% to clarithromycin, 76.1% to clindamycin and 11.7% to trimethoprim-sulfamethoxazole; no isolates were resistant to vancomycin, linezolid, tigecycline or daptomycin. ESBL-producing E coli accounted for 0.4% (18 of 4133) of all isolates and 3.7% (18 of 493) of E coli isolates. All 18 ESBL-producing E coli were PCR-positive for CTX-M, with bla(CTX-M-15) occurring in 72% (13 of 18) of isolates. All ESBL-producing E coli displayed a multidrug-resistant phenotype (resistant to third-generation cephalosporins and one or more other classes of antimicrobials), with 77.8% of isolates resistant to ciprofloxacin, 55.6% resistant to trimethoprim-sulfamethoxazole, 27.8% resistant to gentamicin and 26.3% resistant to doxycycline; all isolates were susceptible to ertapenem, meropenem and tigecycline. VRE accounted for 0.4% (17 of 4133) of all isolates and 6.7% (17 of 255) of enterococci isolates; 88.2% of VRE had the vanA genotype. Isolated VRE that were tested were uniformly susceptible to linezolid, tigecycline and daptomycin.
MRSA isolated in Canadian ICUs in 2005 and 2006 was predominately health care-associated (90.7%), ESBL-producing E coli were all CTX-M producers (72% bla(CTX-M-15)) and VRE primarily harboured a vanA genotype (88.2%). MRSA, ESBL-producing E coli and VRE were frequently multidrug resistant.
The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada 06/2008; 19(3):243-9. · 1.54 Impact Factor
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ABSTRACT: We tested the in vitro activity of 15 antimicrobials against Gram-positive cocci and 12 antimicrobials against Gram-negative bacilli versus 3931 isolates (20 most common organisms) obtained between September 1, 2005, and June 30, 2006, from 19 intensive care units (ICUs) across Canada. The most active (based upon MIC only) agents against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis were dalbavancin, daptomycin, linezolid, tigecycline, and vancomycin with MIC(90) (microg/mL) of 0.06 and < or =0.03, 0.25 and 0.12, 2 and 1, 0.5 and 0.5, and 1 and 2, respectively. The most active agents against vancomycin-resistant enterococci were daptomycin, linezolid, and tigecycline with MIC(90) (microg/mL) of 1, 4, and 0.12, respectively. The most active agents against Escherichia coli were amikacin, cefepime, meropenem, piperacillin/tazobactam, and tigecycline with MIC(90) (microg/mL) of 4, < or =1, < or =0.12, 8, and 0.5, respectively. The most active agents against extended-spectrum beta-lactamase-producing E. coli were meropenem and tigecycline with MIC(90) (microg/mL) of < or =0.12 and 1, respectively. The most active agents against Pseudomonas aeruginosa were amikacin, cefepime, meropenem, and piperacillin/tazobactam with MIC(90) (microg/mL) of 16, 32, 16, and 64, respectively. The most active agents against Stenotrophomonas maltophilia were tigecycline and trimethoprim/sulfamethoxazole with MIC(90) (microg/mL) of 4 and 4, respectively. The most active agents against Acinetobacter baumannii were fluoroquinolones (e.g., levofloxacin), meropenem, and tigecycline with MIC(90) (microg/mL) of 0.5, 1, and 2, respectively. In conclusion, the most active agents versus Gram-positive cocci and Gram-negative bacilli obtained from Canadian ICUs were daptomycin, linezolid, tigecycline, dalbavancin and amikacin, cefepime, meropenem, piperacillin/tazobactam, and tigecycline (not P. aeruginosa), respectively.
Diagnostic Microbiology and Infectious Disease 06/2008; 62(1):67-80. · 2.53 Impact Factor
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George G Zhanel, Mel DeCorby,
Nancy Laing,
Barb Weshnoweski,
Ravi Vashisht,
Franil Tailor,
Kim A Nichol,
Aleksandra Wierzbowski,
Patricia J Baudry,
James A Karlowsky,
Philippe Lagacé-Wiens,
Andrew Walkty,
Melissa McCracken,
Michael R Mulvey,
Jack Johnson,
Daryl J Hoban
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ABSTRACT: Between 1 September 2005 and 30 June 2006, 19 medical centers collected 4,180 isolates recovered from clinical specimens from patients in intensive care units (ICUs) in Canada. The 4,180 isolates were collected from 2,292 respiratory specimens (54.8%), 738 blood specimens (17.7%), 581 wound/tissue specimens (13.9%), and 569 urinary specimens (13.6%). The 10 most common organisms isolated from 79.5% of all clinical specimens were methicillin-susceptible Staphylococcus aureus (MSSA) (16.4%), Escherichia coli (12.8%), Pseudomonas aeruginosa (10.0%), Haemophilus influenzae (7.9%), coagulase-negative staphylococci/Staphylococcus epidermidis (6.5%), Enterococcus spp. (6.1%), Streptococcus pneumoniae (5.8%), Klebsiella pneumoniae (5.8%), methicillin-resistant Staphylococcus aureus (MRSA) (4.7%), and Enterobacter cloacae (3.9%). MRSA made up 22.3% (197/884) of all S. aureus isolates (90.9% of MRSA were health care-associated MRSA, and 9.1% were community-associated MRSA), while vancomycin-resistant enterococci (VRE) made up 6.7% (11/255) of all enterococcal isolates (88.2% of VRE had the vanA genotype). Extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae occurred in 3.5% (19/536) and 1.8% (4/224) of isolates, respectively. All 19 ESBL-producing E. coli isolates were PCR positive for CTX-M, with bla CTX-M-15 occurring in 74% (14/19) of isolates. For MRSA, no resistance against daptomycin, linezolid, tigecycline, and vancomycin was observed, while the resistance rates to other agents were as follows: clarithromycin, 89.9%; clindamycin, 76.1%; fluoroquinolones, 90.1 to 91.8%; and trimethoprim-sulfamethoxazole, 11.7%. For E. coli, no resistance to amikacin, meropenem, and tigecycline was observed, while resistance rates to other agents were as follows: cefazolin, 20.1%; cefepime, 0.7%; ceftriaxone, 3.7%; gentamicin, 3.0%; fluoroquinolones, 21.1%; piperacillin-tazobactam, 1.9%; and trimethoprim-sulfamethoxazole, 24.8%. Resistance rates for P. aeruginosa were as follows: amikacin, 2.6%; cefepime, 10.2%; gentamicin, 15.2%; fluoroquinolones, 23.8 to 25.5%; meropenem, 13.6%; and piperacillin-tazobactam, 9.3%. A multidrug-resistant (MDR) phenotype (resistance to three or more of the following drugs: cefepime, piperacillin-tazobactam, meropenem, amikacin or gentamicin, and ciprofloxacin) occurred frequently in P. aeruginosa (12.6%) but uncommonly in E. coli (0.2%), E. cloacae (0.6%), or K. pneumoniae (0%). In conclusion, S. aureus (MSSA and MRSA), E. coli, P. aeruginosa, H. influenzae, Enterococcus spp., S. pneumoniae, and K. pneumoniae are the most common isolates recovered from clinical specimens in Canadian ICUs. A MDR phenotype is common for P. aeruginosa isolates in Canadian ICUs.
Antimicrobial Agents and Chemotherapy 05/2008; 52(4):1430-7. · 4.84 Impact Factor
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ABSTRACT: Two glycopeptide analogues of vancomycin and teicoplanin have been developed with improved pharmacokinetic/pharmacodynamic parameters. Dalbavancin was derived from teicoplanin, and telavancin is a derivative of vancomycin. The half-life of dalbavancin in humans is 147-258 h (6-11 days) allowing for weekly administration. Dalbavancin possesses more potent in vitro activity than vancomycin or teicoplanin. Dalbavancin has been investigated in uncomplicated and complicated skin and skin structure infections (SSSIs) in clinical trials and has demonstrated equivalent or superior (versus vancomycin only) efficacy versus comparators. Telavancin exhibits a dual mechanism of action, low potential for resistance development and is active against resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Clinical trials involving SSSIs have demonstrated equivalent or superior (versus vancomycin for MRSA) efficacy compared with a standard therapy. Both telavancin and dalbavancin show promise as alternative treatments for patients with serious infections caused by resistant Gram-positive pathogens.
Expert Review of Anticancer Therapy 03/2008; 6(1):67-81. · 3.28 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Two glycopeptide analogues of vancomycin and teicoplanin have been developed with improved pharmacokinetic/pharmacodynamic parameters. Dalbavancin was derived from teicoplanin, and telavancin is a derivative of vancomycin. The half-life of dalbavancin in humans is 147-258 h (6-11 days) allowing for weekly administration. Dalbavancin possesses more potent in vitro activity than vancomycin or teicoplanin. Dalbavancin has been investigated in uncomplicated and complicated skin and skin structure infections (SSSIs) in clinical trials and has demonstrated equivalent or superior (versus vancomycin only) efficacy versus comparators. Telavancin exhibits a dual mechanism of action, low potential for resistance development and is active against resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Clinical trials involving SSSIs have demonstrated equivalent or superior (versus vancomycin for MRSA) efficacy compared with a standard therapy. Both telavancin and dalbavancin show promise as alternative treatments for patients with serious infections caused by resistant Gram-positive pathogens.
Expert Review of Anticancer Therapy 01/2008; 6(1):67-81. · 3.28 Impact Factor
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Journal of Antimicrobial Chemotherapy 07/2006; 57(6):1262-3. · 5.07 Impact Factor
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ABSTRACT: Antimicrobial resistance is a growing problem among upper respiratory tract pathogens. Resistance to beta-lactam drugs among Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes is increasing. As safe and well-tolerated antibiotics, macrolides play a key role in the treatment of community-acquired upper respiratory tract infections (RTIs). Their broad spectrum of activity against gram-positive cocci, such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, has led to the widespread use of macrolides for empiric treatment of upper RTIs and as alternatives for patients allergic to beta-lactams. Macrolide resistance is increasing among pneumococci and recently among S. pyogenes, and is associated with increasing use of the newer macrolides, such as azithromycin. Ribosomal target modification mediated by erm(A) and erm(B) genes and active efflux due to mef(A) and mef(E) are the principal mechanisms of resistance in both S. pneumoniae and S. pyogenes. Recently, ribosomal protein and RNA mutations have been found to be responsible for acquired resistance to macrolides in S. pneumoniae, S. pyogenes, and H. influenzae. Although macrolides are only weakly active against macrolide-resistant streptococci species, producing an efflux pump (mef), and are inactive against pathogens with ribosomal target modification (erm), treatment failures are uncommon. Therefore, macrolide therapy, for now, remains a good alternative for treatment of upper RTIs; however, continuous monitoring of the local resistance patterns is essential.
Current Allergy and Asthma Reports 04/2006; 6(2):171-81. · 2.50 Impact Factor
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ABSTRACT: Antimicrobial resistance is a growing problem among upper respiratory tract pathogens. Resistance to beta-lactam drugs among Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes is increasing. As safe and well-tolerated antibiotics, macrolides play a key role in the treatment of community-acquired upper respiratory tract infections (RTIs). Their broad spectrum of activity against gram-positive cocci, such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, has led to the widespread use of macrolides for empiric treatment of upper RTIs and as alternatives for patients allergic to b-lactams. Macrolide resistance is increasing among pneumococci and recently among S. pyogenes, and is associated with increasing use of the newer macrolides, such as azithromycin. Ribosomal target modification mediated by erm(A) and erm(B) genes and active efflux due to mef(A) and mef(E) are the principal mechanisms of resistance in S. pneumoniae and S. pyogenes. Recently, ribosomal protein and RNA mutations have been found responsible for acquired resistance to macrolides in S. pneumoniae, S. pyogenes, and H. influenzae. Although macrolides are only weakly active against macrolide-resistant streptococci species producing an efflux pump (mef) and are inactive against pathogens with ribosomal target modification (erm), treatment failures are uncommon. Therefore, macrolide therapy, for now, remains a good alternative for treatment of upper RTIs; however, continuous monitoring of the local resistance patterns is essential.
Current Infectious Disease Reports 06/2005; 7(3):175-184.
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ABSTRACT: The association between macrolide resistance mechanisms and bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro pharmacodynamic model, assessed azithromycin activity against macrolide-susceptible and -resistant S. pneumoniae simulating clinically achievable free serum (S), epithelial lining fluid (ELF) and middle ear fluid (MEF) concentrations.
Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Azithromycin was modelled simulating a dosage of 500 mg/250 mg by mouth, once a day [free S: maximum concentration (Cmax) 0.2 mg/L, t1/2 68 h; free ELF Cmax 1.0 mg/L, t1/2 68 h] and 10 mg/kg by mouth, once a day (free MEF: Cmax 1.0 mg/L, t1/2 68 h) using a one compartment model. Starting inocula were 1 x 10(6) cfu/mL in Mueller-Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log10 cfu/mL versus initial inoculum).
Free azithromycin concentrations in serum, ELF and MEF simulating time above the MIC (T > MIC) of 100% [area under the curve to MIC (AUC0-24/MIC] > or = 36.7] were bactericidal (> or = 3 log10 killing) at 24 and 48 h versus macrolide-susceptible S. pneumoniae. Against macrolide-resistant S. pneumoniae, free serum concentrations providing T > MIC of 0% or AUC0-24/MIC < or = 1.1 demonstrated no bacterial inhibition followed by regrowth at 24 and 48 h, whereas free ELF and MEF providing T > MIC of 0% or AUC0-24/MIC of 4.6 produced a bacteriostatic (0.2-0.5 log10 killing at 24 h) effect with a mef(A) strain with an azithromycin MIC of 2 mg/L. Against mef(A)-positive S. pneumoniae strains with azithromycin MICs > or = 4 mg/L, no bacterial killing occurred at any time point and rapid regrowth was observed simulating ELF or MEF T > MIC of 0% or AUC0-24/MIC < or = 2.3.
Azithromycin serum, ELF and MEF concentrations rapidly eradicated macrolide-susceptible S. pneumoniae but did not eradicate macrolide-resistant S. pneumoniae regardless of resistance phenotype.
Journal of Antimicrobial Chemotherapy 07/2003; 52(1):83-8. · 5.07 Impact Factor
