Kim Nichol

The glycylcyclines: A comparative review with the tetracyclines

The tetracycline class of antimicrobials exhibit a broad-spectrum of activity against numerous pathogens, including Gram-positive and Gram-negative bacteria, as well as atypical organisms. These compounds are bacteriostatic, and act by binding to the bacterial 30S ribosomal subunit and inhibiting protein synthesis. The tetracyclines have been used successfully for the treatment of a variety of infectious diseases including community-acquired respiratory tract infections and sexually transmitted diseases, as well in the management of acne. The use of tetracyclines for treating bacterial infections has been limited in recent years because of the emergence of resistant organisms with efflux and ribosomal protection mechanisms of resistance. Research to find tetracycline analogues that circumvented these resistance mechanisms has lead to the development of the glycylcyclines.The most developed glycylcycline is the 9-tert-butyl-glycylamido derivative of minocycline, otherwise known as tigecycline (GAR-936). The glycylcyclines exhibit antibacterial activities typical of earlier tetracyclines, but with more potent activity against tetracycline-resistant organisms with efflux and ribosomal protection mechanisms of resistance. The glycylcyclines are active against other resistant pathogens including methicillin-resistant staphylococci, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci.Tigecycline is only available in an injectable formulation for clinical use unlike currently marketed tetracyclines that are available in oral dosage forms. Tigecycline has a significantly larger volume of distribution (>10 L/kg) than the other tetracyclines (range of 0.14 to 1.6 L/kg). Protein binding is approximately 68%. Presently no human data are available describing the tissue penetration of tigecycline, although studies in rats using radiolabelled tigecycline demonstrated good penetration into tissues. Tigecycline has a half-life of 36 hours in humans, less than 15% of tigecycline is excreted unchanged in the urine. On the basis of available data, it does not appear that the pharmacokinetics of tigecycline are markedly influenced by patient gender or age.The pharmacodynamic parameter that best correlates with bacteriological eradication is time above minimum inhibitory concentration. Several animal studies have been published describing the efficacy of tigecycline. Human phase 1 and 2 clinical trials have been completed for tigecycline. Phase 2 studies have been conducted in patients with complicated skin and skin structure infections, and in patients with complicated intra-abdominal infections have been published as abstracts. Both studies concluded that tigecycline was efficacious and well tolerated. Few human data are available regarding the adverse effects or drug interactions resulting from tigecycline therapy; however, preliminary data report that tigecycline can be safely used, is well tolerated and that the adverse effects experienced were typical of the tetracyclines (i.e. nausea, vomiting and headache).Tigecycline appears to be a promising new antibacterial based on in vitro and pharmacokinetic/pharmacodynamic activity; however more clinical data are needed to fully evaluate its potential.

Antimicrobial-Resistant Pathogens in Intensive Care Units in Canada: Results of the Canadian National Intensive Care Unit (CAN-ICU) Study, 2005-2006

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 β-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 blaCTX-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.

Macrolide-Resistant Streptococcus pneumoniae in Canada during 1998-1999: Prevalence of mef(A) and erm(B) and Susceptibilities to Ketolides

ABSTRACT In this study (1998–1999), we collected 215 macrolide-resistantStreptococcus pneumoniae isolates from an ongoing Canadian Respiratory Organism Surveillance Study involving 23 centers representing all regions of Canada. The prevalence of erythromycin-resistant S. pneumoniae was 8% (215 of 2,688). Of the 215 isolates, 48.8% (105 of 215) were PCR positive formef(A) and 46.5% (100 of 215) were PCR positive forerm(B). The ketolides telithromycin and ABT-773 demonstrated excellent activity against both mef(A) (MIC for 90% of strains [MIC90], 0.06 and 0.03 μg/ml, respectively) and erm(B) (MIC90, 0.06 and 0.03 μg/ml, respectively) strains of S. pneumoniae.

Antimicrobial susceptibility of 3931 organisms isolated from intensive care units in Canada: Canadian National Intensive Care Unit Study, 2005/2006

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.

Molecular characterization of fluoroquinolone resistant Streptococcus pneumoniae clinical isolates obtained from across Canada

There is little published data detailing fluoroquinolone resistance in clinical isolates of S. pneumoniae. The purpose of this study was to characterize the resistance mechanisms of 34 fluoroquinolone-resistant S. pneumoniae clinical isolates obtained from medical centers in 8 of 10 Canadian provinces between 1997 and 2000. The quinolone resistance determining regions of gyrA, parC, and parE from the isolates were sequenced. The isolates were evaluated for reserpine-sensitive efflux of ciprofloxacin and the new fluoroquinolones: gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin. The isolates were typed using pulsed field gel electrophoresis. The majority of the isolates were genetically unrelated. Lower level fluoroquinolone resistance (ciprofloxacin MIC 4-8 microg/ml) was associated with amino acid substitutions in ParC, while higher level resistance (ciprofloxacin MIC > or = 16 microg/ml) was associated with amino acid substitutions in both ParC and GyrA. ParE substitutions were not associated with clinical resistance. Twelve of 34 (35%) isolates demonstrated reserpine-sensitive efflux of ciprofloxacin. Efflux alone conferred low level ciprofloxacin resistance in 3 isolates. Significant reserpine-sensitive efflux of the new fluoroquinolones was not observed.

Pharmacodynamic Modeling of Clarithromycin against Macrolide-Resistant [PCR-Positive mef(A) or erm(B)] Streptococcus pneumoniae Simulating Clinically Achievable Serum and Epithelial Lining Fluid Free-Drug Concentrations

ABSTRACT The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug Cp maximum of 2 μg/ml, t1/2 of 6 h; in ELF, CELF(total) maximum of 35μg/ml, t1/2 of 6 h; CELF(free) maximum of 14 μg/ml, t1/2 of 6 h). Starting inocula were 106 CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of ≥90% (AUC0-24/MIC ratio, ≥61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC0-24/MIC ratios of ≥30.5 to 38) resulted in a 1.2 to 2.0 log10 CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of ≤8% (AUC0-24/MIC ratio, ≤17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 μg/ml. However, mef(A) isolates for which MICs are ≥16 μg/ml along with erm(B) may result in bacteriological failures.

Comparison of Antimicrobial Resistance Profiles among Extended-Spectrum-β-Lactamase-Producing and Acquired AmpC β-Lactamase-Producing Escherichia coli Isolates from Canadian Intensive Care Units

ABSTRACT Resistance profiles were compared among 18 extended-spectrum-β-lactamase-producing (ESBL) and 27 acquired AmpC β-lactamase-producing Escherichia coli isolates collected from Canadian intensive care units from 2005 to 2006. ESBL-producing E. coli isolates were more likely to be gentamicin resistant (P < 0.03), fluoroquinolone resistant (P < 0.0001), and multidrug resistant (P < 0.0001) than AmpC-producing E. coli isolates.

Telavancin: Mechanisms of Action, In Vitro Activity, and Mechanisms of Resistance

Telavancin is a semisynthetic lipoglycopeptide derivative of vancomycin. Telavancin has a dual mechanism of antibacterial action, disrupting peptidoglycan synthesis and cell membrane function. In 2014, the Clinical and Laboratory Standards Institute (CLSI) revised the antimicrobial susceptibility testing method for telavancin, resulting in minimum inhibitory concentration (MIC) determinations that are more accurate and reproducible and demonstrate greater in vitro potency than shown with the previous testing method. The CLSI testing method changes coincided with revised telavancin MIC interpretive break point criteria for susceptibility approved by the US Food and Drug Administration for Staphylococcus aureus (≤0.12 µg/mL), Streptococcus pyogenes (≤0.12 µg/mL), Streptococcus agalactiae (≤0.12 µg/mL), Streptococcus anginosus group (≤0.06 µg/mL), and Enterococcus faecalis (vancomycin susceptible, ≤0.25 µg/mL). Telavancin is equally potent against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). It demonstrates activity against isolates of heterogeneous vancomycin-intermediate S. aureus and vancomycin-intermediate S. aureus but is poorly active against vancomycin-resistant S. aureus. It also demonstrates potent activity against Staphylococcus epidermidis and Streptococcus spp. (MIC90 ≤0.03 µg/mL). Thus far, it has not been possible to select for high-level telavancin resistance in the laboratory using serially passaged clinical isolates of MRSA and MSSA.

Ketolides: an emerging treatment for macrolide-resistant respiratory infections, focusing on S. pneumoniae

Resistance to antibiotics in community acquired respiratory infections is increasing worldwide. Resistance to the macrolides can be class-specific, as in efflux or ribosomal mutations, or, in the case of erythromycin ribosomal methylase (erm)-mediated resistance, may generate cross-resistance to other related classes. The ketolides are a new subclass of macrolides specifically designed to combat macrolide-resistant respiratory pathogens. X-ray crystallography indicates that ketolides bind to a secondary region in domain II of the 23S rRNA subunit, resulting in an improved structure–activity relationship. Telithromycin and cethromycin (formerly ABT-773) are the two most clinically advanced ketolides, exhibiting greater activity towards both typical and atypical respiratory pathogens. As a subclass of macrolides, ketolides demonstrate potent activity against most macrolide-resistant streptococci, including ermB- and macrolide efflux (mef)A-positive Streptococcus pneumoniae. Their pharmacokinetics display a long half-life as well as extensive tissue distribution and uptake into respiratory tissues and fluids, allowing for once-daily dosing. Clinical trials focusing on respiratory infections indicate bacteriological and clinical cure rates similar to comparators, even in patients infected with macrolide-resistant strains.

Ceftaroline pharmacodynamic activity versus community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus, heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus using an in vitro model

BACKGROUND This study assessed the pharmacodynamics of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA), heteroresistant (h) vancomycin-intermediate S. aureus (hVISA), VISA and vancomycin-resistant S. aureus (VRSA) using an in vitro model. METHODS Two methicillin-susceptible S. aureus (MSSA), one community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, one hVISA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 × 10⁶ cfu/mL and ceftaroline dosed every 12 h (at 0 and 12 h) to simulate the ƒC(max) and t(½) obtained after administering 600 mg intravenously every 12 h (ƒC(max), 16 mg/L; t(½), 2.6 h). Samples were collected over 24 h to assess viable growth and changes in ceftaroline MIC over time. RESULTS Ceftaroline ƒT(> MIC) of ≥ 92% (ceftaroline MICs, ≤ 1 mg/L) was bactericidal (≥ 3 log₁₀ killing) against MSSA, CA-MRSA, HA-MRSA, hVISA, VISA and VRSA at 12 and 24 h. No bacterial regrowth occurred over the study period and no change in ceftaroline MIC was observed. CONCLUSIONS Ceftaroline ƒT(> MIC) of ≥ 92% (ceftaroline MICs, ≤ 1 mg/L) was bactericidal (≥ 3 log₁₀ killing) against MSSA, CA-MRSA, HA-MRSA, hVISA, VISA and VRSA at 12 and 24 h.