Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.

In vitro activity of Oritavancin against gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2015.

Gram-positive bacterial pathogens isolated from patient specimens submitted to 15 Canadian hospital laboratories from 2011 to 2015 were tested in the coordinating laboratory for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute M07-A10 (2015) broth microdilution method. Oritavancin's in vitro activity was equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against methicillin-susceptible Staphylococcus aureus (n=2680; oritavancin MIC90, 0.12µg/mL; 99.9% oritavancin-susceptible), methicillin-resistant S. aureus (n=728; oritavancin MIC90, 0.12µg/mL; 99.7% oritavancin-susceptible), Streptococcus pyogenes (n=218; oritavancin MIC90, 0.25µg/mL; 100% oritavancin-susceptible), Streptococcus agalactiae (n=269; oritavancin MIC90, 0.12µg/mL; 100% oritavancin-susceptible), and vancomycin-susceptible Enterococcus faecalis (n=508; oritavancin MIC90, 0.06µg/mL; 100% oritavancin-susceptible). Oritavancin, dalbavancin, and telavancin demonstrated equivalent in vitro activities (MIC90, µg/mL) against 602 isolates of MSSA (0.06, 0.06, 0.06, respectively) and 144 isolates of MRSA (0.12, 0.06, 0.06, respectively) collected in 2015.

Solithromycin: A Novel Fluoroketolide for the Treatment of Community-Acquired Bacterial Pneumonia.

Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation. However, unlike telithromycin, which binds to two sites on the ribosome, solithromycin has three distinct ribosomal binding sites. Its desosamine sugar interacts at the A2058/A2059 cleft in domain V (as all macrolides do), an extended alkyl-aryl side chain interacts with base pair A752-U2609 in domain II (similar to telithromycin), and a fluorine at C-2 of solithromycin provides additional binding to the ribosome. Studies describing solithromycin activity against Streptococcus pneumoniae have reported that it does not induce erm-mediated resistance because it lacks a cladinose moiety, and that it is less susceptible than other macrolides to mef-mediated efflux due to its increased ribosomal binding and greater intrinsic activity. Solithromycin has demonstrated potent in vitro activity against the most common CABP pathogens, including macrolide-, penicillin-, and fluoroquinolone-resistant isolates of S. pneumoniae, as well as Haemophilus influenzae and atypical bacterial pathogens. Solithromycin displays multi-compartment pharmacokinetics, a large volume of distribution (>500 L), approximately 67% bioavailability when given orally, and serum protein binding of 81%. Its major metabolic pathway appears to follow cytochrome P450 (CYP) 3A4, with metabolites of solithromycin undergoing biliary excretion. Its serum half-life is approximately 6-9 h, which is sufficient for once-daily administration. Pharmacodynamic activity is best described as fAUC0-24/MIC (the ratio of the area under the free drug concentration-time curve from 0 to 24 h to the minimum inhibitory concentration of the isolate). Solithromycin has completed one phase II and two phase III clinical trials in patients with CABP. In the phase II trial, oral solithromycin was compared with oral levofloxacin and demonstrated similar clinical success rates in the intention-to-treat (ITT) population (84.6 vs 86.6%). Clinical success in the clinically evaluable patients group was 83.6% of patients receiving solithromycin compared with 93.1% for patients receiving levofloxacin. In SOLITAIRE-ORAL, a phase III trial which assessed patients receiving oral solithromycin or oral moxifloxacin for CABP, an equivalent (non-inferior) early clinical response in the ITT population was demonstrated for patients receiving either solithromycin (78.2%) or moxifloxacin (77.9%). In a separate phase III trial, SOLITAIRE-IV, patients receiving intravenous-to-oral solithromycin (79.3%) demonstrated non-inferiority as the primary outcome of early clinical response in the ITT population compared with patients receiving intravenous-to-oral moxifloxacin (79.7%). Overall, solithromycin has been well tolerated in clinical trials, with gastrointestinal adverse events being most common, occurring in approximately 10% of patients. Transaminase elevation occurred in 5-10% of patients and generally resolved following cessation of therapy. None of the rare serious adverse events that occurred with telithromycin (i.e., hepatotoxicity) have been noted with solithromycin, possibly due to the fact that solithromycin (unlike telithromycin) does not possess a pyridine moiety in its chemical structure, which has been implicated in inhibiting nicotinic acetylcholine receptors. Because solithromycin is a possible substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp), it may display drug interactions similar to macrolides such as clarithromycin. Overall, the in vitro activity, clinical efficacy, tolerability, and safety profile of solithromycin demonstrated to date suggest that it continues to be a promising treatment for CABP.

Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens.

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 fAUC(0-24h)/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).

Ceftazidime-avibactam: a novel cephalosporin/ß-lactamase inhibitor combination.

Avibactam (formerly NXL104, AVE1330A) is a synthetic non-ß-lactam, ß-lactamase inhibitor that inhibits the activities of Ambler class A and C ß-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 ß-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to ß-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 ß-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 ß-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.

Baseline epidemiology of Streptococcus pneumoniae serotypes in Canada prior to the introduction of the 13-valent pneumococcal vaccine.

Changes in the epidemiology of Streptococcus pneumoniae were reported worldwide after the introduction of the 7-valent pneumococcal vaccine, particularly an increase in multi-drug resistant (MDR) 19A strains. Subsequently, a 13-valent pneumococcal vaccine (PCV-13) has been introduced. This study assessed the incidence of S. pneumoniae serotypes in all age groups prior to the introduction of PCV-13 in Canada (2007-2009). Eight hundred S. pneumoniae isolates from respiratory specimens and blood cultures were collected as part of a Canadian surveillance study (CANWARD) from patients in 15 tertiary-care centers. Serotyping was performed by the Quellung method and antimicrobial susceptibility testing was performed by broth microdilution in accordance with the Clinical and Laboratory Standards Institute guidelines. The most common serotypes were 19A (8.6%), 3 (7.3%), 22F (6.0%), 4 (4.6%), 5 (4.4%), and 11A (4.4%); and the first serotype 6D isolate in Canada was identified. Serotypes 5, 7F, and 19A were significantly (p<0.001) more frequently isolated from bloodstream infections. Considerable serotype variability was noted for different age groups: 15B (p<0.01) and 19A (p<0.001) were more frequently isolated from children ≤2 years old. Overall, 46.4% of currently circulating S. pneumoniae serotypes in Canada are included in PCV-13. Notably, 87.5% of MDR-S. pneumoniae were covered by PCV-13. Accordingly, PCV-13 will provide coverage against a significant proportion of circulating S. pneumoniae strains in Canada, including the critical antimicrobial-resistant strains.

Antimicrobial resistance in urinary tract pathogens in Canada from 2007 to 2009: CANWARD surveillance study.

From January 2007 to December 2009, an annual Canadian national surveillance study (CANWARD) tested 2,943 urinary culture pathogens for antimicrobial susceptibilities according to Clinical and Laboratory Standards Institute guidelines. The most frequently isolated urinary pathogens were as follows (number of isolates, percentage of all isolates): Escherichia coli (1,581, 54%), enterococci (410, 14%), Klebsiella pneumoniae (274, 9%), Proteus mirabilis (122, 4%), Pseudomonas aeruginosa (100, 3%), and Staphylococcus aureus (80, 3%). The rates of susceptibility to trimethoprim-sulfamethoxazole (SXT) were 78, 86, 84, and 93%, respectively, for E. coli, K. pneumoniae, P. mirabilis, and S. aureus. The rates of susceptibility to nitrofurantoin were 96, 97, 33, and 100%, respectively, for E. coli, enterococci, K. pneumoniae, and S. aureus. The rates of susceptibility to ciprofloxacin were 81, 40, 86, 81, 66, and 41%, respectively, for E. coli, enterococci, K. pneumoniae, P. mirabilis, P. aeruginosa, and S. aureus. Statistical analysis of resistance rates (resistant plus intermediate isolates) by year for E. coli over the 3-year study period demonstrated that increased resistance rates occurred only for amoxicillin-clavulanate (from 1.8 to 6.6%; P < 0.001) and for SXT (from 18.6 to 24.3%; P = 0.02). For isolates of E. coli, in a multivariate logistic regression model, hospital location was independently associated with resistance to ciprofloxacin (P = 0.026) with higher rates of resistance observed in inpatient areas (medical, surgical, and intensive care unit wards). Increased age was also associated with resistance to ciprofloxacin (P < 0.001) and with resistance to two or more commonly prescribed oral agents (amoxicillin-clavulanate, ciprofloxacin, nitrofurantoin, and SXT) (P = 0.005). We conclude that frequently prescribed empirical agents for urinary tract infections, such as SXT and ciprofloxacin, demonstrate lowered in vitro susceptibilities when tested against recent clinical isolates.

New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin.

Dalbavancin, oritavancin and telavancin are semisynthetic lipoglycopeptides that demonstrate promise for the treatment of patients with infections caused by multi-drug-resistant Gram-positive pathogens. Each of these agents contains a heptapeptide core, common to all glycopeptides, which enables them to inhibit transglycosylation and transpeptidation (cell wall synthesis). Modifications to the heptapeptide core result in different in vitro activities for the three semisynthetic lipoglycopeptides. All three lipoglycopeptides contain lipophilic side chains, which prolong their half-life, help to anchor the agents to the cell membrane and increase their activity against Gram-positive cocci. In addition to inhibiting cell wall synthesis, telavancin and oritavancin are also able to disrupt bacterial membrane integrity and increase membrane permeability; oritavancin also inhibits RNA synthesis. Enterococci exhibiting the VanA phenotype (resistance to both vancomycin and teicoplanin) are resistant to both dalbavancin and telavancin, while oritavancin retains activity. Dalbavancin, oritavancin and telavancin exhibit activity against VanB vancomycin-resistant enterococci. All three lipoglycopeptides demonstrate potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis regardless of their susceptibility to meticillin, as well as Streptococcus spp. Both dalbavancin and telavancin are active against vancomycin-intermediate S. aureus (VISA), but display poor activity versus vancomycin-resistant S. aureus (VRSA). Oritavancin is active against both VISA and VRSA. Telavancin displays greater activity against Clostridium spp. than dalbavancin, oritavancin or vancomycin. The half-life of dalbavancin ranges from 147 to 258 hours, which allows for once-weekly dosing, the half-life of oritavancin of 393 hours may allow for one dose per treatment course, while telavancin requires daily administration. Dalbavancin and telavancin exhibit concentration-dependent activity and AUC/MIC (area under the concentration-time curve to minimum inhibitory concentration ratio) is the pharmacodynamic parameter that best describes their activities. Oritavancin's activity is also considered concentration-dependent in vitro, while in vivo its activity has been described by both concentration and time-dependent models; however, AUC/MIC is the pharmacodynamic parameter that best describes its activity. Clinical trials involving patients with complicated skin and skin structure infections (cSSSIs) have demonstrated that all three agents are as efficacious as comparators. The most common adverse effects reported with dalbavancin use included nausea, diarrhoea and constipation, while injection site reactions, fever and diarrhoea were commonly observed with oritavancin therapy. Patients administered telavancin frequently reported nausea, taste disturbance and insomnia. To date, no drug-drug interactions have been identified for dalbavancin, oritavancin or telavancin. All three of these agents are promising alternatives for the treatment of cSSSIs in cases where more economical options such as vancomycin have been ineffective, in cases of reduced vancomycin susceptibility or resistance, or where vancomycin use has been associated with adverse events.

Detection and characterization of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates in Canada: results from the Canadian Nosocomial Infection Surveillance Program, 1995-2006.

We describe the epidemiology of heterogeneously resistant Staphylococcus aureus (hVISA) identified in Canadian hospitals between 1995 and 2006. hVISA isolates were confirmed by the population analysis profiling-area under the curve method. Only 25 hVISA isolates (1.3% of all isolates) were detected. hVISA isolates were more likely to have been health care associated (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.9 to 14.2) and to have been recovered from patients hospitalized in central Canada (OR, 3.0; 95% CI, 1.2 to 7.4). There has been no evidence of vancomycin "MIC creep" in Canadian strains of methicillin (meticillin)-resistant S. aureus, and hVISA strains are currently uncommon.

Association between fluoroquinolone usage and a dramatic rise in ciprofloxacin-resistant Streptococcus pneumoniae in Canada, 1997-2006.

This study evaluated the prevalence of fluoroquinolone usage and investigated the association between usage and resistance in respiratory isolates of Streptococcus pneumoniae in Canada. Fluoroquinolone susceptibility testing was conducted on S. pneumoniae collected from 25 medical centres across Canada over nine study years. Fluoroquinolone prescriptions and consumption figures were derived from data in the IMS Health, Canada CompuScript Audit. Between 1997 and 2006, 11825 S. pneumoniae isolates were collected. Ciprofloxacin resistance rates increased significantly (P<0.01) during the study from 0% to 4.5% in children (0-15 years), from 0.2% to 5.4% in adults (16-64 years) and from 1.4% to 11.6% in the elderly (> or = 65 years). Outpatient ciprofloxacin and respiratory fluoroquinolone prescriptions increased by 55.6% (38.2 prescriptions/1000 population to 59.4 prescriptions/1000 population; P<0.01) and 416.2% (5.3 prescriptions/1000 to 27.4 prescriptions/1000; P<0.01), respectively. Ciprofloxacin and respiratory fluoroquinolone consumption increased by 10.6% [1.1 defined daily doses (DDDs)/1000/day to 1.2 DDDs/1000/day; P=0.02] and 38.2% (0.5 to 0.7 DDDs/1000/day; P=0.02), respectively, from 2001 to 2006. A strong association between ciprofloxacin use and resistance (R(2)=0.89) was identified. Fluoroquinolone resistance in S. pneumoniae increased significantly in Canada from 1997 to 2006 in conjunction with increased ciprofloxacin and respiratory fluoroquinolone consumption. Ciprofloxacin usage appears to be the biggest driver of resistance; however, total fluoroquinolone usage is also important.