Oritavancin in vitro activity against Gram-positive organisms from European medical centers: a 10-year longitudinal overview from the SENTRY Antimicrobial Surveillance Program (2010-2019).

To assess oritavancin in vitro activity against clinically relevant Gram-positive pathogens in European (EU) hospitals, a total of 51,531 consecutive and unique clinical isolates collected in 2010-2019 were evaluated. All isolates were tested by CLSI broth microdilution methods. The key resistance phenotypes differed considerably between Eastern Europe (E-EU) and Western Europe (W-EU), respectively: methicillin-resistant (MR) Staphylococcus aureus 27.7%/22.9%; multidrug resistant (MDR) S. aureus, 19.7%/15.2%; MR coagulase-negative staphylococci, 77.3%/61.9%; vancomycin-resistant enterococci (E. faecium), 44.2%/20.9%; and MDR E. faecium, 63.8%/55.4%. There were no substantive differences in oritavancin minimum inhibitory concentration (MIC) values for the different species/organism groups over time or by EU region. Oritavancin inhibited 99.9% and 99.1% of all S. aureus and coagulase-negative staphylococci at 0.12 mg/L, respectively, and all isolates of E. faecalis and E. faecium at ≤0.5 mg/L. Oritavancin susceptibility rates against ß-hemolytic and Viridans group streptococci isolates were 98.1% and 99.4%, respectively. Oritavancin had potent activity in vitro against this contemporary collection of European Gram-positive isolates from 2010 to 2019.

Development of Modernized Acinetobacter baumannii Susceptibility Test Interpretive Criteria for Recommended Antimicrobial Agents Using Pharmacometric Approaches.

Acinetobacter baumannii-Acinetobacter calcoaceticus complex (referred to herein as A. baumannii) treatment guidelines contain numerous older antimicrobial agents with susceptibility test interpretive criteria (STIC, also known as susceptibility breakpoints) set using only epidemiological data. We utilized a combination of in vitro surveillance data, preclinical murine thigh and lung infection models, population pharmacokinetics, simulation, and pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses to evaluate A. baumannii STIC for four commonly recommended antimicrobials from different classes (amikacin, ceftazidime, ciprofloxacin, and minocycline). Antimicrobial in vitro surveillance data were based on 1,647 clinical A. baumannii isolates obtained from 109 centers in the United States and Europe. Among these isolates, 5 were selected for evaluation in murine infection models based on fitness and MIC variability. PK and dose-ranging studies were conducted using neutropenic murine thigh and lung infection models The MIC ranges for the 5 isolates evaluated were as follows: amikacin, 2 to 32 µg/mL; ceftazidime, 4 to 16 µg/mL; ciprofloxacin, 0.12 to 2 µg/mL; minocycline, 0.25 to 4 µg/mL. All organisms grew ≥1.5 log10 CFU in both models in untreated controls. Plasma and epithelial lining fluid (ELF) pharmacokinetics for all drugs were determined in mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. For each isolate, 5 dose levels of each drug were tested individually in the thigh and lung infection model. The inoculum ranged from 7.9 to 8.4 and 6.8 to 7.7 log10 CFU/mL for the lung and thigh models, respectively. PK/PD targets associated with net bacterial stasis and 1- and 2-log10 CFU reductions from baseline were identified for each organism/infection model using Hill-type models. Population pharmacokinetic models for each agent were identified from the literature. Using demographic variables for simulated patients with hospital-acquired or ventilator-associated bacterial pneumonia or urinary tract infections (including acute pyelonephritis) who were administered maximal dosing regimens of each agent, estimates of protein binding, and ELF penetration ratios based on data from the literature, free-drug plasma and total-drug concentration-time profiles were generated, and PK/PD indices by MIC were calculated. Percent probabilities of attaining median and randomly assigned PK/PD targets associated with the above-described endpoints were determined. Recommended susceptible breakpoints for each agent were those representing the highest MIC at which the percent probabilities of achieving PK/PD targets associated with a 1-log10 CFU reduction from baseline approached or were ≥90%. The following susceptible breakpoints for A. baumannii were identified: amikacin, ≤8 µg/mL for pneumonia; ceftazidime, ≤32 and ≤8 µg/mL for pneumonia; ciprofloxacin, ≤1 µg/mL; and minocycline, ≤0.5/≤1 µg/mL which correspond to the standard and high minocycline dosing regimens of 200 mg per day and 200 mg every 12 h, respectively. Implementation of appropriate STIC will help clinicians optimally use the above-described agents and improve the likelihood of successful patient outcomes.

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 µg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

Oritavancin in vitro activity against gram-positive organisms from European and United States medical centers: results from the SENTRY Antimicrobial Surveillance Program for 2010-2014.

The in vitro activity of oritavancin was assessed against 44,715 gram-positive pathogens causing infections in European and United States (US) hospitals (2010-2014). There were no substantive differences (>±2-fold dilution) in oritavancin MIC50 or MIC90 values for different species/organism groups over time or by region. Oritavancin (99.9% susceptible) showed modal MIC, MIC50, and MIC90 results of 0.03, 0.03, and 0.06-0.12 mg/L when tested against Staphylococcus aureus, regardless of methicillin susceptibility, year, or region. Coagulase-negative staphylococci from the US and Europe demonstrated equal MIC50 values for oritavancin (MIC50, 0.03 mg/L). Oritavancin inhibited 99.9% of Enterococcus faecalis and all E. faecium at ≤0.5 mg/L, including vancomycin-resistant isolates. Oritavancin exhibited MIC50 results of 0.03 and ≤0.008 mg/L when tested against ß-hemolytic and viridans group streptococci isolates, respectively, regardless of geographical region. Oritavancin maintained potent activity in vitro against this contemporary collection of European and US gram-positive isolates over 5 years (2010-2014).

Antimicrobial activity of ceftobiprole and comparator agents when tested against contemporary Gram-positive and -negative organisms collected from Europe (2015).

Susceptibility testing of ceftobiprole and comparators against 12,240 isolates was performed following CLSI/EUCAST guidelines. The percentage of susceptible MRSA isolates was higher for ceftobiprole (96.5% susceptible) than for ceftaroline (86.2% susceptible). Both ceftobiprole (MIC50/90, 0.5/2 mg/L) and ceftaroline (MIC50/90, 0.25/1 mg/L) demonstrated potent activity against coagulase-negative staphylococci. Ceftobiprole demonstrated good potency against Enterococcus faecalis (MIC50/90 values of 0.5/2 mg/L); ceftaroline (MIC50/90, 2/8 mg/L) was 4-fold less active against these strains. Ceftobiprole activity was comparable to that of the other ß-lactam agents tested against S. pneumoniae (MIC90, 0.5 mg/L vs 0.12-2 mg/L [other ß-lactams]), viridans-group streptococci (MIC90,0.25 mg/L vs 0.006-1 mg/L [other ß-lactams]), and ß-hemolytic streptococci (MIC90,0.03 mg/L vs 0.015-0.06 mg/L [other ß-lactams]). Overall, 73.8% of Enterobacteriaceae isolates tested were susceptible to ceftobiprole. Ceftobiprole inhibited 70.4% of P. aeruginosa at ≤4 mg/L and all isolates of Haemophilus influenzae and Moraxella catarrhalis at ≤ 0.5 mg/L. Ceftobiprole was active in vitro against a broad range of clinically-relevant contemporary Gram-positive and Gram-negative bacterial isolates.

Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in the Asia-Pacific region (minus China, Australia and New Zealand): report from an Antimicrobial Surveillance Programme (2013-2015).

The aim of this study was to evaluate the in vitro activity of ceftolozane/tazobactam and comparator agents tested against Enterobacteriaceae and Pseudomonas aeruginosa isolates from patients in the Asia-Pacific (APAC) region with healthcare-associated infections. Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a well-established ß-lactamase inhibitor. A total of 1963 Gram-negative organisms (489 P. aeruginosa and 1474 Enterobacteriaceae) were consecutively collected using a prevalence-based approach from 14 medical centres in the APAC region. Antimicrobial susceptibility testing was performed by broth microdilution method as described by the CLSI and the results were interpreted according to EUCAST and CLSI breakpoint criteria. Ceftolozane/tazobactam [MIC50/90, 0.25/4 µg/mL; 89.2/85.8% susceptible (CLSI/EUCAST)] and meropenem [MIC50/90, ≤0.06/≤0.06 µg/mL; 96.3/96.5% susceptible (CLSI/EUCAST)] were the most active compounds tested against Enterobacteriaceae. Isolates displayed susceptibility rates to other ß-lactam agents ranging from 85.8/81.0% for piperacillin/tazobactam to 74.4/72.7% for cefepime and 72.8/68.1% for ceftazidime using CLSI/EUCAST breakpoints. Among the Enterobacteriaceae isolates, 3.6% were carbapenem-resistant Enterobacteriaceae (CRE) and 25.6% exhibited an extended-spectrum ß-lactamase (ESBL) non-CRE phenotype. Ceftolozane/tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (MIC50/90, 0.5/16 µg/mL), but not against isolates with a CRE phenotype (MIC50/90, >32/>32 µg/mL). Ceftolozane/tazobactam was the most potent (MIC50/90, 0.5/4 µg/mL) ß-lactam agent tested against P. aeruginosa isolates, inhibiting 90.8% at an MIC of ≤4 µg/mL. Pseudomonas aeruginosa exhibited high rates of susceptibility to amikacin [91.2/89.4% (CLSI/EUCAST)] and colistin [98.4/100.0% (CLSI/EUCAST)]. Ceftolozane/tazobactam was the most active ß-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than available cephalosporins when tested against Enterobacteriaceae.

In Vitro Activity of the Novel Lactone Ketolide Nafithromycin (WCK 4873) against Contemporary Clinical Bacteria from a Global Surveillance Program.

Nafithromycin (WCK 4873), a novel antimicrobial agent of the lactone ketolide class, is currently in phase 2 development for treatment of community-acquired bacterial pneumonia (CABP). A total of 4,739 nonduplicate isolates were selected from a 2014 global surveillance program at medical institutions located in 43 countries within the United States, Europe, Latin America, and the Asia-Pacific region. Nafithromycin and comparator agents were used for susceptibility testing by reference broth microdilution methods. Nafithromycin was active against Staphylococcus aureus (MIC50/90, 0.06/>2 µg/ml), including erythromycin-resistant strains exhibiting an inducible clindamycin resistance phenotype (MIC50/90, 0.06/0.06 µg/ml) and telithromycin-susceptible strains (MIC50/90, 0.06/0.06 µg/ml), but it exhibited limited activity against most telithromycin-resistant and clindamycin-resistant isolates that were constitutively resistant to macrolides (MIC50/90, >2/>2 µg/ml). Nafithromycin was very active (MIC50/90, 0.015/0.06 µg/ml) against 1,911 Streptococcus pneumoniae strains, inhibiting all strains, with MIC values of ≤0.25 µg/ml. Telithromycin susceptibility was 99.9% for Streptococcus pneumoniae strains, and nafithromycin was up to 8-fold more potent than telithromycin. Overall, 37.9% of S. pneumoniae strains were resistant to erythromycin, and 19.7% were resistant to clindamycin. Nafithromycin was highly active against 606 Streptococcus pyogenes strains (MIC50/90, 0.015/0.015 µg/ml), inhibiting 100.0% of isolates at ≤0.5 µg/ml, and MIC50/90 values (0.015/0.015 to 0.03 µg/ml) were similar for the 4 geographic regions. Nafithromycin and telithromycin demonstrated comparable in vitro activities against 1,002 Haemophilus influenzae isolates and 504 Moraxella catarrhalis isolates. Overall, nafithromycin showed potent in vitro activity against a broad range of contemporary (2014) global pathogens. These results support the continued clinical development of nafithromycin for treatment of CABP.

Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Australia and New Zealand: Report from an Antimicrobial Surveillance Program (2013-2015).

OBJECTIVES: To evaluate the in vitro activity of ceftolozane-tazobactam and comparator agents tested against isolates of Enterobacteriaceae and Pseudomonas aeruginosa from patients in Australia and New Zealand with healthcare-associated infection. METHODS: A total of 1459 gram-negative organisms (440 P. aeruginosa and 1019 Enterobacteriaceae) were consecutively collected from 11 medical centers located in Australia and New Zealand. The organisms were tested for susceptibility by broth microdilution methods as described by the CLSI M07-A10 document and the results interpreted according to EUCAST and CLSI breakpoint criteria. RESULTS: Ceftolozane-tazobactam (MIC50/90, 0.25/0.5µg/mL; 97.7/95.9% susceptible [CLSI/EUCAST]), meropenem (MIC50/90, ≤0.06/≤0.06µg/mL; 99.8/99.9% susceptible [CLSI/EUCAST]) and amikacin (MIC50/90, 2/4µg/mL; 99.8/99.6% susceptible [CLSI/EUCAST]) were the most active compounds tested against Enterobacteriaceae. Enterobacteriaceae isolates displayed susceptibility rates to other ß-lactam agents ranging from 95.3/94.4% for cefepime, 94.1/91.4% for piperacillin-tazobactam, and 93.3/91.5% for ceftazidime using CLSI/EUCAST breakpoints. Among the Enterobacteriaceae isolates tested, 0.1% were CRE and 6.6% exhibited an ESBL non-CRE phenotype. Whereas ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (MIC50/90, 0.5/2µg/mL), it lacked useful activity (MIC, >32µg/mL) against the single isolate with a CRE resistant phenotype. Ceftolozane-tazobactam was the most potent (MIC50/90, 0.5/2µg/mL) ß-lactam agent tested against P. aeruginosa isolates, inhibiting 95.7% at an MIC of ≤4µg/mL. CONCLUSIONS: Ceftolozane-tazobactam was the most active ß-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than currently available cephalosporins and piperacillin-tazobactam when tested against Enterobacteriaceae.

Gepotidacin (GSK2140944) In Vitro Activity against Gram-Positive and Gram-Negative Bacteria.

Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic that inhibits bacterial DNA replication and has in vitro activity against susceptible and drug-resistant pathogens. Reference in vitro methods were used to investigate the MICs and minimum bactericidal concentrations (MBCs) of gepotidacin and comparator agents for Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli Gepotidacin in vitro activity was also evaluated by using time-kill kinetics and broth microdilution checkerboard methods for synergy testing and for postantibiotic and subinhibitory effects. The MIC90 of gepotidacin for 50 S. aureus (including methicillin-resistant S. aureus [MRSA]) and 50 S. pneumoniae (including penicillin-nonsusceptible) isolates was 0.5 µg/ml, and for E. coli (n = 25 isolates), it was 4 µg/ml. Gepotidacin was bactericidal against S. aureus, S. pneumoniae, and E. coli, with MBC/MIC ratios of ≤4 against 98, 98, and 88% of the isolates tested, respectively. Time-kill curves indicated that the bactericidal activity of gepotidacin was observed at 4× or 10× MIC at 24 h for all of the isolates. S. aureus regrowth was observed in the presence of gepotidacin, and the resulting gepotidacin MICs were 2- to 128-fold higher than the baseline gepotidacin MICs. Checkerboard analysis of gepotidacin combined with other antimicrobials demonstrated no occurrences of antagonism with agents from multiple antimicrobial classes. The most common interaction when testing gepotidacin was indifference (fractional inhibitory concentration index of >0.5 to ≤4; 82.7% for Gram-positive isolates and 82.6% for Gram-negative isolates). The postantibiotic effect (PAE) of gepotidacin was short when it was tested against S. aureus (≤0.6 h against MRSA and MSSA), and the PAE-sub-MIC effect (SME) was extended (>8 h; three isolates at 0.5× MIC). The PAE of levofloxacin was modest (0.0 to 2.4 h), and the PAE-SME observed varied from 1.2 to >9 h at 0.5× MIC. These in vitro data indicate that gepotidacin is a bactericidal agent that exhibits a modest PAE and an extended PAE-SME against Gram-positive and -negative bacteria and merits further study for potential use in treating infections caused by these pathogens.

Antimicrobial activity of tigecycline and cefoperazone/sulbactam tested against 18,386 Gram-negative organisms from Europe and the Asia-Pacific region (2013-2014).

A total of 18,386 organisms, including 13,224 Enterobacteriaceae, 3536 Pseudomonas aeruginosa, 1254 Acinetobacter spp., and 372Stenotrophomonas maltophilia were collected from Western Europe (WEU; n=10,021), Eastern Europe (EEU; n=4957), and the Asia-Pacific region (APAC; n=3408 [1052 from China]) in 2013-2014 as part of the SENTRY Antimicrobial Surveillance Program and tested by a reference broth microdilution method for susceptibility against tigecycline, cefoperazone/sulbactam, and comparator agents. Overall, 95.3% of Enterobacteriaceae were susceptible (≤1µg/mL; EUCAST) to tigecycline (MIC50/90, 0.12/1µg/mL) with regional EUCAST susceptibility rates of 94.8-97.8% (98.9-99.6% inhibited at ≤2µg/mL [US FDA]). Among Acinetobacter spp., 66.1% (EEU) and 79.5% (WEU) were inhibited at ≤1µg/mL of tigecycline (94.9% and 97.3% inhibited at ≤2µg/mL; pan-European MIC50/90, 1/2µg/mL). For S. maltophilia, 65.4% (China) to 88.9% (EEU) of the isolates were inhibited at ≤1µg/mL of tigecycline. Cefoperazone/sulbactam inhibited 94.6/83.5/91.5% of Enterobacteriaceae at ≤16µg/mL in WEU/EEU/APAC, respectively.

In Vitro Activity of Delafloxacin against Contemporary Bacterial Pathogens from the United States and Europe, 2014.

The in vitro activities of delafloxacin and comparator antimicrobial agents against 6,485 bacterial isolates collected from medical centers in Europe and the United States in 2014 were tested. Delafloxacin was the most potent agent tested against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus, Streptococcus pneumoniae, viridans group streptococci, and beta-hemolytic streptococci and had activity similar to that of ciprofloxacin and levofloxacin against certain members of the Enterobacteriaceae Overall, the broadest coverage of the tested pathogens (Gram-positive cocci and Gram-negative bacilli) was observed with meropenem and tigecycline in both Europe and the United States. Delafloxacin was shown to be active against organisms that may be encountered in acute bacterial skin and skin structure infections, respiratory infections, and urinary tract infections.

Update of the activity of telavancin against a global collection of Staphylococcus aureus causing bacteremia, including endocarditis (2011-2014).

The efficacy and safety of telavancin is under evaluation for the treatment of subjects with complicated Staphylococcus aureus bacteremia and S. aureus right-sided infective endocarditis. This study evaluated the telavancin activity against a global collection of S. aureus causing bloodstream infections (BSI), including endocarditis, to support the development of bacteremia/endocarditis clinical indications. This study included a total of 4191 S. aureus [1490 methicillin-resistant S. aureus (MRSA)], which were unique (one per patient) clinical isolates recovered from blood samples collected during 2011-2014 in a global network of hospitals. All isolates were deemed responsible for BSI, including endocarditis, by local guidelines. Isolates were tested for susceptibility by broth microdilution. Telavancin (MIC50/90, 0.03/0.06 µg/ml) inhibited all S. aureus at ≤0.12 µg/ml, the breakpoint for susceptibility. Equivalent minimum inhibitory concentration (MIC) values (MIC50/90, 0.03/0.06 µg/ml) were obtained for telavancin against methicillin-susceptible S. aureus (MSSA) and MRSA isolates, as well as MRSA from community and healthcare origins. Similar telavancin activities (MIC50, 0.03 µg/ml) were observed against MRSA subsets from North America and Europe, while isolates from the Asia-Pacific (APAC) and Latin America regions had MIC50 values of 0.06 µg/ml. MRSA with vancomycin MIC values of 2-4 µg/ml and the multidrug resistance (MDR) subset had telavancin MIC50 results of 0.06 µg/ml, although the MIC100 result obtained against these subsets remained identical to those of MSSA (MIC100, 0.12 µg/ml, respectively). This study updates the telavancin in vitro activity, which continues to demonstrate great potency against invasive S. aureus, regardless of the susceptibility phenotype or demographic characteristics (100.0% susceptible), and supports the sought-after subsequent indications.

In Vitro Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae.

Gepotidacin (formerly GSK2140944) is a novel, first-in-class, triazaacenaphthylene antibacterial that inhibits bacterial DNA gyrase and topoisomerase IV via a unique mechanism and has demonstrated in vitro activity against Neisseria gonorrhoeae, including drug-resistant strains, and also targets pathogens associated with other conventional and biothreat infections. Broth microdilution was used to evaluate the MIC and minimum bactericidal concentration (MBC) activity of gepotidacin and comparators against 25 N. gonorrhoeae strains (including five ciprofloxacin-nonsusceptible strains). Gepotidacin activity was also evaluated against three N. gonorrhoeae strains (including a ciprofloxacin-nonsusceptible strain) for resistance development, against three N. gonorrhoeae strains (including two tetracycline- and azithromycin-nonsusceptible strains) using time-kill kinetics and checkerboard methods, and against two N. gonorrhoeae strains for the investigation of postantibiotic (PAE) and subinhibitory (PAE-SME) effects. The MIC50 and MIC90 for gepotidacin against the 25 N. gonorrhoeae isolates tested were 0.12 and 0.25 µg/ml, respectively. The MBC50 and MBC90 for gepotidacin were 0.25 and 0.5 µg/ml, respectively. Gepotidacin was bactericidal, and single-step resistance selection studies did not recover any mutants, indicating a low rate of spontaneous single-step resistance. For combinations of gepotidacin and comparators tested using checkerboard methods, there were no instances where antagonism occurred and only one instance of synergy (with moxifloxacin; fractional inhibitory concentration, 0.375). This was not confirmed by in vitro time-kill studies. The PAE for gepotidacin against the wild-type strain ranged from 0.5 to >2.5 h, and the PAE-SME was >2.5 h. These in vitro data indicate that further study of gepotidacin is warranted for potential use in treating infections caused by N. gonorrhoeae.

Antimicrobial activity of daptomycin tested against gram-positive strains collected in European hospitals: results from 7 years of resistance surveillance (2003-2009).

Daptomycin is a cyclic lipopeptide approved by the European medicines Agency (EMEA) for the treatment of complicated skin and soft tissue infections (cSSTI) and Staphylococcus aureus bacteremia and endocarditis. We evaluated the in vitro activity of daptomycin and comparators tested against clinical isolates from european hospitals over a 7-year period (2003-2009). A total of 36,769 consecutive isolates were collected in 34 medical centers located in 13 European countries, Turkey and Israel. the collection included S. aureus (18,352; 27.2% oxacillin-resistant [MRSA]); coagulase-negative staphylococci (CoNS; 6,874), Enterococcus spp. (7,241; 9.4% vancomycin-resistant), ß-hemolytic (3,009), viridans group streptococci (1,176), and Streptococcus bovis/gallolyticus (107). The organisms were isolated mainly from patients with bloodstream infection (56%) or cSSTI (23%). Daptomycin was very active against S. aureus and CoNS (MIC(50/90), 0.25/0.5 mg/l for both organisms), and its activity was not adversely influenced by oxacillin resistance. All Enterococcus faecalis strains were susceptible to daptomycin (MIC(50/90), 1/1 mg/l). Daptomycin (MIC(50/90), 2/2 mg/l; 100.0% susceptible) and linezolid (MIC(50/90), 1/2 mg/l; 99.7% susceptible) were the most active agents tested against vancomycin-resistant E. faecium. Vancomycin- resistant and -susceptible enterococcal strains were equally susceptible to daptomycin. Daptomycin was also active against ß-hemolytic streptococci (MIC(50/90), 0.06/0.25 mg/l; 100.0% susceptible), viridans group streptococci (MIC(50/90), 0.25/0.5 mg/l; 99.8% susceptible) and S. bovis (MIC(50/90), 0.06/0.12 mg/l; 100.0% susceptible).In summary, daptomycin was very potent against this large collection (36,769) of Gram-positive organisms isolated in european hospitals, and its activity remained stable across the 7-year period evaluated (2003-2009), using reference methods and interpretive criteria. Decreases in daptomycin potency were not observed since EMEA approval and widespread clinical use, and emerging resistance to other compounds did not adversely influence daptomycin activity against contemporary Gram-positive species.

Eight-year (2002-2009) summary of the linezolid (Zyvox® Annual Appraisal of Potency and Spectrum; ZAAPS) program in European countries.

The linezolid surveillance network (ZAAPS program) has been monitoring linezolid activity and susceptibility rates for eight years (2002-2009) in european medical centers. Samples from 12-24 sites annually in 11 countries were monitored by a central laboratory design using reference MIC methods with international and regional interpretations (EUCAST). A total of 13,404 gram-positive pathogens were tested from 6 pathogen groups. Linezolid remained without documented resistance from 2002 through 2005, but beginning in 2006 resistant strains emerged at very low rates among Staphylococcus aureus (G2576T mutant in ireland, 2007), coagulase-negative staphylococci (CoNS; usually Staphylococcus epidermidis, France and Italy in 2006-2009) and enterococci (Enterococcus faecium in Germany [2006, 2008, 2009] and E. faecalis in Sweden [2008], United Kingdom [2008] and Germany [2009]); all but one strain having a target mutation. A mobile cfr was detected in an italian CoNS strain (2008 and 2009), and clonal spread was noted for linezolid-resistant strains (PFGE results). Overall the linezolid susceptibility rates were >99.9, 99.7 and 99.6% for S. aureus, CoNS and enterococci, respectively; and all streptococcal strains were susceptible (MIC(90), 1 mg/l). In conclusion, the ZAAPS program surveillance confirmed high, sustained levels of linezolid activity from 2002-2009 and without evidence of MIC creep or escalating resistance in gram-positive pathogens across monitored european nations.

Telavancin Activity against gram-positive bacteria isolated from patients with skin and skin-structure infections.

Telavancin is approved in the United States and Canada for the treatment of complicated skin and skin structure infections (cSSSI) in adults caused by susceptible Gram-positive organisms. The antimicrobial activity of telavancin and comparators was evaluated against 5,027 (2007-2008) Gram-positive bacteria responsible for SSSI in medical centers in Asia-Pacific, European, Latin American, and North American regions. Telavancin was active against Staphylococcus aureus (MIC50(/)90, 0.12/0.25 mg/l; 100.0% susceptible) and coagulase-negative staphylococci (MIC50(/)90, 0.12/0.25 mg/l). telavancin inhibited all Enterococcus faecalis, including four strains displaying a VanB phenotype, at ≤ 1 mg/L (MIC50(/)90, 0.25/0.5 mg/l), except for two isolates with a VanA phenotype (MIC, >2 mg/l). Vancomycin-susceptible and VanB vancomycin-resistant E. faecium were inhibited by telavancin at ≤ 0.25 mg/L, while this drug exhibited elevated MIC values (≥ 0.5 mg/l) against E. faecium of VanA phenotype (MIC50(/)90, 2/>2 mg/l). Telavancin was potent against ß-haemolytic streptococci (MIC50(/)90, 0.03/0.12 mg/l; 100.0% susceptible) and viridans group streptococci (MIC50(/)90, 0.03/0.06 mg/l; 100.0% susceptible). These in vitro data document the activity of telavancin against contemporary Gram-positive isolates and support its clinical use for the treatment of cSSSI caused by the indicated pathogens.

Sustained antimicrobial activity of tigecycline against methicillin-resistant Staphylococcus aureus (MRSA) from United States Medical Centers from 2004 through 2008.

Tigecycline, a glycylcycline, has been approved by the United States Food and Drug Administration (USA-FDA) for the treatment of complicated skin and skin structure infections, intra-abdominal infections and community-acquired bacterial pneumonia. based on broth microdilution minimum inhibitory concentration (MIC) testing, tigecycline demonstrated sustained high activity (MIC(50/90), 0.12/0.25 mg/L) against a contemporary collection (10,242) of methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) collected from 32 USA hospitals over a 5-year period (2004-2008). Tigecycline MIC distribution did not vary significantly during the study period and only three isolates (0.03%) were non-susceptible at USA-FDA breakpoints. Vancomycin (MIC(90), 1 mg/L), trimethoprim/sulfamethoxazole (MIC( 90), <0.5 mg/L) and linezolid (MIC(90), 2 mg/L) were also very active. The results of this study indicate that tigecycline potency and spectrum against MRSA have not changed since its initial regulatory approval by the USA-FDA.

Update on the in vitro activity of daptomycin tested against 17,193 Gram-positive bacteria isolated from European medical centers (2005-2007).

The antimicrobial susceptibility patterns of 17,193 Gram-positive isolates consecutively collected from 28 medical centers in 12 countries in europe and israel in 2005-2007 were evaluated by Clinical and laboratory Standards institute (CLSI) broth microdilution methods supplemented with calcium to 50 mg/l for testing daptomycin. Overall, the rate of methicillin-resistant Staphylococcus aureus (MRSA) was 28.3%, varying from 32.3% in 2005 to 27.1% in 2006 and 28.5% in 2007. Vancomycin resistance rates were 0.8% and 21.5% among Enterococcus faecalis and E. faecium, respectively. Among E. faecium, vancomycin resistance increased from 17.9% in 2005 to 26.3% in 2007, and varied from 0.0% in Spain, Sweden and Switzerland to as high as 54.6% in ireland for 2007. All isolates tested, except for seven CoNS (0.2%; 3,234 tested) were considered susceptible to daptomycin using breakpoints established by the United States food and Drug Administration, the CLSI and the EUCAST. Daptomycin was very active against all Gram-positive species with the highest minimum inhibitory concentration (MIC) results being 1, 4, 2 and 4 mg/l for S. aureus, coagulase-negative staphylococci, E. faecalis and E. faecium, respectively. Daptomycin activity was not adversely influenced by resistance to oxacillin among staphylococci or to vancomycin among enterococci.