In Vitro Activity of Gepotidacin, a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor, against a Broad Spectrum of Bacterial Pathogens.

Gepotidacin inhibits bacterial DNA replication through a mode different from that of fluoroquinolones. Gepotidacin and comparators were tested by broth and agar dilution against clinical isolates. The in vitro activities of gepotidacin were comparable against methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) isolates (MIC90, 0.5 µg/ml). The gepotidacin MIC90s were as follows (in micrograms per milliliter) for the indicated bacteria: Streptococcus pyogenes, 0.25; Escherichia coli, 2; Moraxella catarrhalis, ≤ 0.06; Streptococcus pneumoniae (0.25), Haemophilus influenzae, 1; Clostridium perfringens, 0.5; and Shigella spp., 1, including levofloxacin-resistant subsets. Gepotidacin warrants further investigation for clinical development.

In vitro activity of tedizolid against Staphylococcus aureus and Streptococcus pneumoniae collected in 2013 and 2014 from sites in Latin American countries, Australia, New Zealand, and China.

Tedizolid is an oxazolidinone with an antimicrobial in vitro potency advantage against Gram-positive bacterial pathogens compared to other currently marketed drugs in this class, including linezolid. Tedizolid was compared to linezolid when tested against Staphylococcus aureus and Streptococcus pneumoniae isolates collected from countries in Latin America and the Asia-Pacific. Isolates were tested by broth microdilution susceptibility methods against tedizolid, linezolid, and non-class comparators in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. The activity of tedizolid against S. aureus was potent and consistent in Latin America (MIC90, 0.5 mg/L), Australia and New Zealand (MIC90, 0.25 mg/L), and China (MIC90, 0.5 mg/L). Based on MIC90 results, tedizolid was four- to eight-fold more active than linezolid against S. aureus, including both methicillin-susceptible and -resistant isolates. Only two tedizolid non-susceptible strains were observed; both had intermediate minimum inhibitory concentration (MIC) values of 1 mg/L, for which the MICs of linezolid was higher (≥2 mg/L). Tedizolid (MIC90, 0.25 mg/L) was four-fold more potent than linezolid (MIC90, 1 mg/L) against S. pneumoniae in all countries that provided isolates. The findings from this study support the global clinical development of tedizolid for Gram-positive infections.

Comparative in vitro activity of gemifloxacin, ciprofloxacin, levofloxacin and ofloxacin in a North American surveillance study.

The in vitro activity of gemifloxacin, a new fluoroquinolone, was compared to three marketed fluoroquinolones; ciprofloxacin, levofloxacin and ofloxacin against over 4,000 recent clinical isolates covering 29 species isolated in the United States and Canada between 1997-1999. Based on MIC(90)s, gemifloxacin was the most potent fluoroquinolone tested against a majority of Gram-positive isolates: Streptococcus pneumoniae, penicillin resistant S. pneumoniae, macrolide resistant S. pneumoniae, ciprofloxacin non-susceptible (MIC > or = 4 microg/mL) S. pneumoniae, S. pyogenes, S. agalactiae, viridans streptococci, Enterococcus faecalis, methicillin susceptible Staphylococcus aureus, methicillin resistant S. aureus, S. epidermidis, S. hemolyticus, and S. saprophyticus. Against Enterobacteriaceae and aerobic non-Enterobacteriaceae Gram-negatives, gemifloxacin was usually comparable to ciprofloxacin and levofloxacin and more potent than ofloxacin for the following species: Citrobacter freundii, Enterobacter aerogenes, E. cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, P. vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter lwoffii, A. baumannii, Burkholderia cepacia, Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Gemifloxacin was generally 16-64 fold more potent than the other fluoroquinolones tested against Gram-positive organisms and retains excellent activity comparable with ciprofloxacin and levofloxacin against a majority of Gram-negative pathogens.

Antimicrobial susceptibilities of clinical isolates of Haemophilus influenzae and Moraxella catarrhalis collected during 1999-2000 from 13 countries.

OBJECTIVE: To determine antimicrobial activity against Haemophilus influenzae and Moraxella catarrhalis. METHODS: A central laboratory performed NCCLS susceptibility testing for all isolates and beta-lactamase and capsular serotype determinations for H. influenzae. RESULTS: A total of 2712 H. influenzae and 1079 M. catarrhalis were collected. H. influenzae susceptibilities were >90% for amoxicillin/clavulanate, cefaclor, loracarbef, cefprozil, cefuroxime, ciprofloxacin, azithromycin and clarithromycin and were <80% for trimethoprim/sulfamethoxazole and ampicillin. 19.3% were beta-lactamase positive. The most common serotype was type-b (5.6%); 86.1% were nontypeable. M. catarrhalis had MIC90 within therapeutic range for all antimicrobials except ampicillin. CONCLUSION: The conclusion of the study is that antimicrobials, except ampicillin and trimethoprim/sulfamethoxazole, remain good empiric choices against H. influenzae and M. catarrhalis.

Determining incidence of extended spectrum beta-lactamase producing Enterobacteriaceae, vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus in 38 centres from 17 countries: the PEARLS study 2001-2002.

The PEARLS study prospectively monitored selected nosocomial pathogens from 38 centres in 13 European, three Middle Eastern countries and South Africa during 2001-2002. Extended spectrum beta-lactamase (ESBL) production rates among Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp. were 5.4% (142/2609), 18.2% (401/2,206) and 8.8% (204/2,328), respectively, for all study sites. The overall ESBL production rate for the combined Enterobacteriaceae was 10.5% (747/7,143), highest in Egypt, 38.5%, and Greece, 27.4%, and lowest in The Netherlands, 2.0%, and Germany, 2.6%. IEF, PCR and DNA sequencing determined 10.7% false positives among Enterobacter spp. when using NCCLS guidelines to screen for ESBL production. The prevalence of nosocomial methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium was 32.4% (294/908) and 8.7% (83/949), respectively. PEARLS provides baseline data against which prospective changes in resistant determinants and outcomes can be measured in this ongoing study.

In vitro activity of gemifloxacin and contemporary oral antimicrobial agents against 27247 Gram-positive and Gram-negative aerobic isolates: a global surveillance study.

This study was a multi-centre, multi-country surveillance of 27247 Gram-positive and Gram-negative isolates collected from 131 study centres in 44 countries from 1997 to 2000. MICs of gemifloxacin were compared with penicillin, amoxicillin-clavulanic acid, cefuroxime, azithromycin, clarithromycin, trimethoprim-sulphamethoxazole, ciprofloxacin, grepafloxacin and levofloxacin by broth microdilution. Penicillin resistance in Streptococcus pneumoniae was extremely high in the Middle East (65.6%), Africa (64.0%) and Asia (60.4%) and lower in North America (40.3%), Europe (36.9%) and the South Pacific (31.8%). Macrolide resistance in S. pneumoniae was highest in Asia (51.7%) but varied widely between laboratories in Europe (26.0%), North America (21.6%), the Middle East (13.7%), the South Pacific (10.6%) and Africa (10.0%). All the study quinolones were highly active against penicillin-resistant and macrolide-resistant S. pneumoniae. Overall, gemifloxacin had the lowest MIC(90) at 0.06 mg/l with MICs 4-64-fold lower than ciprofloxacin, levofloxacin and grepafloxacin against S. pneumoniae. Gemifloxacin MICs were more potent than grepafloxacin > levoflaxacin > ciproflaxin against the Gram-positive aerobes and shared comparable Gram-negative activity with ciprofloxacin and levofloxacin.

Comparative in vitro potency of amoxycillin-clavulanic acid and four oral agents against recent North American clinical isolates from a global surveillance study.

The in vitro activity of amoxycillin-clavulanic acid was compared with four comparator oral antimicrobial agents; ampicillin, azithromycin, cefuroxime and trimethoprim-sulphamethoxazole against 4536 recent clinical isolates covering 29 species isolated in the US and Canada between 1997 and 1999. Based upon Minimum inhibitory concentrations (MICs), amoxycillin-clavulanic acid was the most active agent against many Gram-positive species and phenotypes including methicillin susceptible Staphylococcus aureus (MSSA) Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae including penicillin intermediate and macrolide resistant strains and was as active as ampicillin against Streptococcus agalactiae, penicillin resistant S. pneumoniae and viridans streptococci. Against Enterobacteriaceae amoxycillin-clavulanic acid in general, displayed weak activity with only Proteus mirabilis and Proteus vulgaris displaying levels of susceptibility above the 90th percentile. Amoxycillin-clavulanic acid had significant activity against many species of Gram-negative non-Enterobacteriaceae including Haemophilus influenzae, Haemophilus parainfluenzae and Moraxella catarrhalis but negligible activity against Burkholderia cepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Amoxycillin-clavulanic acid continues to retain excellent activity against the majority of targeted pathogens despite 20 years of clinical use.

In vitro activity of tigecycline and comparators against carbapenem-resistant Enterobacteriaceae in Africa-Middle East countries: TEST 2007-2012.

Multidrug-resistant (MDR) Enterobacteriaceae are an emerging concern for healthcare providers. Infections caused by MDR pathogens are associated with increased costs, length of hospital stay, and morbidity and mortality rates. Carbapenem-resistant Enterobacteriaceae (CRE) continue to increase, and infections with these organisms are observed worldwide not only as hospital-acquired infections but also as community-acquired infections. Increasing antimicrobial resistance dictates the need for continued surveillance studies of common and MDR pathogens. The Tigecycline Evaluation Surveillance Trial (TEST) examined the susceptibility of pathogens isolated in Africa and the Middle East from 2007 to 2012. A total of 4155 Enterobacteriaceae isolates were evaluated to determine the in vitro activity and changes in resistance patterns for tigecycline and comparators. Carbapenem resistance was found in 191 (4.6%) of the isolates tested. Klebsiella pneumoniae was the most common CRE (64.9%), followed by Enterobacter cloacae (14.1%) and Escherichia coli (9.9%). Tigecycline MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) were 2µg/mL against all of these enteric species, with susceptibility rates of 96.8%, 92.6% and 100%, respectively. Tigecycline had in vitro activity against CRE, with a 95.3% susceptibility rate.

In vitro activity of tigecycline against isolates collected from complicated skin and skin structure infections and intra-abdominal infections in Africa and Middle East countries: TEST 2007-2012.

Complicated skin and skin structure infections (cSSSIs) and intra-abdominal infections (IAIs) are problematic due to decreasing therapeutic options available against multidrug-resistant pathogens common among these types of infections. A total of 2245 isolates from African and the Middle Eastern (AfME) countries were collected to determine in vitro activity for tigecycline and comparators during 2007-2012 as part of the Tigecycline Evaluation Surveillance Trial program. Tigecycline was launched in the AfME in 2007 and remains active against a wide range of targeted pathogens worldwide. Isolates were recovered from cSSSI (1990) and IAI (255) from 38 sites in 11 AfME countries. Staphylococcus aureus was the most common species from cSSSI (27.9%), and the methicillin-resistant S. aureus rate was 25%. Enterococcus spp. (7.1%) and Streptococcus agalactiae (2.9%) were other common Gram-positive pathogens represented. Enterobacter spp. (14.5%), Pseudomonas aeruginosa (13.9%), Escherichia coli (11.4%), Klebsiella spp. (10.9%), and Acinetobacter spp. (7.2 %) were the most common Gram-negative species collected. Tigecycline MIC(90) values were 0.25 µg/mL against S. aureus. E. coli and Enterobacter spp. had tigecycline MIC(90) values of 1 and 2 µg/mL, respectively. E. coli was the most frequently collected species from IAI (28.3%), followed by Klebsiella spp. (20.8%), Enterococcus spp. (11.8%), and Stenotrophomonas maltophilia (6.3%). Isolates collected from IAI had the following tigecycline MIC(90) values: E. coli (1 µg/mL), Klebsiella spp. and other Enterobacteriaceae (2 µg/mL), Enterococcus spp. (0.25 µg/mL), and S. maltophilia (1 µg/mL). Tigecycline in vitro activity was observed against a broad spectrum of bacterial species, including strains resistant to other antimicrobial classes.

Susceptibility of European Escherichia coli clinical isolates from intra-abdominal infections, extended-spectrum ß-lactamase occurrence, resistance distribution, and molecular characterization of ertapenem-resistant isolates (SMART 2008-2009).

A total of 3160 clinical isolates of Escherichia coli from intra-abdominal infections were collected during 2008-2009 from 13 European countries. The frequency of extended-spectrum ß-lactamase (ESBL)-producing isolates in Europe was 11%. The most active antibiotics tested were typically imipenem, ertapenem, and amikacin, although the activity of all non-carbapenem antibiotics was lower when tested against ESBL-positive isolates than when tested against ESBL-negative isolates. Ertapenem exhibited 99.3% susceptibility with all isolates, and 96.8% susceptibility with ESBL-positive isolates. With application of the ertapenem CLSI clinical breakpoint for resistance (MIC ≥1 mg/L), only six isolates (0.2%) were ertapenem-resistant, and only three of these were available for molecular characterization. Of those three, only one was ESBL-positive (CTX-M-14), and two were carbapenemase-positive (OXA-48). All three were negative for, VIM, NDM and KPC carbapenemases. Although the level of ertapenem resistance in E. coli is very low, further monitoring of ertapenem susceptibility and molecular characterization of ertapenem-resistant isolates is needed.

Trending eight years of in vitro activity of ertapenem and comparators against Escherichia coli from intra-abdominal infections in North America--SMART 2002-2009.

During 2002 - 2009, 2,885 Escherichia coli intra-abdominal isolates were collected from North America in the Study for monitoring Antimicrobial Resistance trends (SmARt) surveillance program. the incidence of extendedspectrum beta-lactamase producing isolates ranged from 1.7% in 2005 to 7.2% in 2004 and 2006, and was 6.8% in 2009. Susceptibility trends showed that there were only minor fluctuations in susceptibility to ertapenem and imipenem with no significant decrease over time. By contrast, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, ciprofloxacin, and levofloxacin exhibited significantly higher minimum inhibitory concentrations against E. coli overall (p<0.05) and (except for cefoxitin) against extended-spectrum beta-lactamase producing isolates. Piperacillin-tazobactam also had significantly diminished activity against E. coli overall, but paradoxically showed significantly increased activity against extendedspectrum beta-lactamase producing isolates. Ertapenem and imipenem susceptibility of E. coli in North America remained consistently high during the period 2002 through 2009, and continuing updates from SMART will be helpful in detecting any changes that occur in the future.

A comparative study of the in-vitro activity of cefepime and other antimicrobial agents against penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae.

Using the national surveillance programme of USA hospitals, we selected 162 strains of Streptococcus pneumoniae for sensitivity testing using the NCCLS breakpoints for benzylpenicillin and the oxacillin discs screen test. Included in the group of isolates were 85 relatively penicillin-resistant and 33 penicillin-resistant strains. The activity of cefepime, a new cephalosporin, was compared with other cephalosporins and penicillins as well as some non-beta-lactam antimicrobials. Imipenem was the most active agent but, cefepime, cefotaxime, ceftriaxone and ciprofloxacin were only slightly less active. The least active agents were ceftazidime, cefuroxime, piperacillin/tazobactam and ticarcillin/clavulanate. Cefepime is a potential alternative treatment to penicillin, particularly when penicillin-resistant and relatively penicillin-resistant S. pneumoniae are encountered. The clinical importance of screening for penicillin resistance by the use of the oxacillin disc is emphasized.

In-vitro activity of cefepime and other antimicrobials: survey of European isolates.

Cefepime, a new cephalosporin which has a broad-spectrum of activity was tested in vitro against 1961 Gram-positive and Gram-negative clinical isolates obtained from European hospitals. Cefepime was highly active against Gram-negative organisms, inhibiting over 94% of strains tested. The overall susceptibility rate for cefepime against all isolates was 81%. Cefepime was more active than any of the third-generation cephalosporins tested against species capable of producing type I beta-lactamases, e.g. Enterobacter cloacae, Citrobacter freundii, and Enterobacter aerogenes. The activity of cefepime against Pseudomonas aeruginosa was similar to that of ceftazidime and substantially greater than those of cefotaxime and ceftriaxone. All cephalosporins except ceftazidime exhibited high activity against methicillin-susceptible Staphylococcus aureus but poor activity was observed against methicillin-resistant strains. Overall susceptibility to cefepime is lower in Europe than it is in North America.

Antibiotic susceptibilities among recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis from fifteen countries.

Between July 1998 and July 1999, 3,060 Haemophilus influenzae and 1,486 Moraxella catarrhalis strains were isolated in 31 centers in 15 countries in order to determine their antimicrobial susceptibilities and the presence of beta-lactamase production in Haemophilus influenzae. Overall 17.1% of the Haemophilus influenzae isolates were beta-lactamase positive, while more than 95% were susceptible to amoxicillin/clavulanate, cefaclor, loracarbef, cefuroxime, azithromycin and ciprofloxacin. Eleven (0.3%) isolates were beta-lactamase positive and ampicillin resistant and 7 (0.2%) isolates were ciprofloxacin resistant. The minimum inhibitory concentrations for 90% of the isolates tested were lowest for ciprofloxacin (0.03) and highest for cefprozil (8) against Moraxella catarrhalis.

Comparative in vitro potency of gemifloxacin and fluoroquinolones against recent European clinical isolates from a global surveillance study.

Gemifloxacin, a new fluoroquinolone with enhanced activity against gram-positive aerobes, was compared to ciprofloxacin, levofloxacin and ofloxacin against 21,464 recent isolates from 16 European countries. Gemifloxacin was the most potent fluoroquinolone against streptococci including penicillin-, macrolide- and ciprofloxacin-resistant Streptococcus pneumoniae, Staphylococcus aureus, coagulase-negative staphylococci, Acinetobacter spp., Haemophilus spp. and Moraxella catarrhalis. This drug was more potent than or comparable to ciprofloxacin against members of the family Enterobacteriaceae, Burkholderia cepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Gemifloxacin is a promising fluoroquinolone with potent in vitro activity.

A comparative In vitro surveillance study of gemifloxacin activities against 2,632 recent Streptococcus pneumoniae isolates from across Europe, North America, and South America. The Gemifloxacin Surveillance Study Research Group.

From 1997 to 1999, 94 study centers in 15 European, 3 North American, and 2 South American countries contributed 2,632 isolates of Streptococcus pneumoniae to an international antimicrobial susceptibility testing study. Only 62.0% of isolates were susceptible to penicillin, while 22.3% were penicillin intermediate and 15.6% were penicillin resistant. Resistance to trimethoprim-sulfamethoxazole (24.4%), azithromycin (26.0%), and clarithromycin (27.1%) was also highly prevalent. For the penicillin-resistant isolates (n = 411), the MICs at which 90% of isolates are inhibited (MIC(90)s) for gemifloxacin, levofloxacin, ofloxacin, clarithromycin, and azithromycin were 0.03, 1, 2, >16, and >64 microgram/ml, respectively. Similarly, for isolates resistant to both azithromycin and clarithromycin (n = 649), gemifloxacin, levofloxacin, ofloxacin, and penicillin MIC(90)s were 0.03, 1, 2, and 4 microgram/ml, respectively. Overall rates of resistance to trovafloxacin (0.3%), levofloxacin (0.3%), grepafloxacin (0.6%), and ofloxacin (0.7%) were low. For ofloxacin-intermediate and -resistant isolates (n = 142), gemifloxacin had the lowest MIC(90) (0.12 microgram/ml) compared to the MIC(90)s of trovafloxacin (0.5 microgram/ml), grepafloxacin (1 microgram/ml), and levofloxacin (2 microgram/ml). For all S. pneumoniae isolates tested, gemifloxacin MICs were

Comparative in vitro surveillance of amoxicillin-clavulanic acid and four oral comparators against 21232 clinical isolates from europe.

The present study was conducted to determine the in vitro activity of amoxicillin-clavulanic acid compared to that of four newer antimicrobial agents (ampicillin, azithromycin, cefuroxime and trimethoprim-sulfamethoxazole). All of the agents were tested against 21232 recent clinical isolates encompassing 37 species submitted from 16 European countries between 1997 and 1999. After 20 years of clinical use, amoxicillin-clavulanic acid continues to retain much of its initial activity against targeted gram-positive organisms, selected gram-negative organisms and major respiratory pathogens.