In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017.

Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hard-to-treat molds, including Fusarium and Scedosporium In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC50, 0.008 µg/ml; MIC90, 0.06 µg/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, APX001A (MIC50, 0.25 µg/ml; MIC90, 0.5 µg/ml) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC50], 0.015 µg/ml; MEC90, 0.03 µg/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06 µg/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin- and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.

Delafloxacin In Vitro Broth Microdilution and Disk Diffusion Antimicrobial Susceptibility Testing Guidelines: Susceptibility Breakpoint Criteria and Quality Control Ranges for an Expanded-Spectrum Anionic Fluoroquinolone.

Delafloxacin, a recently approved anionic fluoroquinolone, was tested within an international resistance surveillance program. The in vitro susceptibilities of 7,914 indicated pathogens causing acute bacterial skin and skin structure infections (ABSSSI) were determined using Clinical and Laboratory Standards Institute (CLSI) broth microdilution MIC testing methods. The U.S. Food and Drug Administration (FDA) susceptibility testing breakpoints and quality control ranges for routine broth microdilution and disk diffusion methods were confirmed. The delafloxacin MIC50/90 (% susceptibility) results were as follows: Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), 0.008/0.25 µg/ml (92.8%); Staphylococcus lugdunensis, 0.016/0.03 µg/ml (99.3%); Streptococcus pyogenes, 0.016/0.03 µg/ml (100.0%); Streptococcus anginosus group, 0.008/0.016 µg/ml (100.0%); Enterococcus faecalis, 0.12/1 µg/ml (66.2%); and Enterobacteriaceae, 0.12/4 µg/ml (69.5%). The FDA clinical breakpoints were used to assess intermethod test agreement between delafloxacin MIC and disk diffusion methods for the indicated pathogens. The intermethod susceptibility test categorical agreement for delafloxacin was acceptable, with only 0.4% very major, false-susceptible errors among S. aureus strains. Across all FDA-indicated species, the selected breakpoints produced only 0.0 to 1.7% rates of serious (very major and major errors) intermethod error. Quality control ranges for these standardized delafloxacin susceptibility test methods were calculated from three multilaboratory (12 total sites) studies for six control organisms. In conclusion, the application of FDA MIC breakpoints for delafloxacin against contemporary (2014 to 2016) isolates of ABSSSI pathogens provides additional support for the use of delafloxacin in the treatment of adults with ABSSSI. Delafloxacin MIC and disk diffusion susceptibility testing methods have been standardized for clinical application, achieving high intermethod categorical agreement.

Evolving oxazolidinone resistance mechanisms in a worldwide collection of enterococcal clinical isolates: results from the SENTRY Antimicrobial Surveillance Program.

Objectives: This study evaluated the oxazolidinone resistance mechanisms among a global collection of enterococcal clinical isolates. The epidemiology of optrA-carrying isolates and the optrA genetic context were determined. Methods: Enterococcal isolates (26 648) from the SENTRY Antimicrobial Surveillance Program (2008-16) were identified by MALDI-TOF MS and MICs were determined by broth microdilution. Isolates with linezolid MICs of ≥4 mg/L were screened for resistance mechanisms. Isolates carrying optrA had their genome sequenced for genetic context and epidemiology information. Results: Thirty-six Enterococcus faecalis and 66 Enterococcus faecium had linezolid MICs of ≥4 mg/L (0.38% of surveillance enterococci). E. faecalis had a linezolid MIC range of 4-16 mg/L, while E. faecium displayed higher values (4-64 mg/L). Nine E. faecalis had G2576T mutations and optrA was detected in 26 (72.2%) isolates from the Asia-Pacific region, North America, Latin America and Europe; 3 isolates also produced Cfr [Thailand (1)] or Cfr(B) [Panama (2)]. All E. faecium isolates had G2576T alterations, while three isolates from the USA had concomitant presence of cfr(B). The optrA gene was plasmid- and chromosome-located in 22 and 3 E. faecalis, respectively. One isolate signalled hybridization on plasmid and chromosome. The genetic context of optrA varied. E. faecalis belonging to the same clonal complex were detected in distinct geographical regions. Also, genetically distinct isolates from Ireland had an identical optrA context, indicating plasmid dissemination. Conclusions: Alterations in 23S rRNA remained the main oxazolidinone resistance mechanism in E. faecium, while optrA prevailed in E. faecalis. These results demonstrate global dissemination of optrA and warrant surveillance for monitoring.

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).

Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014).

Omadacycline is an aminomethylcycline with in vitro activity against many gram-negative pathogens. Omadacycline and comparators were tested against Enterobacteriaceae from urinary tract infections (UTIs) selected from a 2014 global surveillance program and compared to results of isolates from 2010 surveillance. The omadacycline MIC50/90 for Enterobacteriaceae collected during 2014 was 2/≥8 µg/mL (1/4 µg/mL minus Proteus, Providencia, and Morganella spp.). The MIC50/90 for E. coli was 1/2 µg/mL, similar to that in 2010 (MIC50/90, 0.5/2 µg/mL). The MICs for 91.7% of Klebsiella spp. isolates in 2014 (89.7%, 2010) were ≤4 µg/mL. In 2010 and 2014, a total of 100.0% and 95.8% of ESBL screen-positive (SP) phenotype E. coli and 73.9% and 75.0% of ESBL SP Klebsiella spp., respectively, exhibited MIC values at ≤4 µg/mL. Omadacycline was active against UTI-causing Enterobacteriaceae isolates from NA and EU. Further study of omadacycline to treat UTIs caused by Enterobacteriaceae may be indicated.

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.

Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014).

The activity of omadacycline and comparators when tested against a subset of Streptococcus pneumoniae from US and European regions of a 2014 global surveillance program (304 isolates) are reported. These MIC results were compared to those obtained when testing S. pneumoniae from 2010 surveillance (1,834 isolates). The omadacycline MIC50/90 for S. pneumoniae (2014) was 0.06/0.06µg/mL, similar to 2010 (MIC50/90, 0.06/0.12µg/mL). The omadacycline MIC90 (0.06-0.12µg/mL) was similar for the penicillin-susceptible, -intermediate, -resistant, multidrug-resistance (MDR; ≥3 classes), and ceftriaxone nonsusceptible subgroups. Omadacycline MIC90 values were 0.06-0.12µg/mL for S. pneumoniae from the US and Europe. There was a high degree of resistance with doxycycline, erythromycin and trimethoprim-sulfamethoxazole in both US and EU. For penicillin-resistant S. pneumoniae, resistance to doxycycline and tetracycline in US/Europe was 64.2/61.0% and 63.8/60.5%, respectively, erythromycin 91.2/75.1, and ceftriaxone 7.3/4.0%. The potent activity of omadacycline against S. pneumoniae indicates that omadacycline merits further study in bacterial pneumonia, especially where MDR may be a concern.

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.

In Vitro Activity of Delafloxacin and Microbiological Response against Fluoroquinolone-Susceptible and Nonsusceptible Staphylococcus aureus Isolates from Two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections.

Delafloxacin is an investigational anionic fluoroquinolone antibiotic with broad-spectrum in vitro activity, including activity against Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The in vitro activity of delafloxacin and the percent microbiological response in subjects infected with fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus isolates were determined from two global phase 3 studies of delafloxacin versus vancomycin plus aztreonam in patients with acute bacterial skin and skin structure infections (ABSSSI). Patients from 23 countries, predominately the United States but also Europe, South America, and Asia, were enrolled. The microbiological intent-to-treat (MITT) population included 1,042 patients from which 685 S. aureus isolates were submitted for identification and susceptibility testing per CLSI guidelines at the central laboratory (JMI Laboratories, North Liberty, IA). The comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Nonsusceptibility to these antibiotics was determined using CLSI breakpoints. S. aureus isolates were 33.7% levofloxacin nonsusceptible (LVX-NS). The delafloxacin MIC90 values against levofloxacin-nonsusceptible S. aureus, methicillin-resistant S. aureus (MRSA), and methicillin-susceptible S. aureus isolates were all 0.25 µg/ml. Delafloxacin demonstrated high rates of microbiological response against LVX-NS isolates as well as isolates with documented mutations in the quinolone resistance-determining region (QRDR). S. aureus was eradicated or presumed eradicated in 98.4% (245/249) of delafloxacin-treated patients. Similar eradication rates were observed for delafloxacin-treated subjects with levofloxacin-nonsusceptible S. aureus isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%). Microbiological response rates of 98.6% were observed with delafloxacin-treated subjects with S. aureus isolates with the S84L mutation in gyrA and the S80Y mutation in parC, the most commonly observed mutations in global phase 3 studies. The data suggest that delafloxacin could be a good option for the treatment of infections caused by S. aureus isolates causing ABSSSI, including MRSA isolates, where high rates of ciprofloxacin and levofloxacin nonsusceptibility are observed. (The phase 3 studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT01984684 and NCT01811732.).

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.

In vitro activity of doripenem and other carbapenems against contemporary Gram-negative pathogens isolated from hospitalised patients in the Asia-Pacific region: results of the COMPACT Asia-Pacific Study.

The Comparative Activity of Carbapenems Testing (COMPACT) Study was designed to determine the in vitro potency of doripenem compared with imipenem and meropenem against a large number of contemporary Gram-negative pathogens from more than 100 centres across Europe and the Asia-Pacific region and to assess the reliability of Etest methodology for doripenem minimum inhibitory concentration (MIC) determination against these pathogens. Data from eight countries within the Asia-Pacific region, which collected 1612 bacterial isolates, are presented here. Etest methodology was found to be a reliable method for MIC determination. Doripenem showed in vitro activity similar to or better than meropenem and at least four-fold better than imipenem against Enterobacteriaceae. Against Pseudomonas aeruginosa, doripenem was also the most active of the three carbapenems in vitro. However, in vitro results do not necessarily correlate with clinical outcome.

Comparison of broth microdilution, agar dilution, and Etest for susceptibility testing of doripenem against gram-negative and gram-positive pathogens.

The susceptibility of 513 clinical isolates to doripenem was determined by broth microdilution, agar dilution, and Etest. Overall agreements for Etest and agar dilution MIC values compared to reference broth microdilution at +/-1 log(2) dilution were 88% and 94%, respectively. Etest MIC values demonstrated 98% agreement within +/-2 log(2) dilutions compared to the reference broth microdilution method.

Development of a standardized susceptibility test for campylobacter with quality-control ranges for ciprofloxacin, doxycycline, erythromycin, gentamicin, and meropenem.

A standardized agar dilution susceptibility testing method was developed for Campylobacter that consisted of testing on Mueller-Hinton medium supplemented with 5% defibrinated sheep blood in an atmosphere of 10% CO2, 5% O2, and 85% N2. Campylobacter jejuni ATCC 33560 was identified as a quality-control (QC) strain. Minimal inhibitory concentration (MIC) QC ranges were determined for two incubation time/temperature combinations: 36 degrees C for 48 hr and 42 degrees C for 24 hr. Quality-control ranges were determined for ciprofloxacin, doxycycline, erythromycin, gentamicin, and meropenem. For all antimicrobial agents tested at both temperatures, 95-100% of the QC MIC results fell within recommended QC ranges. Twenty-one Campylobacter clinical isolates, encompassing five species of Campylobacter (C. jejuni, C. coli, C. jejuni, subsp. doylei, C. fetus, and C. lari) were tested in conjunction with the C. jejuni QC strain. While C. jejuni and C. coli could be reliably tested under both test conditions, growth of C. jejuni subsp. doylei, C. fetus, and C. lari isolates was inconsistent when incubated at 42 degrees C. Therefore, it is recommended that these species only be tested at 36 degrees C.