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The VITEK®2 AES β-lactam phenotypes of 488 Enterobacterales from North and Latin America generated by the VITEK®2 were compared to the resistance genotypes provided by whole genome sequencing (WGS). The AES provided phenotypic reports for 447 (91.6 %) isolates, including isolates harbouring carbapenemases (195; 43.6 %), ESBLs (103; 23.0 %) and transferable AmpCs (tAmpC; 28; 6.3 %) genes, as well as wildtype isolates (WT; 121; 27.1 %). Overall, the AES report was accurate for 433/447 (96.9 %) isolates. The AES accurately reported carbapenemase, ESBL, and tAmpC phenotypes for 93.7 %, 93.7 %, and 98.4 % of isolates, respectively, and sensitivity/specificity rates were 96.4 %/91.7 %, 98.1 %/92.4 %, 82.1 %/99.5 %, and 100 %/98.8 %. 14 isolates carrying carbapenemase (7 total; 3 KPC, 2 MBL, 2 OXA-48-like), ESBL (2), and tAmpC-encoding genes (5) were not correctly identified by AES. The AES phenotypic report detected resistance mechanisms among Enterobacterales rapidly and could significantly aid future antimicrobial stewardship initiatives and patient care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JMI Laboratories reports financial support and equipment, drugs, or supplies were provided by bioMérieux SA. Co-author previously employed by bioMerieux – DS. CGC is currently a bioMerieux employee. Corresponding author is a member of the DMID editorial board – CGC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. JMI Laboratories was contracted to perform services in 2022 for AbbVie, Inc., AimMax Therapeutics, Amicrobe, Inc., Appili Therapeutics, Armata Pharmaceuticals, Astellas Pharma, Inc., Basilea Pharmaceutica AG, Becton, Dickinson and Company, bioMérieux, Biosergen AB, Bugworks, Cerba Research NV, Cidara Therapeutics, Cipla USA Inc., ContraFect Corporation, CorMedix Inc., Crestone, Inc., Curza Global, LLC, Diamond V, Discuva Ltd., Entasis Therapeutics, Enveda Biosciences, Evopoint Biosciences, Fedora Pharmaceuticals, Fox Chase Chemical Diversity Center, Genentech, Gilead Sciences, Inc., GSK plc, Institute for Clinical Pharmacodynamics, Iterum Therapeutics plc, Janssen Biopharma, Johnson & Johnson, Kaleido Biosciences, LifeMine Therapeutics, Medpace, Inc, Lysovant Sciences, Inc, Meiji Seika Pharma, Melinta Therapeutics, Menarini Group, Merck & Co., MicuRx Pharmaceutical Inc., Mundipharma International Ltd., Mutabilis, Nabriva Therapeutics, National Cancer Institute, National Institutes of Health, Ohio State University, Omnix Medical Ltd., Paratek Pharmaceuticals, Pfizer, PolyPid Ltd., PPD, Prokaryotics, Inc., Pulmocide Ltd, Qpex Biopharma, Revagenix, Roche Holding AG, Roivant Sciences, Scynexis, Inc., SeLux Diagnostics, Shionogi & Co., Ltd., Sinovent Pharmaceuticals, Inc., Spero Therapeutics, Sumitovant Biopharma, Inc., TenNor Therapeutics, ThermoFisher Scientific, U.S. Food and Drug Administration, VenatoRx Pharmaceuticals, Washington University, Watershed Medical, LLC, Wockhardt, Zoetis, Inc. 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Hoffmann-La Roche Ltd., ICON plc, Idorsia Pharmaceuticals Ltd., Iterum Therapeutics plc, Laboratory Specialists, Inc., Melinta Therapeutics, Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc, NAEJA-RGM, Novartis AG, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Polyphor Ltd., Pharmaceutical Product Development, LLC, Prokaryotics Inc., Qpex Biopharma, Inc., Roivant Sciences, Ltd., Safeguard Biosystems, Scynexis, Inc., SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Spero Therapeutics, Summit Pharmaceuticals International Corp., Synlogic, T2 Biosystems, Inc., Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, Theravance Biopharma, University of Colorado, University of Southern California-San Diego, University of North Texas Health Science Center, VenatoRx Pharmaceuticals, Inc., Viosera Therapeutics, Vyome Therapeutics Inc., Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare., (Copyright © 2024. Published by Elsevier Inc.)

Candida auris is an evolving and concerning global threat. Of particular concern are bloodstream infections related to central venous catheters. We evaluated the activity of taurolidine, a broad-spectrum antimicrobial in catheter lock solutions, against 106 C . auris isolates. Taurolidine was highly active with a MIC 50 /MIC 90 of 512/512 mg/L, over 20-fold lower than lock solution concentrations of ≥13,500 mg/L. Our data demonstrate a theoretical basis for taurolidine-based lock solutions for prevention of C. auris catheter-associated infections., Competing Interests: J.L.C., E.H., X.T., and A.P. are all employees of CorMedix Inc.; B.E.R. is a consultant to CorMedix Inc.

We assessed ceftaroline disk diffusion breakpoints for Staphylococcus aureus when applying revised Clinical and Laboratory Standards Institute (CLSI) ceftaroline MIC breakpoints. Disk-MIC correlation was evaluated by testing a challenge collection ( n = 158) of methicillin-resistant S. aureus (MRSA) isolates composed of 106 randomly selected isolates plus 52 isolates with decreased susceptibility to ceftaroline (MIC, 1 to 16 μg/ml). Disk diffusion was performed with 30-μg disks and Mueller-Hinton agar from 2 manufacturers each. Revised CLSI susceptible (S)/susceptible dose-dependent (SDD)/resistant (R) MIC breakpoints of ≤1/2 to 4/≥8 μg/ml were applied. The disk breakpoints that provided the lowest error rates were CLSI S/R breakpoints of ≥25 mm/≤19 mm, with no very major (VM) or major (Ma) errors and with minor (Mi) error rates of 0.0% for ≥2 doubling dilutions above the I or SDD (≥I + 2), 22.1% for I or SDD plus or minus 1 doubling dilution (I ± 1), and 2.3% for ≤2 doubling dilutions below the I or SDD ≤I - 2 (overall Mi error rate, 16.5%). No mutation in the penicillin-binding protein 2a (PBP2a) was observed in 5 of 15 isolates with a ceftaroline MIC of 2 μg/ml; 3 of 11 isolates with a ceftaroline MIC of 1 μg/ml exhibited mutations in the penicillin-binding domain (PBD; 1 isolate) or in the non-PBD (2 isolates). All isolates except 1, with a ceftaroline MIC of ≥4 μg/ml, showed ≥1 mutation in the PBD and/or non-PBD. In summary, results from the disk diffusion method showed a good correlation with those from the reference broth microdilution method. Our results also showed that the ceftaroline MIC distribution of isolates with no mutations in the PBP2a goes up to 4 μg/ml, and reference broth microdilution and disk diffusion methods do not properly separate wild-type from non-wild-type isolates., (Copyright © 2018 Sader et al.)

We evaluated the correlation between MIC and disk diffusion inhibition zones when testing ceftazidime-avibactam, using the 30/20-μg disk and the disk diffusion and MIC breakpoints established by the U.S. FDA and the Clinical and Laboratory Standards Institute (CLSI). Organisms used included 2 groups of Enterobacteriaceae isolates and 2 groups of Pseudomonas aeruginosa isolates; 1 group of each consisted of randomly selected isolates and the second group consisted of a challenge group from thousands of surveillance isolates with an increased proportion of organisms displaying ceftazidime-avibactam MIC values close to the breakpoints. Broth microdilution, disk diffusion tests, and data analysis were performed according to reference standardized methods. Ceftazidime-avibactam breakpoints of ≤8/4 (susceptible) and ≥16/4 μg/ml (resistant) for MIC and ≥21/≤20 mm for disk diffusion, as established by the U.S. FDA and the CLSI, were applied for Enterobacteriaceae and P. aeruginosa Ceftazidime-avibactam MIC and disk zone (30/20-μg disk) correlation were acceptable when testing Enterobacteriaceae (overall, very major [VM] and major [Ma] error rates of 0.4% and 0.0%, respectively) and nearly so when testing P. aeruginosa (2.3% VM and 2.9% Ma errors). In summary, disk diffusion and broth microdilution testing results demonstrated good categorical agreement for ceftazidime-avibactam against Enterobacteriaceae and P. aeruginosa , using 30/20-μg disks., (Copyright © 2018 American Society for Microbiology.)

A total of 840 clinically relevant viridans group streptococci (VGS) isolates (1/patient episode) were collected from 71 US medical centers in 2013-2014. These organisms were tested for susceptibility by reference broth microdilution methods against ceftaroline and selected comparator agents. All isolates were speciated by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry and were primarily from skin/soft tissue (32.6%) and bloodstream (32.3%) infections. Ceftaroline was highly active against all VGS species/groups with MIC50 and MIC90 values ranging from ≤0.015 to 0.03μg/mL and ≤0.015 to 0.06μg/mL, respectively. The highest ceftaroline MIC value was only 0.5μg/mL (0.5% of strains) and ceftaroline (MIC50/90, 0.03/0.06μg/mL) was 8-fold more active than ceftriaxone (MIC50/90, 0.25/0.5μg/mL). The VGS groups most susceptible to ceftaroline were Streptococcus mutans and Streptococcus bovis (MIC90, ≤0.015μg/mL), whereas the highest ceftaroline MIC values were observed among Streptococcus mitis and Streptococcus sanguinis groups. In summary, ceftaroline exhibited potent in vitro activity against VGS, including many uncommonly isolated species/groups for which very limited susceptibility information is currently available to guide therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The antifungal broth microdilution (BMD) method of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) was compared with Clinical and Laboratory Standards Institute (CLSI) BMD method M27-A3 for amphotericin B, flucytosine, anidulafungin, caspofungin, micafungin, fluconazole, isavuconazole, itraconazole, posaconazole, and voriconazole susceptibility testing of 357 isolates of Candida. The isolates were selected from global surveillance collections to represent both wild-type (WT) and non-WT MIC results for the azoles (12% of fluconazole and voriconazole results were non-WT) and the echinocandins (6% of anidulafungin and micafungin results were non-WT). The study collection included 114 isolates of Candida albicans, 73 of C. glabrata, 76 of C. parapsilosis, 60 of C. tropicalis, and 34 of C. krusei. The overall essential agreement (EA) between EUCAST and CLSI results ranged from 78.9% (posaconazole) to 99.6% (flucytosine). The categorical agreement (CA) between methods and species of Candida was assessed using previously determined CLSI epidemiological cutoff values. The overall CA between methods was 95.0% with 2.5% very major (VM) and major (M) discrepancies. The CA was >93% for all antifungal agents with the exception of caspofungin (84.6%), where 10% of the results were categorized as non-WT by the EUCAST method and WT by the CLSI method. Problem areas with low EA or CA include testing of amphotericin B, anidulafungin, and isavuconazole against C. glabrata, itraconazole, and posaconazole against most species, and caspofungin against C. parapsilosis, C. tropicalis, and C. krusei. We confirm high level EA and CA (>90%) between the 2 methods for testing fluconazole, voriconazole, and micafungin against all 5 species. The results indicate that the EUCAST and CLSI methods produce comparable results for testing the systemically active antifungal agents against the 5 most common species of Candida; however, there are several areas where additional steps toward harmonization are warranted., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We evaluated the ability of four commercial MIC testing systems (MicroScan, Vitek 2, Phoenix, and Etest) to detect vancomycin MIC values of ≤1 to ≥2 in 200 methicillin-resistant Staphylococcus aureus (MRSA) strains compared to the Clinical and Laboratory Standards Institute broth microdilution (BMD) reference methods. Compared to the BMD method, absolute agreement (0 ± dilution) was highest for the Phoenix system (66.2%) and the MicroScan turbidity method (61.8%), followed by the Vitek 2 system (54.3%). The Etest produced MIC values 1 to 2 dilutions higher than those produced by the BMD method (36.7% agreement). Of interest, the MicroScan system (prompt method) was more likely to overcall an MIC value of 1 mg/liter (74.1%), whereas the Phoenix (76%) and Vitek 2 (20%) systems had a tendency to undercall an MIC of 2 mg/liter. The ability to correctly identify vancomycin MIC values of 1 and 2 has clinical implications and requires further evaluation.

External laboratory proficiency programs are an important requirement for test quality assurance (EQA) and compliance to regulatory guidelines (Clinical Laboratory Improvement Amendments and inspections). The American Proficiency Institute (API) regularly distributes EQA sample challenges (test events) including an Educational Sample (ES) for antimicrobial susceptibility testing. Beginning in 2007, API has sent 3 ES samples annually, each a well-characterized (molecular/phenotypic methods) strain having an interesting/emerging mechanism of resistance. Hundreds of USA laboratories, usually serving small- to medium-size hospitals and clinics, participate in the API ungraded ES test event. Analysis of responses is made and reported electronically as ES critiques addressing contemporary susceptibility testing issues that affect patient therapy. Seven Gram-positive (+) and 8 Gram-negative (-) ES strains were tested over the 5 years (2007-2011) with organism identification (graded) accuracy of 95.3% (range, 91.0-99.2%) for Gram (-) and 97.0% (range, 94.2-100.0%) for Gram (+) challenges. Susceptibility testing categorical accuracy was generally greatest for the disk diffusion test (91.0/97.0%) compared to the MIC methods (commercial automated or manual) combined (89.9/96.1%, for Gram [-]/Gram [+], respectively). The most worrisome observations of these ES samples were as follows: 1) poor recognition of ESBL- and serine carbapenemase-producing strains (various types including Klebsiella pneumoniae carbapanemase) due to delayed application of Clinical and Laboratory Standards Institute [CLSI] guidelines; 2) overcalling of ESBL in organisms having wild-type non-ESBL enzymes (OXA series; OXA, 1/30) due to commercial system or participant interpretive error; and 3) occasional drug-bug discords noted in nonfermentative Gram (-) bacilli. In conclusion, the API ES series of ungraded susceptibility testing challenges (accuracy was >90%) has been well received by subscribers and has provided detailed educational opportunities to improve laboratory testing performance. ES samples have delivered guidance to enable laboratories to rapidly comply with CLSI document changes of interpretive breakpoints such as those for β-lactams when testing Enterobacteriaceae and Pseudomonas aeruginosa; the program was sustained into 2012 and beyond to document quality of susceptibility tests in USA laboratories., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Fusidic acid (CEM-102) is a steroidal antimicrobial agent with focused Gram-positive activity that acts by preventing bacterial protein synthesis via interacting with elongation factor G. A collection of 114 wild-type isolates (> 80 species) was used to define the contemporary limits of fusidic acid spectrum against Gram-positive and Gram-negative species. Reference broth microdilution and anaerobic agar dilution methods were performed. Modifications of standardized test methods included adding 10% human serum and adjusting the medium pH to 5, 6, and 8. Synergy was assessed by the checkerboard method and time-kill studies. Mutational rates to resistance were determined at 4 x, 8 x, and 16 x MIC. Against Gram-positive pathogens, fusidic acid MIC values ranged from 0.06 to 32 microg/mL with the greatest potency against Staphylococcus aureus, Corynebacterium spp., and Micrococcus luteus (MIC results, 0.25, < or = 0.12, and < or = 0.5 microg/mL, respectively). Enterococci and streptococci were less susceptible (MIC ranges, 2-8 and 16-32 microg/mL, respectively). Fusidic acid activity against Gram-negative species was more limited (all MIC values, > or = 2 microg/mL) except for Empedobacter brevis, Moraxella catarrhalis and Neisseria meningitidis. A 4-fold increase in fusidic acid MIC results was observed when 10% serum was added to the broth. Decreasing medium pH to 5.0 to 6.0 negated the protein binding effects. Among the 8 antimicrobial combinations tested, gentamicin and rifampin enhanced the activity when combined with fusidic acid (no antagonism). Fusidic acid in vitro activity was most improved when combined with rifampin. Single-step mutational rates ranged from 1.2 x 10(-6) for 4x MIC to 9.8 x 10(-8) for 16 x MIC. In conclusion, these in vitro results for fusidic acid tested against contemporary strains confirm a persisting antimicrobial spectrum, especially against staphylococci and some other Gram-positive species., (2010 Elsevier Inc. All rights reserved.)

The Meropenem Yearly Susceptibility Test Information Collection Program is a global, longitudinal resistance surveillance network of more than 100 medical centers worldwide monitoring the susceptibility of bacterial pathogens to carbapenems and other broad-spectrum agents. Between 1999 and 2004, a total of 10-16 US medical centers referred up to 200 nonduplicate isolates from clinical infections to a central processing laboratory. Over this 6-year period, the antimicrobial activity of 12 broad-spectrum agents was assessed against 15990 bacterial isolates using Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) reference methods. Analysis of the MIC results by year within organism species and/or organism groups revealed a continued decrease in fluoroquinolone susceptibility (ciprofloxacin and levofloxacin), especially among indole-positive Proteae (-22.1%), Escherichia coli (-17.0%), Enterobacter species (-10.0%), and Proteus mirabilis (-7.6%) isolates. Antibiogram analysis of strains demonstrating multidrug resistance from the same institutions were further characterized by automated ribotyping and pulsed-field gel electrophoresis to determine clonality. In 2004, a total of 165 selected multidrug-resistant (MDR) strains produced 64 different ribotypes with the largest representing 31 Escherichia coli isolates from 6 medical centers. Other clusters were also identified within single medical centers among Enterobacter cloacae (6 strains), Providencia stuartii (5 strains), and Morganella morganii (4 strains). A significant clonal outbreak encompassing 40 Acinetobacter baumannii isolates from 3 centers in a single endemic region was identified in 1999 and has persisted through 2004. Continued surveillance of these broad-spectrum antimicrobial agents against MDR pathogens appears warranted to monitor the incidence and spread of resistant clones causing serious infections. Possible emergence of resistance mechanisms via clonal dissemination proves to be among the principle threats that compromise carbapenem therapy, where meropenem maintains the broadest spectrum of coverage.

Objectives: This study assessed the activity of ceftibuten, ceftibuten combined with the active form (VNRX-5236) of the β-lactamase inhibitor VNRX-7145 and comparators against a challenge set of Gram-negative pathogens.Methods: Two hundred and five Enterobacterales carrying plasmid AmpC (53 isolates), ESBL (50), KPC (50), OXA-48-like (49) or OXA-48-like with KPC (3) encoding genes were selected. Susceptibility was determined by broth microdilution. VNRX-5236 and avibactam were tested at a fixed concentration of 4 mg/L.Results: Ceftibuten/VNRX-5236 (MIC50/90 0.12/1 mg/L) MIC values were 256-fold lower than those of ceftibuten (MIC50/90 32/256 mg/L) for all Enterobacterales and 2- to 4-fold lower than those of ceftazidime/avibactam (MIC50/90 0.5/2 mg/L). For isolates producing a plasmid-encoded AmpC, VNRX-5236 decreased ceftibuten MIC (MIC50/90 0.12/1 mg/L) by at least 512-fold compared with ceftibuten (MIC50/90 128/>256 mg/L). Ceftibuten/VNRX-5236 (MIC50/90 0.06/0.12 mg/L) and meropenem (MIC50/90 ≤0.03/0.06 mg/L; 100% susceptible) showed comparable activities against ESBL isolates and these agents had MIC90 values 4- to 8-fold lower than that of ceftazidime/avibactam (MIC50/90 0.25/0.5 mg/L; 100% susceptible). Ceftibuten/VNRX-5236 (MIC50/90 0.12/0.5 mg/L) had the lowest MIC for KPC producers, followed by ceftazidime/avibactam (MIC50/90 2/4 mg/L; 98.0% susceptible). The same MIC90 values were obtained for ceftibuten/VNRX-5236 (MIC50/90 0.25/1 mg/L) and ceftazidime/avibactam (MIC50/90 1/1 mg/L; 100.0% susceptible) for isolates carrying blaOXA-48-like. VNRX-5236 decreased the ceftibuten MIC at least 16-fold for three isolates carrying blaOXA-48-like and blaKPC.Conclusions: VNRX-5236 rescued the in vitro activity of ceftibuten against Enterobacterales carrying common serine β-lactamases, including ESBL, AmpC and the KPC and OXA-48-like carbapenemases. Ceftibuten/VNRX-5236 may have potential as an oral treatment for infections caused by resistant Enterobacterales, while sparing carbapenems. [ABSTRACT FROM AUTHOR]

Background: POL7306 belongs to a new class of peptidomimetic outer-membrane-protein-targeting antibiotics with a novel mechanism of action. POL7306 is in development for the treatment of infections caused by antimicrobial-resistant Gram-negative bacteria and has demonstrated low cytotoxicity and nephrotoxicity.Methods: A total of 891 isolates were collected by the SENTRY Antimicrobial Surveillance Program from 134 medical centres in Europe (n = 424; 41 centres in 18 nations), the USA (n = 411 isolates from 67 centres), the Asia-Pacific region (n = 24; 15 centres in 6 nations) and Latin America (n = 32; 11 centres in 9 nations) and included 558 Enterobacterales, 310 non-fermenters and 23 fastidious organisms. Susceptibility testing was performed using the reference broth microdilution method and the medium was supplemented with 0.002% polysorbate-80 for testing POL7306. Resistant subsets were characterized by WGS.Results: POL7306 demonstrated potent in vitro activity against Enterobacterales [including carbapenem-resistant (MIC50/90, 0.06/0.25 mg/L), ESBL-producing (MIC50/90, 0.06/0.12 mg/L), KPC-producing (MIC50/90, 0.12/0.25 mg/L), MBL-producing (MIC50/90, 0.06/0.25 mg/L), colistin-non-susceptible, mcr-negative (MIC50/90, 0.5/2 mg/L) and mcr-positive (MIC50/90, 0.12/0.25 mg/L) Enterobacterales], Pseudomonas aeruginosa (MIC50/90, 0.25/0.25 mg/L), Acinetobacter baumannii (MIC50/90, 0.06/0.12 mg/L) and Stenotrophomonas maltophilia (MIC50/90, 0.06/0.25 mg/L).Conclusions: POL7306 demonstrated potent activity against a large collection of Gram-negative organisms collected worldwide that included colistin-resistant, XDR and ESBL- and carbapenemase-producing isolates for which there are currently limited treatment options. [ABSTRACT FROM AUTHOR]

The antimicrobial activities of several β-lactam agents were tested by broth microdilution alone and in combination with a new polymyxin analog, SPR741 (at a fixed concentration of 8 mg/L), against a challenge set of clinical isolates (202 Escherichia coli and 221 Klebsiella pneumoniae isolates). Using Clinical and Laboratory Standards Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility criteria for each partner antibiotic, mecillinam–SPR741, temocillin–SPR741, and piperacillin–tazobactam–SPR741 combinations had susceptibility rates higher (85.6–100.0%) than the respective agents tested alone (47.5–88.7%) against extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae. Temocillin–SPR741 (97.8% susceptible) had MIC50 (minimum inhibitory concentration) and MIC90 results of 0.5 and 2 mg/L, respectively, against K. pneumoniae carbapenemase (KPC)-producing E. coli, 8- to 16-fold lower than temocillin alone (MIC50/90, 8/16 mg/L; 65.2% susceptible). The mecillinam MIC50/MIC90 results dropped to 1/4 mg/L (from 128/>256 mg/L when tested alone) against metallo-β-lactamase (MBL)-producing E. coli. These MICs for mecillinam–SPR741 resulted in a susceptibility rate of 96.9% versus 9.4% for mecillinam. In general, a decrease in MICs for β-lactams (MIC90, >32 mg/L) in the presence of SPR741 was not observed against KPC-, MBL- or OXA-48-like-producing K. pneumoniae. These study results indicate that some agents had a significant increase in in vitro activity in the presence of SPR741 and could become potential strategic options for treating serious infections caused by multidrug-resistant Enterobacteriaceae. [ABSTRACT FROM AUTHOR]

Abstract Fosfomycin and comparators were susceptibility tested against over 2200 contemporary clinical isolates from US medical centers. Fosfomycin was active against Enterobacterales (MIC 50/90 , 4/16 μg/mL), including multidrug-resistant isolates. Potent activity was exhibited against gram-positive organisms, including Staphylococcus aureus (MIC 50/90 , 4/8 μg/mL). Fosfomycin may provide a promising alternative option for treatment of infections where resistant bacteria may occur. Highlights • Fosfomycin was active against gram-positive and -negative bacteria from USA. • It was active against Enterobacterales that included multidrug-resistant isolates. • Fosfomycin may offer a treatment alternative where resistant bacteria may occur. [ABSTRACT FROM AUTHOR]

Background: Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein-targeting antibiotics. Murepavadin acts by binding to LPS transport protein D and is being developed for the treatment of hospital-acquired and ventilator-associated pneumonia caused by Pseudomonas aeruginosa.Objectives: To evaluate the antimicrobial activity of murepavadin against XDR P. aeruginosa.Methods: A total of 785 clinical isolates of XDR P. aeruginosa were collected in 2016-17 through the SENTRY Antimicrobial Surveillance Program from 34 medical centres in 21 European nations (n = 353) and 75 medical centres in North America (n = 432). Isolates were categorized as XDR when susceptible (CLSI) to ≤2 of the following antimicrobial classes: antipseudomonal cephalosporins, carbapenems, broad-spectrum penicillin/β-lactamase inhibitor combinations, fluoroquinolones, aminoglycosides and polymyxins. Susceptibility testing was performed by the reference broth microdilution method and EUCAST and CLSI interpretative criteria were applied.Results: Murepavadin (MIC50/90, 0.12/0.25 mg/L) inhibited 96.7% of isolates at ≤0.5 mg/L and was 8-fold more active than colistin (MIC50/90, 1/2 mg/L). Only seven isolates (0.9%) exhibited murepavadin MIC values >4 mg/L. Colistin (MIC50/90, 1/2 mg/L; 93.6% susceptible) was the most active comparator, followed by ceftolozane/tazobactam (MIC50/90, 2/>32 mg/L; 70.6% susceptible) and tobramycin (MIC50/90, 8/>8 mg/L; 47.5% susceptible). Murepavadin remained active against isolates that were non-susceptible to colistin (n = 50; MIC50/90, 0.25/0.25 mg/L), ceftolozane/tazobactam (n = 231; MIC50/90, 0.12/0.25 mg/L) and/or tobramycin (n = 412; MIC50/90, 0.12/0.25 mg/L).Conclusions: Murepavadin exhibited potent activity against a large collection of clinical XDR P. aeruginosa isolates from Europe and North America, including isolates that were non-susceptible to colistin, ceftolozane/tazobactam and/or tobramycin. [ABSTRACT FROM AUTHOR]

Background: Zidebactam is a β-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and β-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections.Objectives: To evaluate the in vitro activities of cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant β-lactamase types.Methods: β-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against cefepime/zidebactam, cefepime and zidebactam.Results: Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90  ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-β-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including β-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many β-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)].Conclusions: Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant β-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to evaluate the in vitro activity of CD101, a novel echinocandin with a long serum elimination half-life, and comparator (anidulafungin and caspofungin) antifungal agents against a collection of Candida and Aspergillus spp. isolates.Methods: CD101 and comparator agents were tested against 106 Candida spp. and 67 Aspergillus spp. isolates, including 27 isolates of Candida harbouring fks hotspot mutations and 12 itraconazole non-WT Aspergillus, using CLSI and EUCAST reference susceptibility broth microdilution (BMD) methods.Results: Against WT and fks mutant Candida albicans, Candida glabrata and Candida tropicalis, the activity of CD101 [MIC90 = 0.06, 0.12 and 0.03 mg/L, respectively (CLSI method values)] was comparable to that of anidulafungin (MIC90 = 0.03, 0.12 and 0.03 mg/L, respectively) and caspofungin (MIC90 = 0.12, 0.25 and 0.12 mg/L, respectively). WT Candida krusei isolates were very susceptible to CD101 (MIC = 0.06 mg/L). CD101 activity (MIC50/90 = 1/2 mg/L) was comparable to that of anidulafungin (MIC50/90 = 2/2 mg/L) against Candida parapsilosis. CD101 (MIC mode = 0.06 mg/L for C. glabrata) was 2- to 4-fold more active against fks hotspot mutants than caspofungin (MIC mode = 0.5 mg/L). CD101 was active against Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger and Aspergillus flavus (MEC90 range = ≤0.008-0.03 mg/L). The essential agreement between CLSI and EUCAST methods for CD101 was 92.0%-100.0% among Candida spp. and 95.0%-100.0% among Aspergillus spp.Conclusions: The activity of CD101 is comparable to that of other members of the echinocandin class for the prevention and treatment of serious fungal infections. Similar results for CD101 activity versus Candida and Aspergillus spp. may be obtained with either CLSI or EUCAST BMD methods. [ABSTRACT FROM AUTHOR]

Pexiganan, in Phase 3 clinical development for topical use, exhibited bactericidal activity in vitro against Gram-positive and -negative isolates and was also shown to have a low potential for resistance development in broth serial passage experiments. Susceptibility studies were performed against bacterial isolates (110 total from 2004 to 2013; primarily from skin and soft tissue infections) selected for elevated MIC values (non-wildtype [WT] distributions) to bacitracin, polymyxin B, neomycin, mupirocin, retapamulin, fusidic acid, or gentamicin. A narrow range of pexiganan MIC values (4–32 μg/mL) against Staphylococcus aureus was observed (MIC 50 and MIC 90 values, 16 μg/mL) with a pexiganan mode and MIC 50 value for the subsets of isolates with non-WT MIC values to bacitracin and neomycin ( n = 14), fusidic acid ( n = 11), mupirocin ( n = 12) and retapamulin ( n = 11) at 16 μg/mL. For coagulase-negative staphylococci (CoNS), the pexiganan mode and MIC 50 values were 4 μg/mL. The pexiganan mode and MIC 50 for each non-WT CoNS subset was also 4 μg/mL. Pexiganan MIC values for Enterococcus faecium was 8 μg/mL, but E. faecalis isolates exhibited MIC values that ranged from 128–256 μg/mL. Pexiganan was active against β-hemolytic streptococci including non-WT subsets (MIC range, 4–64 μg/mL). MIC values for pexiganan varied by species for viridans group streptococci, with highest values occurring for Streptococcus oralis . The broad bactericidal spectrum of pexiganan activity and low potential for resistance selection offers the possibility that this experimental agent may be able to play an important role in the current environment of emerging multi-drug resistant pathogens. [ABSTRACT FROM AUTHOR]

Objectives: S-649266 is a parenteral siderophore cephalosporin antibiotic with a catechol moiety on its side chain. The in vitro antimicrobial activity of S-649266 against non-fermenting Gram-negative bacteria was evaluated and compared with the activities of meropenem, levofloxacin, cefepime, ceftazidime and piperacillin/tazobactam.Methods: MIC values of S-649266 were determined in Mueller-Hinton broth or Iso-Sensitest broth supplemented with apo-transferrin.Results: S-649266 showed potent in vitro activity against the non-fermenting Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-β-lactamase-producing P. aeruginosa. MIC90s of S-649266 for A. baumannii, P. aeruginosa and S. maltophilia were 2, 1 and 0.5 mg/L, respectively, whereas MIC90s of meropenem were >16 mg/L. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA-type β-lactamases, and P. aeruginosa producing metallo-β-lactamases such as IMP type and VIM type. MIC90 values for these A. baumannii strains and P. aeruginosa strains were 8 and 4 mg/L, respectively.Conclusions: S-649266 is a novel antibiotic with potent in vitro activity against a range of non-fermenting Gram-negative bacteria, including MDR strains. [ABSTRACT FROM AUTHOR]

Abstract: As part of Meropenem Yearly Susceptibility Test Information Collection/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and aminoglycosides was noted over the 10-year span (P < 0.0001), which was significantly reduced compared with the average susceptibility of all sites. Introduction of quinolone prophylaxis has led to a significant decline in susceptibility of E. coli to all quinolones. The organisms remain susceptible to carbapenems, cefepime, and piperacillin/tazobactam. Periodic surveillance allows for detection of resistance patterns and adjustment of empiric antibiotic choice in patients at high risk for infection. [Copyright &y& Elsevier]

Abstract: The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program was a global, longitudinal antimicrobial resistance surveillance network of more than 100 medical centers worldwide monitoring the susceptibility of meropenem and selected other broad-spectrum comparator agents. In 1999, and from 2000 through 2008, a total of 10 or 15 United States (USA) medical centers each forwarded 200 nonduplicate clinical isolates from serious infections to a central processing laboratory. Over the 10-year period of this surveillance program, the activity of meropenem and an average of 11 other antimicrobial agents were assessed against a total of 27 289 bacterial isolates using Clinical and Laboratory Standards Institute reference methods. Meropenem consistently demonstrated low resistance rates against Enterobacteriaceae species isolates through 2008 and did not exhibit a widespread change in resistance rates over the monitored interval. In fact, the incidence of emerging carbapenemase-producing (KPC-type) Klebsiella spp. showed a decline in 2008 compared to the steeply increasing rates observed from 2004 to 2007. Moreover, the KPC serine carbapenemases have spread to other Enterobacteriaceae species monitored by the MYSTIC Program. Greatest increases in antimicrobial resistance rates were observed for the fluoroquinolones (ciprofloxacin, levofloxacin) among all species monitored by the MYSTIC Program. Current susceptibility rates for meropenem when tested against prevalent pathogens were Pseudomonas aeruginosa (439 strains, 85.4% susceptible), Enterobacteriaceae (1537 strains, 97.3% susceptible), methicillin-susceptible staphylococci (460 strains, 100.0% susceptible), Streptococcus pneumoniae (125 strains, 80.2% at meningitis susceptibility breakpoints), other streptococci (159 strains, 90.0–100.0% susceptible), and Acinetobacter spp. (127 strains, 45.7% susceptible), the widest spectrum among β-lactams tested in 2008 and throughout the last decade. Continued local surveillance of broad-spectrum agents following the completion of the MYSTIC Program (USA) appears critical to detect emerging resistances among pathogens causing the most serious infections requiring carbapenem agents. [Copyright &y& Elsevier]

Gram-negative bacilli (n = 15,377) were tested against colistin (polymyxin E) and polymyxin B by a commercial broth microdilution method (Sensititre®). Among Pseudomonas aeruginosa and Acinetobacter spp., colistin and polymyxin B MIC values were within ±1 doubling dilution for >99.0% of strains. Among Klebsiella spp. and Escherichia coli , 55.0 and 53.2% of strains displayed a colistin MIC 2-fold lower than polymyxin B, but polymyxin B was slightly more potent than colistin against strains with decreased susceptibility to either polymyxin. [ABSTRACT FROM AUTHOR]

Abstract: Accurate determination of in vitro activity for polymyxin class agents has consistently been a problem due to their physical–chemical characteristics that can be influenced by the constituents of reference and/or standardized susceptibility testing methods. We evaluated the impact of using polysorbate 80 (P-80), a surfactant, in reference broth microdilution (BMD) methods when testing polymyxin B and colistin against 247 clinical strains of Enterobacteriaceae (124 strains), Acinetobacter spp. (60 strains), and Pseudomonas aeruginosa (63 strains). All testing was performed in frozen-form BMD panels with and without 0.002% P-80. MIC results for both polymyxins were generally 4- to 8-fold lower when P-80 was added to the testing broth compared to Mueller-Hinton broth without the surfactant. Decreases were greatest in organisms having MIC values at ≤2 μg/mL and among Acinetobacter spp. Polymyxins should be tested with P-80 to more accurately assess the potencies of these agents necessary to treat multidrug-resistant Gram-negative bacilli. [Copyright &y& Elsevier]

Background Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study tested the equivalency of minimal inhibitory concentrations (MICs) obtained by 2 reference susceptibility testing methods, agar dilution (AD) and broth microdilution (BMD), for gepotidacin against Gram-positive and Gram-negative organisms. Methods Susceptibility testing for both methods was performed on a total of 733 clinical isolates recovered largely in 2016 from over 120 medical centers worldwide. For N. gonorrhoeae , only the AD method is recommended by CLSI, therefore BMD was performed using Fastidious Broth for comparison purposes. Essential agreement (EA) based on evaluable results was calculated as the number of isolates with MICs within one 2-fold dilution of the reference method divided by the total number of results. Equivalency was defined using the 95% criteria from the FDA's class II controls document. Results The EA observed for gepotidacin with these 2 methods was 85.8% overall and 98.3% when H. influenzae and N. gonorrhoeae isolates were excluded. Slightly higher gepotidacin MICs were observed when tested by BMD for each of these species/groups; this trend was especially prominent for E. coli and S. pyogenes. Gepotidacin tested against H. influenzae (73.1%) or N. gonorrhoeae (28.6%) species had much lower EAs. Conclusion Equivalency (EA >95%) was established between AD and BMD methods for determining gepotidacin susceptibility results against Staphylococcus spp. Streptococcus spp. and E. coli. However, for N. gonorrhoeae and H. influenzae , equivalency between the 2 methods was not established; therefore, future antimicrobial susceptibility testing for gepotidacin against these organisms should adhere to the methods for which quality control ranges and breakpoints are approved. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Among 1846 fungal clinical isolates from 31 countries, echinocandin resistance in Candida spp. ranged from 0.0% to 2.8% (highest for anidulafungin versus Candida glabrata ), and fluconazole resistance was noted among 11.9% and 11.6% of the C . glabrata and Candida tropicalis , respectively. Two isolates of Aspergillus fumigatus displayed elevated MICs for itraconazole and carried cyp51a mutations encoding TR 34 L98H. All Cryptococcus neoformans had azole MIC values below epidemiological cutoff values. The increasing resistance among certain species and more frequent reports of breakthrough infections in patients undergoing antifungal therapy highlights the importance of antifungal surveillance to guide therapy for patients with invasive fungal infections. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the susceptibility rates for piperacillin/tazobactam tested against Pseudomonas aeruginosa isolates from the Asia-Pacific (APAC), Europe (EU), Latin America (LA), and North America (NA) for 1997 to 2007. A total of 25 460 isolates were tested originating from APAC (4441), EU (7695), LA (4277), and NA (9047). All testing was performed by reference broth microdilution methods. The samples were collected from >110 medical centers and samples averaging >30 nations/year. For this analysis, results from 1997 to 2007, 1997 to 1999, 2005 to 2007, APAC, EU, LA, and NA were assessed against several broad-spectrum β-lactams, including cefepime, ceftazidime, imipenem, meropenem, and piperacillin alone, for a total of 12 agents overall. Using P. aeruginosa breakpoints (≤64 μg/mL), piperacillin/tazobactam had the broadest coverage (% susceptible) in 2 regions (EU, LA) and, overall, at 83.6% followed by meropenem (83.0%) > imipenem (79.7%) > piperacillin (79.5%) > cefepime (77.5%) > ceftazidime (75.8%). Other non–β-lactam activity results were ciprofloxacin at only 71.5% susceptible, but tobramycin and polymyxin B had higher susceptibility rates (81.0% and 99.5%, respectively). Trends toward piperacillin/tazobactam resistance were noted between 1997 to 1999 and 2000 to 2007 in APAC (−11.6% susceptibility), NA (−4.0%), and EU (−2.3%). LA susceptibility rates were lowest overall but actually increased recently by +2.9% (current rate, 79.4% susceptible). For β-lactamase inhibitor combinations, susceptibility rates were higher for piperacillin/tazobactam when compared in all regions with piperacillin alone (+2.6–7.1%) and greatest for LA isolates. In contrast, ticarcillin/clavulanate susceptibility rates were lower than ticarcillin tested alone in NA (−1.5%, antagonism), and this agent only inhibited 70.3% of isolates worldwide. In conclusion, piperacillin/tazobactam remained a very active β-lactam when tested in vitro against clinical isolates of P. aeruginosa found in the SENTRY Program (1997–2007). Trends toward slightly decreased susceptibility were noted in all regions over the last decade (except LA); only polymyxins had susceptibility rates at >90%. Resistance surveillance programs should be sustained to document emerging resistance patterns of old and newer agents for difficult-to-treat pathogens such as P. aeruginosa. [Copyright &y& Elsevier]

Abstract: CEM-101 is a novel fluorinated macrolide–ketolide with potent activity against bacterial pathogens that are susceptible or resistant to other macrolide–lincosamide–streptogramin B (MLSB)–ketolide agents. CEM-101 is being developed for oral and parenteral use in moderate to moderately severe community-acquired bacterial pneumonia. The objective of this study was to assess the activity of CEM-101 and comparators against contemporary respiratory tract infection (RTI) isolates. A worldwide sample of organisms was used, including Streptococcus pneumoniae [n =168; 59.3% erythromycin-resistant and 18 multidrug-resistant (MDR) serogroup 19A strains], Moraxella catarrhalis (n =21; 11 β-lactamase positive), Haemophilus influenzae (n =100; 48 β-lactamase positive), Haemophilus parainfluenzae and Haemophilus haemolyticus (n =12), and Legionella pneumophila (n =30). Testing and interpretation were performed using reference Clinical and Laboratory Standards Institute methods. CEM-101 was very potent against S. pneumoniae [minimum inhibitory concentration for 90% of the organisms (MIC90)=0.25mg/L; highest MIC at 0.5mg/L] and was 2- and ≥32-fold more active than telithromycin and clindamycin, respectively. CEM-101 also demonstrated potent activity against S. pneumoniae MDR-19A strains (MIC90=0.5mg/L). CEM-101 was the most potent antimicrobial agent tested against L. pneumophila, with all MIC values at ≤0.015mg/L (telithromycin MIC90=0.03mg/L). CEM-101 was as potent as azithromycin against Haemophilus spp. RTI pathogens (MIC90=2mg/L), with no variations for β-lactamase production. CEM-101 MIC values against M. catarrhalis were all at ≤0.5mg/L. Interestingly, CEM-101 potency was ca. 6log2 dilutions greater than telithromycin MIC results among 44 β-haemolytic streptococci having telithromycin MICs ≥2mg/L. CEM-101 exhibited the greatest potency and widest spectrum of activity against RTI pathogens among the tested MLSB–ketolide agents (azithromycin, clarithromycin, erythromycin, telithromycin, clindamycin and quinupristin/dalfopristin) and was comparable overall with levofloxacin. [Copyright &y& Elsevier]

Susceptibility patterns of 15 antimicrobial agents were assessed for 3,400 isolates of β-hemolytic (βhS) and viridans group (VgS) streptococci in the four regions of the SENTRY Antimicrobial Surveillance Program: Asia-Pacific (APAC), Europe (EU), Latin America (LA) and North America (NA). In 1997 through 2000, SENTRY Program monitors tested strains by reference broth microdilution methods and results were interpreted using National Committee for Clinical Laboratory Standards criteria. Among the βhS processed, 81.9% of strains were either Streptococcus pyogenes (n = 650) or S. agalactiae (n = 1,190). The VgS were generally classified as unspeciated α-hemolytic streptococci (n = 512; 44%) or S. mitis (n = 254; 22%). Seven quinolones, two β-lactams, erythromycin (ER), clindamycin (CM), quinupristin/dalfopristin (Q/D), vancomycin (VA), teicoplanin (TP) and linezolid (LZ) were tested. Rank order of susceptibility for βhS isolates was: ceftriaxone (CTX) = Q/D = VA = TP = LZ (100.0%) > gatifloxacin (GATI) = trovafloxacin (TROV, 99.8%) > levofloxacin (LEVO; 99.7%) > penicillin (PEN; 99.3%) > grepafloxacin (GREPA; 97.4%) > CM (94.4%) > ER (85.5%). ER versus βhS had the highest MIC90 values (2 μg/ml) and the lowest susceptibility rates across all regions (range, 81.4% in NA to 97.3% in LA). Among the VgS, susceptibility rank order was: VA = TP = LZ (100.0%) > Q/D (99.1%) > GATI = LEVO = TROVA (98.0%) > GREPA (96.5%) > CTX (92.8%) > CM (90.3%) > PEN (68.6%) > ER (64.5%). Macrolide resistance in both streptococcal species groups of the M-phenotype was highest in the Americas, with erm-patterns predominating in EU and APAC regions. BMS284756 among the monitored new agents showed a four- to eight-fold greater potency versus these streptococcal isolates when compared to the other six tested quinolones. Like Streptococcus pneumoniae, these other streptococci appear to have acquired numerous resistances and require continued surveillance to direct adequate therapies. [Copyright &y& Elsevier]