Determination of MIC Quality Control Ranges for Ceftibuten-Avibactam (Fixed 4 µg/mL), a Novel ß-Lactam/ß-Lactamase Inhibitor Combination.

Ceftibuten/ARX-1796 (avibactam prodrug) is a novel oral antibacterial combination in early clinical development for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis. ARX-1796 is the novel avibactam prodrug being combined with ceftibuten for oral dosing that is converted to active avibactam in vivo. A Clinical and Laboratory Standards Institute (CLSI) M23 (2018) tier 2 broth microdilution quality control (QC) study was conducted with ceftibuten-avibactam to establish MIC QC ranges. Ceftibuten-avibactam broth microdilution QC ranges were approved for Escherichia coli ATCC 25922 (0.016/4 to 0.12/4 µg/mL), E. coli NCTC 13353 (0.03/4 to 0.12/4 µg/mL), Klebsiella pneumoniae ATCC 700603 (0.06/4 to 0.25/4 µg/mL), K. pneumoniae ATCC BAA-1705 (0.03/4 to 0.25/4 µg/mL), and K. pneumoniae ATCC BAA-2814 (0.12/4 to 0.5/4 µg/mL) by the CLSI Subcommittee on Antimicrobial Susceptibility Testing in January 2022. Approved ceftibuten-avibactam QC ranges will support future clinical development, device manufacturers, and routine patient care.

In vitro activity of KHP-3757 (a novel LpxC inhibitor) and comparator agents against recent and molecularly characterized Pseudomonas aeruginosa isolates from a global surveillance program (2017-2018).

This study evaluated the in vitro activity of KHP-3757 (a novel LpxC inhibitor) and comparator agents against recent, geographically diverse, Pseudomonas aeruginosa isolates from a global surveillance program as well as molecularly characterized extended-spectrum-ß-lactamase-positive, metallo-ß-lactamase-positive, and colistin-resistant strains. KHP-3757 (MIC50/90, 0.25/0.5 mg/L; 97.4% inhibited at ≤0.5 mg/L) demonstrated potent in vitro activity based on MIC90 values against P. aeruginosa isolates including extended-spectrum-ß-lactamase-positive, metallo-ß-lactamase-positive, and colistin-resistant strains outperforming other comparator agents.

Correlation between Broth Microdilution and Disk Diffusion Results when Testing Ceftazidime-Avibactam against a Challenge Collection of Enterobacterales Isolates: Results from a Multilaboratory Study.

We assessed the ceftazidime-avibactam disk diffusion breakpoints that provide the lowest discrepancy error rates by testing an Enterobacterales isolate collection with ceftazidime-avibactam MIC values near the breakpoints. Isolates (n = 112) were susceptibility tested by broth microdilution and disk diffusion methods in 3 laboratories. Current disk diffusion breakpoints (≥21/≤20 mm for susceptible/resistant) provided the lowest error rates, but confirmatory MIC testing is indicated for isolates with inhibition zones of 20 to 22 mm.

Development of Broth Microdilution MIC and Disk Diffusion Antimicrobial Susceptibility Test Quality Control Ranges for the Combination of Cefepime and the Novel ß-Lactamase Inhibitor Enmetazobactam.

Third-generation cephalosporin resistance among Enterobacteriaceae, mediated by the spread of extended-spectrum ß-lactamases (ESBLs), is a very serious medical concern with limited therapeutic options. Enmetazobactam (formerly AAI101) is a novel penicillanic sulfone ß-lactamase inhibitor active against a wide range of ESBLs. The combination of enmetazobactam and cefepime has entered phase 3 development in patients with complicated urinary tract infections. Using the Clinical and Laboratory Standards Institute (CLSI) M23 tier 2 study design, broth microdilution MIC and disk diffusion quality control (QC) ranges were determined for cefepime-enmetazobactam. Enmetazobactam was tested at a fixed concentration of 8 µg/ml in the MIC assay, and a cefepime-enmetazobactam disk mass of 30/20 µg was used in the disk diffusion assay. Escherichia coli ATCC 25922, E. coli ATCC 35218, E. coli NCTC 13353, Klebsiella pneumoniae ATCC 700603, and Pseudomonas aeruginosa ATCC 27853 were chosen as reference strains. The CTX-M-15-producing E. coli NCTC 13353 isolate is recommended for routine testing to control for inhibition of ESBL activity by enmetazobactam. Broth microdilution MIC QC ranges spanned 3 to 4 doubling dilutions and contained 99.6% to 100.0% of obtained MIC values for the five reference strains. Disk diffusion yielded inhibition zone diameter QC ranges that spanned 7 mm and encompassed 97.1% to 100.0% of the obtained values. Quality control ranges were approved by the CLSI in 2017 (broth microdilution MIC) and 2019 (disk diffusion). The established QC ranges will ensure that appropriate assay performance criteria are attained using CLSI reference methodology when determining the susceptibility of clinical isolates to cefepime-enmetazobactam.

Determination of MIC and disk diffusion quality control guidelines for meropenem-vaborbactam, a novel carbapenem/boronic acid ß-lactamase inhibitor combination.

Meropenem-vaborbactam is a carbapenem/cyclic boronic acid ß-lactamase inhibitor combination primarily active against Gram-negative bacilli, including those harboring class A serine carbapenemases such as Klebsiella pneumoniae carbapenemase (KPC). A Clinical and Laboratory Standards Institute M23-A4 (Tier 2) quality control study established broth microdilution and disk diffusion ranges for reference strains. Two KPC-producing K. pneumoniae ATCC strains are recommended for quality control testing.

Cefiderocol MIC quality control ranges in iron-depleted cation-adjusted Mueller-Hinton broth using a CLSI M23-A4 multi-laboratory study design.

Cefiderocol (formerly S-649266) is a new catechol-substituted parenteral siderophore cephalosporin with potent in vitro antibacterial activity against Gram-negative isolates including multidrug-resistant strains. A recent study following CLSI M23-A4 quality control guidelines established cefiderocol MIC QC ranges against Escherichia coli ATCC 25922 (0.06-0.5 µg/mL) and Pseudomonas aeruginosa ATCC 27853 (0.06-0.5 µg/mL).

Multicenter Investigation of Gepotidacin (GSK2140944) Agar Dilution Quality Control Determinations for Neisseria gonorrhoeae ATCC 49226.

Gepotidacin, a novel triazaacenaphthylene antibacterial agent, is the first in a new class of type IIA topoisomerase inhibitors with activity against many biothreat and conventional pathogens, including Neisseria gonorrhoeae To assist ongoing clinical studies of gepotidacin to treat gonorrhea, a multilaboratory quality assurance investigation determined the reference organism (N. gonorrhoeae ATCC 49226) quality control MIC range to be 0.25 to 1 µg/ml (88.8% of gepotidacin MIC results at the 0.5 µg/ml mode).

Assessment of pathogen frequency and resistance patterns among pediatric patient isolates: report from the 2004 SENTRY Antimicrobial Surveillance Program on 3 continents.

Selecting empiric or directed therapy for pathogens isolated from pediatric patients can be problematic. Many antimicrobial agents are not indicated for use in pediatric patients, and regional variations of resistance mechanisms have been reported. The purpose of this study was to analyze antimicrobial resistance patterns and pathogen occurrence rates in pediatric-aged patient infections on 3 continents using data from the SENTRY Antimicrobial Surveillance Program. A total of 3537 clinical isolates were collected from 47 medical centers in 2004. With a protocol that dictated a sampling of 80 consecutive isolates from children (< or =18 years of age), all samples were forwarded to a central laboratory for reference susceptibility testing. Broth microdilution methods and current Clinical and Laboratory Standards Institute breakpoint criteria were used. The 15 most frequently observed pathogens accounted for 93.6% of all isolates. Staphylococcus aureus was the most common pathogen isolated in North America (27.4%) and Europe (19.0%), but Escherichia coli was most common in Latin America (19.3%). All Streptococcus pneumoniae strains from North America and Latin America were susceptible to the newer fluoroquinolones, gatifloxacin and levofloxacin. However, 2 S. pneumoniae strains from Italy were resistant to gatifloxacin, levofloxacin, and ciprofloxacin (> or =4 microg/mL). Ribotype and pulsed-field gel electrophoresis patterns found that these resistant pneumococci were clonal. Numerous strains of Klebsiella spp. (22.5%), E. coli (4.5%), and Proteus mirabilis (4.9%) exhibited phenotypic extended-spectrum beta-lactamase resistance patterns. Four Pseudomonas aeruginosa strains (3 from Latin America and 1 from Europe) were multidrug resistant, 2 P. aeruginosa isolates from Turkey were resistant to polymyxin B (> or =4 microg/mL), and 8.7% of Stenotrophomonas maltophilia isolates from Latin America were resistant to the "drug of choice", trimethoprim/sulfamethoxazole. Physicians should be aware of pathogen occurrences that vary by children's age, geographic location, and prior antimicrobial exposure. Therefore, continued surveillance will be necessary to monitor emerging antimicrobial resistance in the pediatric patient population, especially because new agents such as the fluoroquinolones are used to a greater extent in this age group.

Activity of gatifloxacin tested against isolates from pediatric patients: report from the SENTRY Antimicrobial Surveillance Program (North America, 1998-2003).

The SENTRY Antimicrobial Surveillance Program has monitored the activity of antimicrobial agents worldwide since 1997. The increasing number of clinical failures with established anti-infectives (penicillins, other beta-lactams, macrolides) among pediatric patients has stressed the importance for alternative therapeutic options. Ciprofloxacin has been recently approved for expanded use as treatment of complicated urinary tract infections in children, and gatifloxacin has been used successfully in clinical trials in selected children with severe or refractory otitis media. We evaluated the activity of gatifloxacin against strains isolated from children < 7 years of age and compared this to the general patient population (all ages included) using the SENTRY Program database. A total of 59826 North American isolates were collected, of which 4641 were from children (< 7 years old); all isolates were tested using reference broth microdilution methods. In contrast to the general population (GP), gatifloxacin resistance rates were very low among isolates from this younger patient group. Gatifloxacin susceptibility rates were > 84% for all pathogens evaluated in younger patients. All Streptococcus pneumoniae strains from children < 7 years old were susceptible to gatifloxacin, and susceptibility among the Enterobacteriaceae species was > 98%. The greatest difference in susceptibility rates between the younger children and the GP was observed among nonfermentative gram-negative bacilli (95.0-100% versus 64.8-83.7%, respectively) and Enterococcus faecalis (94.7% versus 58.4%). Gatifloxacin susceptibilities of Pseudomonas aeruginosa and Acinetobacter spp. isolates from the pediatric population were > or = 95% (> 97% for ciprofloxacin) compared to the GP at only 64.8-69.1%. In conclusion, gatifloxacin remains very active against bacterial isolates from children < 7 years, indicative of the limited exposure of this population to fluoroquinolones. Continued resistance surveillance will be necessary to monitor the activity of the fluoroquinolone class as they are introduced for specific clinical indications into the pediatric age groups, especially if re-studied against S. pneumoniae (refractory otitis media) and P. aeruginosa (cystic fibrosis associated pneumonia).

Omiganan pentahydrochloride (MBI 226), a topical 12-amino-acid cationic peptide: spectrum of antimicrobial activity and measurements of bactericidal activity.

The activity of omiganan pentahydrochloride (formerly MBI 226; a synthetic cationic peptide) was assessed against 1,437 recent clinical bacterial isolates and 214 recent clinical yeast isolates. The omiganan was highly active, and minimal bactericidal concentrations or minimal fungicidal concentrations were either equal to or two- to fourfold higher than MICs. Kill curve experiments showed a clear pattern of bactericidal activity.