Amoxicillin-clavulanate Breakpoints Against Enterobacterales: Rationale for Revision by the Clinical and Laboratory Standards Institute.

Amoxicillin-clavulanate (AMC) is among the most frequently prescribed antibiotics globally. It has broad antibacterial activity against gram-positive, gram-negative, and anaerobic bacteria, and has been utilized to treat infections caused by a broad range of pathogens. AMC breakpoints against Enterobacterales were initially set in the 1980s but since then increases in antibiotic resistance, advances in pharmacokinetic (PK)/pharmacodynamic (PD) analyses, and publication of additional clinical data prompted a reassessment by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing. Based on this contemporary reappraisal, the CLSI retained the Enterobacterales breakpoints but revised comments regarding dosing associated with use of the AMC breakpoints in the 2022 supplement of M100. This viewpoint provides insight into the CLSI breakpoint reevaluation process and summarizes the data and rationale used to support these revisions to the AMC Enterobacterales breakpoint.

Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection.

CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.

7-Year (2015-21) longitudinal surveillance of lefamulin in vitro activity against bacterial pathogens collected worldwide from patients with respiratory tract infections including pneumonia and characterization of resistance mechanisms.

OBJECTIVES: Lefamulin (Xenleta™), a pleuromutilin antibiotic, was approved for the oral and IV treatment of community-acquired bacterial pneumonia (CABP) in adults in 2019/2020. This study evaluated the in vitro activity of lefamulin and comparators against 19 584 unique bacterial isolates collected from patients with community-acquired respiratory tract infections and hospitalized patients with pneumonia within the global SENTRY Antimicrobial Surveillance Program during 2015-21. METHODS: Isolates were susceptibility tested by the CLSI broth microdilution method, and resistance mechanisms were investigated in isolates with elevated lefamulin MICs. RESULTS: Lefamulin exhibited potent antibacterial activity against the most common and typical CABP pathogens tested, including Streptococcus pneumoniae [MIC50/90, 0.06/0.25 mg/L; 99.9% susceptible (S)], Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/L; 99.6% S), Haemophilus influenzae (MIC50/90, 0.5/2 mg/L; 99.1% S) and Moraxella catarrhalis (MIC50/90, 0.06/0.12 mg/L; 100.0% S). Potent activity was also observed against the less common pneumonia pathogens: ß-haemolytic (MIC50/90 of 0.03/0.06 mg/L) and viridans group Streptococcus spp. (MIC50/90 of 0.06/0.25 mg/L) and Haemophilus parainfluenzae (MIC50/90 of 1/4 mg/L). Lefamulin's activity was not adversely affected by resistance to macrolides, penicillin, tetracyclines, fluoroquinolones and other resistance phenotypes. Non-susceptibility/resistance to lefamulin was rare and primarily determined by ribosomal protection through vga(A) variants in S. aureus, overexpression of AcrAB-TolC efflux pump in H. influenzae or modifications in L3, L4 and 23SrRNA in Streptococcus spp. CONCLUSIONS: Based on the coverage of the most important CABP pathogens and lacking cross-resistance, lefamulin may represent a valuable empirical treatment option for ambulatory and hospitalized patients with CABP, particularly in settings with high prevalence of resistance.

Global Epidemiology and Mechanisms of Resistance of Acinetobacter baumannii-calcoaceticus Complex.

Acinetobacter baumannii-calcoaceticus complex is the most commonly identified species in the genus Acinetobacter and it accounts for a large percentage of nosocomial infections, including bacteremia, pneumonia, and infections of the skin and urinary tract. A few key clones of A. baumannii-calcoaceticus are currently responsible for the dissemination of these organisms worldwide. Unfortunately, multidrug resistance is a common trait among these clones due to their unrivalled adaptive nature. A. baumannii-calcoaceticus isolates can accumulate resistance traits by a plethora of mechanisms, including horizontal gene transfer, natural transformation, acquisition of mutations, and mobilization of genetic elements that modulate expression of intrinsic and acquired genes.

Antimicrobial Activity of Gepotidacin Tested against Escherichia coli and Staphylococcus saprophyticus Isolates Causing Urinary Tract Infections in Medical Centers Worldwide (2019 to 2020).

The in vitro activities of gepotidacin and comparator agents against 3,560 Escherichia coli and 344 Staphylococcus saprophyticus collected from female (81.1%) and male (18.9%) patients with urinary tract infections (UTIs) in a global prospective surveillance program in 2019 to 2020 were determined. Isolates collected from 92 medical centers in 25 countries, including the United States, Europe, Latin America, and Japan, were tested for susceptibility by reference methods in a central monitoring laboratory. Gepotidacin inhibited 98.0% (3,488/3,560 isolates) of E. coli and 100% (344/344 isolates) of S. saprophyticus at gepotidacin concentrations of ≤4 µg/mL and ≤0.25 µg/mL, respectively. This activity was largely unaffected with isolates that demonstrated resistance phenotypes to other oral standard-of-care antibiotics, including amoxicillin-clavulanic acid, cephalosporins, fluoroquinolones, fosfomycin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Gepotidacin also inhibited 94.3% (581/616 isolates) of E. coli isolates with an extended-spectrum ß-lactamase-producing phenotype, 97.2% (1,085/1,129 isolates) of E. coli isolates resistant to ciprofloxacin, 96.1% (874/899) of E. coli isolates resistant to trimethoprim-sulfamethoxazole, and 96.3% (235/244 isolates) of multidrug-resistant E. coli isolates at gepotidacin concentrations of ≤4 µg/mL. In summary, gepotidacin demonstrated potent activity against a large collection of contemporary UTI E. coli and S. saprophyticus strains collected from patients worldwide. These data support the further clinical development of gepotidacin as a potential treatment option for patients with uncomplicated UTIs.

Antimicrobial activity of ceftibuten-avibactam against a global collection of Enterobacterales from patients with urinary tract infections (2021).

We evaluated the in vitro activity of ceftibuten-avibactam against Enterobacterales causing urinary tract infection (UTI). A total of 3216 isolates (1/patient) were consecutively collected from patients with UTI in 72 hospitals from 25 countries in 2021 then susceptibility tested by CLSI broth microdilution. Ceftibuten-susceptible breakpoints currently published by EUCAST (≤ 1 mg/L) and CLSI (≤ 8 mg/L) were applied to ceftibuten-avibactam for comparison. The most active agents were ceftibuten-avibactam (98.4%/99.6% inhibited at ≤ 1/ ≤ 8 mg/L), ceftazidime-avibactam (99.6% susceptible [S]), amikacin (99.1%S), and meropenem (98.2%S). Ceftibuten-avibactam (MIC50/90, 0.03/0.06 mg/L) was fourfold more potent than ceftazidime-avibactam (MIC50/90, 0.12/0.25 mg/L) based on MIC50/90 values. The most active oral agents were ceftibuten (89.3%S; 79.5% inhibited at ≤ 1 mg/L), levofloxacin (75.4%S), and trimethoprim-sulfamethoxazole (TMP-SMX; 73.4%S). Ceftibuten-avibactam inhibited 97.6% of isolates with an extended-spectrum ß-lactamase phenotype, 92.1% of multidrug-resistant isolates, and 73.7% of carbapenem-resistant Enterobacterales (CRE) at ≤ 1 mg/L. The second most active oral agent against CRE was TMP-SMX (24.6%S). Ceftazidime-avibactam was active against 77.2% of CRE isolates. In conclusion, ceftibuten-avibactam was highly active against a large collection of contemporary Enterobacterales isolated from patients with UTI and exhibited a similar spectrum to ceftazidime-avibactam. Ceftibuten-avibactam may represent a valuable option for oral treatment of UTI caused by multidrug-resistant Enterobacterales.

Activity of Oritavancin against Gram-Positive Pathogens Causing Bloodstream Infections in the United States over 10 Years: Focus on Drug-Resistant Enterococcal Subsets (2010-2019).

Oritavancin displayed potent and stable activity (MIC90 range of 0.06 to 0.5 mg/L) over a 10-year period (2010 to 2019) against Gram-positive pathogens that cause bloodstream infections (BSI), including methicillin-resistant Staphylococcus aureus (MRSA) and resistant subsets of Enterococcus spp. Daptomycin and linezolid were also active against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus (VRE). Only oritavancin and linezolid remained active against Enterococcus faecium isolates displaying an elevated daptomycin MIC (i.e., 2 to 4 mg/L). Proportions of methicillin-resistant S. aureus and vancomycin-resistant Enterococcus within the respective S. aureus and enterococcal populations decreased over this period.

In Vitro Activity of Tebipenem against Various Resistant Subsets of Escherichia coli Causing Urinary Tract Infections in the United States (2018 to 2020).

This study investigated the activity of an oral carbapenem, tebipenem, against various molecularly characterized subsets of Escherichia coli. A total of 15.0% of E. coli isolates (360/2,035 isolates) met the MIC criteria for screening for ß-lactamases. Most of those isolates (74.7% [269/360 isolates]) carried blaCTX-M. The CTX-M distribution varied (50% to 86%) among Census Regions, as did that of plasmid AmpC genes (up to 41% among E. coli isolates from the New England Region). Tebipenem and intravenous carbapenems showed uniform activity against various E. coli subsets.

In vitro activity of the orally bioavailable ceftibuten/VNRX-7145 (VNRX-5236 etzadroxil) combination against a challenge set of Enterobacterales pathogens carrying molecularly characterized ß-lactamase genes.

OBJECTIVES: This study assessed the activity of ceftibuten, ceftibuten combined with the active form (VNRX-5236) of the ß-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 ß-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.

Antimicrobial activity of cefepime/zidebactam (WCK 5222), a ß-lactam/ß-lactam enhancer combination, against clinical isolates of Gram-negative bacteria collected worldwide (2018-19).

BACKGROUND: Zidebactam, a bicyclo-acyl hydrazide ß-lactam 'enhancer' antibiotic, in combination with cefepime (WCK 5222) is under clinical development for the treatment of resistant Gram-negative infections. OBJECTIVES: To evaluate the in vitro activity of cefepime/zidebactam and comparators against 24 220 Gram-negative bacteria. METHODS: Organisms were consecutively collected in 2018-19 from 137 medical centres located in the USA (n = 9140), Western Europe (W-EU; n = 5929), Eastern Europe (E-EU; n = 3036), the Asia-Pacific region (APAC; n = 3791) and Latin America (LATAM; n = 2324). The isolates were susceptibility tested using the broth microdilution method as part of the SENTRY Program. Cefepime/zidebactam was tested at a 1:1 ratio. RESULTS: Cefepime/zidebactam was highly active against Enterobacterales (MIC50/90 0.03/0.25 mg/L; 99.9% inhibited at ≤8 mg/L) and retained potent activity against carbapenem-resistant Enterobacterales (CRE) isolates (97.8% inhibited at ≤8 mg/L). CRE rates varied widely from 1.1% in the USA to 1.9% in W-EU, 3.6% in APAC and 14.6% in E-EU (3.9% overall). The most common carbapenemase genes observed overall were blaKPC (37.6% of CRE), blaOXA-48-like (30.0%) and blaNDM (23.8%). Resistance to ceftazidime/avibactam among CRE was elevated in APAC (64.8%), E-EU (25.5%) and LATAM (20.7%). Against Pseudomonas aeruginosa, cefepime/zidebactam inhibited 99.2% of isolates at ≤8 mg/L and susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam was lowest in E-EU (83.9% and 82.0%, respectively). Cefepime/zidebactam exhibited good activity against Stenotrophomonas maltophilia (80.0% inhibited at ≤8 mg/L) and Burkholderia cepacia (89.4% inhibited at ≤8 mg/L). CONCLUSIONS: Cefepime/zidebactam demonstrated potent in vitro activity against a large worldwide collection of contemporary clinical isolates of Gram-negative bacteria.

Antimicrobial activities of aztreonam-avibactam and comparator agents tested against Enterobacterales from European hospitals analysed by geographic region and infection type (2019-2020).

The purpose of this study is to evaluate the activities of aztreonam-avibactam and comparator agents against Enterobacterales isolates from European medical centres as well as the occurrence of carbapenemases (CPEs). A total of 11,655 Enterobacterales isolates were collected consecutively in 2019-2020 from 38 medical centres located in Western Europe (W-EU; n = 8,784; 25 centres in 10 countries) and the Eastern European and Mediterranean region (E-EU; n = 2,871; 13 centres in 10 countries). Isolates were susceptibility tested by broth microdilution methods in a monitoring laboratory. The antimicrobial susceptibility and frequency of key resistance phenotypes were assessed and stratified by geographic region and infection type. Isolates that showed resistance to carbapenems (CRE) and/or elevated MICs (> 8 mg/L) for aztreonam-avibactam were screened for ß-lactamase-encoding genes by whole-genome sequencing. Aztreonam-avibactam inhibited 99.9% of Enterobacterales at ≤ 8 mg/L (MIC50/90, ≤ 0.03/0.12 mg/L) and retained potent activity against CRE (MIC50/90, 0.25/0.5 mg/L), multidrug-resistant isolates (MDR; MIC50/90, 0.12/0.5 mg/L), and extensively drug-resistant (XDR) isolates (MIC50/90, 0.25/0.5 mg/L). Susceptibility to comparator agents was consistently lower among isolates from E-EU compared to W-EU for all infection types evaluated. CRE rates varied from 0.6% (urinary tract infection [UTI]) to 2.3% (bloodstream infection) in W-EU, and from 6.1% (UTI) to 17.0% (pneumonia) in E-EU. A CPE-encoding gene was identified in 360 of 424 (84.9%) CRE isolates, and the most common CPEs were blaKPC (36.3% of CRE), blaOXA-48 type (27.1% of CRE), and the MBLs (25.7% of CRE). All CPE producers were inhibited at an aztreonam-avibactam concentration of ≤ 8 mg/L. Aztreonam-avibactam demonstrated potent activity across the evaluated geographic regions and infection types.

Increasing frequency of OXA-48-producing Enterobacterales worldwide and activity of ceftazidime/avibactam, meropenem/vaborbactam and comparators against these isolates.

OBJECTIVES: To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance. METHODS: Among 55?>162 Enterobacterales isolates, 354 carbapenem-resistant isolates carried genes encoding OXA-48-like enzymes. Isolates were susceptibility tested for ceftazidime/avibactam and comparators by broth microdilution methods. Analysis of ß-lactam resistance mechanisms and MLST was performed in silico using WGS data. RESULTS: OXA-48-like-producing isolates increased from 0.5% (94/18 656) in 2016 to 0.9% (169/18?>808) in 2018. OXA-48 was the most common variant; isolates primarily were Klebsiella pneumoniae (318/354 isolates) from Europe and adjacent countries. MLST analysis revealed a diversity of STs, but K. pneumoniae belonging to ST395, ST23 and ST11 were observed most frequently. Thirty-nine isolates harboured MBLs and were resistant to most agents tested. The presence of blaCTX-M-15 (258 isolates), OmpK35 nonsense mutations (232) and OmpK36 alterations (316) was common among OXA-48 producers. Ceftazidime, cefepime and aztreonam susceptibility rates, when applying CLSI breakpoints, were 12%-15% lower for isolates carrying ESBLs alone and with either or both OmpK35 stop codons and OmpK36 alterations. Meropenem and, remarkably, meropenem/vaborbactam were affected by specific OmpK36 alterations when a deleterious mutation also was observed in OmpK35. These mechanisms caused a decrease of 12%-42% in the susceptibility rates for meropenem and meropenem/vaborbactam. Ceftazidime/avibactam susceptibility rates were >98.9%, regardless of the presence of additional ß-lactam resistance mechanisms. CONCLUSIONS: Guidelines for the treatment of infections caused by OXA-48-producing isolates are scarce and, as the dissemination of these isolates continues, studies are needed to help physicians understand treatment options for these infections.

Aztreonam/avibactam activity against clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019.

BACKGROUND: Aztreonam is a monobactam stable to hydrolysis by metallo-ß-lactamases (MBLs) and avibactam is a non-ß-lactam ß-lactamase inhibitor that effectively inhibits serine carbapenemases (CPs). Aztreonam/avibactam is under clinical development for treatment of serious infections caused by Gram-negative bacteria, including MBL-producers. OBJECTIVES: To evaluate the in vitro activity of aztreonam/avibactam against clinical Enterobacterales isolates. METHODS: 8787 Enterobacterales were collected consecutively from 64 medical centres located in Western Europe (W-EU; n = 4616; 26 centres in 10 nations), Eastern Europe (E-EU; n = 1554; 11 centres in 9 nations), the Asia-Pacific region (APAC; n = 1456; 17 centres in 9 nations), and Latin America (LATAM; n = 1161; 10 centres in 6 nations). Susceptibility tests were performed by reference broth microdilution methods and interpreted according to EUCAST criteria. RESULTS: 99.9% of isolates were inhibited at aztreonam/avibactam MIC of ≤8 mg/L (MIC50/90, ≤0.03/0.12 mg/L), including 99.7% of carbapenem-resistant (CRE; n = 396; MIC50/90, 0.25/0.5 mg/L) and 99.7% of multidrug-resistant isolates (n = 1706; MIC50/90, 0.06/0.5 mg/L). CRE rates were 1.2%, 12.9%, 5.2%, and 5.8% in W-EU, E-EU, APAC, and LATAM, respectively (4.5% overall). A CP was identified in 90.2% of CRE isolates. The most common CPs were variants of KPC (35.9% of CRE), NDM (29.0%), and OXA-48 (26.8%). The highest aztreonam/avibactam MIC value among MBL-producers (n = 110; MIC50/90, 0.12/0.5 mg/L) was 2 mg/L. Susceptibility rates for ceftriaxone, meropenem, levofloxacin, and amikacin were highest in W-EU (80.9%, 99.0%, 80.7% and 97.9%, respectively) and lowest in E-EU (52.0%, 88.9%, 54.1%, and 84.2%, respectively). CONCLUSIONS: Our results support clinical development of aztreonam/avibactam to treat infections caused by Enterobacterales, including MBL-producers.

Investigation of mechanisms responsible for decreased susceptibility of aztreonam/avibactam activity in clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019.

BACKGROUND: The combination aztreonam/avibactam is currently under Phase 3 trials for the treatment of serious infections caused by Gram-negative bacteria including those with MBLs. OBJECTIVES: To investigate the resistance mechanisms in Enterobacterales exhibiting aztreonam/avibactam MICs of ≥4 mg/L. METHODS: Among 8787 Enterobacterales, 17 (0.2%) isolates exhibited an aztreonam/avibactam MIC of ≥4 mg/L. Isolates were sequenced and screened for ß-lactamases. Sequences of porins, penicillin-binding protein 3 (PBP3) and expression levels of AmpC and AcrA were evaluated. RESULTS: Eleven (11/4154 isolates; 0.26%) Escherichia coli, three (3/1981; 0.15%) Klebsiella pneumoniae and three (3/628; 0.5%) Enterobacter cloacae were identified. All E. coli showed either an 'YRIK' or 'YRIN' insertion in PBP3. In general, these isolates carried blaCMY and/or blaCTX-M variants, except for one isolate from Korea that also produced NDM-5 and one isolate from Turkey that produced OXA-48. Two DHA-1-producing K. pneumoniae overexpressed acrA and had a premature stop codon in either OmpK35 or OmpK36, whereas a third K. pneumoniae carried blaPER-2 and had a premature stop codon in OmpK35. All three E. cloacae expressed AmpC at levels ≥570-fold, but sequence analysis did not reveal known amino acid alterations associated with decreased avibactam binding or increased hydrolysis of ß-lactams. Minor amino acid polymorphisms within OmpC, OmpF and PBP3 were noted among the E. cloacae. CONCLUSIONS: A small number of isolates (0.2%) met the inclusion criteria. E. coli showed altered PBP3 as the most relevant resistance mechanism, whereas K. pneumoniae had multiple resistance mechanisms. Further investigations are needed to clarify resistance in E. cloacae.

Meropenem-Vaborbactam Activity against Carbapenem-Resistant Enterobacterales Isolates Collected in U.S. Hospitals during 2016 to 2018.

The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant Enterobacterales (CRE) isolates identified among 13,929 Enterobacterales isolates collected from U.S. hospitals during 2016 to 2018 were evaluated. CRE rates were higher in the Middle Atlantic census division (3.5%) than in the other divisions (range, 0.0% for the West North Central division to 1.4% for the West South Central division). Among the CRE isolates, 134 carried carbapenemase genes, and these included 72 isolates carrying blaKPC-3, 51 isolates carrying blaKPC-2, 4 isolates carrying blaNDM-1, 3 isolates carrying blaSME-4, 2 isolates carrying blaVIM-1, 1 isolate carrying blaOXA-232, and 1 isolate carrying blaKPC-4 Meropenem-vaborbactam was active against 95.4% of the CRE isolates and 94.8% of the carbapenem-producing Enterobacterales (CPE) isolates when applying the CLSI breakpoints. All isolates producing serine carbapenemases were inhibited by meropenem-vaborbactam at ≤8 mg/liter. One Citrobacter freundii isolate carrying blaKPC-3 had a meropenem-vaborbactam MIC of 8 mg/liter and was resistant according to CLSI breakpoints (the isolate was susceptible when the EUCAST criterion of an MIC of ≤8 mg/liter for susceptible was applied), had disrupted OmpC and OmpF sequences, and overexpressed AcrAB-TolC. All carbapenemase-negative CRE isolates (n = 18) were inhibited by meropenem-vaborbactam at ≤4 mg/liter, and the MIC values of this combination ranged from 0.25 to 4 mg/liter. Among 7 isolates carrying metallo-ß-lactamases and/or oxacillinases with carbapenemase activity, meropenem-vaborbactam susceptibility was 14.3% and 57.1% when applying CLSI and EUCAST breakpoints, respectively. CRE isolates were resistant to many comparator agents, and the most active agents were tigecycline, colistin, and amikacin (to which 63.2% to 96.7% of the isolates were susceptible). Understanding the epidemiology of CRE isolates in U.S. hospitals and the resistance mechanisms among these isolates is important to form guidelines for the treatment of infections caused by these organisms, which have high mortality rates.

Activity of Plazomicin Tested against Enterobacterales Isolates Collected from U.S. Hospitals in 2016-2017: Effect of Different Breakpoint Criteria on Susceptibility Rates among Aminoglycosides.

Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.

In Vitro Activity Analysis of a New Polymyxin, SPR741, Tested in Combination with Antimicrobial Agents against a Challenge Set of Enterobacteriaceae, Including Molecularly Characterized Strains.

The activities of azithromycin, fusidic acid, vancomycin, doxycycline, and minocycline were evaluated alone and in combination with SPR741. A total of 202 Escherichia coli and 221 Klebsiella pneumoniae isolates were selected, and they included a genome-sequenced subset (n = 267), which was screened in silico for ß-lactamase, macrolide-lincosamide-streptogramin (MLS), and tetracycline (tet) genes. Azithromycin (>16 mg/liter), fusidic acid (>64 mg/liter), vancomycin (>16 mg/liter), and SPR741 (>8 mg/liter) showed off-scale MICs when each was tested alone against all isolates. MIC50/90 results of 0.5/8 mg/liter, 4/>32 mg/liter, 16/>16 mg/liter, 2/32 mg/liter, and 0.25/4 mg/liter were obtained for azithromycin-SPR741, fusidic acid-SPR741, vancomycin-SPR741, doxycycline-SPR741 and minocycline-SPR741, respectively, against all isolates. Overall, azithromycin-SPR741 (MIC90, 2 to 4 mg/liter) and minocycline-SPR741 (MIC90, 0.5 to 2 mg/liter) showed the lowest MIC90 values against different subsets of E. coli isolates, except for azithromycin-SPR741 (MIC90, 16 mg/liter) against the AmpC and metallo-ß-lactamase subsets. In general, minocycline-SPR741 (MIC90, 2 to 8 mg/liter) had the lowest MIC90 against K. pneumoniae isolates producing different groups of ß-lactamases. The azithromycin-SPR741 MIC (MIC50/90, 2/32 mg/liter) was affected by MLS genes (MIC50/90 of 0.25/2 mg/liter against isolates without MLS genes), whereas doxycycline-SPR741 (MIC50/90, 0.5/2 versus 8/32 mg/liter) and minocycline-SPR741 (MIC50/90, 0.25/1 versus 1/8 mg/liter) MIC results were affected when tested against isolates carrying tet genes in general. However, minocycline-SPR741 inhibited 88.2 to 92.9% of tet-positive isolates regardless of the tet gene. The azithromycin-SPR741 MIC results (MIC50/90, 1/16 mg/liter) against isolates with enzymatic MLS mechanisms were lower than against those with ribosomal protection (MIC50/90, 16/>32 mg/liter). SPR741 increased the in vitro activity of tested codrugs at different levels and seemed to be dependent on the species and resistance mechanisms of the respective codrug.

Assessment of Tedizolid In Vitro Activity and Resistance Mechanisms against a Collection of Enterococcus spp. Causing Invasive Infections, Including Isolates Requiring an Optimized Dosing Strategy for Daptomycin from U.S. and European Medical Centers, 2016 to 2018.

High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium isolates. Only 3.3% and 2.1% of E. faecalis isolates had elevated daptomycin MIC (≥2 mg/liter) and vancomycin resistance, respectively. In contrast, 37.4% to 40.3% of E. faecium isolates exhibited these phenotypes. Tedizolid inhibited 98.9% to 100.0% of enterococci causing serious invasive infections, including resistant subsets. Oxazolidinone resistance was mainly driven by G2576T; however, optrA and poxtA genes were also detected, including poxtA in the United States and Turkey.

Ceftobiprole Activity against Bacteria from Skin and Skin Structure Infections in the United States from 2016 through 2018.

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), beta-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC50/90, 0.5/1 mg/liter; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [MRSA]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum ß-lactamase [ESBL] phenotype). A total of 74.4% of P. aeruginosa, 100% of beta-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/liter. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016 to 2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for a potential ABSSSI indication.

In Vitro Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates.

KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-ß-lactamase (ESBL)- and metallo-ß-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.