In vitro and in vivo activity of cefiderocol against Achromobacter spp. and Burkholderia cepacia complex, including carbapenem-non-susceptible isolates.

Achromobacter spp. and Burkholderia cepacia complex (Bcc) are rare but diverse opportunistic pathogens associated with serious infections, which are often multidrug resistant. This study compared the in vitro antibacterial activity of the siderophore antibiotic cefiderocol against Achromobacter spp. and Bcc isolates with that of other approved antibacterial drugs, including ceftazidime-avibactam, ciprofloxacin, colistin, imipenem-relebactam, and meropenem-vaborbactam. Isolates were collected in the SIDERO multinational surveillance program. Among 334 Achromobacter spp. isolates [76.6% from respiratory tract infections (RTIs)], cefiderocol had minimum inhibitory concentration (MIC)50/90 of 0.06/0.5 µg/mL overall and 0.5/4 µg/mL against 52 (15.6%) carbapenem-non-susceptible (Carb-NS) isolates. Eleven (3.3%) Achromobacter spp. isolates overall and 6 (11.5%) Carb-NS isolates were not susceptible to cefiderocol. Among 425 Bcc isolates (73.4% from RTIs), cefiderocol had MIC50/90 of ≤0.03/0.5 µg/mL overall and ≤0.03/1 µg/mL against 184 (43.3%) Carb-NS isolates. Twenty-two (5.2%) Bcc isolates overall and 13 (7.1%) Carb-NS isolates were not susceptible to cefiderocol. Cumulative MIC distributions showed cefiderocol to be the most active of the agents tested in vitro against both Achromobacter spp. and Bcc. In a neutropenic murine lung infection model and a humanized pharmacokinetic immunocompetent rat lung infection model, cefiderocol showed significant bactericidal activity against two meropenem-resistant Achromobacter xylosoxidans strains compared with untreated controls (P < 0.05) and vehicle-treated controls (P < 0.05), respectively. Meropenem, piperacillin-tazobactam, ceftazidime, and ciprofloxacin comparators showed no significant activity in these models. The results suggest that cefiderocol could be a possible treatment option for RTIs caused by Achromobacter spp. and Bcc.

In vitro activity of ceftazidime-avibactam against clinical isolates of Enterobacterales and Pseudomonas aeruginosa from sub-Saharan Africa: ATLAS Global Surveillance Program 2017-2021.

OBJECTIVES: To report the in vitro susceptibility of Enterobacterales (n = 3905) and Pseudomonas aeruginosa (n = 1,109) isolates, collected from patients in sub-Saharan Africa (four countries) in 2017-2021, to a panel of 10 antimicrobial agents with a focus on ceftazidime-avibactam activity against resistant phenotypes and ß-lactamase carriers. METHODS: MICs were determined by CLSI broth microdilution and interpreted using both 2022 CLSI and EUCAST breakpoints. ß-lactamase genes were identified in select ß-lactam-nonsusceptible isolate subsets using multiplex PCR assays. RESULTS: Among Enterobacterales, 96.2% of all isolates were ceftazidime-avibactam-susceptible (MIC90, 0.5 µg/mL), including all serine carbapenemase-positive (n = 127), 99.6% of ESBL-positive, carbapenemase-negative (n = 730), 91.9% of multidrug resistant (MDR; n = 1817), and 42.7% of DTR (difficult-to-treat resistance; n = 171) isolates. Metallo-ß-lactamase (MBL) genes were identified in most (n = 136; 91.2%) ceftazidime-avibactam-resistant isolates (3.5% of all Enterobacterales isolates). Ceftazidime-avibactam percent susceptible values ranged from 99.5% (Klebsiella species other than Klebsiella pneumoniae) to 92.5% (K. pneumoniae) for the various Enterobacterial taxa examined. Greater than 90% of Enterobacterales isolates from each country (Cameroon, Ivory Coast, Nigeria, South Africa) were ceftazidime-avibactam-susceptible. Among P. aeruginosa, 88.9% of all isolates were ceftazidime-avibactam-susceptible (MIC90, 16 µg/mL). Most (88.5%) MBL-negative, meropenem-resistant (n = 78), 68.1% of MDR (n = 385), and 19.2% of DTR isolates (n = 99) were ceftazidime-avibactam-susceptible. MBL genes were identified in 43.1% of ceftazidime-avibactam-resistant isolates (n = 53; 4.8% of all P. aeruginosa isolates). Country-specific ceftazidime-avibactam percent susceptible values for P. aeruginosa ranged from 94.1% (Cameroon) to 76.2% (Nigeria). CONCLUSION: Reference in vitro antimicrobial susceptibility testing demonstrated that most recent Enterobacterales (96%) and P. aeruginosa (89%) clinical isolates from four sub-Saharan African countries were ceftazidime-avibactam susceptible.

In vitro activity of cefiderocol against MBL-producing Gram-negative bacteria collected in North America and Europe in five consecutive annual multinational SIDERO-WT surveillance studies (2014-2019).

OBJECTIVES: To evaluate the in vitro antibacterial activity of cefiderocol, a siderophore cephalosporin against MBL-producing clinical isolates. METHODS: MBL-producing strains were selected from clinical isolates of Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii complex collected in North America and Europe in five consecutive annual multinational SIDERO-WT surveillance studies from 2014 to 2019. MICs of cefiderocol and comparator agents were determined by the broth microdilution method according to the CLSI guideline. RESULTS: A total of 452 MBL-producing strains consisting of 200 Enterobacterales, 227 P. aeruginosa and 25 A. baumannii complex were identified. The highest number of MBL-producing Enterobacterales strains were detected in Greece. MBL-producing strains of both P. aeruginosa and A. baumannii complex were isolated most frequently in Russia. For Enterobacterales, 91.5% or 67.5% of MBL-producing strains had cefiderocol MIC values ≤4 mg/L (CLSI susceptibility breakpoint) or ≤2 mg/L (EUCAST susceptibility breakpoint), respectively. All MIC values of cefiderocol for MBL-producing P. aeruginosa strains were ≤4 mg/L (CLSI susceptibility breakpoint), and 97.4% of them had cefiderocol MIC values ≤2 mg/L (EUCAST susceptibility breakpoint). For A. baumannii complex, 60.0% or 44.0% of MBL-producing strains had cefiderocol MIC values ≤4 mg/L (CLSI susceptibility breakpoint) or ≤2 mg/L (EUCAST pharmacokinetic-pharmacodynamic susceptibility breakpoint), respectively. Against all types of MBL-producing strains, MIC distribution curves of cefiderocol were located in the lowest numerical values, compared with other ß-lactams and ß-lactam/ß-lactamase inhibitor combinations tested and ciprofloxacin. CONCLUSIONS: Although the types of MBL-producing strains isolated by country varied, cefiderocol showed potent in vitro activity against all types of MBL-producing Gram-negative bacteria regardless of the bacterial species.

Relebactam restores susceptibility of resistant Pseudomonas aeruginosa and Enterobacterales and enhances imipenem activity against chromosomal AmpC-producing species: analysis of global SMART 2018-2020.

BACKGROUND: Carbapenem-resistant bacteria are an increasing problem in clinical practice; thus, it is important to identify ß-lactamase inhibitors (e.g., relebactam) that can restore carbapenem susceptibility. We report analyses of relebactam enhancement of imipenem activity against both imipenem-nonsusceptible (NS) and imipenem-susceptible (S) Pseudomonas aeruginosa and Enterobacterales. Gram-negative bacterial isolates were collected for the ongoing Study for Monitoring Antimicrobial Resistance Trends global surveillance program. Clinical and Laboratory Standards Institute-defined broth microdilution minimum inhibitory concentrations (MIC) were used to determine the imipenem and imipenem/relebactam antibacterial susceptibilities of P. aeruginosa and Enterobacterales isolates. RESULTS: Between 2018 and 2020, 36.2% of P. aeruginosa (N = 23,073) and 8.2% of Enterobacterales (N = 91,769) isolates were imipenem-NS. Relebactam restored imipenem susceptibility in 64.1% and 49.4% of imipenem-NS P. aeruginosa and Enterobacterales isolates, respectively. Restoration of susceptibility was largely observed among K. pneumoniae carbapenemase-producing Enterobacterales and carbapenemase-negative P. aeruginosa. Relebactam also caused a lowering of imipenem MIC among imipenem-S P. aeruginosa and Enterobacterales isolates from chromosomal Ambler class C ß-lactamase (AmpC)-producing species. For both imipenem-NS and imipenem-S P. aeruginosa isolates, relebactam reduced the imipenem MIC mode from 16 µg/mL to 1 µg/mL and from 2 µg/mL to 0.5 µg/mL, respectively, compared with imipenem alone. CONCLUSIONS: Relebactam restored imipenem susceptibility among nonsusceptible isolates of P. aeruginosa and Enterobacterales and enhanced imipenem susceptibility among susceptible isolates of P. aeruginosa and isolates from Enterobacterales species that can produce chromosomal AmpC. The reduced imipenem modal MIC values with relebactam may result in a higher probability of target attainment in patients.

In Vitro Activity of Cefiderocol Against Meropenem-Nonsusceptible Gram-Negative Bacilli with Defined ß-Lactamase Carriage: SIDERO-WT Surveillance Studies, 2014-2019.

We examined the in vitro susceptibility of meropenem-nonsusceptible Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex isolates from five consecutive annual SIDERO-WT surveillance studies (2014-2019) to cefiderocol and comparator agents in the context of their carbapenemase carriage. 1,003 Enterobacterales, 1,758 P. aeruginosa, and 2,809 A. baumannii complex isolates from North America and Europe that were meropenem nonsusceptible (CLSI M100, 2022) were molecularly characterized for ß-lactamase content by PCR followed by Sanger sequencing or by whole genome sequencing. Among Enterobacterales, 91.5% of metallo-ß-lactamase (MBL)-producing, 98.4% of KPC-producing, 97.3% of OXA-48 group-producing, and 98.7% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among P. aeruginosa, 100% of MBL-producing, 100% of GES carbapenemase-producing, and 99.8% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among A. baumannii complex, 60.0% of MBL-producing, 95.6% of OXA-23 group-producing, 89.5% of OXA-24 group-producing, 100% of OXA-58 group-producing, and 95.5% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Cefiderocol was inactive against A. baumannii complex isolates carrying a PER or VEB ß-lactamase (n = 103; 15.5% susceptible). Ceftazidime-avibactam and ceftolozane-tazobactam were inactive against MBL-carrying and A. baumannii complex isolates; ceftolozane-tazobactam was also inactive against serine carbapenemase-carrying Enterobacterales and P. aeruginosa. In summary, cefiderocol was highly active in vitro against Gram-negative isolates carrying MBLs and serine carbapenemases, as well as carbapenemase-negative, meropenem-nonsusceptible isolates.

Multicenter Clinical Performance Evaluation of Omadacycline Susceptibility Testing of Enterobacterales on VITEK 2 Systems.

We present the first performance evaluation results for omadacycline on the VITEK 2 and VITEK 2 Compact Systems (bioMérieux, Inc.). The trial was conducted at four external sites and one internal site. All sites were in the United States, geographically dispersed as follows: Indianapolis, IN; Schaumburg, IL; Wilsonville, OR; Cleveland, OH; and Hazelwood, MO. In this multisite study, omadacycline was tested against 858 Enterobacterales on the VITEK 2 antimicrobial susceptibility test (AST) Gram-negative (GN) card, and the results were compared to the Clinical and Laboratory Standards Institute broth microdilution (BMD) reference method. The results were analyzed and are presented as essential agreement (EA), category agreement (CA), minor error (mE) rates, major error (ME) rates, and very major error (VME) rates following the US Food and Drug Administration (FDA) and International Standards Organization (ISO) performance criteria requirements. Omadacycline has susceptibility testing interpretive criteria (breakpoints) established by the FDA only; nevertheless, the analysis was also performed using the ISO acceptance criteria to satisfy the registration needs of countries outside the United States. The analysis following FDA criteria (including only Klebsiella pneumoniae and Enterobacter cloacae) showed the following performance: EA = 97.9% (410/419), CA = 94.3% (395/419), VME = 2% (1/51), with no ME present. The performance following ISO criteria (including all Enterobacterales tested) after error resolutions was EA = 98.1% (842/858) and CA = 96.9% (831/858). No ME or VME were observed. The VITEK 2 test met the ISO and FDA criteria of ≥ 95% reproducibility, and ≥ 95% quality control (QC) results within acceptable ranges for QC organisms. In June 2022, the omadacycline VITEK 2 test received FDA 510(k) clearance (K213931) FDA as a diagnostic device to be used in the treatment of acute bacterial skin and skin-structure infections caused by E. cloacae and K. pneumoniae, and for treatment of community-acquired bacterial pneumonia caused by K. pneumoniae. The new VITEK 2 AST-GN omadacycline test provides an alternative to the BMD reference method testing and increases the range of automated diagnostic tools available for determining omadacycline MICs in Enterobacterales.

Multidrug-resistant Gram-negative bacilli recovered from respiratory and blood specimens from adults: the ATLAS surveillance program in European hospitals, 2018-2020.

The population of people ≥65 years of age is increasing in Europe. Pneumonia is a prominent cause of infection in this age group. These patients may be at heightened risk of infection caused by multidrug-resistant (MDR) organisms owing to their frequent and prolonged contact with healthcare facilities as well as frequent exposure to antimicrobials and medical devices. However, ATLAS surveillance data did not demonstrate any difference in the incidence of MDR Gram-negative pathogens among patients ≥65 years of age and those aged <65 years. Higher rates of carbapenem-resistant Enterobacterales (CRE) and MDR Pseudomonas aeruginosa were observed in patients aged 18-64 years (10.7% and 32.3%, respectively) than in patients aged ≥65 years (5.0% and 25.4%, respectively). Significant therapeutic gaps were identified for CRE, carbapenem-resistant Acinetobacter baumannii (65.9% of isolates tested) and MDR P. aeruginosa, which continue to be prevalent in European hospitals. Among the antimicrobials evaluated, only colistin provided >75% in vitro coverage for these pathogens.

In Vitro Activity of Ceftibuten-Avibactam against ß-Lactamase-Positive Enterobacterales from the ATLAS Global Surveillance Program.

Ceftibuten is an established, oral, third-generation cephalosporin in early clinical development in combination with an oral prodrug of avibactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. We evaluated the in vitro activity of ceftibuten-avibactam against 1,165 Enterobacterales isolates selected from the 2016-2020 ATLAS global surveillance program based upon their ß-lactamase genotype, ß-lactam-susceptible phenotype, species identification, and specimen source (95.8% urine). MICs were determined by CLSI broth microdilution. Avibactam was tested at a fixed concentration of 4 µg/mL. Molecular methods were used to identify ß-lactamase genes. Ceftibuten-avibactam inhibited 90% (MIC90) of ESBL-producing (n = 645), KPC-producing (n = 60), chromosomal AmpC-positive (n = 100), OXA-48-like-producing (n = 50), and acquired AmpC-producing (n = 110) isolates at concentrations of 0.12, 0.5, 1, 2, and 4 µg/mL, respectively. At concentrations of ≤1 and ≤8 µg/mL, ceftibuten-avibactam inhibited 98.4 and 99.2% of ESBL-positive isolates; 96.7 and 100% of KPC-positive isolates; 91.0 and 99.0% of chromosomal AmpC-positive isolates; 86.0 and 96.0% of OXA-48-like-positive isolates; and 85.5 and 91.8% of acquired AmpC-positive isolates. Against ESBL-producing, KPC-producing, chromosomal AmpC-positive, OXA-48-like-producing, and acquired AmpC-producing isolates, ceftibuten-avibactam was 256-, 128-, >64-, >32-, and > 16-fold more potent than ceftibuten alone. The potency of ceftibuten-avibactam was 4-fold greater than ceftazidime-avibactam against ESBL-producing (ceftibuten-avibactam MIC90, 0.12 µg/mL; ceftazidime-avibactam MIC90, 0.5 µg/mL) and KPC-producing (0.5 µg/mL; 2 µg/mL) isolates, equivalent to ceftazidime-avibactam (MIC90, 2 µg/mL) against OXA-48-like-producing isolates, 2-fold less active than ceftazidime-avibactam (1 µg/mL; 0.5 µg/mL) against chromosomal AmpC-positive isolates, and 4-fold less active than ceftazidime-avibactam (4 µg/mL; 1 µg/mL) against acquired AmpC-producing isolates. Continued development of ceftibuten-avibactam appears justified.

In vitro antibacterial activities of cefiderocol against Gram-negative clinical strains isolated from China in 2020.

OBJECTIVES: Cefiderocol (CFDC) is a parenteral siderophore cephalosporin that is active against Gram-negative bacteria, including carbapenem-resistant isolates. We report the in vitro activity of CFDC and other antibiotics against 1738 clinical isolates of Gram-negative bacilli (GNB) provided by five medical centres in five provinces of China in 2020 METHODS: Antibiotic susceptibility testing was performed using the Clinical and Laboratory Standards Institute broth microdilution method. RESULTS: Against Pseudomonas aeruginosa and Acinetobacter Spp., the CFDC concentration inhibiting the growth of 90% of the isolates (MIC90) (0.5 µg/mL) was identical and did not change by the carbapenem resistance phenotype. The susceptibility rate of P. aeruginosa and Acinetobacter Spp. to CFDC was high (> 98%) and was similar against isolates with and without meropenem resistance. The MIC of CFDC for all Stenotrophomonas maltophilia isolates (20 isolates) was ≤1 µg/mL and the MIC90 was 0.12 µg/mL. Considerable differences were noted in the susceptibility to CFDC between all tested Enterobacterales isolates and meropenem-non-susceptible Enterobacterales isolates. The MIC90 of CFDC was 1 µg/mL for all tested Enterobacterales isolates and 8 µg/mL for meropenem-non-susceptible Enterobacterales isolates. CONCLUSIONS: CFDC demonstrated potent in vitro activity against a recent collection of clinical isolates, including meropenem-non-susceptible isolates, obtained from medical centres in mainland China.

In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.

Taniborbactam is a novel cyclic boronate ß-lactamase inhibitor in clinical development in combination with cefepime. We assessed the in vitro activity of cefepime-taniborbactam and comparators against a 2018-2020 collection of Enterobacterales (n = 13,731) and Pseudomonas aeruginosa (n = 4,619) isolates cultured from infected patients attending hospitals in 56 countries. MICs were determined by CLSI broth microdilution. Taniborbactam was tested at a fixed concentration of 4 µg/mL. Isolates with cefepime-taniborbactam MICs of ≥16 µg/mL underwent whole-genome sequencing. ß-lactamase genes were identified in meropenem-resistant isolates by PCR/Sanger sequencing. Against Enterobacterales, taniborbactam reduced the cefepime MIC90 value by >64-fold (from >16 to 0.25 µg/mL). At ≤16 µg/mL, cefepime-taniborbactam inhibited 99.7% of all Enterobacterales isolates; >97% of isolates with multidrug-resistant (MDR) and ceftolozane-tazobactam-resistant phenotypes; ≥90% of isolates with meropenem-resistant, difficult-to-treat-resistant (DTR), meropenem-vaborbactam-resistant, and ceftazidime-avibactam-resistant phenotypes; 100% of VIM-positive, AmpC-positive, and KPC-positive isolates; 98.7% of extended-spectrum ß-lactamase (ESBL)-positive; 98.8% of OXA-48-like-positive; and 84.6% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value by 4-fold (from 32 to 8 µg/mL). At ≤16 µg/mL, cefepime-taniborbactam inhibited 97.4% of all P. aeruginosa isolates; ≥85% of isolates with meropenem-resistant, MDR, and meropenem-vaborbactam-resistant phenotypes; >75% of isolates with DTR, ceftazidime-avibactam-resistant, and ceftolozane-tazobactam-resistant phenotypes; and 87.4% of VIM-positive isolates. Multiple potential mechanisms, including carriage of IMP, certain alterations in PBP3, permeability (porin) defects, and possibly, upregulation of efflux were present in most isolates with cefepime-taniborbactam MICs of ≥16 µg/mL. We conclude that cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM metallo-ß-lactamases (MBLs).

Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-ß-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection.

Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate ß-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) Enterobacterales producing serine ß-lactamases (Ambler class A, C, and D). In vivo, ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236). To more completely define the breadth of ceftibuten-ledaborbactam's activity against important antimicrobial-resistant pathogens, we assessed its in vitro activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of Enterobacterales, including MDR organisms, extended-spectrum-ß-lactamase (ESBL)-positive organisms, and organisms that are nonsusceptible and resistant to other antimicrobials. MICs were determined by CLSI broth microdilution and interpreted using both CLSI and EUCAST breakpoints. Ledaborbactam was tested at a fixed concentration of 4 µg/mL. ß-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected ß-lactam-resistant isolate subsets. At ≤1 µg/mL, ceftibuten-ledaborbactam (MIC90, 0.25 µg/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacin-nonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibuten-resistant (MIC >1 µg/mL), and 54.1% of carbapenem-nonsusceptible isolates. Against specific ESBL genotype-positive isolates (AmpC negative, serine carbapenemase negative, and metallo-ß-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (MIC90, 0.25 µg/mL), 91.5% of CTX-M-1 group (MIC90, 0.5 µg/mL), and 88.2% of SHV-positive (MIC90, 2 µg/mL) isolates at ≤1 µg/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC90, 2 µg/mL) and 82.9% of OXA-48-group-positive (MIC90, 2 µg/mL) isolates at ≤1 µg/mL. Continued development of ceftibuten-ledaborbactam appears warranted.

In Vitro Activity of Sulbactam-Durlobactam against Global Isolates of Acinetobacter baumannii-calcoaceticus Complex Collected from 2016 to 2021.

Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination designed to treat serious Acinetobacter baumannii-calcoaceticus complex (ABC) infections, including carbapenem-non-susceptible and multidrug-resistant (MDR) isolates. The current study characterized the in vitro activity of sulbactam-durlobactam against a collection of 5,032 ABC clinical isolates collected in 33 countries across the Asia/South Pacific region, Europe, Latin America, the Middle East, and North America from 2016 to 2021. The sulbactam-durlobactam MIC50 and MIC90 were 1 and 2 µg/mL, respectively, for all ABC isolates tested. The addition of durlobactam (at a fixed concentration of 4 µg/mL) to sulbactam decreased its MIC50 by 8-fold (from 8 to 1 µg/mL) and its MIC90 by 32-fold (from 64 to 2 µg/mL) for all ABC isolates. The in vitro activity of sulbactam-durlobactam was maintained across individual ABC species, years, global regions of collection, specimen sources, and resistance phenotypes, including MDR and extensively drug-resistant (XDR) isolates. At 4 µg/mL (preliminary sulbactam-durlobactam susceptible MIC breakpoint), sulbactam-durlobactam inhibited 98.3% of all ABC isolates and >96% of sulbactam-, imipenem-, ciprofloxacin-, amikacin-, and minocycline-non-susceptible isolates; as well as colistin-resistant, MDR, and XDR isolates. Most imipenem-non-susceptible ABC isolates (96.8%, 2,488/2,570) were carbapenem-resistant A. baumannii (CRAB); 96.9% (2,410/2,488) of CRAB isolates were sulbactam-durlobactam-susceptible. More than 80% of ABC isolates had sulbactam-durlobactam MIC values that were ≥2 doubling-dilutions (4-fold) lower than sulbactam alone. Only 1.7% (84/5,032) of ABC isolates from 2016 to 2021 had sulbactam-durlobactam MIC values of >4 µg/mL. Of the 84 isolates, 94.0% were A. baumannii, 4.8% were A. pittii, and 1.2% were A. nosocomialis. In summary, sulbactam-durlobactam demonstrated potent antibacterial activity against a 2016 to 2021 collection of geographically diverse clinical isolates of ABC isolates, including carbapenem-non-susceptible and MDR isolates.

Antimicrobial activity of ceftazidime-avibactam and comparators against levofloxacin-resistant Escherichia coli collected from four geographic regions, 2012-2018.

BACKGROUND: Increases in resistance to fluoroquinolones have been correlated with the use of levofloxacin in the treatment of infections caused by Escherichia coli. The analysis presents the in vitro activity of ceftazidime-avibactam and comparator agents against 10,840 levofloxacin-resistant E. coli isolates collected from four geographic regions (Africa/Middle East, Europe, Asia/South Pacific, Latin America) between 2012 and 2018. METHODS: Non-duplicate clinical isolates of E. coli were collected from participating centres and shipped to IHMA, Inc., (Schaumburg, IL, USA). Susceptibility testing was performed with frozen broth microdilution panels manufactured by IHMA, according to CLSI guidelines. Levofloxacin-resistance was defined at a minimum inhibitory concentration of ≥ 2 mg/L. Isolates collected between 2012 and 2015 were tested for extended-spectrum ß-lactamase (ESBL) activity by determining susceptibility to cefotaxime, cefotaxime-clavulanate, ceftazidime, and ceftazidime-clavulanate as recommended by CLSI guidelines. Isolates collected between 2016 and 2018 were identified as ESBL-positive by genotype using multiplex polymerase chain reaction assays. RESULTS: A total of 74.8% of levofloxacin-resistant E. coli isolates in the analysis were from three culture sources: urinary tract infections (N = 3229; 29.8%), skin and skin structure infections (N = 2564; 23.7%) and intra-abdominal infections (N = 2313; 21.3%). Susceptibility rates to ceftazidime-avibactam were consistently high in all regions against both ESBL-positive (97.0% in Asia/South Pacific to 99.7% in Africa/Middle East and Latin America) and ESBL-negative isolates (99.4% in Asia/South Pacific to 100% in Latin America). Susceptibility was also high in each region among ESBL-positive and ESBL-negative isolates to colistin (≥ 98.5%), imipenem (≥ 96.5%), meropenem (≥ 96.5%) and tigecycline (≥ 94.1%). CONCLUSIONS: Antimicrobial susceptibility to ceftazidime-avibactam among levofloxacin-resistant E. coli isolates, including ESBL-positive isolates, collected from four geographical regions between 2012 and 2018 was consistently high. Susceptibility to the comparator agents colistin, tigecycline, imipenem and meropenem was also high.

In Vitro Activity of Ceftibuten/VNRX-5236 against Urinary Tract Infection Isolates of Antimicrobial-Resistant Enterobacterales.

Ceftibuten/VNRX-7145 is a cephalosporin/boronate ß-lactamase inhibitor combination under development as an oral treatment for complicated urinary tract infections caused by Enterobacterales producing serine ß-lactamases (Ambler class A, C, and D). In vivo, VNRX-7145 (VNRX-5236 etzadroxil) is cleaved to the active inhibitor, VNRX-5236. We assessed the in vitro activity of ceftibuten/VNRX-5236 against 1,066 urinary isolates of Enterobacterales from a 2014-2016 global culture collection. Each isolate tested was preselected to possess a multidrug-resistant (MDR) phenotype that included nonsusceptibility to amoxicillin-clavulanate and resistance to levofloxacin. MICs were determined by CLSI broth microdilution. VNRX-5236 was tested at a fixed concentration of 4 µg/ml. Ceftibuten/VNRX-5236 inhibited 90% of all isolates tested (MIC90) at 2 µg/ml; MIC90s for ESBL- (n = 566), serine carbapenemase- (n = 116), and acquired AmpC-positive (n = 58) isolate subsets were ≤0.25, >32, and 8 µg/ml, respectively. At concentrations of ≤1, ≤2, and ≤4 µg/ml, ceftibuten/VNRX-5236 inhibited 89.1, 91.7, and 93.1% of all isolates tested; 96.5, 97.7, and 98.4% of ESBL-positive isolates; 75.9, 81.9, and 81.9% of serine carbapenemase-positive isolates; and 70.7, 81.0, and 87.9% of acquired AmpC-positive isolates. Ceftibuten/VNRX-5236 at concentrations of ≤1, ≤2, and ≤4 µg/ml inhibited 85-89, 89-91, and 91-92% of isolates that were not susceptible (defined by CLSI and EUCAST breakpoint criteria) to nitrofurantoin, trimethoprim-sulfamethoxazole, and/or fosfomycin, (as part of their MDR phenotype), oral agents commonly prescribed to treat uncomplicated urinary tract infections. The potency of ceftibuten/VNRX-5236 (MIC90, 2 µg/ml) was similar (within one doubling-dilution) to intravenous-only agents ceftazidime-avibactam (MIC90 2 µg/ml) and meropenem-vaborbactam (MIC90 1 µg/ml). Continued investigation of ceftibuten/VNRX-5236 is warranted.

In Vitro Susceptibility of Gram-Negative Pathogens to Cefiderocol in Five Consecutive Annual Multinational SIDERO-WT Surveillance Studies, 2014 to 2019.

We report in vitro susceptibility data from five consecutive annual SIDERO-WT surveillance studies (2014 to 2019) for cefiderocol and comparators tested against Gram-negative clinical isolates from North America and Europe. CLSI broth microdilution was used to determine MICs for Enterobacterales (n = 31,896), Pseudomonas aeruginosa (n = 7,700), Acinetobacter baumannii complex (n = 5,225), Stenotrophomonas maltophilia (n = 2,030), and Burkholderia cepacia complex (n = 425). MICs were interpreted by CLSI-approved clinical breakpoints (February 2021). Cefiderocol inhibited 99.8, 96.7, 91.6, and 97.7% of all Enterobacterales, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 µg/mL (susceptible breakpoint). Cefiderocol inhibited 99.9, 99.8, 100, and 99.8% of all P. aeruginosa, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 µg/mL (susceptible breakpoint). Cefiderocol inhibited 96.0% of all A. baumannii complex isolates and 94.2% of meropenem-nonsusceptible isolates at ≤4 µg/mL (susceptible breakpoint) and 98.6% of S. maltophilia isolates at ≤1 µg/mL (susceptible breakpoint). B. cepacia complex isolates were tested with a MIC50 of ≤0.03 µg/mL and MIC90 of 0.5 µg/mL. Annual cefiderocol percent susceptible rates for Enterobacterales (North America range, 99.6 to 100%/year; Europe range, 99.3 to 99.9%/year) and P. aeruginosa (North America range, 99.8 to 100%; Europe range, 99.9 to 100%) were unchanged from 2014 to 2019. Annual percent susceptible rates for A. baumannii complex demonstrated sporadic, nondirectional differences (North America range, 97.5 to 100%; Europe range, 90.4 to 97.5%); the wider range for Europe (∼7%) was due to isolates from Russia. Annual percent susceptible rates for S. maltophilia showed minor, nondirectional differences (North America range, 96.4 to 100%; Europe range, 95.6 to 100%). We conclude that clinical isolates of Enterobacterales (99.8% susceptible), P. aeruginosa (99.9%), A. baumannii (96.0%), and S. maltophilia (98.6%) collected in North America and Europe from 2014 to 2019 were highly susceptible to cefiderocol.

In Vitro Activity of Gepotidacin against Gram-Negative and Gram-Positive Anaerobes.

Gepotidacin (formerly GSK2140944) is a first-in-class triazaacenaphthylene antibacterial currently in phase III clinical trials. When tested against Gram-negative (n = 333) and Gram-positive (n = 225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates at concentrations of 4 and 2 µg/mL, respectively. Given gepotidacin's in vitro activity against the anaerobic isolates tested, further study is warranted to better understand the utility of gepotidacin in the treatment of infections caused by clinically relevant anaerobic organisms.

Collective assessment of antimicrobial susceptibility among the most common Gram-negative respiratory pathogens driving therapy in the ICU.

OBJECTIVES: To describe the pathogen predominance and to evaluate the probability of covering the most common Gram-negative pathogens collectively in both empirical and early adjustment prescribing scenarios in ICU patients with respiratory infections. METHODS: Data were collected from an international cohort of hospitals as part of the SMART Surveillance Program (2018). Susceptibility testing (mg/L) was performed by broth microdilution methods. RESULTS: 7171 Gram-negative respiratory isolates from adult ICU patients across 209 hospitals from 56 different countries were studied. Overall, the most common ICU respiratory pathogens isolated were Pseudomonas aeruginosa (25%), Klebsiella pneumoniae (18%), Acinetobacter baumannii (14%), and Escherichia coli (11%), with inter-regional differences among these pathogens. Among Enterobacterales, 36% were ESBL positive. When the collective susceptibility profile of this set of pathogens (P. aeruginosa plus Enterobacterales; comprising 78% of all organisms isolated) was performed, ceftolozane/tazobactam (84%), followed by meropenem (81%), provided the most reliable in vitro activity in the empirical prescribing scenario compared with other ß-lactam antibiotics. P. aeruginosa co-resistance was common among first-line ß-lactam antibiotics. If P. aeruginosa was non-susceptible to piperacillin/tazobactam, less than one-third were susceptible to meropenem or ceftazidime. In contrast, ceftolozane/tazobactam offered in vitro coverage in over two-thirds of these resistant pathogens. CONCLUSIONS: Ceftolozane/tazobactam demonstrated high cumulative susceptibility levels and in vitro activity in both empirical and adjustment antibiotic prescribing scenarios. High frequency of co-resistance undermines reliable coverage for Gram-negative pathogens already resistant to first-line agents. Ceftolozane/tazobactam would offer additional coverage in this setting.

Activity of imipenem/relebactam and comparators against gram-negative pathogens from patients with bloodstream infections in the United States and Canada - SMART 2018-2019.

Bloodstream infections (BSI) are often caused by drug-resistant pathogens, and novel antimicrobials are needed. We examined the activity of imipenem/relebactam against BSI pathogens from US and Canada: >99% of non-Morganellaceae Enterobacterales, including 100% of MDR isolates, and >94% of Pseudomonas aeruginosa were imipenem/relebactam-susceptible. Imipenem/relebactam could provide an important treatment option.

Prevalence of RND efflux pump regulator variants associated with tigecycline resistance in carbapenem-resistant Acinetobacter baumannii from a worldwide survey.

OBJECTIVES: To determine the most common tigecycline resistance mechanisms in carbapenem-resistant Acinetobacter baumannii isolates obtained during the global Tigecycline Evaluation Surveillance Trial (TEST). METHODS: Tigecycline MICs were determined by broth microdilution. WGS was used to screen for the previously identified tigecycline resistance mechanisms, as well as mutations in resistance-nodulation-cell division (RND)-type efflux pump regulators. RESULTS: From a total 313 isolates, 113 genetically unique tigecycline-resistant isolates were analysed. The most frequent and worldwide distributed mechanism associated with tigecycline resistance was disruption of adeN, which encodes the repressor of the RND efflux pump AdeIJK, either by IS elements or nucleotide deletions causing premature stop codons. However, mutations leading to amino acid substitutions and disruption by IS elements within the two-component regulatory system adeRS, which regulates expression of the AdeABC efflux pump, correlate with higher tigecycline MICs, but these were found less frequently and were mainly restricted to Southern European countries. Furthermore, an altered version of tviB was identified in several tigecycline-resistant isolates that did not have putative resistance mutations within RND-type regulators. The resistance determinants tet(A) and tet(X), as well as resistance mutations in putative resistance determinants trm, plsC, rrf, msbA and genes encoding 30S ribosomal proteins, were not identified in any isolate. CONCLUSIONS: The most prevalent tigecycline resistance mechanisms were caused by alterations in the regulators of RND-type efflux pumps. These data provide the basis for further characterization of regulator alterations and their contribution to increased efflux and tigecycline resistance, and also should be taken into account in drug discovery programmes to overcome the contribution of efflux pumps.