Contemporary Evaluation of Tebipenem In Vitro Activity against Enterobacterales Clinical Isolates Causing Urinary Tract Infections in US Medical Centers (2019-2020).

Tebipenem pivoxil is an oral broad-spectrum carbapenem. This study evaluated the activity of tebipenem and comparators against UTI Enterobacterales from US hospitals (2019-2020). 3,576 Enterobacterales causing UTI in 52 centers in 9 US Census Divisions were included. Susceptibility testing followed the CLSI broth microdilution method. Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis with an MIC of ≥2 µg/mL for ceftazidime, ceftriaxone, and/or aztreonam were designated ESBL. Isolates were also grouped based on MDR phenotype. Tebipenem, meropenem, and ertapenem had MIC90 against Enterobacterales of 0.06 µg/mL, 0.06 µg/mL and 0.03 µg/mL, respectively. Low susceptibility results for aztreonam (87.1% susceptible), cefazidime (88.1%), ceftriaxone (84.8%), and other agents were observed. Tebipenem and ertapenem were equally potent (MIC90, 0.015 to 0.03 µg/mL) against E. coli and K. pneumoniae, whereas ertapenem showed an MIC 8-fold lower than tebipenem against P. mirabilis. Oral agents, such as amoxicillin-clavulanate, levofloxacin, and trimethoprim-sulfamethoxazole, showed elevated nonsusceptibility rates in the Middle Atlantic region (26, 45, 47, and 41%, respectively). ESBL prevalence varied from 7% to 16%, except in the Middle Atlantic region (42%). The carbapenems were active against ESBL and MDR isolates (93.7 to 96.8% susceptible). Elevated rates of ESBL in UTI pathogens in US hospitals were noted as well as a uniform in vitro potency (MIC90) of tebipenem and the intravenous carbapenems, regardless of phenotype. IMPORTANCE The occurrence of urinary-tract Enterobacterales pathogens producing ESBL enzymes in community and nosocomial settings continues to increase, as does the coresistance to fluoroquinolones, trimethoprim-sulfamethoxazole and nitrofurantoin often exhibited by these pathogens. This scenario complicates the clinical empirical and guided management of UTI by precluding the use of oral and many intravenous options. Oral options appear compromised even among some ESBL-negative isolates, against which the use of parenteral agents may be required. In addition, the interregional variability of susceptibility results of US UTI pathogens provides a less predictable susceptibility pattern to inform empirical treatment decisions. This study evaluated the in vitro activity of tebipenem against contemporary uropathogens, including those resistant to currently available oral options.

Activity of meropenem/vaborbactam and comparators against non-carbapenemase-producing carbapenem-resistant Enterobacterales isolates from Europe.

Background: Carbapenem-resistant Enterobacterales (CRE) isolates have disseminated worldwide. CREs usually produce a carbapenemase; however, some isolates are negative for known carbapenemases. In this study, we evaluated the activity of meropenem/vaborbactam and comparators against CREs without a carbapenemase (nonCP CREs) collected from European hospitals from 2016 to 2019. Materials and methods: 23 043 Enterobacterales clinical isolates were collected in 41 hospitals located in 20 countries. Susceptibility (S) testing was performed using the broth microdilution method. CLSI/EUCAST (2021) interpretive criteria were used. 978 CREs were identified with MICs >2 mg/L to meropenem or imipenem. Whole-genome sequencing was performed on each CRE isolate. 125 isolates were negative for carbapenemase genes, including bla KPC, bla NDM, bla IMP, bla VIM and bla OXA-48-like. NonCP CRE isolates were analysed for the presence of other ß-lactamases, multilocus sequence types (ST) and mutations in outer membrane protein (OMP) sequences. Results: Most nonCP CRE were Klebsiella pneumoniae (KPN; n = 97/125). 84.0% of nonCP CRE (n = 105) were from Poland, including 88 KPN. The most common ß-lactamase was bla CTX-M-15 in 92/125 isolates. OMP disruptions or alterations were noted among 76 KPN. Among KPN isolates that had MLST typing, 30 belonged to ST11, 18 to ST152 and 17 to ST147, while 13 other STs were observed. Susceptibility to meropenem/vaborbactam was 96.0/97.6% (CLSI/EUCAST) while meropenem was 2.4/8.0%S. Conclusions: Meropenem/vaborbactam had potent in vitro activity against CRE isolates that lacked known carbapenemases. Resistance mechanisms observed among nonCP CREs included acquired ß-lactamases and OMP alterations. These results indicate that meropenem/vaborbactam may be a useful treatment for infections caused by nonCP CREs.

Five-year analysis of the in vitro activity of tedizolid against a worldwide collection of indicated species causing clinical infections: results from the Surveillance of Tedizolid Activity and Resistance (STAR) programme.

Objectives: The Surveillance of Tedizolid Activity and Resistance (STAR) programme monitored the tedizolid activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group. We evaluated the antimicrobial susceptibility of 47 400 unique Gram-positive clinical isolates from the STAR programme collected from USA (21 243), Europe (17 674), Asia-Pacific (4954) and Latin America (3529) medical centres (2015-19). Methods: All isolates were tested for susceptibility by reference broth microdilution method. WGS and in silico analysis were performed on linezolid-non-susceptible (NS) isolates. Results: Tedizolid was active against ≥99.9% of S. aureus (100.0% of MSSA and >99.9% of MRSA), E. faecalis, S. pyogenes, S. agalactiae and S. anginosus group isolates, with MIC50 values ranging from 0.12 to 0.25 mg/L and MIC90 values of 0.25 mg/L. Linezolid, vancomycin and daptomycin were also active agents against these organisms. Tedizolid inhibited all VRE and 73.1% of linezolid-NS E. faecalis isolates. Ampicillin and daptomycin retained 100.0% activity against VRE and linezolid-NS E. faecalis isolates. Linezolid-NS E. faecalis isolates carried mostly the optrA gene. G2576T alterations in the 23S rRNA were observed in one linezolid-NS S. aureus isolate and one linezolid-NS E. faecalis isolate. Conclusions: No resistance trends were observed for tedizolid during the study period.

Tedizolid in vitro activity against Gram-positive clinical isolates causing bone and joint infections in hospitals in the USA, Europe, Latin America, and the Asia-Pacific region (2015-2019).

As bone and joint infections (BJIs) frequently require prolonged, systemic antibiotic use, tedizolid is an attractive candidate for BJI therapy in adults and children. Tedizolid activity was evaluated against 1,193 Gram-positive isolates causing BJI in American (USA), European (EUR), Latin American (LATAM), and Asian-Pacific (APAC) medical centers. Isolates consecutively collected from 2015 to 2019 were susceptibility tested by CLSI broth microdilution. Staphylococcus aureus (69.2%) was the most common pathogen with a 25.9% MRSA rate and tedizolid MIC50/90 of 0.12/0.25 mg/L (100% susceptible). Tedizolid exhibited MIC50/90 values of 0.12/0.12 mg/L (98.9% susceptible) for CoNS (7.5% of BJI), 0.12/0.25 mg/L for streptococci, and 0.25/0.25 mg/L for enterococci. Overall, high susceptibility rates (100.0%) for linezolid, daptomycin, and vancomycin were observed. In summary, tedizolid had potent in vitro activity against contemporary Gram-positive cocci causing BJI in adults and children in USA, EUR, LATAM, and APAC hospitals.

Activity of Ceftolozane-Tazobactam Against Gram-Negative Isolates from Australia and New Zealand as part of the PACTS Surveillance 2016-2018.

OBJECTIVES: Ceftolozane-tazobactam (C-T) is an anti-pseudomonal cephalosporin combined with a well-described ß-lactamase inhibitor. Ceftolozane-tazobactam has enhanced activity against Pseudomonas aeruginosa, and activity against Enterobacterales isolates that produce extended-spectrum ß-lactamases (ESBLs) or AmpC cephalosporinases. In this study, we analysed the susceptibility of Gram-negative isolates to C-T and comparators collected in Australia and New Zealand from 2016 to 2018 as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance. METHODS: A total of 1693 nonduplicate Enterobacterales and 435 P. aeruginosa isolates were collected prospectively from hospitalized patients in six medical centres in Australia and two in New Zealand. Susceptibilities (S) to C-T and comparators were determined using broth microdilution. EUCAST breakpoints were used. Isolates with multi-drug resistant (MDR), extensively drug resistant (XDR), extended-spectrum ß-lactamase non-carbapenem resistant (ESBL, non-CRE) phenotype, and CRE were analysed. RESULTS: For P. aeruginosa, 97.5% were S to C-T while 89.9% were S to meropenem. According to EUCAST criteria, 86.4% were susceptible-increased exposure to piperacillin-tazobactam. MDR and XDR P. aeruginosa isolates had 76.7% and 65.4% S to C-T, respectively; 34.9% and 19.2% S to meropenem, respectively; and 23.3% and 15.4% were susceptible-increased exposure to piperacillin-tazobactam, respectively. Meropenem (99.8% S), amikacin (99.1% S), and C-T (96.5% S) were the most active against Enterobacterales. Susceptibilities to C-T were 94.3% for ESBL, non-CRE phenotype, and 78.4% for MDR isolates. Only three CRE and five XDR isolates were identified. CONCLUSIONS: These in vitro data indicate that C-T is a potent antimicrobial with activity against MDR and XDR P. aeruginosa, as well as ESBL, non-CRE phenotype isolates and MDR Enterobacterales.

In Vitro Activity of Cefiderocol against U.S. and European Gram-Negative Clinical Isolates Collected in 2020 as Part of the SENTRY Antimicrobial Surveillance Program.

Cefiderocol is a siderophore-conjugated cephalosporin with broad activity against Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia. Cefiderocol was approved by the FDA for treatment of complicated urinary tract infection, hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia and by the European Medicines Agency (EMA) for aerobic GN infections in adults with few treatment options. In this study, we analyzed the susceptibility of cefiderocol against GN clinical isolates that were collected from hospitalized patients in the United States and Europe in 2020 as part of the SENTRY Antimicrobial Surveillance Program. GN isolates, including 8,047 Enterobacterales, 2,282 P. aeruginosa, 650 Acinetobacter species, and 338 S. maltophilia isolates, were consecutively collected from patients in 66 hospitals in 19 countries. Susceptibility testing was performed using the CLSI broth microdilution method, and cefiderocol was tested in iron-depleted cation-adjusted Mueller-Hinton broth. Cefiderocol activity against resistant isolates, including CRE and extensively drug-resistant (XDR) isolates, was determined. Enterobacterales susceptibility to cefiderocol was 99.8% (CLSI), and CRE susceptibility was 98.2%. Cefiderocol was the most active antimicrobial against all P. aeruginosa isolates with MIC50/90 values of 0.12/0.5 mg/L, respectively (99.6% susceptible). A total of 256 P. aeruginosa isolates were XDR, 97.3% were susceptible to cefiderocol, and 7.4% were susceptible to meropenem. Acinetobacter susceptibility to cefiderocol was 97.7%. S. maltophilia susceptibility to cefiderocol was 100.0% (CLSI, 2021) and 97.9% (CLSI, 2022). These in vitro data suggest that cefiderocol is an important therapeutic option for the treatment of infections caused by Gram-negative pathogens, including isolates resistant to carbapenems with few therapeutic options. IMPORTANCE Cefiderocol is the first siderophore-conjugated cephalosporin approved for use in the treatment of human bacterial infections. Cefiderocol has broad-spectrum Gram-negative activity against difficult-to-treat bacterial pathogens that can cause serious infections. Our study examines the activity of cefiderocol against a large global collection of Gram-negative clinical isolates collected from hospitalized patients in 2020. In addition, we compare the activities of cefiderocol and recently approved ß-lactam-ß-lactamase inhibitor combinations against various antimicrobial-resistant pathogen groups including carbapenem-resistant Enterobacterales, meropenem-resistant Pseudomonas aeruginosa, and meropenem-resistant Acinetobacter spp. as well as isolates resistant to most classes of antimicrobial drugs. Cefiderocol was the most active antimicrobial tested against the isolates in this study. Our in vitro data suggest that cefiderocol may be useful for treatment of serious infections caused by drug-resistant Gram-negative organisms for patients with limited treatment options.

Antimicrobial susceptibility of Gram-negative bacteria from intensive care unit and non-intensive care unit patients from United States hospitals (2018-2020).

We evaluated the antimicrobial susceptibility of Gram-negative bacteria recovered from ICU patients in US hospitals and compared them to those from non-ICU patients from the same hospitals during the same period. Overall, 4,680 isolates from ICU patients and 16,263 isolates from non-ICU patients were collected from 70 US medical centers in 2018-2020 and susceptibility tested by the broth microdilution method. Ceftazidime-avibactam and ceftolozane-tazobactam were the most active agents against P. aeruginosa and retained activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates. Minocycline and trimethoprim-sulfamethoxazole were very active against S. maltophilia, whereas most antimicrobial agents exhibited low susceptibility to A. baumannii. Ceftazidime-avibactam and meropenem-vaborbactam were the most active agents against Enterobacterales, and retained potent activity against ESBL producers, carbapenem-resistant Enterobacterales (CRE), MDR, and XDR isolates. In summary, antimicrobial susceptibility was generally lower and the occurrence of ESBL, CRE, MDR, and XDR phenotypes were clearly higher among ICU compared to non-ICU isolates.

Activity of the Novel Aminomethylcycline KBP-7072 and Comparators against 1,057 Geographically Diverse Recent Clinical Isolates from the SENTRY Surveillance Program, 2019.

KBP-7072 is a novel broad-spectrum tetracycline (aminomethylcycline) antibacterial in clinical development (oral and intravenous formulations) for the treatment of acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and complicated intra-abdominal infections. KBP-7072 is active against many of the World Health Organization priority pathogens. In this study, KBP-7072 and tetracycline class comparators were susceptibility tested against 1,057 geographically diverse surveillance isolates from 2019 according to Clinical and Laboratory Standards Institute (CLSI) guidelines. KBP-7072 demonstrated potent in vitro activity against Gram-positive and Gram-negative bacterial pathogens. KBP-7072 was active against Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/liter), methicillin-resistant S. aureus (MIC50/90, 0.06/0.12 mg/liter), S. lugdunensis (MIC50/90, 0.03/0.03 mg/liter), and other coagulase-negative staphylococci (MIC50/90, 0.06/0.25 mg/liter). KBP-7072 was active against Enterococcus faecalis (MIC50/90, 0.03/0.06 mg/liter) and vancomycin-susceptible and -nonsusceptible E. faecium (MIC50/90, 0.03/0.03 mg/liter); Streptococcus pneumoniae (MIC50/90, ≤0.015/0.03 mg/liter), including penicillin- and tetracycline-resistant strains; S. agalactiae (MIC50/90, 0.03/0.06 mg/liter), including macrolide-resistant strains; S. pyogenes (MIC50/90, 0.03/0.03 mg/liter); and viridans group streptococci, including S. anginosus group (MIC50/90, ≤0.015/0.03 mg/liter) isolates. KBP-7072 inhibited 90.2% (MIC50/90, 0.25/2 mg/liter) of all Enterobacterales isolates, including expanded-spectrum ß-lactamase-phenotype strains at ≤2 mg/liter. KBP-7072 demonstrated potent activity against Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia isolates (MIC50/90 values, 0.5/1 mg/liter), Haemophilus influenzae (MIC50/90, 0.12/0.25 mg/liter; 100.0% inhibited at ≤0.25 mg/liter), and Moraxella catarrhalis (MIC50/90, 0.06/0.06 mg/liter). Based on MIC90 values, KBP-7072 in vitro activity was generally superior to that the other tetracycline class comparators tested. The potent activity of KBP-7072, including resistant organism groups, merits further clinical investigation in infections where these organisms are likely to occur.

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.

Frequency of occurrence and antimicrobial susceptibility of bacteria isolated from respiratory samples of patients hospitalized with pneumonia in Western Europe, Eastern Europe and the USA: results from the SENTRY Antimicrobial Surveillance Program (2016-19).

BACKGROUND: The SENTRY Antimicrobial Surveillance Program monitors the frequency of occurrence and antimicrobial susceptibility of organisms from various infection types worldwide. OBJECTIVES: To evaluate the SENTRY programme results for organisms isolated from respiratory samples of patients hospitalized with probable pneumonia. METHODS: A total of 28 918 bacterial isolates were consecutively collected (one per patient) in 2016-19 from 121 medical centres located in western Europe (W-EU; n = 7966), eastern Europe (E-EU; n = 3182) and the USA (n = 17 770) and then susceptibility tested by reference broth microdilution methods in a central laboratory. RESULTS: Gram-negative bacilli (GNB) represented 76.3%, 88.6% and 69.1% of organisms; non-fermentative (NF) GNB accounted for 26.9%, 51.8% and 34.6% of organisms in W-EU, E-EU and USA, respectively. Pseudomonas aeruginosa susceptibility to piperacillin/tazobactam and meropenem was 75.4% and 76.9% in W-EU, 57.4% and 48.3% in E-EU, and 76.1% and 74.8% in the USA, respectively. Only 10.4% of Acinetobacter baumannii isolates from E-EU were meropenem susceptible compared with 45.8% in W-EU and 58.8% in the USA. Overall MRSA rates were 21.4% in W-EU and 28.7% in E-EU. In the USA, MRSA rates decreased from 44.8% in 2016 to 40.1% in 2019. Carbapenem resistance among Enterobacterales decreased continuously in the USA from 3.0% in 2016 to 1.7% in 2019 (2.4% overall) and was higher in E-EU (16.6%) than W-EU (2.2%). Klebsiella pneumoniae susceptibility to meropenem was 91.3%, 72.5% and 95.3% in W-EU, E-EU and the USA, respectively. CONCLUSIONS: Rank order and antimicrobial susceptibility of bacteria isolated from patients with pneumonia widely varied by geography. MDR NF-GNB represented an important cause of pneumonia.

Minocycline Activity against Unusual Clinically Significant Gram-Negative Pathogens.

The minocycline susceptibility of 3,856 isolates including Burkholderia, Achromobacter, Alcaligenes, Aeromonas, and Stenotrophomonas maltophilia from the SENTRY surveillance (2014 to 2019) were analyzed. The susceptibilities of these species (%S) were Achromobacter spp. (n = 411; 92.6%), Burkholderia cepacia species complex (n = 199; 85.9%), Aeromonas spp. (n = 127; 99.2%), Chryseobacterium spp. (n = 59; 94.9%), Alcaligenes faecalis (n = 42; 88.1%), and S. maltophilia (n = 2,287; 99.5%). These data suggest that minocycline is a useful treatment option for infections caused by unusual Gram-negative pathogens.

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.

Susceptibility trends of ceftolozane/tazobactam and comparators when tested against U.S. gram-negative bacterial surveillance isolates (2012-2018).

Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a ß-lactamase inhibitor. Ceftolozane/tazobactam has been approved in >60 countries for treating complicated urinary tract infections, acute pyelonephritis, complicated intra-abdominal infections (with metronidazole), and hospital-acquired pneumonia, including ventilator-associated pneumonia in adults. We analyzed susceptibilities for 35,882 gram-negative isolates collected from patients in 35 US medical centers from 2012 to 2018. The rate of multi-drug resistant Enterobacterales was stable (9.5%-10.1%), while the P. aeruginosa multi-drug resistance rate increased from 15.5% in 2012 to 22.9% in 2018. The carbapenem-resistant Enterobacterales rates varied from 0.9% to 2.2% and extended-spectrum ß-lactamase phenotypes increased from 10.5% to 16.8%. The most active drugs against P. aeruginosa were ceftolozane/tazobactam (95.8%-97.5% susceptible) and amikacin (93.9%-98.0%); against Enterobacterales, amikacin (97.9%-98.8%), meropenem (97.7%-98.8%), and ceftolozane/tazobactam (93.3%-95.6%) were the most active. These data suggest that ceftolozane/tazobactam has effective in vitro activity against organisms causing serious gram-negative infections.

Antimicrobial activity of dalbavancin against clinical isolates of coagulase-negative staphylococci from the USA and Europe stratified by species.

OBJECTIVES: To evaluate the in vitro activity of dalbavancin compared with vancomycin, daptomycin and other agents against a large collection of coagulase-negative staphylococci (CoNS) isolates. METHODS: A total of 5088 CoNS causing clinically significant infection were consecutively collected from 122 medical centres in the USA and Europe over 6 years (2014-2019). Isolates were tested for susceptibility by the reference broth microdilution method. Species identification was confirmed by MALDI-TOF. Most isolates were from bloodstream infections (BSIs) (53.5%) or skin/skin structure infections (28.5%). RESULTS: Staphylococcus epidermidis was the most common species overall (54.6%) and for BSI (61.3%). The second most common species were Staphylococcus lugdunensis overall (12.3%) and Staphylococcus hominis for BSI (14.7%). Dalbavancin (MIC50/90, 0.03/0.06 mg/L) inhibited >99.9% of CoNS isolates at ≤0.25 mg/L (susceptible breakpoint for Staphylococcus aureus per CLSI). All species were inhibited at ≤0.25 mg/L dalbavancin, except some S. epidermidis (>99.9%) and Staphylococcus warneri (98.9%) isolates. Staphylococcus capitis and Staphylococcus simulans exhibited the lowest dalbavancin MIC50/90 values (0.015/0.03 mg/L) and Staphylococcus haemolyticus and Staphylococcus saprophyticus the highest (MIC50/90, 0.06/0.12 mg/L); 47.8% of S. epidermidis and 34.7% of S. haemolyticus exhibited decreased susceptibility to vancomycin (MIC ≥ 2 mg/L) and 23.2% of S. capitis and 28.4% of S. warneri showed decreased susceptibility to daptomycin (MIC ≥ 1 mg/L). CONCLUSION: Antimicrobial susceptibility varied widely among CoNS species. Dalbavancin inhibited >99.9% and 99.1% of isolates at the US-FDA and EUCAST breakpoints, respectively. Clinical studies of dalbavancin for treatment of CoNS infections should be considered based on these in vitro data.

Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam and Comparators Tested Against Pseudomonas aeruginosa and Klebsiella pneumoniae Isolates from United States Medical Centers in 2016-2018.

Very few antimicrobial agents remain active against Pseudomonas aeruginosa and Klebsiella pneumoniae in some geographic regions. We evaluated the in vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, and comparator agents against 6,210 P. aeruginosa and 6,041 K. pneumoniae isolates consecutively collected from 85 U.S. medical centers across 37 states in 2016-2018. Antimicrobial susceptibility was determined by reference broth microdilution method. K. pneumoniae isolates found to have elevated MICs for broad-spectrum cephalosporins were submitted to whole-genome sequencing analysis to detect resistance genes. Ceftazidime-avibactam (97.1% susceptible [S]) and ceftolozane-tazobactam (97.0%S) were the most active compounds against P. aeruginosa and retained activity against meropenem-nonsusceptible (88.5-89.0%S), piperacillin-tazobactam-nonsusceptible (86.6-87.0%S), and other resistant subsets of isolates. The most active agents against K. pneumoniae per CLSI criteria were ceftazidime-avibactam (>99.9%S), amikacin (98.4%S), and meropenem (97.1%S). Ceftolozane-tazobactam was active against 95.3% of K. pneumoniae but showed limited activity against extended-spectrum ß-lactamase and carbapenemase producers (82.9% and 0.0%S, respectively).

Update on the in vitro activity of dalbavancin against indicated species (Staphylococcus aureus, Enterococcus faecalis, ß-hemolytic streptococci, and Streptococcus anginosus group) collected from United States hospitals in 2017-2019.

This study updates dalbavancin activity against contemporary (2017-2019) isolates of indicated species/groups (n = 16,451). Isolates from 71 hospitals were tested by broth microdilution method. All isolates were susceptible to dalbavancin. Dalbavancin MIC50/90 values remained stable for Staphylococcus aureus, vancomycin-susceptible Enterococcus faecalis, ß-hemolytic streptococci, and Streptococcus anginosus group since its clinical approval.

Update on the activity of delafloxacin against acute bacterial skin and skin-structure infection isolates from European hospitals (2014-2019).

OBJECTIVES: Delafloxacin is a broad-spectrum anionic fluoroquinolone with activity against Gram-positive and Gram-negative organisms, including methicillin-resistant Staphylococcus aureus. Both oral and intravenous formulations were approved for use in the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) due to Gram-positive and Gram-negative organisms by the US Food and Drug Administration (2017) and European Medicines Agency (2019), and for community-acquired bacterial pneumonia by the FDA (2019). The SENTRY Antimicrobial Surveillance Program has monitored the susceptibility of delafloxacin in the USA and Europe since 2014. The purpose of this study is to provide an update on delafloxacin activity against ABSSSI isolates primarily collected from hospitalised patients in Europe. METHODS: A total of 11,866 non-duplicate ABSSSI isolates were collected from 2014 to 2019 from 46 European medical centres in 24 countries. Susceptibilities were determined by broth microdilution. Results were interpreted using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (2020). RESULTS: The most common isolate wasS. aureus (37.8%; n = 4484), followed by Escherichia coli (11.0%) and Streptococcus spp. (10.0%). Delafloxacin susceptibility for S. aureus was 92.4% (MIC50/90, ≤0.004/0.25 mg/L), streptococci 98.4% and E. coli 58.1%. Delafloxacin was more active against S. aureus than levofloxacin (84.0% intermediate; MIC50/90, 0.25/>4 mg/L) and moxifloxacin (84.3% susceptible; MIC50/90, ≤0.06/2 mg/L). Susceptibility of E. coli was similar for the three quinolones. CONCLUSIONS: Delafloxacin had broad-spectrum activity and improved potency against Gram-positive pathogens compared with levofloxacin and moxifloxacin. These data suggest that delafloxacin may be a useful therapeutic choice for the most common causes of ABSSSI.

Activity of ceftolozane-tazobactam and comparators when tested against bacterial surveillance isolates collected from patients at risk of infections caused by resistant gram-negative pathogens.

Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a ß-lactamase inhibitor. Ceftolozane-tazobactam has been approved for treatment of complicated urinary tract infections and acute pyelonephritis, for complicated intra-abdominal infections (with metronidazole) in adults, and for hospital-acquired bacterial pneumonia including ventilator-associated bacterial pneumonia. This study analyzed gram-negative pathogen susceptibility in US and European patients who are considered at risk for infections caused by pathogens resistant to commonly used antimicrobials: patients in the intensive care unit (ICU), patients on the hematology/oncology or transplant service who may be immunocompromised, and patients >65 years old (yo). ICU patients had the lowest susceptibility for Enterobacterales and PSA. The susceptibility for isolates from the immunocompromised and >65 yo groups was similar. Ceftolozane-tazobactam was the most active agent against PSA, with ≥90%S for >65 yo and immunocompromised, and >80%S for ICU. Meropenem and ceftolozane-tazobactam were the most active agents against Enterobacterales.

Frequency and antimicrobial susceptibility of bacteria causing bloodstream infections in pediatric patients from United States (US) medical centers (2014-2018): therapeutic options for multidrug-resistant bacteria.

Studies evaluating large series of pediatric patients with bloodstream infections (BSIs) are scarce. We evaluated the frequency and antimicrobial susceptibility of organisms isolated from pediatric patients with BSI and therapeutic options for BSI caused by multidrug-resistant (MDR) organisms. A total of 2423 organisms were consecutively collected from 33 US medical centers between 2014 and 2018, and susceptibility was tested by reference broth microdilution methods. Isolates with an extended-spectrum ß-lactamase phenotype were screened for ß-lactamase genes. Overall, 40.2% of organisms were Gram-negative bacteria, 57.0% Gram-positives, and 2.8% Candida spp. The 5 most common organisms were Staphylococcus aureus (26.0%), Escherichia coli (13.0%), coagulase-negative staphylococci (8.3%), Enterococcus faecalis (7.1%), and Klebsiella pneumoniae (6.9%). Among S. aureus, 26.0% were oxacillin-resistant and 99.8% were susceptible to ceftaroline (MIC50/90, 0.25/0.5 mg/L). Enterobacterales and Pseudomonas aeruginosa isolates combined represented >85% of Gram-negative bacteria, and all isolates (100.0%) were susceptible to ceftazidime-avibactam.

Omadacycline invitro activity against a molecularly characterized collection of clinical isolates with known acquired tetracycline resistance mechanisms.

Omadacycline and tigecycline MIC90 values were 2 µg/mL and 0.25 µg/mL, respectively, against Staphylococcus aureus carrying tet(M), whereas the minocycline, tetracycline, and doxycycline values were > 8 µg/mL. Similarly, omadacycline and tigecycline remained active against Enterococcus faecalis and Streptococcus pneumoniae harboring tet(L)and/or tet(M)(MIC90, 0.06-0.25 µg/mL), whereas other tetracyclines were inactive (MIC90, >8 µg/mL). Omadacycline and tigecycline remained more potent than minocycline, tetracycline, and doxycycline against Enterobacteriaceae carrying tet. This study demonstrates the effectiveness of modern tetracyclines, omadacycline, and tigecycline against isolates with tetracycline resistance genes.