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.

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.

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.

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 Gram-Positive and -Negative Pathogens Collected from the United States in 2006 and 2016.

Ceftobiprole is an advanced cephalosporin with potent activity against Gram-positive and Gram-negative bacteria that has been approved in many European and non-European countries to treat community- and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). This study reports on the activity of ceftobiprole against a large set of clinical isolates obtained from hospitalized patients in the United States in 2016 that caused serious infections, including pneumonia, bacteremia, and skin and skin structure infections. To assess any potential temporal changes in ceftobiprole activity, the 2016 results were compared to corresponding MIC data from a 2006 U.S. survey that included key target pathogens. Ceftobiprole exhibited potent activity against Staphylococcus aureus (including methicillin-resistant S. aureus isolates, which were 99.3% susceptible), coagulase-negative staphylococci (100% susceptible), Enterococcus faecalis (100% susceptible), Streptococcus pneumoniae (99.7% susceptible), and other tested streptococci. Similarly, ceftobiprole was highly active against Enterobacteriaceae isolates that did not exhibit an extended-spectrum ß-lactamase (ESBL) phenotype, including Escherichia coli (99.8% susceptible) and Klebsiella pneumoniae (99.6% susceptible). A total of 99.6% of all Haemophilus influenzae and Moraxella catarrhalis isolates were inhibited at ≤1 mg/liter ceftobiprole, and 72.7% of the Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. With the exception of decreased cephalosporin susceptibility among Enterobacteriaceae isolates, which correlates with an increased prevalence of ESBL-producing isolates, ceftobiprole had similar activities against the isolate sets collected in 2006 and 2016. Therefore, ceftobiprole remains highly active when tested in vitro against a large number of current Gram-positive or Gram-negative pathogens that cause serious infections.

ZAAPS programme results for 2016: an activity and spectrum analysis of linezolid using clinical isolates from medical centres in 42 countries.

Objectives: To report the linezolid activity, resistance mechanisms and epidemiological typing of selected isolates observed during the 2016 Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) programme. Methods: A total of 8325 organisms were consecutively collected from 76 centres in 42 countries (excluding the USA). Broth microdilution susceptibility testing was performed and isolates displaying linezolid MICs of ≥4 mg/L were molecularly characterized. Results: Linezolid inhibited 99.8% of all Gram-positive pathogens at the respective susceptible breakpoints and showed a modal MIC of 1 mg/L, except for CoNS, for which the modal MIC result was 0.5 mg/L. Among isolates displaying linezolid MICs of ≥4 mg/L, one Staphylococcus aureus (linezolid MIC of 4 mg/L) harboured cfr and belonged to ST72, while four CoNS (MICs of 16-32 mg/L; ST2) showed drug target alterations. Two Enterococcus faecium (ST117) from a single site in Rome were linezolid non-susceptible (MICs of 8 mg/L) and had G2576T mutations. Eight linezolid-non-susceptible Enterococcus faecalis (MICs of 4 mg/L; 4 sites in 4 countries; ST256, ST480, ST766 and ST775) carried optrA and isolates carrying optrA from the same medical centre were genetically related. One Streptococcus gallolyticus (MIC of 4 mg/L) and one Streptococcus mitis (MIC of 16 mg/L) carried optrA and G2576T mutations, respectively. Conclusions: These results document the continued long-term in vitro potency of linezolid. Alterations in the 23S rRNA and/or L3/L4 proteins remain the main oxazolidinone resistance mechanisms in E. faecium and CoNS, whereas optrA emerged as the sole mechanism in E. faecalis. Surveillance and infection control will be important strategies to detect optrA and prevent it from disseminating.

Antimicrobial Susceptibility Trends among Staphylococcus aureus Isolates from U.S. Hospitals: Results from 7 Years of the Ceftaroline (AWARE) Surveillance Program, 2010 to 2016.

We evaluated trends in Staphylococcus aureus antimicrobial susceptibility in U.S. hospitals in the 2010-2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth microdilution methods. Methicillin-resistant S. aureus (MRSA) rates decreased from 50.0% (in 2010) to 42.2% (in 2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim-sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against methicillin-susceptible S. aureus (MSSA) and MRSA (97.2% susceptible) with no marked variations.

Five-Year Summary of In Vitro Activity and Resistance Mechanisms of Linezolid against Clinically Important Gram-Positive Cocci in the United States from the LEADER Surveillance Program (2011 to 2015).

This report describes linezolid susceptibility testing results for 6,741 Gram-positive pathogens from 60 U.S. sites collected during 2015 for the LEADER Program. In addition, the report summarizes linezolid in vitro activity, resistance mechanisms, and molecular typing obtained for 2011 to 2015. During 2015, linezolid showed potent activity in testing against Staphylococcus aureus, inhibiting >99.9% of 3,031 isolates at ≤2 µg/ml. Similarly, linezolid showed coverage against 99.2% of coagulase-negative staphylococci, 99.7% of enterococci, and 100.0% of Streptococcus pneumoniae, virdans group, and beta-hemolytic streptococcus isolates tested. The overall linezolid resistance rate remained a modest <1% from 2011 to 2015. Staphylococci, especially Staphylococcus epidermidis, showed a range of linezolid resistance mechanisms. Increased annual trends for the presence of cfr among Staphylococcus aureus isolates were not observed, but 64.3% (9/14) of the isolates with decreased susceptibility (MIC, ≥4 µg/ml) to linezolid carried this transferrable gene (2011 to 2015). The cfr gene was detected in 21.9% (7/32) of linezolid-resistant staphylococci other than S. aureus from 2011 to 2015. The optrA gene was noted in half (2/4) of the population of linezolid-nonsusceptible Enterococcus faecalis isolates from 2011 to 2015, while linezolid-nonsusceptible Enterococcus faecium isolates showed alterations predominantly (16/16) in the 23S rRNA gene (G2576T). This report confirms a long record of linezolid activity against Gram-positive isolates in the United States since regulatory approval in 2000 and reports the oxazolidinones evolving resistance mechanisms.

ZAAPS Program results for 2015: an activity and spectrum analysis of linezolid using clinical isolates from medical centres in 32 countries.

OBJECTIVES: To report the linezolid in vitro activity obtained during the 2015 ZAAPS Program. METHODS: In total, 7587 organisms causing documented infections were consecutively collected in 65 centres in 32 ex-USA countries. Broth microdilution susceptibility testing was performed. Isolates displaying linezolid MIC results of ≥ 4 mg/L were molecularly characterized. RESULTS: Linezolid inhibited >99.9% of Staphylococcus aureus at ≤ 2 mg/L, with MIC50 results of 1 mg/L, regardless of methicillin resistance. A similar linezolid MIC50 result (0.5 mg/L) was observed for CoNS, with the vast majority of isolates (99.7%) also inhibited at ≤ 2 mg/L. Three CoNS (linezolid MIC, 16-64 mg/L) from Italy were found to contain alterations in the 23S rRNA and/or L3/L4 ribosomal proteins. One isolate also harboured cfr. Linezolid exhibited consistent modal MIC and MIC50 results (1 mg/L) for enterococci regardless of species or vancomycin resistance. One Enterococcus faecalis (linezolid MIC, 8 mg/L) from Galway, Ireland, carried optrA. One Enterococcus faecium (linezolid MIC, 16 mg/L) from Italy contained a G2576T mutation in the 23S rRNA. All Streptococcus pneumoniae, viridans group streptococci and ß-haemolytic streptococci were inhibited by linezolid at ≤ 2, ≤ 2 and ≤ 1 mg/L, respectively, with equivalent MIC90 results (1 mg/L for all groups). CONCLUSIONS: These results document the continued long-term and stable in vitro potency of linezolid and a limited number of isolates with decreased susceptibility to linezolid (MIC, ≥4 mg/L). The latter isolates showed primarily mutations in the 23S rRNA gene and/or L3/L4 proteins, with plasmid-mediated resistance (cfr and optrA) also present, albeit at a low prevalence.

Linezolid Surveillance Results for the United States (LEADER Surveillance Program 2014).

Thelinezolidexperience andaccuratedetermination ofresistance (LEADER) surveillance program has monitored linezolid activity, spectrum, and resistance since 2004. In 2014, a total of 6,865 Gram-positive pathogens from 60 medical centers from 36 states were submitted. The organism groups evaluated wereStaphylococcus aureus(3,106), coagulase-negative staphylococci (CoNS; 797), enterococci (855),Streptococcus pneumoniae(874), viridans group streptococci (359), and beta-hemolytic streptococci (874). Susceptibility testing was performed by reference broth microdilution at the monitoring laboratory. Linezolid-resistant isolates were confirmed by repeat testing. PCR and sequencing were performed to detect mutations in 23S rRNA, L3, L4, and L22 proteins and acquired genes (cfrandoptrA). The MIC50/90forStaphylococcus aureuswas 1/1 µg/ml, with 47.2% of isolates being methicillin-resistantStaphylococcus aureus Linezolid was active against allStreptococcus pneumoniaestrains and beta-hemolytic streptococci with a MIC50/90of 1/1 µg/ml and against viridans group streptococci with a MIC50/90of 0.5/1 µg/ml. Among the linezolid-nonsusceptible MRSA strains, one strain harboredcfronly (MIC, 4 µg/ml), one harbored G2576T (MIC, 8 µg/ml), and one containedcfrand G2576T with L3 changes (MIC, ≥8 µg/ml). Among CoNS, 0.75% (six isolates) of all strains demonstrated linezolid MIC results of ≥4 µg/ml. Five of these were identified asStaphylococcus epidermidis, four of which containedcfrin addition to the presence of mutations in the ribosomal proteins L3 and L4, alone or in combination with 23S rRNA (G2576T) mutations. Six enterococci (0.7%) were linezolid nonsusceptible (≥4 µg/ml; five with G2576T mutations, including one with an additionalcfrgene, and one strain withoptrAonly). Linezolid demonstrated excellent activity and a sustained susceptibility rate of 99.78% overall.

Update on linezolid in vitro activity through the Zyvox Annual Appraisal of Potency and Spectrum Program, 2013.

Linezolid showed MIC50s and MIC90s of 1 µg/ml (for both) against Staphylococcus aureus. Two S. aureus strains exhibited higher MICs (4 to 8 µg/ml) caused by cfr and/or target site mutations, including the first detection of cfr in Poland. Linezolid (MIC50 and MIC90, 0.5 and 1 µg/ml) had potent MICs against coagulase-negative staphylococci (CoNS). Four CoNS had MICs of 16 to 128 µg/ml due to alterations in 23S rRNA and/or L3/L4. Linezolid inhibited all enterococci and streptococci at ≤2 µg/ml, except for one Enterococcus faecium strain (MIC, 8 µg/ml; G2576T [Escherichia coli numbering] mutation).

Ceftaroline activity against bacterial pathogens frequently isolated in U.S. medical centers: results from five years of the AWARE surveillance program.

A total of 84,704 isolates were collected from 191 medical centers in 2009 to 2013 and tested for susceptibility to ceftaroline and comparator agents by broth microdilution methods. Ceftaroline inhibited all Staphylococcus aureus isolates at ≤2 µg/ml and was very active against methicillin-resistant strains (MIC at which 90% of the isolates tested are inhibited [MIC90], 1 µg/ml; 97.6% susceptible). Among Streptococcus pneumoniae isolates, the highest ceftaroline MIC was 0.5 µg/ml, and ceftaroline activity against the most common Enterobacteriaceae species (MIC50, 0.12 µg/ml; 78.9% susceptible) was similar to that of ceftriaxone (MIC50, ≤0.25 µg/ml; 86.8% susceptible).

Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) program: report of linezolid activity over 9 years (2004-12).

OBJECTIVES: To summarize the activity and spectrum of linezolid and comparators tested against 7972 Gram-positive clinical isolates as part of the Zyvox(®) Annual Appraisal of Potency and Spectrum (ZAAPS) Program for 2012. Moreover, to provide molecular characterization for associated resistance mechanisms and epidemiological typing. METHODS: A total of 7972 isolates were collected from 73 medical centres (33 countries) on five continents. Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A9 document. MIC interpretations were based on CLSI and EUCAST criteria. RESULTS: Linezolid showed MIC50 and MIC90 results of 1 and 2 mg/L, respectively, when tested against Staphylococcus aureus. These isolates were inhibited by linezolid at ≤2 mg/L, except for four S. aureus exhibiting higher MIC values (4-8 mg/L), which had cfr and/or target site mutations, including a first detection of cfr in an isolate from Brazil. Coagulase-negative staphylococci (CoNS) were susceptible to linezolid (MIC50/90, 0.5/1 mg/L), with only eight isolates exhibiting high MIC results (16-32 mg/L). These CoNS had cfr and/or single or multiple target site alterations in 23S rRNA and/or ribosomal proteins (L3, L4). The same species of linezolid-resistant CoNS collected from the same hospital were clonally related to those observed in previously surveyed years. Linezolid exhibited stable modal MIC and MIC50 results when tested against enterococci, regardless of the species or vancomycin resistance phenotype; in addition, linezolid inhibited all streptococci at ≤2 mg/L. CONCLUSIONS: This surveillance report documents stable linezolid activity and susceptibility rates against a large and longitudinal collection of clinical isolates worldwide.

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.

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.

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.

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.

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.

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.