Global Surveillance Program Research Articles

The InVitro Activity of Rezafungin Against Uncommon Species of Candida.

Invasive candidiasis (IC) is increasing due to the rising numbers of immunocompromised patients. Increasing azole resistance rates and daily dosing required for most echinocandins have complicated its treatment. The approval of rezafungin has provided an option for weekly echinocandin treatment. The susceptibility of less common Candida spp. to rezafungin is unclear. We looked at the minimum inhibitory concentrations (MICs) of rezafungin and comparator agents against Candida spp. collected as part of a global surveillance program. The CLSI reference broth microdilution method was performed to test 590 clinical isolates of 28 different Candida species, including Candida auris. Species-specific interpretative criteria by breakpoints or epidemiological cutoff values were applied where available. Rezafungin was within ±2-fold MIC50/90 values of other echinocandins against all Candida spp. The lowest rezafungin MIC50/90 values were noted against C. kefyr (0.03/0.06 mg/L) and C. pelliculosa (0.015/0.03 mg/L). Higher rezafungin MIC50/90 values were noted for C. guilliermondii (1/1 mg/L) and for isolates in the C. parapsilosis complex (C. orthopsilosis, 0.5/1 mg/L, C. metapsilosis, 0.12/0.5 mg/L). Rezafungin was active against 97.7% of C. dubliniensis and 95.4% of C. auris by CLSI breakpoints. For fluconazole, 69.7% of C. guilliermondii, 85.7% of C. orthopsilosis, and 100% of C. metapsilosis were wildtype by ECV, and 10.8% of C. auris were susceptible by CDC breakpoint. Rezafungin was highly active by invitro testing against less common Candida spp. Rezafungin MICs were comparable to other echinocandins. Rezafungin is a desirable therapeutic alternative due to its reduced dosing frequency.

Molecular characterization of clinically isolated Pseudomonas aeruginosa with varying resistance to ceftazidime-avibactam and ceftolozane-tazobactam collected as a part of the ATLAS global surveillance program from 2020 to 2021.

Ceftazidime-avibactam (CZA) and ceftolozane-tazobactam (C/T) are important agents for treating multidrug-resistant P. aeruginosa infections. In this study, we evaluated the molecular characteristics of 300 globally collected clinical P. aeruginosa isolates non-susceptible (NS) to CZA, C/T, or both agents. Isolates were CZA-NS and C/T-NS (n = 57), CZA-susceptible (S) and C/T-NS (n = 145), or CZA-NS and C/T-S (n = 98) selected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) surveillance program from 2020 to 2021. Characterization was by whole-genome sequencing. Analysis was performed to identify β-lactamase genes and mutations that impact efflux regulation, AmpC regulation, and target binding (PBP3). Of the 57 CZA-NS+C/T-NS isolates, 64.9% carried a metallo-β-lactamase (MBL), and a cumulative 84.2% carried any non-intrinsic β-lactamase [i.e., not Pseudomonas-derived cephalosporinase (PDC) or OXA-50-like]. Of the 145 CZA-S+C/T-NS isolates, 26.2% carried an extended-spectrum β-lactamase (ESBL) and no carbapenemase, 17.9% carried a serine-carbapenemase, and 42.1% were negative for non-intrinsic β-lactamases. Of 98 CZA-NS+C/T-S isolates, 34.7% carried mutations previously described as causing an upregulation of the MexAB-OprM efflux pump, while only 9.2% carried a non-intrinsic β-lactamase, and no resistance mechanism was identified in 29.6% of these isolates. MBLs were present in most isolates NS to both agents. More than half of the CZA-S+C/T-NS isolates carried serine β-lactamases. The most frequently identified resistance mechanism identified in CZA-NS+C/T-S isolates was a marker indicating the upregulation of MexAB-OprM. No mechanism was identified that is thought to support resistance to these agents in numerous isolates. This may be due in part to the fact that whole genome sequencing (WGS) cannot directly measure gene expression of chromosomal resistance mechanisms.

Rapid species differentiation and typing of Acinetobacter baumannii

Acinetobacter (A.) baumannii has emerged as a difficult-to-treat nosocomial bacterial human pathogen. A. baumannii is to be dealt with under the “One Health” approach, and its surveillance in human, animal, and environmental settings assumes paramount importance in understanding its plausible transmission dynamics. Accurate identification of A. baumannii, its clonal complexes, and sequence types is important for understanding the epidemiological distribution, evolutionary relationships, and transmission dynamics. A wide range of genotyping techniques are applied for the differentiation of the Acinetobacter calcoaceticus-baumannii (ACB) complex. However, there is no single straight-forward genotype method applied for rapid assays. Currently, two multilocus sequence typing (MLST) Oxford and Pasture schemes exist; though considered a gold standard for sequence typing, harmonizing the schemes is not a straightforward process. The whole genome sequencing-based core-genome multilocus sequence typing (cgMLST) and core single nucleotide polymorphism (cgSNP) are robust and precise sequence typing; however, they are expensive, depending on the quality of sequencing and demand a higher level of computational skills. In the past decade, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) based species identification has been successfully employed for rapid discrimination of the ACB complex. MALDI typing is rapid, easier, cheaper, and as reliable as molecular methods. Strain level A. baumannii identification confidence improved upon augmentation of existing databases with in-house reference spectra of well-defined isolates. The application of artificial intelligence and machine learning might be useful in clonal sequence types (ST)-level identification. The genus Acinetobacter’s taxonomic classification is evolving, and newer STs are being described; hence, the establishment of a central repository of A. baumannii reference spectra will help in harmonizing across the laboratories and help in the global level surveillance program on A. baumannii in “One Health” perspective. This review sheds light on the challenges related to techniques employed for the identification of Acinetobacter and the potential application and future perspectives of MALDI-TOF MS.

The novel 2024 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations and superseded WHO N. gonorrhoeae reference strains-phenotypic, genetic and reference genome characterization.

MDR and XDR Neisseria gonorrhoeae strains remain major public health concerns internationally, and quality-assured global gonococcal antimicrobial resistance (AMR) surveillance is imperative. The WHO global Gonococcal Antimicrobial Surveillance Programme (GASP) and WHO Enhanced GASP (EGASP), including metadata and WGS, are expanding internationally. We present the phenotypic, genetic and reference genome characteristics of the 2024 WHO gonococcal reference strains (n = 15) for quality assurance worldwide. All superseded WHO gonococcal reference strains (n = 14) were identically characterized. The 2024 WHO reference strains include 11 of the 2016 WHO reference strains, which were further characterized, and four novel strains. The superseded WHO reference strains include 11 WHO reference strains previously unpublished. All strains were characterized phenotypically and genomically (single-molecule PacBio or Oxford Nanopore and Illumina sequencing). The 2024 WHO reference strains represent all available susceptible and resistant phenotypes and genotypes for antimicrobials currently and previously used (n = 22), or considered for future use (n = 3) in gonorrhoea treatment. The novel WHO strains include internationally spreading ceftriaxone resistance, ceftriaxone resistance due to new penA mutations, ceftriaxone plus high-level azithromycin resistance and azithromycin resistance due to mosaic MtrRCDE efflux pump. AMR, serogroup, prolyliminopeptidase, genetic AMR determinants, plasmid types, molecular epidemiological types and reference genome characteristics are presented for all strains. The 2024 WHO gonococcal reference strains are recommended for internal and external quality assurance in laboratory examinations, especially in the WHO GASP, EGASP and other GASPs, but also in phenotypic and molecular diagnostics, AMR prediction, pharmacodynamics, epidemiology, research and as complete reference genomes in WGS analysis.

Global trends in carbapenem- and difficult-to-treat-resistance among World Health Organization priority bacterial pathogens: ATLAS surveillance program 2018–2022

ObjectivesTo report trends in carbapenem resistance and difficult-to-treat resistance (DTR) among clinical isolates of Gram-negative priority pathogens collected by the ATLAS global surveillance program from 2018 to 2022. MethodsReference broth microdilution testing was performed in a central laboratory for 79,214 Enterobacterales, 30,504 Pseudomonas aeruginosa, and 13,500 Acinetobacter baumannii-calcoaceticus complex isolates collected by a constant set of 157 medical centres in 49 countries in Asia Pacific (APAC), Europe (EUR), Latin America (LATAM), Middle East-Africa (MEA), and North America (NA) regions. MICs were interpreted by 2023 CLSI M100 breakpoints. β-lactamase genes were identified for meropenem-nonsusceptible (MIC ≥2 mg/L) Enterobacterales isolates. ResultsCarbapenem-resistant Enterobacterales (CRE) detection increased (P < 0.05) in APAC, EUR, LATAM, and MEA regions and decreased in NA, while annual DTR percentages increased in all five regions. Carbapenem-resistant P. aeruginosa (CRPA; decreased in MEA region) and carbapenem-resistant A. baumannii-calcoaceticus complex (CRAB; decreased in MEA region and increased in EUR) remained relatively stable over time in all regions, although notably, annual percentages of CRAB and DTR A. baumannii-calcoaceticus complex isolates were consistently >25 percentage points lower in NA than in other regions. For all regions except NA, the majority of changes in CRE percentages could be attributed to hospital-acquired infections. Among meropenem-nonsusceptible Enterobacterales, KPC was the most frequent carbapenemase in NA and EUR each year. NDM was the most prevalent carbapenemase detected in 2022 in other global regions. ConclusionCRE, CRPA, CRAB, and DTR rates vary among global regions over time highlighting the need for continuing surveillance to inform treatment strategies and antimicrobial stewardship.

Minimum inhibitory concentrations of antifungals against invasive isolates of Cryptococcus species worldwide: Global antifungal antimicrobial testing leadership and surveillance program, 2010–2020

This study examined the geographic distribution of minimum inhibitory concentrations (MICs) of antifungals against Cryptococcus isolates. Data were collected on the MICs of specific antifungals (amphotericin B, 5-flucytosine, fluconazole, voriconazole, posaconazole, and isavuconazole) against various Cryptococcus species for the period 2010 to 2020 from the Antimicrobial Testing Leadership and Surveillance database. Cryptococcus isolates were collected from samples of blood and cerebrospinal fluid (CSF) from patients hospitalized in different regions worldwide. We applied the epidemiological cutoff values (ECVs) of antifungals against various Cryptococcus species to distinguish wild-type (WT) from non-WT Cryptococcus isolates. A total of 395 isolates of Cryptococcus species cultured from blood (n = 201) or CSF (n = 194) were analyzed. C. grubii (n = 270), C. neoformans (n = 111), and C. gattii (n = 11) were the three predominant species causing bloodstream infections (BSI) or meningitis/meningoencephalitis (MME). The proportion of MICs above the ECV (1 mg/L) for amphotericin B among C. neoformans isolates was significantly lower than that among C. gattii isolates (MICs >0.5 mg/L; P < 0.001), as evaluated using the chi-square test. For most isolates of the three predominant Cryptococcus species, the MICs of new triazoles were ≤0.25 mg/L. The MICs of fluconazole and amphotericin B in the BSI/MME-causing Cryptococcus isolates collected from patients hospitalized in the Asia-Western Pacific region and Europe were significantly lower (i.e., the distributions were more leftward) than those in North America and Latin America. Ongoing monitoring of MIC data for important antifungals against cryptococcosis is crucial.

Activity of ceftolozane/tazobactam, imipenem/relebactam and ceftazidime/avibactam against clinical Gram-negative isolates-SMART United States 2019-21.

Ongoing national and international surveillance efforts are critical components of antimicrobial stewardship, resistance monitoring, and drug development programs. In this report, we summarize the results of ceftolozane/tazobactam, imipenem/relebactam, ceftazidime/avibactam and comparator agent testing against 10 509 Enterobacterales and 2524 Pseudomonas aeruginosa collected by USA clinical laboratories in 2019-21 as part of the SMART global surveillance programme. MICs were determined by CLSI broth microdilution and interpreted using 2023 CLSI M100 breakpoints. Most Enterobacterales were ceftazidime/avibactam susceptible (>99%), meropenem susceptible (99%) and ceftolozane/tazobactam susceptible (94%). Non-Morganellaceae Enterobacterales were also highly susceptible to imipenem/relebactam (99%). Ceftolozane/tazobactam inhibited 94% of Escherichia coli and 89% of Klebsiella pneumoniae with ceftriaxone non-susceptible/non-carbapenem-resistant phenotypes. Against P. aeruginosa, ceftolozane/tazobactam (97% susceptible) was more active than ceftazidime/avibactam (95%) and imipenem/relebactam (91%). MDR and difficult-to-treat resistance (DTR) phenotypes were identified in 13% and 7% of P. aeruginosa isolates, respectively. Ceftolozane/tazobactam remained active against 78% of MDR P. aeruginosa (13% and 23% higher than ceftazidime/avibactam and imipenem/relebactam, respectively) and against 74% of DTR P. aeruginosa (24% and 37% higher than ceftazidime/avibactam and imipenem/relebactam, respectively). Length of hospital stay at the time of specimen collection, ward type and infection type resulted in percent susceptible value differences of >5% across isolate demographic strata for some antimicrobial agent/pathogen combinations. We conclude that in the USA, in 2019-21, carbapenem (meropenem) resistance remained uncommon in Enterobacterales and ceftolozane/tazobactam was more active than both ceftazidime/avibactam and imipenem/relebactam against P. aeruginosa.

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

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

2127. In vitro Activities of Ceftaroline and Comparator Agents against Bacterial Pathogens Frequently Causing Community-Acquired Respiratory Tract Infections in Patients from a Global Population: ATLAS Surveillance Program 2018-2021

Abstract Background Community-acquired bacterial pneumonia (CABP) is a frequent cause of patient morbidity and mortality. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are frequent etiologic agents of CABP. Ceftaroline fosamil is a parenteral cephem approved treatment of patients with CABP caused by S. pneumoniae (including cases with concurrent bacteremia), methicillin-susceptible Staphylococcus aureus (MSSA), H. influenzae, and some species of Enterobacterales. In this study we report the in vitro activity of ceftaroline and comparators against isolates from community-acquired respiratory tract infections (CARTI) collected through a global surveillance program. Methods Clinically relevant, non-duplicate, isolates cultured from respiratory specimens by clinical laboratories in 54 countries in 2018-2021 were collected by the ATLAS Surveillance Program central laboratory (IHMA, Schaumburg, IL, USA). Community-acquired infections were defined as those from patients &amp;lt; 48 hours in hospital. In total, 7,886 isolates of S. pneumoniae, H. influenzae, M. catarrhalis, MSSA, and methicillin-resistant S. aureus (MRSA) were tested. The isolates (n/percent of total) originated from Asia/South Pacific (1,893/24.0%); Europe (4,283/54.3%); Latin America (671/8.5%); Middle East/Africa (659/8.4%); and North America (Canada only) (380/4.8%). Ceftaroline and comparator agent MICs were determined by CLSI M07 broth microdilution methodology. MICs were interpreted using 2023 CLSI M100 MIC breakpoints. Results The in vitro activity of ceftaroline and comparator agents is summarized in the table. Greater than 99% of S. pneumoniae and 100% of MSSA were susceptible to ceftaroline, including penicillin-nonsusceptible S. pneumoniae based on a dosage of 600 mg every 12h. Sixty-two (9.6%) MRSA were ceftaroline-susceptible-dose-dependent (MIC 2-4 µg/mL) based on a dosage of 600 mg every 8h administered over 2h, with the majority from (n) Thailand (9), S. Korea (7), and China (6). Four isolates, from S. Korea (2), China (1), and Ukraine (1) were resistant to CPT (MIC of ≥8 µg/mL). 99.6% of H. influenzae were susceptible to ceftaroline. Conclusion Ceftaroline demonstrated potent in vitro activity against current pathogens associated with CABP from a global collection. Disclosures Meredith Hackel, PhD, Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck &amp; Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

2154. Cross-resistance of Ceftolozane-Tazobactam and Imipenem-Relebactam Against Clinical P. aeruginosa Isolates from Bloodstream and Respiratory Tract Infections– SMART United States 2019-2021

Abstract Background Antimicrobial resistance among Pseudomonas aeruginosa is challenging with limited treatment options. Ceftolozane/tazobactam (C/T) maintains activity against P. aeruginosa resistant to commonly used β-lactams. Imipenem/relebactam (IMI/REL) can restore the activity of IMI against P. aeruginosa. C/T and IMI/REL can be affected by different mechanisms of resistance, and pathogens can be nonsusceptible to one agent but susceptible to the other. We evaluated the activity of C/T and IMI/REL against P. aeruginosa isolates collected from patients with lower respiratory tract (LRTI) and bloodstream (BSI) infections in the United States as part of the global SMART surveillance program. Methods In 2019-2021, 24 US clinical labs collected up to 100 consecutive, aerobic or facultative, gram-negative pathogens from LRTI and up to 50 from BSI. Of 8643 collected isolates, 1986 (23%) were P. aeruginosa. Susceptibility was determined with CLSI broth microdilution and 2023 CLSI breakpoints. Results Among P. aeruginosa BSI and LRTI isolates, 88% were susceptible (S) to both C/T and IMI/REL, 2% were nonsusceptible (NS) to both agents; 8% were S to C/T but not to IMI/REL, and 2% were S to IMI/REL but not to C/T (Table 1). Among MDR and DTR isolates, 45% and 29%, respectively, were S to both C/T and IMI/REL and 11% and 20%, respectively, were NS to both. Among C/T-NS isolates, 57.3% and 44.0% were S to IMI/REL and ceftazidime/avibactam (CZA), respectively (Table 2). Among IMI/REL-NS isolates, 83% were C/T-S, 69% CZA-S, and &amp;lt; 43% were S to all other studied β-lactams and LVX. Among CZA-R isolates, 61% and 47% remained S to C/T and IMI/REL, respectively. Conclusion Resistance to both C/T and IMI/REL was not common among recent clinical isolates of P. aeruginosa from the US, and both agents represent important treatment options. A significant proportion of isolates NS to one agent were S to the other, especially among MDR and DTR isolates. The data suggest that susceptibility to both agents should be tested. Disclosures Sibylle Lob, MD, Merck &amp; Co., Inc.: Honoraria Mark G Wise, PhD, Merck &amp; Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Fakhar Siddiqui, MD, MBA, Merck &amp; Co Inc.: Employee Daniel F. Sahm, PhD, Merck &amp; Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

2119. In Vitro Activity of Aztreonam-Avibactam Against Enterobacterales Isolated from Pediatric and Adult Patients Collected During the ATLAS Global Surveillance Program, 2017-2021

Abstract Background The spread of antimicrobial resistance among clinically isolated Enterobacterales (Eba) threatens public health. Aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs) and avibactam (AVI) inhibits class A, class C, and some class D serine β-lactamases. ATM-AVI is being developed for use against infections caused by drug-resistant Eba, especially those co-producing MBLs and other β-lactamases. This study evaluated the in vitro activity of ATM-AVI and comparators against Eba collected in 2017-2021 from pediatric and adult patients as part of the ATLAS global surveillance program. Methods 84428 non-duplicate Eba isolates were collected from patients in 255 medical centers in 56 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem MIC &amp;gt;1 µg/mL, and a randomly sampled subset of approximately 80% of Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC &amp;gt;1 µg/mL. Results MIC90 values for ATM-AVI of 0.12 µg/ml (pediatric isolates) and 0.25 µg/ml (adult isolates) were observed. Against all Eba isolates, ≤8 µg/ml of ATM-AVI was sufficient to inhibit 99.9% of both pediatric and adult isolates, whereas only 68.0% (pediatric) and 71.9% (adult) of these isolates were susceptible to ATM alone (table). Among isolates that screened positive for an MBL, MIC90 values for ATM-AVI were 0.5 µg/ml (pediatric) and 1 µg/ml (adult) and ATM-AVI inhibited 100% (pediatric) and 99.1% (adult) at concentrations ≤8 µg/ml. In contrast, only 16.1% (pediatric) and 17.9% (adult) of MBL-positive isolates were susceptible to ATM alone. Conclusion Based on MIC90 values, ATM-AVI demonstrated potent in vitro activity against Eba isolated both from pediatric and adult patients. Avibactam’s ability to potentiate ATM against MBL-positive isolates warrants its continued development. Disclosures Mark Estabrook, PhD, Pfizer Inc.: Honoraria Daniel F. Sahm, PhD, Merck &amp; Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

In vitro activity of aztreonam–avibactam against Enterobacterales isolates collected in Latin America, Africa/Middle East, Asia, and Eurasia for the ATLAS Global Surveillance Program in 2019–2021

This study aimed to report reference method antimicrobial susceptibility results for 24,937 recent (2019–2021) clinical isolates of Enterobacterales from 27 countries in Latin America, Eurasia, Africa/Middle East, and Asia with a focus on the investigational combination aztreonam–avibactam against metallo-β-lactamase (MBL) isolates. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution methodology. Minimum inhibitory concentrations (MICs) were interpreted using the CLSI (2022) breakpoints for all agents except aztreonam–avibactam (provisional pharmacokinetic/pharmacodynamic susceptible breakpoint, ≤ 8 mg/L) and tigecycline (US-FDA). Molecular testing for β-lactamase genes was performed on isolates with meropenem MICs ≥ 2 mg/L, ceftazidime–avibactam MICs ≥ 16 mg/L, and/or aztreonam–avibactam MICs ≥ 16 mg/L, and 50% of isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs ≥ 2 mg/L. Aztreonam–avibactam inhibited 99.8% of all Enterobacterales at ≤ 8 mg/L (MIC90, 0.25 mg/L) and maintained activity against phenotypically resistant subsets of multidrug-resistant (MDR) (99.5% susceptible), extensively drug-resistant (XDR) (98.7%), and carbapenem-resistant Enterobacterales (CRE) (99.1%) isolates. At ≤ 8 mg/L, aztreonam–avibactam inhibited 100%, 99.6%, 99.6%, and 98.8% of KPC-, OXA-48-like-, ESBL-, and MBL-carrying isolates, respectively. MBL-positive isolates were most prevalent in India (20.5%), Guatemala (13.8%), and Jordan (13.2%). No differences in the activity of aztreonam–avibactam were observed across the global regions evaluated. At a concentration of ≤ 8 mg/L, aztreonam–avibactam inhibited almost all Enterobacterales collected from developing countries, including MBL-producing isolates. The widespread dissemination of MBLs among Enterobacterales highlights the unmet need for new agents such as aztreonam–avibactam for the treatment of CRE infections.

Temporal and geographical prevalence of carbapenem-resistant Pseudomonas aeruginosa and the in vitro activity of ceftolozane/tazobactam and comparators in Taiwan—SMART 2012–2021

To determine the in vitro activities of ceftolozane/tazobactam (C/T) and comparators against Pseudomonas aeruginosa isolates cultured from hospitalised patient samples in Taiwan from 2012 to 2021 with an additional focus on the temporal and geographical prevalence of carbapenem-resistant P. aeruginosa (CRPA). P. aeruginosa isolates (n=3013) were collected annually by clinical laboratories in northern (two medical centres), central (three medical centres), and southern Taiwan (four medical centres) as part of the SMART global surveillance program. MICs were determined by CLSI broth microdilution and interpreted using 2022 CLSI breakpoints. Molecular β-lactamase gene identification was performed on selected non-susceptible isolate subsets in 2015 and later. Overall, 520 (17.3%) CRPA isolates were identified. The prevalence of CRPA increased from 11.5%-12.3% (2012-2015) to 19.4%-22.8% (2018-2021) (P ≤ 0.0001). Medical centres in northern Taiwan reported the highest percentages of CRPA. C/T, first tested in the SMART program in 2016, was highly active against all P. aeruginosa (97% susceptible), with annual susceptibility rates ranging from 94% (2017) to 99% (2020). Against CRPA, C/T inhibited >90% of isolates each year, with the exception of 2017 (79.4% susceptible). Most CRPA isolates (83%) were molecularly characterised, and only 2.1% (9/433) carried a carbapenemase (most commonly, VIM); all nine carbapenemase-positive isolates were from northern and central Taiwan. The prevalence of CRPA increased significantly in Taiwan from 2012 to 2021 and warrants continued monitoring. In 2021, 97% of all P. aeruginosa and 92% of CRPA in Taiwan were C/T susceptible. Routine in vitro susceptibility testing of clinical isolates of P. aeruginosa against C/T, and other newer β-lactam/β-lactamase inhibitor combinations, appears prudent.

In vitro activity of imipenem/relebactam against non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa in the Asia-Pacific region: SMART 2017-2020

ObjectivesTo describe the in vitro activity of imipenem/relebactam (IMR) against non-Morganellaceae Enterobacterales (NME) and Pseudomonas aeruginosa, including piperacillin/tazobactam-nonsusceptible and meropenem-nonsusceptible isolates, infecting hospitalized patients in the Asia-Pacific region. MethodsFrom 2017 to 2020, 49 clinical laboratories in nine countries in the Asia-Pacific region participated in the SMART global surveillance program and contributed 26 783 NME and 6383 P. aeruginosa. Minimum inhibitory concentrations (MICs) were determined using CLSI broth microdilution and interpreted using CLSI M100 (2021) breakpoints. β-Lactamase genes were identified in selected isolate subsets (2017–2020) and oprD was sequenced in molecularly characterized P. aeruginosa collected in 2020. ResultsAmikacin (97.9% susceptible), IMR (95.8%), meropenem (95.4%), and imipenem (92.6%) were the most active agents against NME. Among piperacillin/tazobactam-nonsusceptible NME (n=4070), 76.1% were IMR-susceptible (range by country, 97.5% [New Zealand] to 50.6% [Vietnam]); 22.4% of meropenem-nonsusceptible NME (n=1225) were IMR-susceptible (range by country, 68.8% [South Korea] to 7.6% [Thailand]). A total of 2.7% of NME carried a metallo-β-lactamase (MBL), 0.9% an OXA-48-like carbapenemase (MBL-negative), and 0.7% a KPC (MBL-negative). Amikacin (94.0% susceptible) and IMR (90.3%) were the most active agents against P. aeruginosa; 71.2% of isolates were imipenem-susceptible. Relebactam increased susceptibility to imipenem by 25.6% (from 40.5% to 66.1%) in piperacillin/tazobactam-nonsusceptible and by 44.8% (from 7.1% to 51.9%) in meropenem-nonsusceptible P. aeruginosa. Only 4.3% of P. aeruginosa were MBL-positive. A total of 70.3% (90/128) of IMR-nonsusceptible P. aeruginosa were oprD-deficient. ConclusionIn 2017–2020, 96% of NME and 90% of P. aeruginosa from the Asia-Pacific region were IMR-susceptible. IMR percent susceptible rates were higher in countries with lower MBL carriage.

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

BackgroundCarbapenem-resistant bacteria are an increasing problem in clinical practice; thus, it is important to identify β-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.ResultsBetween 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 β-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.ConclusionsRelebactam 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.

Implementation of WGS analysis of ESBL-producing Escherichia coli within EU AMR monitoring in livestock and meat.

As WGS comes of age, changes in EU legislation implemented in 2021 allow its usage for systematic monitoring of ESBL-producing Escherichia coli from livestock and meat, replacing phenotypic testing. Presently, phenotypic testing correlates well with antimicrobial resistance predicted from WGS data. WGS has added value in the wealth of additional information that is present in the data. In this study we have detected the resistance phenotypes for a panel of antimicrobials while also analysing the molecular epidemiology of ESBL-producing E. coli. Susceptibility testing was performed with broth microdilution of selectively isolated E. coli. Short-read WGS was performed in parallel and phenotypes predicted based on the sequence data, which was also used to determine the phylogeny of the isolates. The phenotypically determined resistance and the predicted resistance correlated 90%-100% for the different antimicrobial classes. Furthermore, clonal relationships were detected amongst ESBL-producing E. coli within livestock sectors and the meat produced by this sector. Further implementation of WGS analysis of ESBL/AmpC-producing E. coli within the AMR monitoring programme of EU member states and global surveillance programmes will contribute to determining the attribution of livestock in the prevalence of ESBL/AmpC-encoding E. coli in humans.

In vitro activity of imipenem/relebactam against non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa in Latin America: SMART 2018‒2020.

Carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa are being isolated from patient specimens with increasing frequency in Latin America and worldwide. The current study provides an initial description of the in vitro activity of Imipenem/Relebactam (IMR) against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa infecting hospitalized patients in Latin America. From2018to2020, 37clinical laboratories in nine Latin American countries participated in the SMART global surveillance program and contributed 15,466 NME and 3408 P aeruginosa isolates. MICs for IMR and seven comparators were determined using CLSI broth microdilution and interpreted by CLSI M100 (2022) breakpoints. β-lactamase genes were identified in selected isolate subsets. IMR (96.9%susceptible), amikacin(95.9%), meropenem(90.7%), and imipenem(88.7%) were the most active agents against NME. Among piperacillin/tazobactam-nonsusceptible NME (n = 4124), 90.4%of isolates were IMR-susceptible (range by country, 97.2[Chile] to67.0%[Guatemala]) and among meropenem-nonsusceptible NME isolates (n = 1433), 74.0%were IMR-susceptible (94.1%[Puerto Rico] to5.1% [Guatemala]). Overall, 6.3%of all collected NME isolates carried a KPC (metallo-β-lactamase [MBL]-negative), 1.8%an MBL, 0.4%an OXA-48-like carbapenemase (MBL-negative), and 0.1%a GES carbapenemase (MBL-negative). Amikacin (85.2%susceptible) and IMR (80.1%) were the most active agents against P. aeruginosa; only56.5% of isolates were imipenem susceptible. Relebactam increased susceptibility to imipenem by22.0% (from23.9%to45.9%) in piperacillin/tazobactam-nonsusceptible isolates (n = 1031) and by35.5%(from5.5%to41.0%) in meropenem-nonsusceptible isolates (n = 1128). Overall, 7.6%of all collected P. aeruginosa isolates were MBL-positive and0.7%carried a GES carbapenemase. In conclusion, in2018‒2020, almost all NME(97%) and most P. aeruginosa(80%) isolates from Latin America were IMR-susceptible. Continued surveillance of the in vitro activities of IMR and comparator agents against Gram-negative pathogens, and monitoring for β-lactamase changes (in particular for increases in MBLs), is warranted.

Epidemiology of Resistance Determinants Identified in Meropenem-Nonsusceptible Enterobacterales Collected as Part of a Global Surveillance Study, 2018 to 2019.

The objective of this study was to describe the frequency of resistance determinants in meropenem-nonsusceptible (MEM-NS) Enterobacterales isolates collected in 2018 and 2019 as a part of the ATLAS global surveillance program. Among a total of 39,368 Enterobacterales isolates collected in 2018 and 2019, 5.7% were MEM-NS (MIC ≥2 μg/mL). Among the different regions, the proportion of MEM-NS isolates ranged from 1.9% (North America) to 8.4% (Asia/Pacific). The majority of MEM-NS isolates collected were of the species Klebsiella pneumoniae (71.5%). Among the MEM-NS Enterobacterales isolates collected, metallo-β-lactamases (MBL) were identified in 36.7%, KPC in 25.5%, and OXA-48-like in 24.1%. The predominance of resistance mechanisms among MEM-NS isolates varied by region: MBLs were dominant in isolates collected in Africa and Middle East (AfME, 49%) and Asia/Pacific (59.4%), OXA-48-like carbapenemases were predominant in Europe (30%), and KPC in Latin America (51.9%) and North America (53.6%). NDM β-lactamases accounted for the majority of MBLs identified (88.4%). Of the 38 carbapenemase variants identified, NDM-1 (68.7%), KPC-2 (54.6%), OXA-48 (54.3%), and VIM-1 (76.1%) were the common variants within their respective families. Among the MEM-NS isolates, 7.9% co-carried two carbapenemases. Notably, the proportion of MEM-NS Enterobacterales increased from 4.9% in 2018 to 6.4% in 2019. The results of this study show a continuation of the trend of increasing carbapenem-resistance within clinical Enterobacterales with mechanisms of resistance varying across different regions. The existential threat to public health posed by the continued spread of nearly untreatable pathogens requires a multifaceted approach to prevent the collapse of modern medicine.

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

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

In vitro activity of imipenem/relebactam against piperacillin/tazobactam-resistant and meropenem-resistant non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa collected from patients with bloodstream, intra-abdominal and urinary tract infections in Western Europe: SMART 2018-2020.

Introduction. Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents is a significant concern in clinical isolates of Enterobacterales and Pseudomonas aeruginosa; new agents with improved activity are needed.Gap Statement. Publication of current, region-specific data describing the in vitro activity of newer agents such as imipenem/relebactam (IMR) against piperacillin/tazobactam-resistant and carbapenem-resistant Enterobacterales and P. aeruginosa are needed to support their clinical use.Aim. To describe the in vitro activity of IMR against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa isolated from bloodstream, intra-abdominal and urinary tract infection samples by hospital laboratories in Western Europe with a focus on the activity of IMR against piperacillin/tazobactam-resistant and meropenem-resistant isolates.Methodology. From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 9487 NME and 1004 P. aeruginosa isolates. MICs were determined by CLSI broth microdilution testing and interpreted by EUCAST (2021) breakpoints. β-Lactamase genes were identified in selected isolate subsets (2018-2020) and oprD sequenced in molecularly characterized P. aeruginosa (2020).Results. IMR (99.4 % susceptible), amikacin (98.0 %), meropenem (97.7 %) and imipenem (97.6 %) were the most active agents against NME; 83.1 % of NME were piperacillin/tazobactam-susceptible. Relebactam increased imipenem susceptibility of NME from Italy by 8.3 %, from Portugal by 2.9 %, and from France, Germany, Spain and the UK by <1 %. In total, 96.4 % of piperacillin/tazobactam-resistant (n=1601) and 73.7 % of meropenem-resistant (n=152) NME were IMR-susceptible. Also, 0.4 % of NME were MBL-positive, 0.9 % OXA-48-like-positive (MBL-negative) and 1.5 % KPC-positive (MBL-negative). Amikacin (95.4 % susceptible) and IMR (94.1 %) were the most active agents against P. aeruginosa; 81.7 % of isolates were imipenem-susceptible and 79.6 % were piperacillin/tazobactam-susceptible. Relebactam increased susceptibility to imipenem by 12.5 % overall (range by country, 4.3-17.5 %); and by 30.7 % in piperacillin/tazobactam-resistant and 24.3 % in meropenem-resistant P. aeruginosa. In total, 1.6 % of P. aeruginosa isolates were MBL-positive. Seven of eight molecularly characterized IMR-resistant P. aeruginosa isolates from 2020 were oprD-deficient.Conclusion. IMR may be a potential treatment option for bloodstream, intra-abdominal and urinary tract infections caused by NME and P. aeruginosa in Western Europe, including infections caused by piperacillin/tazobactam-resistant and meropenem-resistant isolates.