Antimicrobial Surveillance Program Research Articles

The use of new antibacterial drugs against infections caused by multidrug-resistant Gram-negative bacteria: an Italian real-world evidence study in a Lombardy hospital.

Infections caused by multidrug-resistant (MDR) bacteria are typically associated with high morbidity and mortality, especially in vulnerable individuals such as patients with prolonged hospitalizations, immunocompromised individuals, and the elderly. This study aimed to provide post-marketing surveillance results concerning the prevalence of antibiotic resistance against Gram-negative bacteria through the collaboration of a multidisciplinary team. Patients involved have been treated with new antibacterial drugs, in particular ceftazidime/avibactam (C/A), meropenem/vaborbactam (M/V), cefiderocol, and ceftolozane/tazobactam (C/T). The most resistant bacterial species were Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter baumannii. Italian Drug Agency (AIFA) monitoring records for inpatients have been collected and analyzed, assessing the characteristics of the patients involved. Adverse drug reactions (ADRs) and drugs involved have been reported using a descriptive analytical approach. All data have been collected retrospectively from patient's medical records and entered into an electronic case report form (CRF). Among the 104 treated patients, Klebsiella spp. accounted for 50.1% of infections, Pseudomonas aeruginosa for 32.7%, Acinetobacter baumannii for 3%, and other bacterial species for 1.92% configuring polymicrobial infections. Regarding treatment outcomes, healing was achieved in 61 (58.6%) patients, 23 (22.1%) patients died, 8 (7.7%) patients discontinued empirical therapy, and 3 (2.9%) patients were lost to follow-up. Despite the introduction of new antibacterial drugs active against Gram-negative bacteria is improving the clinical scenario, it is crucial that the use of new antibacterial drugs be implemented by appropriate antimicrobial stewardship, surveillance programs, and monitoring efforts to prevent further spread of resistance. This study showed that the new antibiotics have good efficacy against MDR bacteria and cause negligible side effects.

Trend of distribution and antimicrobial resistance in uropathogens in China from the CHINET antimicrobial resistance surveillance program, a 7-year retrospective study

Trend of distribution and antimicrobial resistance in uropathogens in China from the CHINET antimicrobial resistance surveillance program, a 7-year retrospective study

Global epidemiology and antimicrobial resistance of Enterobacterales harbouring genes encoding OXA-48-like carbapenemases: insights from the results of the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme 2018-2021.

The recent emergence of carbapenem-resistant Enterobacterales poses a major and escalating threat to global public health. This study aimed to analyse the global distribution and antimicrobial resistance of Enterobacterales harbouring variant OXA-48-like carbapenemase-related genes. Enterobacterales isolates were collected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme during 2018-2021. Comprehensive antimicrobial susceptibility testing and β-lactamase gene detection were also conducted, along with statistical analysis of the collected data. Among the 72 244 isolates, 1934 Enterobacterales isolates were identified to harbour blaOXA-48-like genes, predominantly Klebsiella spp. (86.9%). High rates of multidrug resistance were observed, with only ceftazidime/avibactam and tigecycline showing favourable susceptibility. A discrepancy between the genotype and phenotype of carbapenem resistance was evident: 16.8% (233 out of 1384) of the Enterobacterales isolates with blaOXA-48-like genes exhibited susceptibility to meropenem. Specifically, 37.4% (64/95) of Escherichia coli strains with blaOXA-48-like genes displayed meropenem susceptibility, while the corresponding percentages for Klebsiella pneumoniae and Enterobacter cloacae complex were 25.2% (160/1184) and 0% (0/36), respectively (P < 0.05). Geographical analysis revealed that the highest prevalence of blaOXA-48-like genes occurred in Asia, the Middle East and Eastern Europe. The proportion of K. pneumoniae isolates harbouring blaOXA-232 increased from 23.9% in 2018 to 56.0% in 2021. By contrast, the proportion of blaOXA-48 decreased among K. pneumoniae isolates during 2018-2021. This study underscores the widespread and increasing prevalence of blaOXA-48-like genes in Enterobacterales and emphasizes the need for enhanced surveillance, improved diagnostic methods and tailored antibiotic stewardship to combat the spread of these resistant pathogens.

Antimicrobial-resistant Neisseria gonorrhoeae in Europe in 2020 compared with in 2013 and 2018: a retrospective genomic surveillance study

Regular quality-assured whole-genome sequencing linked to antimicrobial resistance (AMR) and patient metadata is imperative to elucidate the shifting gonorrhoea epidemiology, both nationally and internationally. We aimed to examine the gonococcal population in the European Economic Area (EEA) in 2020, elucidate emerging and disappearing gonococcal lineages associated with AMR and patient metadata, compare with 2013 and 2018 whole-genome sequencing data, and explain changes in gonococcal AMR and gonorrhoea epidemiology. In this retrospective genomic surveillance study, we analysed consecutive gonococcal isolates that were collected in EEA countries through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) in 2020, and made comparisons with Euro-GASP data from 2013 and 2018. All isolates had linked AMR data (based on minimum inhibitory concentration determination) and patient metadata. We performed whole-genome sequencing and molecular typing and AMR determinants were derived from quality-checked whole-genome sequencing data. Links between genomic lineages, AMR, and patient metadata were examined. 1932 gonococcal isolates collected in 2020 in 21 EEA countries were included. The majority (81·2%, 147 of 181 isolates) of azithromycin resistance (present in 9·4%, 181 of 1932) was explained by the continued expansion of the Neisseria gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) clonal complexes (CCs) 63, 168, and 213 (with mtrD/mtrR promoter mosaic 2) and the novel NG-STAR CC1031 (semi-mosaic mtrD variant 13), associated with men who have sex with men and anorectal or oropharyngeal infections. The declining cefixime resistance (0·5%, nine of 1932) and negligible ceftriaxone resistance (0·1%, one of 1932) was largely because of the progressive disappearance of NG-STAR CC90 (with mosaic penA allele), which was predominant in 2013. No known resistance determinants for novel antimicrobials (zoliflodacin, gepotidacin, and lefamulin) were found. Azithromycin-resistant clones, mainly with mtrD mosaic or semi-mosaic variants, appear to be stabilising at a relatively high level in the EEA. This mostly low-level azithromycin resistance might threaten the recommended ceftriaxone-azithromycin therapy, but the negligible ceftriaxone resistance is encouraging. The decreased genomic population diversity and increased clonality could be explained in part by the COVID-19 pandemic resulting in lower importation of novel strains into Europe. European Centre for Disease Prevention and Control and Örebro University Hospital.

Fourth national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from patients with complicated urinary tract infections

IntroductionAntimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species. Materials and methodsData were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan. ResultsFluoroquinolone required a minimum inhibitory concentration (MIC) of 2–64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 μg/mL) decreased from 14.7% to 7.7%. DiscussionBacterial strains that produced extended-spectrum β-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years.

High prevalence of ceftriaxone-resistant and XDR Neisseria gonorrhoeae in several cities of Cambodia, 2022-23: WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP).

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global public health concern. Ceftriaxone is the last effective and recommended option for empirical gonorrhoea therapy worldwide, but several ceftriaxone-resistant cases linked to Asia have been reported internationally. During January 2022-June 2023, the WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) investigated N. gonorrhoeae AMR and epidemiological factors in patients from 10 clinical sentinel sites in Cambodia. Urethral swabs from males with urethral discharge were cultured. ETEST determined the MIC of five antimicrobials, and EGASP MIC alert values and EUCAST breakpoints were used. EGASP demographic, behavioural and clinical variables were collected using a standardized questionnaire. From 437 male patients, 306 had positive N. gonorrhoeae cultures, AMR testing and complete epidemiological data. Resistance to ceftriaxone, cefixime, azithromycin and ciprofloxacin was 15.4%, 43.1%, 14.4% and 97.1%, respectively. Nineteen (6.2%) isolates were resistant to all four antimicrobials and, accordingly, categorized as XDR N. gonorrhoeae. These XDR isolates were collected from 7 of the 10 sentinel sites. No EGASP MIC alert values for gentamicin were reported. The nationally recommended cefixime 400 mg plus azithromycin 1 g (65.4%) or ceftriaxone 1 g plus azithromycin 1 g (34.6%) was used for treatment. A high prevalence of ceftriaxone-resistant, MDR and XDR N. gonorrhoeae in several cities of Cambodia were found during 2022-23 in WHO EGASP. This necessitates expanded N. gonorrhoeae AMR surveillance, revision of the nationally recommended gonorrhoea treatment, mandatory test of cure, enhanced sexual contact notification, and ultimately novel antimicrobials for the treatment of gonorrhoea.

Molecular Prevalence of MecA and MecC Genеs in Coagulasе-Positive Staphylococci Isolated From Dogs with Dermatitis and Otitis in Belgrade, Serbia: A One Year Study

Abstract The escalating global concern of antimicrobial resistance in human and veterinary medicine is exacerbated by the inappropriate prescription of antibiotics for bacterial infections in companion animals. This study aimed to determine the distribution of coagulase-positive staphylococci causing clinical skin and ear infections in dogs and to determine methicillin-resistant isolates. A total of 78 staphylococcal strains were isolated from clinical samples taken from patients at the Dermatology Clinic at the Faculty of Veterinary Medicine in Belgrade, Serbia. Multiplex PCR was used for species-specific identification, and mecA and mecC genes were used to determine methicillin resistance, in addition to phenotypic determination, MIC values and detection of PBP2a. Out of the 78 samples analyzed, 65.8% were identified as Staphylococcus pseudintermedius, 22.4% as S. aureus, 7.9% as S. coagulans, and 3.9% as S. intermedius. Four S. aureus isolates exhibited methicillin resistance confirmed by cefoxitin disk diffusion, while five were confirmed with MIC testing and latex agglutination. MecA gene was detected in 29.4% of S. aureus and 30% of S. pseudintermedius isolates. These isolates were classified as methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. pseudintermedius (MRSP), respectively. No isolates carried the mecC gene. This study provides insights into the prevalence of CoPS species and methicillin resistance in isolates from dogs. Continued surveillance is essential to monitor and understand the emergence and dissemination of antimicrobial resistance in veterinary medicine and the results of this study accent the need for establishment of a continuous antimicrobial resistance surveillance program in the Republic of Serbia.

Predictive Modeling of Phenotypic Antimicrobial Susceptibility of Selected Beta-Lactam Antimicrobials from Beta-Lactamase Resistance Genes.

The outcome of bacterial infection management relies on prompt diagnosis and effective treatment, but conventional antimicrobial susceptibility testing can be slow and labor-intensive. Therefore, this study aims to predict phenotypic antimicrobial susceptibility of selected beta-lactam antimicrobials in the bacteria of the family Enterobacteriaceae from different beta-lactamase resistance genotypes. Using human datasets extracted from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program conducted by Pfizer and retail meat datasets from the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS), we used a robust or weighted least square multivariable linear regression modeling framework to explore the relationship between antimicrobial susceptibility data of beta-lactam antimicrobials and different types of beta-lactamase resistance genes. In humans, in the presence of the blaCTX-M-1, blaCTX-M-2, blaCTX-M-8/25, and blaCTX-M-9 groups, MICs of cephalosporins significantly increased by values between 0.34-3.07 μg/mL, however, the MICs of carbapenem significantly decreased by values between 0.81-0.87 μg/mL. In the presence of carbapenemase genes (blaKPC, blaNDM, blaIMP, and blaVIM), the MICs of cephalosporin antimicrobials significantly increased by values between 1.06-5.77 μg/mL, while the MICs of carbapenem antimicrobials significantly increased by values between 5.39-67.38 μg/mL. In retail meat, MIC of ceftriaxone increased significantly in the presence of blaCMY-2, blaCTX-M-1, blaCTX-M-55, blaCTX-M-65, and blaSHV-2 by 55.16 μg/mL, 222.70 μg/mL, 250.81 μg/mL, 204.89 μg/mL, and 31.51 μg/mL respectively. MIC of cefoxitin increased significantly in the presence of blaCTX-M-65 and blaTEM-1 by 1.57 μg/mL and 1.04 μg/mL respectively. In the presence of blaCMY-2, MIC of cefoxitin increased by an average of 8.66 μg/mL over 17 years. Compared to E. coli isolates, MIC of cefoxitin in Salmonella enterica isolates decreased significantly by 0.67 μg/mL. On the other hand, MIC of ceftiofur increased in the presence of blaCTX-M-1, blaCTX-M-65, blaSHV-2, and blaTEM-1 by 8.82 μg/mL, 9.11 μg/mL, 8.18 μg/mL, and 1.04 μg/mL respectively. In the presence of blaCMY-2, MIC of ceftiofur increased by an average of 10.20 μg/mL over 14 years. The ability to predict antimicrobial susceptibility of beta-lactam antimicrobials directly from beta-lactamase resistance genes may help reduce the reliance on routine phenotypic testing with higher turnaround times in diagnostic, therapeutic, and surveillance of antimicrobial-resistant bacteria of the family Enterobacteriaceae.

In vitro activity of ceftazidime-avibactam and comparators against OXA-48-like Enterobacterales collected between 2016 and 2020.

Resistance to carbapenems among Enterobacterales is often due to the production of enzymes that are members of the oxacillinases (OXA)-48-like family. These organisms can also be resistant to other classes of drugs and are difficult to identify and treat. This study evaluated the activity of the drug ceftazidime-avibactam (CAZ-AVI) and other comparator agents against a global collection of Enterobacterales that produce OXA-48-like enzymes. CAZ-AVI was active against blaOXA-48-like Enterobacterales, and only colistin and tigecycline were similarly active among the comparator agents, highlighting the limited treatment options against these organisms. Continued surveillance of the distribution of these OXA 48-like producing Enterobacterales and monitoring of resistance patterns along with the implementation of antimicrobial stewardship measures to guide antibiotic use and appropriate treatment are necessary to avoid drug resistance among these organisms.

In vitro antimicrobial susceptibility data of global meropenem-resistant Acinetobacter baumannii isolates causing pneumonia: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2014–2021, and re-estimations of susceptibility breakpoints and appropriate dosages of important antibiotics for pneumonia treatment

To evaluate the susceptibility of globally pneumonia-causing meropenem-resistant (MEM-R) Acinetobacter baumannii isolates against important antibiotics and estimate appropriate dosages of indicated antibiotics. We extracted the 2014-2021 Antimicrobial Testing of Leadership Surveillance database regarding the susceptibility of MEM-R A. baumannii isolates causing pneumonia against important antibiotics. The susceptibility and carbapenemase-encoding gene (CPEG) data of pneumonia-causing MEM-R A. baumannii isolates from patients hospitalized in intensive care units of five major regions were analyzed. The susceptibility breakpoints (SBP) recommended by the Clinical and Laboratory Standards Institute (CLSI) in 2022, other necessary criteria [SBP of MIC for colistin, 2 mg/L, in the CLSI 2018; and cefoperazone-sulbactam (CFP-SUL), 16 mg/L], and the pharmacokinetic and pharmacodynamic data of indicated antibiotics were employed. Applying the aforementioned criteria, we observed the susceptible rates of colistin, minocycline, and CFP-SUL against the pneumonia-causing MEM-R A. baumannii isolates globally (n = 2905) were 93.2%, 69.1%, and 26.3%, respectively. Minocycline was significantly more active in vitro (MIC ≤4 mg/L) against the pneumonia-causing MEM-R A. baumannii isolates collected from North and South America compared to those from other regions (>90% vs. 58-72%). Additionally, blaOXA-23 and blaOXA-72 were the predominant CPEG in pneumonia-causing MEM-R A. baumannii isolates. After deliberative estimations, dosages of 200 mg minocycline intravenously every 12 h (SBP, 8 mg/L), 100 mg tigecycline intravenously every 12 h (SBP, 1 mg/L), and 160 mg nebulized colistin methanesulphonate every 8 h (SBP, 2 mg/L) are needed for the effective treatment of pneumonia-causing MEM-R A. baumannii isolates.

IMPACT OF ANTIMICROBIAL STEWARDSHIP PROGRAMMES ONBACTERIAL RESISTANCE LEVEL IN THE UAE: A SYSTEMATICREVIEW

Antimicrobial resistance is a global problem that needs to be addressed immediately due to its huge clinical and economic burden ((WHO, 2021a). The death toll associated with antimicrobial resistance approached 5 million cases in 2019 while total cost that can impact the whole society is around £10 billion each year (Antimicrobial Resistance Collaborators, 2022: Smith and Coast, 2012). Eventually, this has motivated the World Health Organization (WHO) to set a global action plan to counteract the antimicrobial resistance all-over the world as a priority issue (WHO, 2015). In 2015, the United Nations (UN) released the updated Sustainability Development Goals (SDG) that is aiming to improve the public health and general well-being of the globe through tackling 17 topics. Treatment and prevention for multiple common infections such as Human Immunodeficiency Virus (HIV), malaria, tuberculosis and others were among the main targets in its agenda (UN, 2019). In UAE, although several initiatives have been adopted such as launching antimicrobial stewardship programmes and surveillance programmes, antimicrobial resistance is still an unresolved issue (National sub-committee for AMR surveillance, 2021 UAE Higher Committee for Antimicrobial Resistance, 2019). The resistance of Acinetobacter species to several cephalosporins and penicillins exceeded 20% (National sub-committee for AMR surveillance, 2021). Current evidence available publicly does not include a systematic review that is evaluating the effect of antimicrobial stewardship programmes on bacterial resistance level in UAE. With the scarcity of data and complexity of the issue, it is important to conduct this systematic review to assess the impact of these programmes on bacterial resistance level and identify gaps and challenges in the implementation.

Health Policy Analysis on the Containment of Antimicrobial Resistance (AMR) in India: A Mixed Methods Study of Antimicrobial Stewardship as a Pivotal Intervention in Tackling AMR

Objective: This policy report aimed at two goals, that is, to report the findings of the literature review and explore the perceptions of the key stakeholders in seeking better insight into the antimicrobial stewardship program (AMSP), and to develop antimicrobial resistance (AMR) policy recommendations for the Ministry of Health and Family Welfare (MoHFW), India, based on the findings from the rapid systematic review of the literature (both published and grey) and the views of key stakeholders. Method: A mixed method approach using literature review and qualitative interviews has been applied. A rapid systematic literature review focusing on the antimicrobial stewardship pro-gram’s key achievements and its implementation and impact, implementation challenges, gaps and barriers, and opportunities, has been carried out, which has been followed by conducting interviews of key stakeholders and reporting the findings along with the recommendations. Results: The findings have shown significant progress towards AMSP, such as expanding to 90 secondary-level hospitals and district-level hospitals/nursing homes, and the Indian Council of Medical Research antimicrobial resistance surveillance and research network (ICMR AMRSN) program. Education, training, and microbiological testing have been found to be the current focus areas. However, there exist challenges, including a lack of leadership support, diagnostic stew-ardship, and staffing of clinical pharmacists and infectious control nurses. Key gaps and barriers identified include setting up microbiology laboratories and hiring ICN nurses and clinical phar-macists. Opportunities have also been identified. Based on these findings, we have made succinct recommendations to address the themes and issues identified. Conclusion: Without new medicines, India will struggle to manage antimicrobial resistance. This situation calls for national oversight. This study has demonstrated AMSP as crucial for fighting this silent pandemic. The Indian government and policymakers must swiftly address critical chal-lenges, gaps, and opportunities. These findings and recommendations might potentially strengthen the future antimicrobial resistance national action plan (AMR NAP).

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.

In vitro activity of aztreonam-avibactam and comparators against Metallo-β-Lactamase-producing Enterobacterales from ATLAS Global Surveillance Program, 2016–2020

ObjectivesMetallo-β-lactamase (MBL)-producing Enterobacterales are a major challenge worldwide due to limited treatment options. Aztreonam-avibactam (ATM-AVI), which is under clinical development, has shown activity against MBL-positive isolates. This study evaluated the prevalence of MBL producers and the nature of enzymes among a global collection of clinical isolates of Enterobacterales from the Antimicrobial Testing Leadership and Surveillance program (ATLAS) surveillance program (2016–2020), and the antimicrobial activity of ATM-AVI and comparators against this collection. MethodsNon-duplicate clinical isolates of Enterobacterales (N = 106 686) collected across 63 countries were analysed. Antimicrobial susceptibility was performed using broth microdilution. Minimum inhibitory concentrations (MICs) were interpreted using Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing breakpoints. Provisional pharmacokinetic/pharmacodynamic breakpoint of ≤8 mg/L was considered for ATM-AVI. β-lactamase genes were characterized by polymerase chain reaction and sequencing. The Cochran Armitage Trend test was used to determine significant trends in percentage of isolates over time. ResultsOverall, MBL-positive isolates were 1.6% of total Enterobacterales isolates globally, with a significant increasing trend observed over time, globally and across regions (P < 0.05). New Delhi MBL (NDM) was the most common MBL (83.3%). ATM-AVI demonstrated potent activity against MBL-positive isolates (MIC ≤8 mg/L: 99.4% isolates inhibited; MIC90, 1 mg/L). Consistent activity was also noted across different regions. Potent activity was demonstrated against different NDM variants and MBL-positive isolates co-carrying other carbapenemases (98.1% and 99.7% isolates inhibited at ≤8 mg/L, respectively). About 0.6% MBL-positive isolates (10/1707) had MICs >8 mg/L for ATM-AVI. ConclusionATM-AVI demonstrated potent activity against MBL-positive isolates, including NDM variants and MBL-positive isolates co-carrying other carbapenemases, and may represent a good option for treating infections caused by MBL-positive Enterobacterales.

Global trends in non-susceptibility rates of Streptococcus pneumoniae isolates to ceftriaxone: Data from the antimicrobial testing leadership and surveillance (ATLAS) programme, 2016–21

To understand the global changes in non-susceptibility rates of Streptococcus pneumoniae to ceftriaxone, we conducted a study using the Antimicrobial Testing Leadership and Surveillance database. A total of 15,717 S. pneumoniae isolates were collected from 2016 to 2021. The minimum inhibitory concentrations (MICs) were determined using broth microdilution. The overall susceptibility rates of S. pneumoniae isolates to penicillin, ceftriaxone and ceftaroline were 63.4%, 94.0% and 99.6%, respectively. The geometric mean of MICs and MIC50/MIC90 values of ceftriaxone were higher in Asia than in other continents. China (33.9%), South Korea (33.8%) and Taiwan (27.6%) had the highest ceftriaxone non-susceptibility rates, followed by Turkey, India, Brazil, Malaysia, South Africa and Colombia, with rates between 10% and 20%. During the study period from 2020 to 2021, Asia had the highest MIC90 value (4 mg/L) for ceftriaxone in S. pneumoniae isolates, and the geometric mean of MICs increased from 0.25 mg/L in 2016–2017 to 0.39 mg/L in 2020–2021. Both Asia (from 83.4% to 75.1%) and Latin America (from 94.2% to 86.3%) showed a decreasing trend in ceftriaxone susceptibility rates from 2016 to 2021. In North America, Europe and Oceania, the susceptibility rate was higher than 95%, and there was no obvious change in the rate during the 6 y. Further analysis of the data from Asia revealed that individuals younger than 6 y of age had a lower susceptibility rate to ceftriaxone (71.6% vs. 81.7%, P < 0.05) than patients ≥6 y. The higher non-susceptibility rates of ceftriaxone in S. pneumoniae in Asia may lead to therapeutic challenges in community-acquired pneumonia.

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.

2128. In Vitro Activity of Ceftibuten-Avibactam and Comparator Agents Against Resistant Enterobacterales from UTIs Collected Globally as Part of the ATLAS Surveillance Program, 2022

Abstract Background Increasing resistance among agents commonly prescribed to treat urinary tract infections (UTIs) indicate that new orally bioavailable agents are needed. Ceftibuten (CTB) is an orally administered third-generation cephalosporin and is in early clinical development being combined with an oral prodrug of avibactam (AVI). AVI is a non-β-lactam inhibitor of Ambler class A β-lactamases, including ESBLs and KPCs, class C (AmpC) β-lactamases, and some class D (OXA-48) β-lactamases. Ceftibuten-avibactam prodrug (CBA) is in early clinical development as a potential oral treatment for complicated urinary tract infections. This study evaluated the in vitro activity of CBA and oral comparators against Enterobacterales from UTIs with drug-resistant phenotypes collected globally as part of the 2022 Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Methods 4,265 non-duplicate clinical isolates from UTIs were collected in 2022 in 55 countries. Susceptibility testing with CBA tested at a fixed concentration of 4 µg/mL AVI and comparators was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. Nonsusceptible (NS)/resistant (R) phenotypes were based on 2023 CLSI breakpoints. MDR was defined as R to ≥1 agent from ≥3 drug classes. Results CBA was the most active compound tested against all Enterobacterales, with the MIC90 value decreasing from 32 µg/mL to 0.12 µg/mL. A total of 96% of all isolates were inhibited at a CBA MIC of ≤1 µg/mL. Percent susceptible of oral comparators ranged from 63.4% to 76.8%. CBA maintained activity against NS/R subsets of Enterobacterales (MIC90 range, 0.25 to 4 µg/mL; 85.0% to 93.2% inhibited at ≤1 µg/mL), including MDR isolates (MIC90, &amp;gt;64 µg/mL; 81.7% inhibited at ≤1 µg/mL). Conclusion Ceftibuten-avibactam demonstrated potent in vitro activity against multidrug-resistant Enterobacterales collected globally. Ceftibuten -avibactam prodrug could be an effective oral therapy for difficult-to-treat infections caused by multidrug-resistant Enterobacterales. 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

2761. Activity of Cefiderocol and Comparator Agents Against Achromobacter and Burkholderia Isolates, Collected During 2020-2022 as Part of SENTRY Antimicrobial Surveillance Program

Abstract Background Achromobacter and Burkholderia species are opportunistic pathogens in individuals with an immunodeficiency, most notably cystic fibrosis. Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria. In this study, the activity of CFDC and comparator agents was determined against isolates of Achromobacter and Burkholderia cepacia species complex, collected in 2020–2022 in Europe and the USA as part of the SENTRY antimicrobial surveillance program. Activity of cefiderocol and comparator agents against Achromobacter and Burkholderia Isolates Methods Minimum inhibitory concentrations (MICs) were determined according to CLSI guidelines against 167 Achromobacter and 160 Burkholderia cepacia species complex isolates, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Comparator agents included β-lactam/β-lactamase inhibitor combinations ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, piperacillin-tazobactam, as well as meropenem, ceftazidime, levofloxacin, amikacin, trimethoprim-sulfamethoxazole, and minocycline. Susceptibility was assessed for agents with CLSI breakpoints. For agents without established CLSI breakpoints, only MIC50, MIC90 and MIC ranges were reported. Results CFDC was the most potent agent tested against Achromobacter, showing MIC50 and MIC90 values of 0.03 and 0.25 µg/mL and all isolates were inhibited at ≤4 µg/mL (Table). Isolates from cystic fibrosis patients (n=15) showed higher MIC50 and MIC90 values for most agents, but CFDC MIC50 and MIC90 values remained low (0.06 and 0.25 µg/mL, respectively). Against Burkholderia cepacia species complex, CFDC was the most potent agent tested, with MIC50 and MIC90 values of 0.06 and 0.5 µg/mL, and 156 out of 160 isolates inhibited at ≤4 µg/mL. None of the comparator agents showed &amp;gt;90% susceptibility against these isolates (Table). Conclusion CFDC showed potent activity against a set of contemporary clinical Achromobacter and Burkholderia cepacia species complex isolates. These in vitro data suggest that CFDC could be an important treatment option for infections caused by these opportunistic pathogens. Disclosures Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson &amp; Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi &amp; Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

2790. Activity of Cefiderocol and Comparator Agents Against Pediatric Isolates of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii-calcoaceticus species complex, and Stenotrophomonas maltophilia from the SENTRY Surveillance Program (2020-2022)

Abstract Background Cefiderocol (CFDC) is a siderophore cephalosporin with broad activity against Gram-negative bacteria including multi-drug resistant isolates. The in vitro activity of CFDC and comparator agents was evaluated against pediatric (0-17 years old) isolates collected in 2020–2022 as part of the SENTRY Antimicrobial Surveillance Program. In vitro Activity of Cefiderocol and Comparator Agents Against Pediatric Isolates Methods 2,249 Enterobacterales (ENT), 707 P. aeruginosa, 194 Acinetobacter baumannii-calcoaceticus complex (ABC) and 220 S. maltophilia from the USA and Europe were tested for susceptibility (%S) by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB). Iron-depleted CAMHB was applied for CFDC. Comparators included newer β-lactam/β-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (I-R) and meropenem-vaborbactam (MVB) as well as ampicillin/sulbactam (SAM) meropenem (MEM) and colistin (CST). %S was interpreted according to 2023 CLSI &amp; EUCAST breakpoints. Carbapenem non-susceptible (CarbNS) was defined as non-susceptibility to imipenem and MEM. Results All agents displayed &amp;gt;96 %S for ENT while CFDC (MIC50/90, 2/4 mg/L; 91.7 %S) was the most active agent against CarbNS ENT. P. aeruginosa susceptibilities to CFDC and BL/BLI combinations were &amp;gt;97.0%. CFDC was the most potent agent against CarbNS P. aeruginosa with MIC50/90 values of 0.12/0.25 mg/L and 100 %S &amp; 98.5 %S per CLSI &amp; EUCAST breakpoints, respectively. ABC susceptibility to CFDC was &amp;gt;97% per CLSI &amp; EUCAST while the susceptibility for MEM was 87.1% (CLSI &amp; EUCAST) and SAM was 80.9% (CLSI). CFDC (MIC50/90, 0.25/1 mg/L; 95.7 %S) displayed better in vitro potency in CarbNS ABC as compared to SAM (MIC50/90, 32/ &amp;gt;64 mg/L; 17.4 %S CLSI) and CST (MIC50/90, 0.5/ &amp;gt;8 mg/L; 78.3%S EUCAST). Among pediatric S. maltophilia, CFDC was the most active agent with MIC50/90, 0.06/0.25 and 100 %S per CLSI &amp; EUCAST breakpoints. Conclusion CFDC was a highly active β-lactam against contemporary pediatric isolates of Enterobacterales, P. aeruginosa, ABC, and S. maltophilia, including CarbNS subsets for which treatment options are limited. These data suggest CFDC may be a valuable treatment for serious Gram-negative infections in pediatric patients. Disclosures Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Anne Henriksen, PhD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson &amp; Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi &amp; Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

2762. Activity of Cefiderocol and Comparator Agents Against Difficult to Treat Resistance (DTR) Gram-negative Isolates, Collected During 2020-2022 as Part of SENTRY Antimicrobial Surveillance Program

Abstract Background Difficult to Treat Resistant (DTR) Gram-negative isolates show treatment-limiting resistance to all first-line agents; β-lactams and fluoroquinolones. Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with a unique mode of entry into bacteria, showing good activity against Gram-negative bacteria. Here, susceptibility of CFDC and comparator agents was determined against DTR isolates of Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus species complex (ABC). Activity of Cefiderocol and Comparator Agents Against Difficult to Treat Resistance (DTR) Gram-negative Isolates Methods Minimum inhibitory concentrations were determined according to CLSI guidelines against 24,084 Enterobacterales, 7,310 P. aeruginosa, and 2,479 ABC isolates, collected in 2020–2022 in Europe and the USA as part of the SENTRY program, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Susceptibility was assessed according to CLSI, EUCAST and FDA breakpoints (BPs). DTR was defined as being non-susceptible, using CLSI BPs, to fluoroquinolones and β-lactams, except for CFDC and β-lactam/β-lactamase inhibitor (BL/BLI) combinations. Results 1.6% (n=387) of the Enterobacterales isolates showed the DTR phenotype, the majority being K. pneumoniae (n=332; 85.8%). The isolates showed high susceptibility to CFDC (95.3% and 81.1% using CLSI/FDA or EUCAST BPs, respectively). Comparator agents, including novel BL/BLI combinations, showed susceptibility of &amp;lt; 80%, except for tigecycline (94.1%, FDA BPs). For P. aeruginosa 4.1% (n=299) showed the DTR phenotype, of which 98.3%, 97.7%, and 89.6% were susceptible to CFDC, according to CLSI, EUCAST and FDA BPs respectively. Colistin was also active (99.7% susceptible, EUCAST BPs) whereas other agents, including novel BL/BLI combinations, had susceptibility of &amp;lt; 65%. Amongst ABC, 47.1% (n=1167) showed the DTR phenotype, and 96.2%, 93.8%, and 89% were susceptible to CFDC according to CLSI, EUCAST and FDA BPs, respectively. Susceptibility to comparator agents was &amp;lt; 40%, except for colistin (81.2%, EUCAST BPs). Conclusion DTR isolates remained susceptible to CFDC, indicative of a low degree of cross resistance with β-lactams, including BL/BLI combinations, and fluoroquinolones. Disclosures Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson &amp; Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi &amp; Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee