Ceftolozane-tazobactam Research Articles

Survival of infection with TEM β-lactamase-producing Escherichia coli with Pan-β-lactam resistance

Antimicrobial resistance is a critical global health issue, significantly contributing to patient mortality. Recent antibiotic developments have aimed to counteract carbapenemase-producing Enterobacterales; however, the impact of their use on the emergence of antibiotic resistance is unknown. This study investigates the first case of a non-carbapenemase-producing, pan-β-lactam-resistant Escherichia coli strain from a patient previously treated with ceftolozane-tazobactam and cefiderocol. This study describes the clinical progression of a 39-year-old ICU patient who developed multiple infections, culminating in the isolation of a pan-β-lactam-resistant E. coli strain (EC554). The resistance profile was characterised through MIC determination, whole-genome sequencing, the use of the β-lactam inactivation method, RT-qPCR, efflux pump inhibition assays, outer membrane protein analysis, and blaTEM transformation. The EC554 isolate displayed resistance to all tested β-lactams and β-lactam-β-lactamase inhibitor combinations. Whole-genome sequencing revealed four plasmids in EC554, with the only β-lactamase gene being blaTEM-252 on the pEC554-PBR-X1-X1 plasmid. We found that the extremely resistant phenotype was attributable to a combination of different mechanisms: a high expression of TEM-252, efflux pump activity, porin loss, and PBP3 mutations. The findings illustrate the complex interplay of multiple resistance mechanisms in E. coli, highlighting the potential for high-level resistance even without carbapenemase production. This study underscores the importance of comprehensively characterising resistance mechanisms in order to inform effective treatment strategies and mitigate the spread of resistant strains.

Development and Validation of a Sensitive Liquid Chromatography-Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Ceftolozane and Tazobactam in Human Plasma Microsamples.

Ceftolozane/tazobactam (C-T) is a novel beta-lactam/beta-lactamase inhibitor combination approved for the treatment of various infections caused by difficult-to-treat Pseudomonas aeruginosa. In critically ill patients, C-T may exhibit significant pharmacokinetic variability, both between individuals and within individuals, warranting therapeutic drug monitoring for clinical purposes. We aim to develop and validate a novel and sensitive analytical method for concurrently determining C and T in human plasma microsamples (3μL). The method was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with positive electrospray ionization and multiple reaction monitoring (MRM) detection modes, employing specific mass transitions for both drugs. Sample preparation was simple, and the chromatographic run lasted only 4 minutes. Validation was conducted according to European Medicines Agency (EMA) guidelines, encompassing specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, and drug stability. The validated method was applied to measure C and T in 32 plasma samples collected from critically ill patients with multidrug-resistant, gram-negative, bacterial infections. The method ensured accurate (BIAS% 2.1-9.6 for C and -2.2 to 15.2 for T) and precise intraday CV% for C: 6.7-5.5; for T: 1.3-8.9; interday CV% for C 6.0-10.8; for T 4.1-10.2) measurements of C-T over a wide concentration range (0.2-200.0 mg/L for C and 0.1-100.0 mg/L for T). Overall, the recovery at quality control concentration levels was high for both C and T (mean values: 90-91 for C and 89-92 for T). Analyte stability was satisfactory in both human plasma and extracts under various storage conditions. The clinical applicability of the assay was confirmed by the reliably quantifying C and T in clinical plasma samples. The developed and validated LC-MS/MS method is sensitive and suitable for monitoring C and T in human plasma microsamples.

Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition.

Ceftolozane-tazobactam (CT) is used for the treatment of complicated infections and for multidrug-resistant strains of Pseudomonas aeruginosa and extended-spectrum beta-lactamase-producing enterobacteria. In certain cases, simultaneous administration of CT and parenteral nutrition (PN) may be required, but compatibility of Y-site co-administration is unknown. The aim of this study was to analyse the physicochemical compatibility of CT Y-site administered with PN. We evaluated a protocolized PN approach for critical patients in our center. We studied both bolus infusion (2 g ceftolozane/1 g tazobactam in 1 h) and continuous infusion (CI) (6 g ceftolozane/3 g tazobactam) strategies. Samples were visually observed against light, microscopically inspected, and pH was analysed using a pH meter. The mean lipid droplet diameter (MDD) was determined via dynamic light scattering. CT concentration was quantified using HPLC-HRMS. No alterations were observed through visual or microscopic inspection. Changes in pH were ≤0.2, and changes in osmolarity were less than 5%. MDD remained below 500 nm (284.5 ± 2.1 for bolus CT and 286.8 ± 7.5 for CI CT). CT concentrations at t = 0 h and t = 24 h remained within prespecified parameters in both infusion strategies. CT is physiochemically compatible with PN during simulated Y-site administration at the tested concentration and infusion rates.

In vitro activity of cefiderocol against carbapenemase-producing and meropenem-non-susceptible Gram-negative bacteria collected in the Japan Antimicrobial Resistant Bacterial Surveillance

ObjectivesThe treatment options available for infections caused by multidrug-resistant Gram-negative pathogens are often limited. Cefiderocol (CFDC) is a novel siderophore cephalosporin that exhibits activity against these pathogens. Several studies have reported the in vitro activity of CFDC against isolates from Europe, the United States, and China, but the activity against carbapenem-resistant bacteria with IMP-type carbapenemase has not been extensively studied. We, therefore, studied the in vitro activities of CFDC against carbapenem-resistant bacteria with available genomic backgrounds based on whole-genome sequencing (WGS) in Japan, where the IMP-type is the predominant carbapenemase produced by Gram-negative rods. MethodsWe selected 603 isolates (528 Enterobacterales, 18 Pseudomonas aeruginosa, and 57 Acinetobacter spp.) from a collection of Gram-negative clinical isolates collected during a Japan Antimicrobial Resistance Bacterial Surveillance program and evaluated the antimicrobial activities of CFDC, ceftolozane/tazobactam (CTLZ/TAZ), imipenem-relebactam (IPM/REL), and ceftazidime/avibactam (CAZ/AVI) against carbapenemase-producing Enterobacterales, carbapenemase-non-producing meropenem-non-susceptible Enterobacterales, and carbapenemase-producing nonfermentative bacteria. ResultsAmong these, 97.7% of carbapenemase-producing Enterobacterales (99.2% of IMP-type carbapenemase-producing Enterobacterales), 100% of carbapenemase-producing P. aeruginosa, and 91.2% of carbapenemase-producing Acinetobacter spp. were susceptible to CFDC, showing better antimicrobial activity than the other antimicrobial agents evaluated in this study. CFDC was highly effective against class A-, B-, and D β-lactamase-harbouring isolates when compared to the other antimicrobial agents. In addition, the relationship between CFDC resistance and three genetic factors involved in resistance was discussed. ConclusionsThis is the first large-scale study to systematically demonstrate the efficacy of CFDC against IMP-type carbapenemase-producing strains with known genomic backgrounds.

Molecular Characteristics of Colistin Resistance in Acinetobacter baumannii and the Activity of Antimicrobial Combination Therapy in a Tertiary Care Medical Center in Lebanon.

(1) Background: Infections with pan-drug-resistant (PDR) bacteria, such as A. baumannii, are becoming increasingly common, especially in healthcare facilities. In this study, we selected 15 colistin-resistant clinical A. baumannii isolates from a hospital in Beirut, Lebanon, to test combination therapies and determine their sequence types (STs) and the mechanism of colistin resistance using whole-genome sequencing (WGS). (2) Methods: Antimicrobial susceptibility testing via broth microdilution against 12 antimicrobials from different classes and growth rate assays were performed. A checkerboard assay was conducted on PDR isolates using six different antimicrobials, each in combination with colistin. Genomic DNA was extracted from all isolates and subjected to WGS. (3) Results: All isolates were resistant to all tested antimicrobials with the one exception that was susceptible to gentamicin. Combining colistin with either meropenem, ceftolozane-tazobactam, or teicoplanin showed synergistic activity. Sequencing data revealed that 67% of the isolates belonged to Pasteur ST2 and 33% to ST187. Furthermore, these isolates harbored a number of resistance genes, including blaOXA-23. Mutations in the pmrC gene were behind colistin resistance. (4) Conclusions: With the rise in antimicrobial resistance and the absence of novel antimicrobial production, alternative treatments must be found. The combination therapy results from this study suggest treatment options for PDR ST2 A. baumannii-infected patients.

Identifying quantitative evidence-based parameters to monitor emerging resistance to new antibiotics

Abstract Background Antimicrobial resistance (AMR) has a major public health burden, and newly-approved molecules have shown fast emerging of resistance. This study aims at assessing and developing an innovative framework to monitor and benchmark emerging resistance to new antibiotics in Europe. Methods Within the European ECRAID-Base project and the EPI-Net platform, data were extracted at two levels: reporting of emerging resistance to the 12 new antibiotics approved by EMA since 2012 and related outbreaks, and active resistance monitoring in national surveillance systems in 32 European countries. The burden of emerging resistance was measured through the following indicators: time lag between approval and first resistance report, average number of outbreaks, trend in the number of yearly publications standardised by the logarithm of the total number and weighted by the pooled resistance rate, and inclusion of new antibiotics in national surveillances. Results Overall, 956 articles reported resistance to new antibiotics since 2012. Resistance to ceftolozane-tazobactam (CLZ-TAZ) was the most reported, followed by ceftazidime-avibactam (CAZ-AVI); resistance to eravacycline and delafloxacin was less reported. For 6 antibiotics, resistance occurred within one year of approval. Out of 35 surveillance systems reviewed, only 13 (in 12 countries) included at least one new antibiotic; CLZ-TAZ and CAZ-AVI, monitored in 11 and 12 countries respectively, were the most surveyed. Resistance trends showed greater increase for imipenem-relebactam, CAZ-AVI, and meropenem-vaborbactam. Nine outbreaks were detected, including 136 patients: CAZ-AVI was responsible for the highest number of outbreaks (five). Conclusions Resistance was detected to new antibiotics, yet very few countries have active monitoring systems to detect it. Appropriate monitoring and benchmarking of emerging resistance to new antibiotics is pivotal to support careful antibiotic policies at country and global level. Key messages • Emerging resistance to new antibiotics was assessed through quantitative parameters: some drug combinations would deserve further attention, given the increased resistance reports and surveillance gap. • Analysis of these parameters might suggest that combinations of existing agents are prone to developing resistance, and hence support focusing research on the development of novel-class drugs.

Comparing ceftolozane/tazobactam versus piperacillin/tazobactam for the initial empiric therapy of urinary tract infections: A retrospective comparative study

IntroductionThis study compares the clinical and microbiological efficacy of ceftolozane/tazobactam (CTLZ/TAZ) and piperacillin/tazobactam (PIPC/TAZ) for treating complicated cystitis or acute pyelonephritis. MethodsPatients who had been treated with empiric antibiotics, CTLZ/TAZ (52 cases) or PIPC/TAZ (47 cases), due to urinary tract infections (UTIs) were eligible for this study. Patients’ demographic backgrounds, types of UTIs, and causative microorganisms isolated from urine or blood bacterial cultures were collected. Short-term clinical efficacy at the end of the initial empiric therapy, long-term clinical efficacy including sequential antibiotic treatments (nonrecurrence rate within 1 month after the initial empiric therapy), and microbiological efficacy were retrospectively compared in both CTLZ/TAZ and PIPC/TAZ groups. ResultsComplicated UTIs were present in most eligible patients, and no significant difference in the patients’ background was observed between the two groups. Escherichia coli and Enterococcus faecalis were the most common microorganisms isolated from urine culture in both groups. The short-term clinical effective rate of CTLZ/TAZ and PIPC/TAZ was 80.8% and 87.2%, respectively. For long-term clinical efficacy, the nonrecurrence rate of UTIs was present in 95.1% and 89.7% of patients with CTLZ/TAZ and PIPC/TAZ, respectively. No significant difference was observed in the short- and long-term effects between the two groups. The microbiological efficacy of the CTLZ/TAZ and PIPC/TAZ groups was 72.7% and 86.0%, respectively. No significant difference in microbiological effects was also observed between the two groups. ConclusionsThis study demonstrated the noninferiority of CTLZ/TAZ to PIPC/TAZ, suggesting that CTLZ/TAZ is an alternative antibiotic used as empiric therapy for UTIs.

In vitro activities of ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam and other comparators against Pseudomonas aeruginosa isolates with discrepant resistance to carbapenems: Data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2012–2021

In this study, we aimed to investigate the in vitro susceptibility and β-lactamase-encoding genes of Pseudomonas aeruginosa isolates with discrepant resistance to various carbapenems. We obtained data on P. aeruginosa isolates from the Antimicrobial Testing Leadership and Surveillance program from 2012 to 2021. Minimum inhibitory concentrations of P. aeruginosa isolates were determined using the broth microdilution method. β-lactamase-encoding genes were identified using multiplex polymerase chain reaction assays. Among the P. aeruginosa isolates tested, the percentages of isolates resistant to imipenem, meropenem, and doripenem were 26.9% (14,447/53,617), 20.5 (14,098/68,897), and 17.5% (3,660/20,946), respectively. Imipenem-resistant P. aeruginosa isolates were more susceptible to all tested antimicrobial agents (except colistin) than the meropenem- or doripenem-resistant P. aeruginosa isolates. Carbapenemase genes were detected in 14.3% (2,020/14,098) of meropenem-resistant P. aeruginosa isolates. Imipenem-resistant meropenem-susceptible P. aeruginosa isolates had higher susceptibility profiles, fewer carbapenemase genes (0.3% [5/1,858] vs. 4.1% [10/242]; p < 0.05), and a lower risk of being classified as multidrug-resistant than the imipenem-susceptible meropenem-resistant isolates (16.1% [299/1,858] vs. .73.6% [178/242]; p < 0.05). Among all β-lactam combination agents, ceftazidime-avibactam and ceftolozane-tazobactam had higher susceptibility rates than meropenem-vaborbactam for meropenem-resistant P. aeruginosa (61.8% and 55.5% vs. 30.2%; p<0.05). In conclusion, discrepancy in the resistance of different P. aeruginosa isolates to various carbapenems suggests their different underlying resistance mechanisms. These findings can be useful for effective resistance trend monitoring and accurate antimicrobial treatment in the future.

Satisfactory In Vitro Activity of Ceftolozane-Tazobactam against Carbapenem-Resistant Pseudomonas aeruginosa But Not against Klebsiella pneumoniae Isolates.

Background: Gram-negative rods are one of the most commonly isolated bacteria within human infections. These microorganisms are typically opportunistic pathogens that pose a serious threat to public health due to the possibility of transmission in the human population. Resistance to carbapenems is one of the most important antimicrobial resistance mechanisms amongst them. The aim of this study was to evaluate ceftolozane-tazobactam in vitro activity against carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae clinical strains. Information on the antimicrobial activity of this antimicrobial against Gram-negative rods was also supplemented with a brief review of the relevant literature. Methods: The research involved 316 strains of Gram-negative rods: P. aeruginosa-206 and K. pneumoniae-110. Results: Of the tested strains, 86.0% P. aeruginosa and 30.0% K. pneumoniae remained susceptible to ceftolozane-tazobactam. Conclusions: Therefore, ceftolozane-tazobactam might be a good option in the treatment of infections caused by carbapenem-resistant P. aeruginosa strains, including those in ICU patients. Meanwhile, due to dissemination of ESBLs among K. pneumoniae strains, infections with this etiology should not be treated with the ceftolozane-tazobactam combination.

Carbapenem-Resistant Klebsiella pneumoniae: Virulence Factors, Molecular Epidemiology and Latest Updates in Treatment Options.

Klebsiella pneumoniae is a Gram-negative opportunistic pathogen responsible for a variety of community and hospital infections. Infections caused by carbapenem-resistant K. pneumoniae (CRKP) constitute a major threat for public health and are strongly associated with high rates of mortality, especially in immunocompromised and critically ill patients. Adhesive fimbriae, capsule, lipopolysaccharide (LPS), and siderophores or iron carriers constitute the main virulence factors which contribute to the pathogenicity of K. pneumoniae. Colistin and tigecycline constitute some of the last resorts for the treatment of CRKP infections. Carbapenemase production, especially K. pneumoniae carbapenemase (KPC) and metallo-β-lactamase (MBL), constitutes the basic molecular mechanism of CRKP emergence. Knowledge of the mechanism of CRKP appearance is crucial, as it can determine the selection of the most suitable antimicrobial agent among those most recently launched. Plazomicin, eravacycline, cefiderocol, temocillin, ceftolozane-tazobactam, imipenem-cilastatin/relebactam, meropenem-vaborbactam, ceftazidime-avibactam and aztreonam-avibactam constitute potent alternatives for treating CRKP infections. The aim of the current review is to highlight the virulence factors and molecular pathogenesis of CRKP and provide recent updates on the molecular epidemiology and antimicrobial treatment options.

1649. Ceftolozane-Tazobactam or Ceftazidime-Avibactam Versus Best Available Therapy in the Treatment of Difficult-to-Treat Pseudomonas aeruginosa Infections: a Retrospective Comparative Effectiveness Analysis of 195 U.S. Hospitals, 2016–2020

Abstract Background Infections due to Pseudomonas aeruginosa displaying difficult-to-treat resistance (DTR-PA) necessitate the use of sub-efficacious and/or toxic “reserve” antibiotics and are associated with considerable morbidity and mortality. Ceftazidime-avibactam (CAZ-AVY) and ceftolozane-tazobactam (CEF-TAZO) are novel ß-lactam/ß-lactamase inhibitors (BLBLI) that tend to retain in vitro activity against DTR-PA. However, little is known about their in vivo effectiveness compared to reserve agents. Methods Inpatients aged ≥ 18 years with ≥1 blood, urine, respiratory, or body fluid culture growing DTR-PA who received targeted therapy with either CAZ-AVY, CEF-TAZO, or Best-Available Therapy (BAT) were identified in the Premier Healthcare Database. Primary outcome was in-hospital mortality or discharge to hospice and secondary outcome was length of hospital stay (LOS) for survivors. The primary outcome was compared for CAZ-AVY vs CEF-TAZO and novel agents (CAZ-AVY or CEF-TAZO) vs BAT using overlap weighting and binomial regression with downstream adjustment controlling for patient and treatment characteristics. The secondary outcomes were compared using overlap weighting and poisson regression with downstream adjustment controlling for patient and treatment characteristics. Results Between 2016 and 2020, 1,552 patients with DTR-PA infections were identified at 105 hospitals, of which 202 (13.0%) were treated with CAZ-AVY, 906 (58.4%) with CEF-TAZO, and 444 (28.6%) with BAT. Patient characteristics were similar among treatment groups (Table 1, Table 2). Overall crude mortality was 15.5%. The adjusted risk of mortality was lower in patients treated with CAZ-AVI (12.5%, 95% CI 7.9–17.1) vs CEF-TAZO (18.8%, 95% CI 15.9–21.8) for a risk difference of 6.3% (95% 1.1–11.5, p = 0.02). The novel agents were not associated with a reduced mortality risk when collectively compared to BAT (risk difference -1.1%, 95% CI -5.4; 3.2%). LOS favoured novel agents and were comparable for CAZ-AVY and CEF-TAZO. Conclusion In this real-world observational study of patients with DTR-PA infections, the novel ß-lactam/ß-lactamase inhibitors were comparably effective against BAT, though the use of CAZ-AVY was associated with a reduced mortality compared to CEF-TAZO. Disclosures All Authors: No reported disclosures.

1005. Financial and clinical impact of ceftolozane/tazobactam global recall on the treatment of multi-drug resistant Pseudomonas in a large health system

Abstract Background In December 2020, ceftolozane/tazobactam (CT) was voluntarily recalled due to failed sterility tests. With this recall, clinicians were forced to utilize alternatives for multi-drug resistant (MDR) Pseudomonas (PSA) infections until CT returned in late December, 2021. While many studies have examined the impact of medication shortages, few have evaluated the impact of antimicrobial shortages. We evaluated the impact of the CT recall by assessing cost, clinical outcomes, and utilization of novel alternative agents. Methods This multi-site retrospective cohort study compared patients treated for MDR PSA prior to the CT recall (Jan-Jul 2020) to patients treated during the CT recall (Jan-Jul 2021) across seven AdventHealth Central Florida (AHCF) adult hospitals. The primary outcome was percentage of patients treated with novel therapies (CT, ceftazidime/avibactam, or cefiderocol). Secondary outcomes included length of therapy (LOT), inpatient mortality, 30-day readmissions, length of say (LOS), pharmacy expenditures, and average cost per case. Results A total of 203 patients with MDR PSA were evaluated: 100 in the pre-recall cohort and 103 in the post-recall cohort. The majority (58%) of patients were male with an average age of 64 years. The most common source of infection in both cohorts was pneumonia, followed by complicated urinary tract infection. Significantly more patients were treated with novel agents as definitive therapy in the post-recall cohort (65% vs. 29%, p&amp;lt; 0.0001). Average LOT for all anti-PSA therapy was 12 days in the pre-recall cohort compared to 14 days in the post-recall cohort (p=0.1753). Inpatient mortality and 30-day readmissions were not statistically different between groups. Hospital LOS was significantly different between the two groups (18 days vs. 25 days, p=0.006). Significantly higher pharmacy expenditures were found in the post recall cohort (Figure 1) and the average cost per case was significantly higher in the post-recall cohort ($125,254 vs. $62,249). Figure 1:Pharmacy Expenditures for Novel Agents Novel agents: cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam Conclusion The CT recall had a significant impact on both economic and clinical outcomes, particularly increased length of stay, length of therapy, and cost to both the patient and health system. Higher utilization of novel agents is concerning given rising rates of PSA resistance. Disclosures Amy L. Carr, PharmD, BCIDP, Shionogi: Advisory Board.

1836. Frequency and Antimicrobial Susceptibility of Gram-negative Bacteria Isolated from Patients with Bloodstream Infections in United States (US) Medical Centers (2020-2021)

Abstract Background Antimicrobial resistance among Gram-negative bacteria (GNB) is a major problem in US hospitals. The development of various β-lactamase inhibitor combinations (BLICs) markedly increased the armamentarium to treat infections caused by GNB in recent years. We evaluated the frequency and antimicrobial susceptibility of GNB causing bloodstream infection (BSI). Methods 5,796 organisms were consecutively collected (1/patient) from patients with BSI in 31 US medical centers in 2020-2021. The collection included 2,893 (49.9%) GNB, which were susceptibility tested against ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), imipenem-relebactam (IMI-REL), and many comparators by CLSI broth microdilution method. Enterobacterales (ENT) isolates with an ESBL phenotype were screened for β-lactamase genes by whole genome sequencing. Results The most common GNBs were E. coli (41.9%), K. pneumoniae (16.1%), P. aeruginosa (10.2%), and E. cloacae (6.8%). Ceftriaxone susceptibility rates were 80.1%, 82.9%, and 74.0% for E. coli, K. pneumoniae, and E. cloacae, respectively. CAZ-AVI and MEM-VAB showed almost complete activity (≥ 99.7%) against ENT, whereas IMI-REL exhibited limited activity against P. mirabilis and indole-positive Proteeae isolates and C-T showed limited activity against E. cloacae, ESBL-phenotype, and multidrug-resistant (MDR) isolates (Table). CAZ-AVI, MEM-VAB, and IMI-REL were active against 84.2%, 57.9%, and 52.6% of carbapenem-resistant ENT (CRE) isolates, respectively. PSA susceptibility to PIP-TAZ, MEM, and CAZ were 86.1%, 88.5%, and 88.5%, respectively. CAZ-AVI (97.6% susceptible [S]), C-T (97.6%S), IMI-REL (99.0%S), and tobramycin (TOB; 98.3%S) were the most active agents against PSA and retained good activity against piperacillin-tazobactam (PIP-TAZ) nonsusceptible (NS), MEM-NS, and multidrug-resistant (MDR) isolates. Conclusion CAZ-AVI and MEM-VAB were the most active agents against ENT and CAZ-AVI; C-T and IMI-REL were the most active BLICs against PSA. The new BLICs represent valuable treatment options for infections caused by MDR GBNs. CAZ-AVI exhibited a more balanced spectrum against ENT and PSA when compared to other BLICs. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Michael D. Huband, BS, AbbVie: Grant/Research Support|Melinta: Grant/Research Support Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

656. Comparative Activity of Newer β-Lactam/β-Lactamase Inhibitor Combinations against Pseudomonas aeruginosa isolates from United States Medical Centers (2020-2021)

Abstract Background P. aeruginosa (PSA) is one of the most common Gram-negative organisms causing infections in hospitalized patients. Prompt administration of an effective antimicrobial is crucial for patients with systemic PSA infection. We evaluated the in vitro activity of ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), imipenem-relebactam (IMI-REL), and many comparator agents against contemporary PSA isolates from US hospitals. Methods 3,184 isolates were consecutively collected from 71 US medical centers in 2020-2021 and susceptibility tested by reference broth microdilution methods in a monitoring laboratory (JMI Laboratories). US FDA and CLSI breakpoints were applied. Results CAZ-AVI (97.0% susceptible [S]), C-T (98.0%S), IMI-REL (97.3%S), and tobramycin (TOB; 96.4%S) were the most active agents against the aggregate PSA isolate collection and retained good activity against piperacillin-tazobactam- (PIP-TAZ) nonsusceptible (NS), MEM-NS, and multidrug-resistant (MDR) isolates (Table 1). All other antimicrobials tested showed limited activity against PIP-TAZ-NS, MEM-NS, and MDR isolates. The most common infection types were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (UTI; 17.0%), and bloodstream infections (11.7%); CAZ-AVI, C-T, and IMI-REL showed consistent activity against isolates from these infection types. Susceptibility to PIP-TAZ and MEM were lower among isolates from pneumonia compared to other infection types (Table 2). CAZ-AVI remained active against 31.7% and 52.5% of C-T-NS and IMI-REL-NS isolates, respectively. C-T remained active against 54.7% and 68.9% of CAZ-AVI-NS and IMI-REL-NS isolates, respectively, and IMI-REL remained active against 64.2% and 64.8% of isolates NS to CAZ-AVI and C-T, respectively. Conclusion CAZ-AVI, C-T, and IMI-REL were highly active and exhibited similar coverage against a large contemporary collection of PSA isolates from US hospitals. Cross resistance among these new β-lactamase inhibitor combinations varied markedly, indicating that all 3 should be tested in the clinical laboratory. These 3 agents represent valuable therapeutic options for PSA infection treatment. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

1310. Antimicrobial Activity of Ceftazidime-Avibactam and Other New β-Lactamase Inhibitor Combinations Tested against Bacterial Isolates from Pediatric Patients from US Medical Centers (2020-2021)

Abstract Background The US FDA expanded the approval of ceftazidime-avibactam (CAZ-AVI) to include pediatric patients aged ≥ 3 months in 2019. We evaluated the in vitro activities of CAZ-AVI, ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), imipenem-relebactam (IMI-REL), and comparators against Enterobacterales (ENT; n=2,391) and P. aeruginosa (PSA; n=414) isolates causing infection in pediatric patients from US medical centers. Methods Among 21,332 organisms (1/patient) collected in 2020-2021 via the INFORM Surveillance Program, 2,805 (13.1%) were from pediatric patients (≤ 17 years-old [yo]). The isolates were consecutively collected from 69 US medical centers and susceptibility tested by reference broth microdilution methods. Susceptibility results were stratified by patient age (≤ 1 yo [1,040 isolates], 2-5 yo [580], 6-12 yo [651], and 13-17 yo [534], and by infection type. ENT isolates with an ESBL phenotype were screened for β-lactamase genes by whole genome sequencing. Results CAZ-AVI and MEM-VAB showed complete activity (100.0% susceptible [S]) against Enterobacterales, whereas C-T and IMI-REL showed limited activity against some organisms (Table). MEM, ceftriaxone (CRO), and gentamicin (GEN) were active against 99.8%, 87.5%, and 93.0% of Enterobacterales, respectively. Enterobacterales susceptibility to CRO varied from 84.7% (6-12 yo) to 89.8% (13-17 yo), susceptibility to GEN varied from 91.9% (6-12 yo) to 94.0% (≤ 1 yo), and susceptibility to the multidrug-resistant (MDR) phenotype varied from 3.7% (≤1 yo) to 4.8% (13-17 yo). CAZ-AVI (99.5%S), C-T (99.8%S), and IMI-REL (98.4%S) were the most active agents against the PSA collection, but CAZ-AVI and C-T showed greater activity than IMI-REL against PSA-resistant subsets. MEM-VAB and MEM exhibited similar activity against PSA (91.3% inhibited at ≤ 2 mg/L for both agents). PSA overall susceptibility for MEM was 91.3%, varying from 87.3% (13-17 yo) to 93.2% (2-5 yo).Piperacillin-tazobactam (PIP-TAZ) was 87.4%, varying from 85.1% (6-12 yo) to 90.1% (13-17 yo). Conclusion CAZ-AVI and MEM-VAB were the most active agents against Enterobacterales and CAZ-AVI. C-T was the most active agents against PSA. Susceptibility differences were observed among age groups. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

1686. Antimicrobial Activity of Aztreonam-avibactam, Ceftazidime-Avibactam, and Comparator Agents against Pseudomonas aeruginosa from Cystic Fibrosis Patients

Abstract Background Aztreonam-avibactam (ATM-AVI) is under clinical development for the treatment of serious infections caused by Gram-negative bacteria, including MBL producers. Four other β-lactamase inhibitor combinations (BL/BLI) have been recently approved by the US FDA: ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), and imipenem-relebactam (IMI-REL). We evaluated the in vitro activity of these 5 BL/BLIs and comparators against P. aeruginosa (PSA) causing cystic fibrosis (CF) pulmonary exacerbation. Methods 383 PSA isolates (1/patient) were recovered from 35 medical centers in the US (n=187) and 12 European countries (EU; n=196) in 2018-2021 and susceptibility tested by CLSI broth microdilution method. Results ATM-AVI inhibited 83.4%/85.2% of isolates from US/EU at ≤8 mg/L. CAZ-AVI (MIC50/90, 2/8 mg/L; 96.3%/95.4% susceptible [S] in US/EU) was the most active agent, followed by IMI-REL (94.7%/92.5%S in US/EU) and C-T (89.8%/91.3%S in US/EU). MEM-VAB (not approved for PSA in the US) and MEM showed similar activity. Tobramycin (TOB)-S rates were 73.3%/85.7% in US/EU (Table 1). Among TOB-non-S (NS) isolates, 84.6% were CAZ-AVI-S and 73.1% were inhibited at ATM-AVI MIC of ≤8 mg/L. CAZ-AVI retained good activity against C-T-NS (61.1%S), IMI-REL-NS (62.1%S), piperacillin-tazobactam (PIP-TAZ)-NS (86.7%S), meropenem (MEM)-NS (86.6%S), and ciprofloxacin (CIP)-NS (92.1%S) isolates (Table 2). Multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes were observed among 40.1%/30.1% and 24.6%/16.8% of isolates from US/EU, respectively. Among MDR isolates, 90.7%/84.7% were CAZ-AVI-S, 65.3%/66.1% were inhibited at ≤8 mg/L of ATM-AVI, and 78.7%/76.3% were TOB-S in US/EU. CAZ-AVI and TOB retained activity against 87.0%/75.8% and 39.1%/63.6% of XDR isolates in US/EU, respectively. Conclusion ATM-AVI and CAZ-AVI exhibited potent activity against PSA isolated from CF patients in US and EU and retained good activity against isolates resistant to other antimicrobials, including MDR and XDR organisms; both compounds showed greater activity than TOB. ATM-AVI and CAZ-AVI may represent a valuable option to treat CF patients with pulmonary exacerbations due to PSA infection. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

Ceftolozane-Tazobactam Pharmacokinetics in the Abdominal Tissue of Patients Undergoing Lower Gastrointestinal Surgery: Dosing Considerations Based on Site-Specific Pharmacodynamic Target Attainment.

Recently, complicated intra-abdominal infections (cIAI) have been caused not only by Escherichiacoli, Klebsiellapneumoniae, Enterobacter cloacae, and Pseudomonasaeruginosa, but also by extended-spectrum β-lactamase-producing Enterobacterales members. Ceftolozane-tazobactam (CTLZ-TAZ) is considered to exhibit therapeutic effects against cIAI. Studies on the concentrations of antibiotics in abdominal tissues directly affected by cIAI are limited. Therefore, in this study, we investigated the pharmacokinetics of CTLZ-TAZ in abdominal tissue and simulated the administration regimen required to achieve the pharmacodynamic target for cIAI-causing bacteria. Patients scheduled for elective lower gastrointestinal surgery were intravenously administered preoperative CTLZ-TAZ (1g CTLZ and 0.5g TAZ). Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected during the surgery, and CTLZ as well as TAZ concentrations were measured. The noncompartmental and compartmental pharmacokinetic parameters were then estimated. Site-specific pharmacodynamic target attainment analysis using 1.5g of CTLZ-TAZ was performed. CTLZ-TAZ was administered to nine patients (once to five patients and twice to four patients). The mean peritoneal fluid-to-plasma ratio (one dose/two doses) for CTLZ was 0.74/1.15, which was slightly higher than the mean peritoneal fluid-to-plasma ratio for TAZ (0.95/1.13). The ratio for subcutaneous adipose was lower than those for peritoneal fluid and peritoneum tissues. We also discovered that the average ratio of CTLZ and TAZ concentrations in all tissues was maintained at or above 2:1. In our investigation of pharmacodynamic target attainment in each tissue, the desired bactericidal effect was attained with all CTLZ-TAZ (1.5g) administration regimens [q12h (3g/day), q8h (4.5g/day), and q6h (6g/day)]. To the best of our knowledge, this is the first study investigating the optimal pharmacodynamic level of CTLZ-TAZ in the abdominal tissue against cIAI-causing bacteria. This study also serves as a guideline for designing an optimal administration regimen based on pharmacodynamic target attainment for cIAI-causing bacteria. The institutional review board of Hiroshima University Hospital, CRB6180006. The Japan Registry of Clinical Trials, jRCTs061190025.

In-vitro Activity of Ceftolozane-Tazobactam Against Multi-Drug ResistantPseudomonas aeruginosa in a Tertiary Care Center in Al-Ahsa, KSA

Abstract Introduction/Objective Pseudomonas aeruginosa is a major nosocomial pathogen often causing serious multi-drug resistant (MDR) infections. Resistant strains, including carbapenem-resistant (CR), are increrasing especially in intensive care units (ICU) which limits treatment options to nephrotoxic aminoglycosides and polymyxins, and results in failure of initial therapy, significant mortality, morbidity and cost. Ceftolozane-tazobactam (CT) is a novel antimicrobial showing good activity against MDR and CR isolates; however, reports of resistance are increasing. Data from KSA is scarce. The aim of this study is to determine the in-vitro activity of CT against MDR and CR P. aeruginosa Methods/Case Report Single-center retrospective observational study of patients with P. aeruginosa infection in 2020 and 2021. Data including susceptibility to anti-pseudomonal drugs were retreived from medical records. Non-duplicate consecutive first isolates from all clinical specimens were included. MDR strains were labeled following international guidelines. Data was analyzed using the Statistical Package for the Social Sciences software (SPSS®). Results (if a Case Study enter NA) Out of 538 isolates collected, 98 (18.2%) were CR and 62 (11.5%) were MDR. MDR isolates were mainly retrieved from respiratory samples (44%), bedsores (29%) and urine (21%). 62% of CR and 76% of MDR isolates were from patients &amp;gt;60 years of age; significantly higher than younger patients. 85% (83/98) of CR and 81% (50/62) of MDR isolates came from ICU patients where the prevalence of CR and MDR was 34% and 20%, respectively; significantly higher than other areas. Overall sensitivity to CT was 97%, 85% for CR and 71% for MDR isolates. Only amikacin performed better with 98% sensitivity overall, 92% for CR and 86% for MDR. Sensitivity to CT in ICU was 94%. CT was effective against 83% of CR and 70% of MDR isolates second only to amikacin (90% and 84%, respectively). Other tested antimicrobials were ineffective against MDR and CR isolates. Conclusion CT shows good in-vitro activity against MDR and CR P. aeruginosa isolates. It may provide a therapeutic option to treat urinary tract infections and hospital-acquired or ventilator-associated pneumoniae especially in critically ill elderly patients. More studies on treatment responses and emergence of resistance are required to establish the role of CT as an effective treatment of serious P. aeruginosa infections.

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

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

In Vitro Activity of Ceftolozane-Tazobactam and Other Antibiotics against Pseudomonas aeruginosa Infection-Isolates from an Academic Medical Center in Thailand.

(1) Background: Resistant Pseudomonas aeruginosa (PA) infections have limited treatment options. Data on the activity of ceftolozane-tazobactam (C-T) against PA in Thailand are limited. Objectives: The objective of this study was to identify the in vitro activity of C-T against general and resistant PA isolates from patients with real clinical infections from the HRH Princess Maha Chakri Sirindhorn Medical Center (MSMC) compared to other antibiotics and to study the resistant molecular patterns of those PA strains which were resistant to C-T. (2) Materials and Methods: This was an in vitro susceptibility study of 100 PA isolates plus an additional seven resistant PA isolates collected from MSMC patients. All PA isolates were tested with susceptibility broth (Sensititre™) and C-T minimal inhibitory concentration (MIC) test strips (Liofilchem, Roseto degli, Abruzzi, Italy). The C-T-resistant PA isolates were analyzed for six β-lactamase genes (blaCTX-M, blaNDM, blaIMP, blaVIM, blaOXA-23 and blaOXA-48) and the mcr-1 gene. (3) Results: A total of 100 PA isolates were collected between January 2020 and January 2021 and between February 2021 and September 2021 for the additional 7 resistant isolates. There were 18 resistant PA isolates (6 MDR, 11 XDR and 1 pan-drug resistant isolate). The overall susceptibility of the initial 100 PA isolates and the 18 resistant PA isolates was 94% and 44.5%, respectively, for C-T. The C-T susceptibility rates for isolates non-susceptible to ceftazidime, piperacillin-tazobactam, carbapenems and antipseudomonal β-lactams were 65.5%, 69.7%, 50% and 44.5%, respectively. Among the 10 isolates which were resistant to C-T, there were only 3 isolates found to have the resistant gene, which included 1 for blaIMP, 1 for blaVIM and 1 for blaNDM. (4) Conclusions: Although C-T was the best susceptibility antibiotic overall for PA isolates and MDR PA isolates at the MSMC, most of the XDR PA isolates and the PDR PA isolate were not susceptible to C-T. The mechanisms for C-T resistance involved multiple factors including the presence of blaIMP, blaVIM and blaNDM.