Antipseudomonal Β-lactams Research Articles

Mechanisms leading to in vivo ceftazidime/avibactam resistance development during treatment of GES-5-producing Pseudomonas aeruginosa infections.

The mechanisms underlying ceftazidime/avibactam resistance development in four ceftazidime/avibactam susceptible/resistant pairs of GES-5-producing ST235 Pseudomonas aeruginosa clinical isolates were investigated. In three of the cases, ceftazidime/avibactam resistance was driven by a single mutation leading to GES-27 (P162Q), GES-29 (P162A), or the novel GES-60 (N136S), as confirmed through cloning experiments. Moreover, these mutations were associated with increased cefiderocol MICs but reduced carbapenem, particularly imipenem/relebactam, resistance. Understanding the complexity of resistance mechanisms to the growing repertoire of antipseudomonal β-lactams is crucial to guide optimized treatments and antimicrobial stewardship measures.

Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients (BEATLE): a randomized, multicentre, open-label, superiority clinical trial

ObjectivesThe efficacy of extended infusions (EI) of β-lactam antibiotics for optimising outcomes in febrile neutropenia is unclear. We assessed whether the administration of β-lactams was more effective in EI than in intermittent infusion (II) for the treatment of febrile neutropenia. MethodsWe performed a randomized, open-label, superiority clinical trial of patients with febrile neutropenia at four Spanish university hospitals. Patients undergoing haematopoietic stem cell transplantation or with acute leukaemia receiving chemotherapy who required empirical antibiotic treatment for febrile neutropenia were randomly assigned (1:1) to receive EI of β-lactam or II after a first dose in bolus. The choice of antipseudomonal β-lactam was left to the discretion of the attending physician. The primary endpoint was treatment success at day 5, defined as defervescence without modifying the antibiotic treatment. Secondary endpoints included adverse events, attainment of the pharmacokinetic/pharmacodynamic target of 50%, 75%, and 100%ƒuT > MIC, and 30-day mortality. ResultsFrom November 19, 2019 to June 22, 2022, 295 patients were screened for eligibility, of whom 150 were randomly assigned to receive EI (n = 77) or II (n = 73) of the antipseudomonal β-lactam of choice. In the intention-to-treat analysis, treatment success at day 5 was achieved in 39/77 patients (50.6%) receiving EI versus 46/73 patients (63.0%) receiving II (risk difference, −12.4%; 95% CI, −29.4 to 4.7; p 0.17). The pharmacokinetic/pharmacodynamic targets of 75% and 100% ƒuT > MIC for empirical treatment were achieved more frequently in the EI group. No statistically significant differences were found between groups in terms of adverse events or 30-day mortality. DiscussionOur findings do not support the routine use of empirical EI of β-lactams in febrile neutropenia. Further studies should consider the clinical heterogeneity of febrile neutropenia and focus on patients with sepsis or septic shock and microbiologically documented infections, particularly those with infections caused by microorganisms less susceptible to β-lactams.

Impact of transferable β-lactamases and intrinsic AmpC amino acid substitutions on the activity of cefiderocol against wild-type and iron uptake-deficient mutants of Pseudomonas aeruginosa.

We aimed to analyse the interplay between impaired iron uptake and β-lactamases on cefiderocol resistance in Pseudomonas aeruginosa. Thirty-one transferable β-lactamases and 16 intrinsic P. aeruginosa AmpC (PDC) variants were cloned and expressed in wild-type (PAO1) and iron uptake-deficient (PAO ΔpiuC) P. aeruginosa backgrounds. MICs of cefiderocol and antipseudomonal β-lactams were determined by reference broth microdilution. Relative to PAO1, deletion of piuC caused a specific 16-fold decrease in cefiderocol activity but negligible effects on the activity of other β-lactams. Among transferable β-lactamases, SHV-12, KPC Ω-loop mutants, NDMs and OXA-15 showed cefiderocol MIC values above the clinical breakpoint (2 mg/L) when expressed in PAO1. When expressed in PAO ΔpiuC, these and the transformants harbouring PER-1, VEB-1, KPC-2, KPC-3, VIM-1, CMY-2, OXA-2 and OXA-14 showed increased MIC values from 16 to >256 mg/L. The PDC variants carrying the Ω-loop changes ΔP215-G222 (PDC-577), E219K (PDC-221 and PDC-558) and the H10 helix change L293P (PDC-219) had the greatest impact on cefiderocol resistance, with MICs of 2-4 mg/L in PAO1 and of up to 32-64 mg/L in PAO ΔpiuC. Widespread enzymes such as GES, CTX-M-9, CTX-M-15, VIM-2-like enzymes, IMPs, DHA-1, FOX-4, OXA-10, OXA-48 and the other PDC variants tested had weaker effects on cefiderocol resistance. We add evidence about the effect of the interplay between iron uptake and β-lactamases on the acquisition of cefiderocol resistance in P. aeruginosa. These findings may help to anticipate the emergence of resistance and optimize the use of cefiderocol against P. aeruginosa infections.

Assessment of the Workflow and Time to Antibiotic Dose Adjustment for Critically Ill Patients Starting Continuous Renal Replacement Therapy.

Background: Acute kidney injury (AKI) remains a common sequela of sepsis necessitating use of continuous renal replacement therapy (CRRT). In the setting of AKI, renally adjusted antimicrobials (eg, β-lactams) are dose reduced to prevent toxicity; however, the extracorporeal clearance of CRRT may lead to subtherapeutic exposures of dose reduced antimicrobials. The present study sought to evaluate the time to dose adjustment to CRRT appropriate doses of antimicrobials after initiation of CRRT. Methods: A retrospective cohort study of patients on CRRT and anti-pseudomonal β-lactams was conducted. CRRT was conducted as continuous veno-venous hemodialysis (CVVHD) per institutional standards. Baseline characteristics were collected including dialysate flow rate. The primary outcome was time to CRRT appropriate dose adjustment. Secondary outcomes included the pharmacist shift (ie, day, evening, or night shift) that CRRT was ordered and initiated. Continuous data were reported as median (IQR). Results: Forty-four patients were included in the analysis. The median dialysate flow rate was 2.3 L/hour (2, 3.1). Of included patients, 75% received cefepime therapy while 25% received meropenem. The median time to CRRT appropriate dosing was 13 hours (6, 20). CRRT was most commonly ordered during day shift (68%) but not started until evening (59%). The observed delay in appropriate dose adjustment may predispose patients to suboptimal antimicrobial exposure and subsequently therapeutic failure. CRRT was often ordered during the day shift but not initiated until evening which led to identification of potential procedural improvements. Conclusions: These data led to the initiation of a pharmacy in basket consult to alert pharmacists in real time of CRRT orders so that once CRRT was started, doses could be appropriately adjusted. Future studies to assess the impact of this process change on both time to appropriate dose and clinical outcomes are warranted.

Early antibiotic de-escalation in patients with severe infections due to bloodstream infection by enterobacterales: A post hoc analysis of a prospective multicentre cohort

Data about antibiotic de-escalation in sepsis associated with the bloodstream and caused by Enterobacterales are scarce. The objectives of this study are to identify factors associated with early de-escalation and to analyse the impact of de-escalation on mortality in patients with Enterobacterales bloodstream infection (BSI) with a Sequential Organ Failure Assessment (SOFA) score ≥ 2. A prospective, multicentre cohort study was performed including episodes of BSI due to Enterobacterales and a SOFA score ≥ 2 who were receiving an active antipseudomonal β-lactam; the isolate should be susceptible to at least 1 narrower-spectrum antibiotic. Variables associated with de-escalation were identified using logistic binary regression. The association of de-escalation with 30-day mortality was investigated. Confounding was controlled by calculating a propensity score used as covariate, as matching variable, and for inverse probability treatment weighting. Of the 582 patients included, de-escalation was performed in 311 (53.4%). Neutropenia (adjusted odds ratio [aOR] = 0.37; 95% confidence interval [95% CI] = 0.18-0.75), central venous catheter (aOR = 0.52; 95% CI = 0.32-0.83), and extended-spectrum β-lactamase (ESBL)-producing isolate (aOR = 0.28; 95% CI = 0.17-0.48) were negatively associated with de-escalation, and urinary tract source was positively associated (aOR = 2.27; 95% CI = 1.56-3.33). The 30-day mortality was 6.8% (21 patients) in de-escalated patients and 14.4% (39) in not de-escalated patients (relative risk, 0.63; 95% CI = 0.44-0.89). In multivariate analysis including the propensity score, de-escalation was not associated with mortality (AOR = 0.98; 95% CI = 0.39-2.47) and was protective in the case of urinary or biliary tract source (AOR = 0.31, 95% CI = 0.09-1.06). Matched and inverse probability treatment weighting analysis showed similar results. These results suggest that early de-escalation from antipseudomonal β-lactams is safe in patients with Enterobacterales bacteremia and SOFA ≥ 2.

Genomic Insights into Vietnamese Extended-Spectrum β-Lactamase-9-Producing Extensively Drug-Resistant Pseudomonas aeruginosa Isolates Belonging to the High-Risk Clone ST357 Obtained from Bulgarian Intensive Care Unit Patients.

Extensively drug-resistant P. aeruginosa (XDR-PA) has been highlighted as a serious public health threat. The present study aimed to explore the genomic characteristics of two Vietnamese extended-spectrum β-lactamase-9 (VEB-9)-producing XDR-PA isolates from Bulgaria in comparison to all blaVEB-9-positive strains with available genomes. The isolates designated Pae51 and Pae52 were obtained from tracheobronchial aspirates of intensive care unit (ICU) patients. Antimicrobial susceptibility testing, whole-genome sequencing, RT-qPCR, and phylogenomic analysis were performed. Pae51 and Pae52 were resistant to most antipseudomonal β-lactams including carbapenems, aminoglycosides, and fluoroquinolones but remained susceptible to colistin and cefiderocol. Numerous resistance determinants were detected: blaVEB-9, blaPDC-3, blaOXA-10, blaOXA-50, aac(6')-II, ant(2″)-Ia, ant(3″)-IIa, aph(3')-IIb, cprP, catB7, dfrB2, sul1, fosA, and tet(A). Both isolates carried complex integrons with blaVEB-9 and tet(A) embedded next to the conservative 3' end sequences. A variety of virulence factors were also identified, including the type III secretion system exotoxin U. Pae51 and Pae52 differed by only four SNPs and belonged to the high-risk clone ST357. To our knowledge, this is the first report of blaVEB-9-positive XDR-PA isolates in Bulgaria presenting a detailed genomic analysis. The development of novel antimicrobial strategies for such pathogens should be an essential part of infection control stewardship practices in ICU wards.

Resistance to ceftazidime-avibactam and other new β-lactams in Pseudomonas aeruginosa clinical isolates: a multi-center surveillance study.

Multidrug-resistant Pseudomonas aeruginosa infections are a growing threat due to the limited therapeutic options available. Ceftazidime-avibactam (CZA) is among the last-resort antibiotics for the treatment of difficult-to-treat P. aeruginosa infections, although resistance due to the acquisition of transferable β-lactamase genes is increasing. With this work, we report that CZA represents a highly active antipseudomonal β-lactam compound (after cefiderocol), and that metallo-β-lactamases (VIM-type) and extended-spectrum β-lactamases (GES and PER-type) production is the major factor underlying CZA resistance in isolates from Southern Italian hospitals. In addition, we reported that such resistance mechanisms were mainly carried by the international high-risk clones ST111 and ST235.

Trends in Empiric Broad-Spectrum Antibiotic Use for Suspected Community-Onset Sepsis in US Hospitals

Little is known about the degree to which suspected sepsis drives broad-spectrum antibiotic use in hospitals, what proportion of antibiotic courses are unnecessarily broad in retrospect, and whether these patterns are changing over time. To describe trends in empiric broad-spectrum antibiotic use for suspected community-onset sepsis. This cross-sectional study used clinical data from adults admitted to 241 US hospitals in the PINC AI Healthcare Database. Eligible participants were aged 18 years or more and were admitted between 2017 and 2021 with suspected community-onset sepsis, defined by a blood culture draw, lactate measurement, and intravenous antibiotic administration on admission. Empiric anti-methicillin-resistant Staphylococcus aureus (MRSA) and/or antipseudomonal β-lactam agent use. Annual rates of empiric anti-MRSA and/or antipseudomonal β-lactam agent use and the proportion that were likely unnecessary in retrospect based on the absence of β-lactam resistant gram-positive or ceftriaxone-resistant gram-negative pathogens from clinical cultures obtained through hospital day 4. Annual trends were calculated using mixed-effects logistic regression models, adjusting for patient and hospital characteristics. Among 6 272 538 hospitalizations (median [IQR] age, 66 [53-78] years; 443 465 male [49.6%]; 106 095 Black [11.9%], 65 763 Hispanic [7.4%], 653 907 White [73.1%]), 894 724 (14.3%) had suspected community-onset sepsis, of whom 582 585 (65.1%) received either empiric anti-MRSA (379 987 [42.5%]) or antipseudomonal β-lactam therapy (513 811 [57.4%]); 311 213 (34.8%) received both. Patients with suspected community-onset sepsis accounted for 1 573 673 of 3 141 300 (50.1%) of total inpatient anti-MRSA antibiotic days and 2 569 518 of 5 211 745 (49.3%) of total antipseudomonal β-lactam days. Between 2017 and 2021, the proportion of patients with suspected sepsis administered anti-MRSA or antipseudomonal therapy increased from 63.0% (82 731 of 131 275 patients) to 66.7% (101 003 of 151 435 patients) (adjusted OR [aOR] per year, 1.03; 95% CI, 1.03-1.04). However, resistant organisms were isolated in only 65 434 cases (7.3%) (30 617 gram-positive [3.4%], 38 844 gram-negative [4.3%]) and the proportion of patients who had any resistant organism decreased from 9.6% to 7.3% (aOR per year, 0.87; 95% CI, 0.87-0.88). Most patients with suspected sepsis treated with empiric anti-MRSA and/or antipseudomonal therapy had no resistant organisms (527 356 of 582 585 patients [90.5%]); this proportion increased from 88.0% in 2017 to 91.6% in 2021 (aOR per year, 1.12; 95% CI, 1.11-1.13). In this cross-sectional study of adults admitted to 241 US hospitals, empiric broad-spectrum antibiotic use for suspected community-onset sepsis accounted for half of all anti-MRSA or antipseudomonal therapy; the use of these types of antibiotics increased between 2017 and 2021 despite resistant organisms being isolated in less than 10% of patients treated with broad-spectrum agents.

In Enterobacterales bacteremia, antipseudomonal β-lactam de-escalation was noninferior to continuation for clinical cure at 3 to 5 d.

López-Cortés LE, Delgado-Valverde M, Moreno-Mellado E, et al; SIMPLIFY study group. Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial. Lancet Infect Dis. 2024;24:375-385. 38215770.

Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial

De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal β-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal β-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal β-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. De-escalation from an antipseudomonal β-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Antibiotic Stewardship: A Handshaking Strategy Among Physicians and Pharmacists to Improve therapeutic Outcomes in Hematology-Oncology.

Background: Infections are highly susceptible in patients with hematological malignancies due to immune suppression, immunosuppressive therapies and disease progression. Rational use of antibiotics following Antimicrobial Stewardship (AMS) guidelines in early detection and response to infection is significant to improve patient care. Objectives: The present study was conducted to determine the impact of clinical pharmacists' interventions (PIs) on antibiotics usage in hematology-oncology set up in Karachi, Pakistan. Methodology: An observational prospective study was conducted for a period of 4 months in a well-known 75-bed teaching hospital, specializing in bone marrow transplantation in Karachi, Pakistan without a structured Antimicrobial stewardship programs (ASPs). The information was gathered from patient medical histories, laboratory, and microbiological records. Results: A total of 876 PIs (1 to 5 per patient) were implemented. Dose modifications or interval changes accounted for the major interventions (n = 190, 21.6%). The majority of all recommendations were related to antipseudomonal β-lactams, aminoglycosides, sulfamethoxazole-trimethoprim and vancomycin. Overall, 94.3% (n = 876) of the 928 PIs were accepted. Conclusion: The PIs and the high physician acceptance rate may be useful for improving the safe use of antibiotics, lowering their toxicity, lowering the need for special-vigilance medications and potentially improving patient care.

356. Impact of CLSI Breakpoint Changes on Unit-Specific Combination Antibiograms for Gram-Negative Respiratory Isolates

Abstract Background In 2023, the CLSI updated aminoglycoside breakpoints for P. aeruginosa and Enterobacterales. The anticipated decrease in aminoglycoside susceptibility rates resulting from these revised breakpoints will impact empiric antibiotic selection for nosocomial pneumonia. This study aims to evaluate the impact of the new breakpoints on the susceptibility rates of various combination antibiotic regimens for Gram-negative pneumonia at Michigan Medicine. Methods The susceptibility rates of single and combination antibiotic regimens were determined by applying the CLSI breakpoints to 221 non-duplicated, first Gram-negative respiratory isolates obtained from patients in the MICU and SICU of Michigan Medicine in 2021. Combination antibiograms were developed to compare susceptibility rates of various potential empiric regimens based on the 2022 vs. 2023 aminoglycoside breakpoints. Subgroup analyses for P. aeruginosa vs. non-P. aeruginosa were performed. Results Comparisons of unit-specific combination antibiograms against all Gram-negative respiratory isolates using 2022 vs. 2023 breakpoints are shown in Table 1. Based on the 2022 breakpoints, overall susceptibility rates for aminoglycosides were higher than those of anti-pseudomonal β-lactams. The addition of an aminoglycoside improved the susceptibility percentages of a β-lactam up to 23%, allowing similar activity with amikacin-based combination therapy to levofloxacin-based. In contrast, based on 2023 breakpoints, the susceptibility rates of amikacin and gentamicin dropped significantly (85.1 to 58.8% and 81.0 to 56.6%, respectively) and combination with these two agents did not provide additional benefit to the β-lactam backbone. The tobramycin susceptibility rate was minimally affected by the breakpoint changes (82.8% vs. 79.2%). Subgroup analyses demonstrated that the decrease in susceptibility percentages for aminoglycosides was largely driven by the breakpoint changes for P. aeruginosa (Table 1). Conclusion The updated 2023 CLSI breakpoints resulted in a substantial decrease in the susceptibility percentages of amikacin and gentamicin which clinicians need to be aware of when choosing empiric antibiotic treatment. Disclosures Virginia M. Pierce, MD, FIDSA, UpToDate, Inc.: Authorship royalties jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant

722. Risk Factors for Infection or Colonization with Ceftolozane/Tazobactam Non-Susceptible Extensively β-Lactam Resistant Pseudomonas aeruginosa

Abstract Background Treatment of infections due to multidrug resistant (MDR) Pseudomonas aeruginosa is complicated by co-resistance amongst traditional anti-pseudomonal β-lactams, as 50% of MDR isolates exhibit extensive β-lactam resistance (EBR, non-susceptible to cefepime, ceftazidime, piperacillin/tazobactam, and meropenem). Ceftolozane/tazobactam (C/T) was developed to combat MDR and EBR P. aeruginosa. Unfortunately, C/T resistance has proliferated. We designed this retrospective case-control study to identify risk factors for C/T non-susceptibility (NS) amongst EBR P. aeruginosa. Methods Between 2015 to 2020, hospitalized adult patients infected or colonized with EBR P. aeruginosa were identified. C/T susceptibility was defined per the 2023 Clinical and Laboratory Standards Institute (CLSI) guidelines (susceptible (S) if minimum inhibitory concentration (MIC) ≤ 4 mg/L, NS if MIC ≥ 8 mg/L). Patients with an EBR P. aeruginosa NS to C/T were classified as cases, whereas those with S isolates were controls. Patients with multiple EBR P. aeruginosa isolates over the study period were only included once. If a patient had a C/T NS isolate, they were classified as cases and the first C/T NS isolate was included as the index culture. If the patient did not have a C/T NS isolate over the study period, they were considered a control and the first C/T S isolate was the index culture. Bivariate and multivariate modeling was performed to identify independent predictors for C/T NS. Results 188 unique patients with C/T susceptibility performed were included in the study; 96 (51%) were C/T NS and 92 (49%) were C/T S. Table 1 shows the bivariate comparisons of key baseline characteristics between groups. Independent predictors of C/T NS are displayed in table 2. Conclusion Independent predictors for C/T NS amongst EBR P. aeruginosa isolates were a history of cancer, cystic fibrosis, and isolation of EBR P. aeruginosa in the past 90 days. While receipt of cefepime or ceftazidime in the past 90 days was associated with C/T NS in bivariate comparisons, the association did not remain in multivariate modeling. C/T exposure was not a statistically significant risk factor, but it was numerically associated with NS and the lack of significance was likely due to the small number of patients (n = 15) who received it. Disclosures Virginia M. Pierce, MD, FIDSA, UpToDate, Inc.: Authorship royalties jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant

An extensively drug-resistant Pseudomonas aeruginosa isolate from Myanmar

ObjectivesAntimicrobial resistance (AMR) including multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa has emerged as one of the serious public health threats across the globe. Southeast Asia is a ‘hot spot’ of antimicrobial-resistant bacteria including MDR P. aeruginosa. Despite Myanmar being located in Southeast Asia and suffering from a high infectious disease burden, data on MDR and XDR P. aeruginosa from Myanmar is limited. In this communication, we report the draft genome of an XDR P. aeruginosa isolate, MMXDRPA001 that was identified during a routine diagnosis in Myanmar. MethodsAn MMXDRPA001 isolate colonising a hospitalised patient was characterised by antibiotic resistance profiling following standard methods and whole-genome sequencing using an Illumina MiSeq platform. The generated reads were de novo assembled using SPAdes (v.3.9.1). Annotation was performed by Prokka (v.1.14.0). Sequence type, antimicrobial resistance and virulence-related genes were predicted from the sequence. The phylogenetic relationships of all P. aeruginosa isolates were determined using core genome single nucleotide polymorphisms (SNPs) analysis utilising Snippy (v.4.6.0) and Gubbins (v.2.3.4). ResultsP. aeruginosa MMXDRPA001 was resistant to most antipseudomonal β-lactams, aminoglycosides and quinolones. The assembly comprised 145 contigs totalling 6,808,493 bases of sequence and a total of 6,183 coding sequences. The isolate belonged to sequence type (ST) 235, contained carbapenemase-encoding gene blaIMP-1 and was clonally related to a previously reported isolate from Thailand. ConclusionsThe identification of an international high-risk clone of ST235 XDR isolate in Myanmar, genomically relating to that from a neighbouring country underscores the need for coordinated AMR surveillance throughout healthcare settings in Myanmar and in the Southeast Asia region.

Treatment Outcomes for Carbapenem-Resistant and Cephalosporin-Susceptible Pseudomonas aeruginosa Pneumonia.

Carbapenem-resistant (Car-R) Pseudomonas aeruginosa is an urgent threat. These isolates may remain susceptible to traditional noncarbapenem antipseudomonal β-lactams, but it is unclear if carbapenem resistance impacts the effectiveness of these agents. The purpose of this study was to compare clinical outcomes in Car-R and cephalosporin-susceptible (Ceph-S) P. aeruginosa pneumonia treated with cefepime versus other susceptible agents. This retrospective cohort study evaluated patients diagnosed with hospital-acquired or ventilator-associated pneumonia who had a respiratory isolate of Car-R Ceph-S P. aeruginosa. Patients were excluded if they had polymicrobial respiratory cultures, other concomitant infections, empyema, death within 3 days of index culture, or received less than 3 days of susceptible therapy. Patients treated with cefepime were compared to other susceptible therapies. The primary endpoint was 30-day in-hospital mortality. Eighty-seven patients were included: cefepime, n = 61; other susceptible therapies, n = 26. There were no differences in 30-day in-hospital mortality between cefepime and other susceptible therapies (19.6% vs. 19.2%, p value = 0.719). In addition, there were no differences between clinical cure rates (cefepime 65.6% vs. other therapies 72 %, p value = 0.47). In multivariate logistic regression, treatment with cefepime (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.11-2.52) was not independently associated with 30-day in-hospital mortality. For the treatment of Car-R Ceph-S P. aeruginosa pneumonia, cefepime showed similar rates of 30-day in-hospital mortality and clinical outcomes when compared to other susceptible therapies. Cefepime may be utilized to conserve novel β-lactam and β-lactamase inhibitors.

Reducing the rate of guideline-discordant therapy for inpatients with community-acquired pneumonia

Background: Despite guidelines recommending shorter durations of therapy and empiric coverage of Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) only for patients with certain risk factors, optimizing therapy for community-acquired pneumonia (CAP) remains a challenge for antimicrobial stewardship (AMS) teams. We investigated the impact of a multimodal AMS initiative on the rate of guideline-discordant empiric antibiotic selection and total duration of therapy for CAP. Methods: A quality improvement initiative was implemented at 9 community hospitals in 2022 to optimize CAP therapy. Education was provided to pharmacists and providers. Alerts were implemented within the electronic medical record to prompt the AMS team to review fluoroquinolones, antipseudomonal β-lactams, and anti-MRSA agents ordered for CAP. Clinical pharmacists reviewed antibiotic orders for CAP at hospital discharge and encouraged providers to prescribe a total antibiotic duration of 5–7 days. For the preintervention period (July– September 2021) and the postintervention period (July to September 2022), a random sample of 320 patients with an antibiotic order for CAP were evaluated retrospectively via chart review. Patients treated for an indication other than CAP were excluded. The primary outcome was the proportion of patients with a total duration of therapy >7 days. Secondary outcomes included average duration of therapy, rate of guideline-discordant empiric therapy, and type of guideline discordance. Results: In total, 317 patients were included. The proportion of patients with a total duration of therapy >7 days decreased from 29% to 14% (P < .01). Average duration of therapy and guideline-discordant empiric therapy also decreased significantly (Table 1). Conclusions: This multifaceted AMS initiative was associated with decreased guideline-discordant empiric therapy and decreased total duration of therapy for CAP.Disclosures: None

Leuconostoc lactis Bacteremia and Neutropenic Fever

Abstract The epidemiology of bacteremic infections in neutropenic patients has shifted from a previous majority involving gram-positive cocci to an increasing preponderance of gram-negative Enterobacteriaceae species and Pseudomonas aeruginosa. Recommended empiric antimicrobial treatment regimens include an antipseudomonal β-lactam or carbapenem agent while considering risk factors for the possibility of extended-spectrum β-lactamase– or carbapenemase-producing organisms. The addition of vancomycin is generally reserved for the chance of gram-positive cocci infection, principally in patients with central intravascular catheters or soft tissue infections. Persistent or breakthrough bacteremia despite receiving this glycopeptide drug should prompt the clinician to contemplate not only the possibility of vancomycin-resistant enterococci, but also other organisms that possess intrinsic resistance vancomycin, including Leuconostoc species.

Empiric Anti-Pseudomonal β-Lactam Monotherapy Versus Fluoroquinolone Combination Therapy in Patients With Hospital-Acquired Pneumonia: A Multicenter Cohort Study With Propensity Score Matching.

There is insufficient data on the benefits of empiric antibiotic combinations for hospital-acquired pneumonia (HAP). We aimed to investigate whether empiric anti-pseudomonal combination therapy with fluoroquinolones decreases mortality in patients with HAP. This multicenter, retrospective cohort study included adult patients admitted to 16 tertiary and general hospitals in Korea between January 1 and December 31, 2019. Patients with risk factors for combination therapy were divided into anti-pseudomonal non-carbapenem β-lactam monotherapy and fluoroquinolone combination therapy groups. Primary outcome was 30-day mortality. Propensity score matching (PSM) was used to reduce selection bias. In total, 631 patients with HAP were enrolled. Monotherapy was prescribed in 54.7% (n = 345) of the patients, and combination therapy was prescribed in 45.3% (n = 286). There was no significant difference in 30-day mortality between the two groups (16.8% vs. 18.2%, P = 0.729) or even after the PSM (17.5% vs. 18.2%, P = 0.913). After the PSM, adjusted hazard ratio for 30-day mortality from the combination therapy was 1.646 (95% confidence interval, 0.782-3.461; P = 0.189) in the Cox proportional hazards model. Moreover, there was no significant difference in the appropriateness of initial empiric antibiotics between the two groups (55.0% vs. 56.8%, P = 0.898). The proportion of multidrug-resistant (MDR) pathogens was high in both groups. Empiric anti-pseudomonal fluoroquinolone combination therapy showed no survival benefit compared to β-lactam monotherapy in patients with HAP. Caution is needed regarding the routine combination of fluoroquinolones in the empiric treatment of HAP patients with a high risk of MDR.

Pseudomonas aeruginosa prosthetic joint-infection outcomes: Prospective, observational study on 43 patients.

Analysis the outcomes of Pseudomonas aeruginosa prosthetic joint infection (PJI), and of their clinical and microbiological characteristics, surgical strategies and antibiotic treatments. Monocenter cohort study in a Bone-and-Joint-Infection Referral Center (08/2004 to 10/2018) including all consecutive P. aeruginosa PJIs. Data were extracted from the prospective database, including the following events: relapses, new PJIs, related deaths. Median [IQR]: among the 43 patients included (28 females; 72 [63-80] years old; 27 hip, 15 knee, and 1 shoulder PJIs), 29 (67%) had underlying comorbidities, 12 (28%) had previously been treated for another PJI and 9 (21%) had undergone previous surgeries for their P. aeruginosa PJI. Eleven (26%) PJIs were polymicrobial, 16 (37%) strains were wild type, 8 (19%) ciprofloxacin-resistant. PJIs were classified as late chronic (n = 33), early postoperative (n = 9) or acute hematogenous infection (n = 1). Forty patients underwent surgery: 27 one-stage and 5 two-stage exchanges, 3 debridement and implant retention, and 5 other surgical strategies. Antibiotic treatments were: 29 received 41 [37-43] days of combination therapy (IV anti-pseudomonal β-lactam and 3-5 days of amikacin, then β-lactam and oral ciprofloxacin), followed by oral ciprofloxacin for a total of 12 weeks; 10 received only IV antibiotics for 83 [77-86] days, including 37 [32-46] days of combination therapy; 49 days of ceftazidime alone for 1. During follow-up lasting 33 [24-64.5] months, 2 relapses, 3 new PJIs, and 2 related deaths occurred. Thirty-three (82%) patients and 93% of those managed with one-stage exchange experienced no event. Outcomes of our cohort's P. aeruginosa PJIs-predominantly monomicrobial, chronic, ciprofloxacin-susceptible, treated with one-stage exchange and prolonged IV antibiotics-were 82% favorable.

Quantifying Gram-Negative Resistance to Empiric Treatment After Repeat ExpoSure To AntimicRobial Therapy (RESTART).

Antibiotic exposure is a primary predictor of subsequent antibiotic resistance; however, development of cross-resistance between antibiotic classes is also observed. The impact of changing to a different antibiotic from that of previous exposure is not established. This was a retrospective, single-center cohort study of hospitalized adult patients previously exposed to an antipseudomonal β-lactam (APBL) for at least 48 hours in the 90 days prior to the index infection with a gram-negative bloodstream or respiratory infection. Susceptibility rates to empiric therapy were compared between patients receiving the same (repeat group) versus a different antibiotic from prior exposure (change group). A total of 197 patients were included (n = 94 [repeat group] and n = 103 [change group]). Pathogen susceptibility to empiric therapy was higher in the repeat group compared to the change group (76.6% vs 60.2%; P = .014). After multivariable logistic regression, repeat APBL was associated with an increased likelihood of pathogen susceptibility (adjusted odds ratio, 2.513; P = .012). In contrast, there was no difference in susceptibility rates between the repeat group and the subgroup of change patients who received an empiric APBL (76.6% vs 78.5%; P = .900). Longer APBL exposure duration (P = .012) and chronic kidney disease (P = .002) were associated with higher nonsusceptibility to the exposure APBL. In-hospital mortality was not significantly different between the repeat and change groups (18.1% vs 23.3%; P = .368). The common practice of changing to a different APBL from that of recent exposure may not be warranted.