Ventilator-associated Bacterial Pneumonia Research Articles

Development of rabbit models of ventilator-associated bacterial pneumonia produced by carbapenem-resistant Pseudomonas aeruginosa.

Ventilator-associated bacterial pneumonia (VABP) is among the most intractable of carbapenem-resistant Gram-negative bacterial infections. New antimicrobial agents are critically needed for the treatment of VABP. However, current conventionally used animal model systems are inadequate to meet this challenge. We, therefore, developed rabbit models of VABP caused by carbapenem-resistant Pseudomonas aeruginosa. Persistently neutropenic New Zealand White rabbits were used throughout the study. The early-phase intubated model (0-24 h) received mechanical ventilation, while the late-phase intubated model (72-96 h) was ambulatory. The following outcome parameters were studied: survival, residual tissue bacterial burden (CFU/g), residual BAL bacterial burden (CFU/mL), lung weights, pulmonary lesion score, histology, O2 saturation, radiographic imaging, and histology. Each anesthetized rabbit received a predetermined endotracheal bacterial inoculum, and ventilators were set to FiO2 = 40% and PEEP = 8 mmHg. Within the first 12 h post-inoculation, mean bacterial burdens in lung tissue and BAL fluid, respectively, were established at approximately 107 CFU/g and 106 CFU/mL, persisted through 24 h in the early-phase model and increased in the late-phase model to approximately 108 CFU/g and 107 CFU/mL. Mean max SpO2 was ≥98 mmHg, and mean nadir SpO2 was ≥68 mmHg. Serial thoracic radiographs demonstrated progressive multilobar pneumonic infiltrates. Lung histology revealed progressive focal bronchopneumonia, coagulative necrosis, intra-alveolar hemorrhage, alveolar epithelial cell necrosis, and bacterial microcolonies. The new rabbit model of VABP produced by carbapenem-resistant Pseudomonas aeruginosa recapitulates the pathophysiological, microbiological, diagnostic imaging, and histological patterns of human disease by which to assess critically needed new antimicrobial agents against this lethal infection.

Cost-effectiveness analysis of CTZ/TAZ for the treatment of ventilated hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in Japan

BackgroundResistant bacterial infections, particularly those caused by gram-negative pathogens, are associated with high mortality and economic burdens. Ceftolozane/tazobactam demonstrated efficacy comparable to meropenem in patients with ventilated hospital-acquired bacterial pneumonia in the ASPECT-NP study. One cost-effectiveness analysis in the United States revealed that ceftolozane/tazobactam was cost effective, but no Japanese studies have been conducted. Therefore, the objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam compared to meropenem for patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia from a health care payer perspective.MethodsA hybrid decision-tree Markov decision-analytic model with a 5-year time horizon were developed to estimate costs and quality-adjusted life-years and to calculate the incremental cost-effectiveness ratio associated with ceftolozane/tazobactam and meropenem in the treatment of patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. Clinical outcomes were based on the ASPECT-NP study, costs were based on the national fee schedule of 2022, and utilities were based on published data. One-way sensitivity analysis and probabilistic sensitivity analysis were also conducted to assess the robustness of our modeled estimates.ResultsAccording to our base-case analysis, compared with meropenem, ceftolozane/tazobactam increased the total costs by 424,731.22 yen (£2,626.96) and increased the quality-adjusted life-years by 0.17, resulting in an incremental cost-effectiveness ratio of 2,548,738 yen (£15,763.94) per quality-adjusted life-year gained for ceftolozane/tazobactam compared with meropenem. One-way sensitivity analysis showed that although the incremental cost-effectiveness ratio remained below 5,000,000 yen (£30,925) for most of the parameters, the incremental net monetary benefit may have been less than 0 depending on the treatment efficacy outcome, especially the cure rate and mortality rate for MEPM and mortality rate for CTZ/TAZ. 53.4% of the PSA simulations demonstrated that CTZ/TAZ was more cost-effective than MEPM was.ConclusionAlthough incremental cost-effectiveness ratio was below ￥5,000,000 in base-case analysis, whether ceftolozane/tazobactam is a cost-effective alternative to meropenem for ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia in Japan remains uncertain. Future research should examine the unobserved heterogeneity across patient subgroups and decision-making settings, to characterise decision uncertainty and its consequences so as to assess whether additional research is required.

Exploration of a Potential DOOR Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here, we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). Through comprehensive examination of data from nearly 4,000 participants enrolled in six registrational trials for HABP/VABP submitted to the FDA between 2005-2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Though infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar. Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design.

Optimization of an in vitro Pseudomonas aeruginosa Biofilm Model to Examine Antibiotic Pharmacodynamics at the Air-Liquid Interface

Pseudomonas aeruginosa is an important cause of lower respiratory tract infections, such as ventilator-associated bacterial pneumonia (VABP). Using inhaled antibiotics to treat VABP can achieve high drug concentrations at the infection site while minimizing systemic toxicities. Despite the theoretical advantages, clinical trials have failed to show a benefit for inhaled antibiotic therapy in treating VABP. A potential reason for this discordance is the presence of biofilm-embedded bacteria in lower respiratory tract infections. Drug selection and dosing are often based on data from bacteria grown planktonically. In the present study, an in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model was optimized to evaluate the activity of simulated epithelial lining fluid exposures of inhaled and intravenous doses of polymyxin B and tobramycin against two P. aeruginosa strains. Antibiotic activity was also determined against the P. aeruginosa strains grown planktonically. Our study revealed that inhaled antibiotic exposures were more active than their intravenous counterparts across biofilm and planktonic populations. Inhaled exposures of polymyxin B and tobramycin exhibited comparable activity against planktonic P. aeruginosa. Although inhaled polymyxin B exposures were initially more active against P. aeruginosa biofilms (through 6 h), tobramycin was more active by the end of the experiment (48 h). Together, these data slightly favor the use of inhaled tobramycin for VABP caused by biofilm-forming P. aeruginosa that are not resistant to either antibiotic. The optimized in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model may be beneficial for the development of novel anti-biofilm agents or to optimize antibiotic dosing for infections such as VABP.

Sulbactam-durlobactam: a β-lactam/β-lactamase inhibitor combination targeting Acinetobacter baumannii.

Sulbactam-durlobactam is a pathogen-targeted β-lactam/β-lactamase inhibitor combination that has been approved by the US FDA for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC) in patients 18years of age and older. Sulbactam is a penicillin derivative with antibacterial activity against Acinetobacter but is prone to hydrolysis by β-lactamases encoded by contemporary isolates. Durlobactam is a diazabicyclooctane β-lactamase inhibitor with activity against Ambler classes A, C and D serine β-lactamases that restores sulbactam activity both in vitro and in vivo against multidrug-resistant ABC. Sulbactam-durlobactam is a promising alternative therapy for the treatment of serious Acinetobacter infections, which can have high rates of mortality.

Perspectives on the use of ceftolozane/tazobactam: a review of clinical trial data and real-world evidence.

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are common healthcare-associated infections linked to high morbidity and mortality. Gram-negative pathogens, such as Pseudomonasaeruginosa, exhibit multidrug resistance and are recognized as major public health concerns, particularly among critically ill patients with HABP/VABP. Ceftolozane/tazobactam is a novel combination antibacterial agent comprising ceftolozane (a potent antipseudomonal cephalosporin) and tazobactam (a β-lactamase inhibitor). Phase III trials have demonstrated non-inferiority of ceftolozane/tazobactam to comparators, leading to the approval of ceftolozane/tazobactam for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. In this article, we review the clinical trial evidence and key real-world effectiveness data of ceftolozane/tazobactam for the treatment of serious healthcare-associated Gram-negative infections, focusing on patients with HABP/VABP.

Animal Models in Regulatory Breakpoint Determination: Review of New Drug Applications of Approved Antibiotics from 2014-2022.

We sought to better understand the utility and role of animal models of infection for Food and Drug Administration (FDA)-approved antibiotics for the indications of community-, hospital-acquired-, and ventilator-associated bacterial pneumonia (CABP, HABP, VABP), complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), and acute bacterial skin and structural infections (ABSSSIs). We reviewed relevant documents from new drug applications (NDA) of FDA-approved antibiotics from 2014-2019 for the above indications. Murine neutropenic thigh infection models supported the choice of a pharmacokinetic-pharmacodynamic (PKPD) target in 11/12 NDAs reviewed. PKPD targets associated with at least a 1-log bacterial decrease were commonly considered ideal (10/12 NDAs) to support breakpoints. Plasma PK, as opposed to organ specific PK, was generally considered most reliable for PKPD correlation. Breakpoint determination was multi-disciplinary, accounting at minimum for epidemiologic cutoffs, non-clinical PKPD, clinical exposure-response and clinical efficacy. Non-clinical PKPD targets in combination with probability of target attainment (PTA) analyses generated breakpoints that were consistent with epidemiologic cutoffs and clinically derived breakpoints. In 6/12 NDAs, there was limited data to support clinically derived breakpoints, and hence the non-clinical PKPD targets in combination with PTA analyses played a heightened role in the final breakpoint determination. Sponsor and FDA breakpoint decisions were in general agreement. Disagreement may have arisen from differences in the definition of the optimal PKPD index or the ability to extrapolate protein binding from animals to humans. Overall, murine neutropenic thigh infection models supported the reviewed NDAs by providing evidence of pre-clinical efficacy and PKPD target determination, and played, in combination with PTA analysis, a significant role in breakpoint determination for labeling purposes.

P14 Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam Real-world Analysis (SPECTRA): results from a multinational, multicentre observational study

Abstract Background Ceftolozane/tazobactam (C/T) has demonstrated efficacy to treat complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI) and hospital acquired bacterial and ventilator-associated bacterial pneumonia. However, physicians, providers, and other stakeholders including payers want broader real-world evidence to inform clinical decisions and optimize healthcare resource use. Methods SPECTRA is a multinational, multicentre, retrospective, inpatient, observational study of patients treated with C/T in Australia, Austria, Germany, Italy, Mexico, Spain and the UK. Adult inpatients treated with ≥48 h of C/T were included. Demographics, clinical characteristics, treatment management patterns, and outcomes were analysed. Results There were 687 patients from 38 participating hospitals in 7 countries. The average age was 57.6 years (SD ±17.3), and most were male (456, 66.4%). The majority had at least one comorbidity (563, 82.0%), with the most common being heart disease (208, 30.3%), immunocompromised state (207, 30.1%) and chronic pulmonary disease (195, 28.4%). The most common indications were pneumonia (204, 29.7%), sepsis (147, 21.4%) and cIAI (106, 15.4%); 162 (23.6%) had multiple sites of infection and 245 (35.7%) were polymicrobial infections. Median C/T treatment was 12.0 days (IQR 11.0). Half of the patients were admitted to the ICU (343, 49.9%), 43.4% of which was related to the infection. Clinical success was 66.1%. All-cause in-hospital mortality was 22.0% with 8.7% being infection related. The 30 day all-cause readmission was 9.8% and 4.7% were infection related. Conclusions C/T was used to treat infections among critically ill patients and for multi-source, polymicrobial infections. Despite the complexity of the patients in this real-world analysis, most C/T patients had beneficial outcomes that are similar to results of controlled clinical trials.

Ceftazidime-avibactam/aztreonam combination synergy against carbapenem-resistant Gram-negative isolates: In vitro study

ABSTRACT Background: The ceftazidime-avibactam combination is able to inhibit ESBLs, AmpCs and Class A carbapenemases and has been recommended for the treatment of complicated UTIs and ventilator-associated bacterial pneumonia. Aims: The present study was undertaken to evaluate the in vitro activity of ceftazidime-avibactam and to determine the synergistic activity of aztreonam/ceftazidime-avibactam combination against carbapenem-resistant Gram-negative bacilli. Materials and Methods: Gram-negative isolates that exhibited resistance to at least one of the carbapenems (imipenem or meropenem) by the Kirby–Bauer disc diffusion method were subjected to phenotypic characterisation by the Vitek-2 automated method. Phenotypically confirmed isolates were subjected to ceftazidime/avibactam-aztreonam synergy testing by disc diffusion method. Results: Twenty-two carbapenem-resistant isolates showed a minimum inhibitory concentration of 4–64 μg/mL for imipenem and 8–64 μg/mL for meropenem. Out of 22 carbapenem-resistant isolates, 18 (81.82%) isolates showed resistance to ceftazidime-avibactam and aztreonam, and 2 (9.09%) isolates showed intermediate resistance to aztreonam. Nine (40.91%) isolates showed synergy to ceftazidime-avibactam/aztreonam combination by disc diffusion method. An increase in zone diameter of 5–23 mm and 5–16 mm was observed with the ceftazidime-avibactam/aztreonam combination for Klebsiella pneumoniae and Escherichia coli, respectively, when compared to ceftazidime-avibactam and aztreonam disc tested alone. Out of 21 Enterobacterales studied, 21 (100%) isolates showed resistance to amoxicillin-clavulanate (≥32 μg/mL) and piperacillin-tazobactam (128 μg/mL), 12 (57.14%) isolates showed resistance to gentamicin (≥16 μg/mL), 5 (23.81%) isolates were resistant to amikacin (≥64 μg/mL), 21 (100%) isolates were resistant to ciprofloxacin (≥4 μg/mL), 19 (90.48%) isolates were resistant to cotrimoxazole (≥320 μg/mL), 21 (100%) isolates were resistant to cefepime (≥16 μg/mL) and 6 (28.57%) isolates were resistant to tigecycline (2 μg/mL). Conclusion: In the present study, 42.86% of Enterobacterales isolates showed synergism to the ceftazidime-avibactam/aztreonam combination. The optimal dosing strategy and in vivo efficacy of this combination need to be evaluated.

Sulbactam-durlobactam susceptibility test method development and quality control ranges for MIC and disk diffusion tests.

Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination developed to treat hospital-acquired and ventilator-associated bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Durlobactam is a diazabicyclooctane β-lactamase inhibitor with potent activity against Ambler classes A, C, and D serine β-lactamases and restores sulbactam activity against multidrug-resistant ABC. Studies were conducted to establish sulbactam-durlobactam antimicrobial susceptibility testing methods for both broth microdilution minimal inhibitory concentration (MIC) and disk diffusion tests as well as quality control (QC) ranges. To establish the MIC test method, combinations of sulbactam and durlobactam were evaluated using a panel of genetically characterized A. baumannii isolates which were categorized as predicted to be susceptible or resistant based on the spectrum of β-lactamase inhibition by durlobactam. MIC testing with doubling dilutions of sulbactam with a fixed concentration of 4 µg/mL of durlobactam resulted in the greatest discrimination of the pre-defined susceptible and resistant strains. Similarly, the sulbactam/durlobactam 10/10 µg disk concentration showed the best discrimination as well as correlation with the MIC test. A. baumannii NCTC 13304 was selected for QC purposes because it assesses the activity of both sulbactam and durlobactam with clear endpoints. Multi-laboratory QC studies were conducted according to CLSI M23 Tier 2 criteria. A sulbactam-durlobactam broth MIC QC range of 0.5/4-2/4 µg/mL and a zone diameter QC range of 24-30 mm were determined for A. baumannii NCTC 13304 and have been approved by CLSI. These studies will enable clinical laboratories to perform susceptibility tests with accurate and reproducible methods.

Sulbactam/durlobactam (Xacduro) for Acinetobacter pneumonia.

The FDA has approved Xacduro (Innoviva), a combination of the beta-lactam antibacterial sulbactam and the beta-lactamase inhibitor durlobactam, for IV treatment of adults with hospital-acquired or ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC).

2557. Development of Rabbit Models of Ventilator-Associated Carbapenem-Resistant Acinetobacter baumannii Pneumonia

Abstract Background Carbapenem-resistant (CR) Gram-negative bacteria are emerging worldwide as global public health threats. Mortality rates from these pathogens are especially high in immunocompromised patients. Ventilator-associated bacterial pneumonia (VABP) is among the most intractable of CR Gram-negative bacterial infections. We therefore aimed to develop rabbit animal models of VABP caused by CR strains of Acinetobacter baumannii. Methods Persistently neutropenic NZW rabbits were used throughout the study. A novel endotracheal tracheostomy system was developed for intubation. The early-phase intubated model (0-24h) received mechanical ventilation, while the late-phase intubated model (72-96h) was ambulatory. Ventilators were set to FiO2=40% and PEEP=8mmHg. The following outcome variables were assessed: survival, residual tissue bacterial burden (log CFU/g), residual BAL bacterial burden (log CFU/mL), lung weights, pulmonary lesion score, histology, pulse O2 saturation, radiographic imaging, pro-inflammatory cytokines, quantitative tissue and BAL PCR, and histology. Results Within the first 12h post-inoculation, mean bacterial burdens in lung tissue and BAL fluid, respectively, which were established at approximately 106 CFU/g and 105 CFU/mL, persisted through 24h in the early-phase model and were increased in the late-phase model (72-96h) to approximately 107 CFU/g, and 106 CFU/mL. Mean Max SpO2 was ≥99 mmHg and mean nadir SpO2 was ≥74 mmHg. Serial thoracic radiographs over the course of 12-96h demonstrated progressive multilobar pneumonic infiltrates, while lung histology revealed progressive development of focal bronchopneumonia, intra-alveolar hemorrhage, alveolar epithelial cell necrosis, macrophage activation, monocytic infiltration, alveolar septal disruption, and microcolonies of bacteria. Conclusion The new rabbit model of VABP produced by CR A. baumannii recapitulates the pathophysiological, microbiological, diagnostic imaging, and histological patterns of human disease by which to assess critically needed new antimicrobial agents against this lethal infection. Disclosures All Authors: No reported disclosures

Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation. A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses. In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid. The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR.

Identifying Predominant Causes of Death Among Hospitalized COVID-19 Patients During Poland's Second and Third Waves.

BACKGROUND Number of confirmed COVID-19 deaths per million population in Poland between November 2020 and May 2021 was one of the largest in Europe. This retrospective study was conducted at a single center in Poland between November 2020 and May 2021to evaluate the morbidity and mortality rates in 581 patients hospitalized with COVID-19. MATERIAL AND METHODS A retrospective single-center study was conducted in a dedicated COVID-19 hospital from November, 2020 to May, 2021. The data of 581 hospitalized patients were analyzed. Multimorbidity was assessed using the Charlson Comorbidity Index, including chronic kidney, respiratory, cardiovascular diseases, diabetes mellitus, cancer, and dementia. The observation period covered admission to the hospital for severe COVID-19 until discharge or death. Diagnosis of COVID-19 was confirmed by quantitative reverse transcription polymerase chain reaction test. Statistical analysis was carried out in the IBM SPSS Statistics program. RESULTS The mortality rate was 35% of all admitted patients. Lung damage was the cause of death in 60%, bacterial superinfection in 26%, arterial thrombosis or thromboembolism in 9%, and heart failure in 5% of patients. The chi-square test showed a significant relationship between sex and the cause of death related to COVID-19 pneumonia and bacterial ventilator-associated pneumonia (VAP). CONCLUSIONS The findings from this study supports findings from other countries that between November 2020 and May 2021, before SARS-CoV-2 vaccination programs were fully implemented and before effective medications and antiviral agents were developed, patients with severe COVID-19 had high rates of morbidity and mortality.

Weighing the Odds: Novel β-Lactam/β-Lactamase Inhibitor Use in Hospital-Acquired and Ventilator-Associated Pseudomonas aeruginosa Pneumonia for Patients Who Are Morbidly Obese.

Pseudomonas aeruginosa is a leading cause of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). Novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations are often used for these infections; however, limited data exist to guide the dosing of BL/BLI in patients who are morbidly obese. Thus, we sought to evaluate the clinical and safety endpoints of patients who are morbidly obese (body mass index ≥35 kg/m2) and non-morbidly obese (<35 kg/m2) and receiving BL/BLI for P aeruginosa HABP/VABP. This retrospective study was based on a cohort of patients hospitalized at 2 urban academic medical centers in Detroit, Michigan, from August 2014 through February 2021 with P aeruginosa HABP/VABP who were receiving BL/BLI (ceftazidime/avibactam, ceftolozane/tazobactam, or meropenem/vaborbactam) for ≥72 continuous hours. The primary endpoint was presumed treatment failure, defined as the presence of all-cause in-hospital mortality or the continuation of infectious symptoms. Analyses were adjusted for possible confounding with inverse probability of treatment weighting. Multivariable regression was used to identify predictors of treatment failure. In total, 285 patients with HABP (61.4%) and/or VABP (56.1%) were enrolled (morbidly obese, n = 95; non-morbidly obese, n = 190). The median Acute Physiology and Chronic Health Evaluation II score was 23 (IQR, 13-26), and 60% of patients were admitted to the intensive care unit at index culture collection. Patients who were morbidly obese demonstrated significantly greater odds of presumed treatment failure vs those who were non-morbidly obese (58.9% vs 37.9%, respectively; adjusted odds ratio, 1.675 [95% CI, 1.465-1.979]). In multivariable analysis, morbid obesity (1.06; 95% CI, 1.02-1.79), prolonged time to BL/BLI initiation (1.47; 95% CI, 1.28-2.66), renal dose-adjusted BL/BLI in the first 48 hours of therapy (1.12; 95% CI, 1.09-1.75), and continuous renal replacement therapy during BL/BLI therapy (1.35; 95% CI, 1.06-1.68) were independently associated with increased odds of presumed treatment failure. Among hospitalized patients receiving BL/BLI for P aeruginosa HABP/VABP, those who were morbidly obese had significantly greater odds of presumed treatment failure when compared with those who were non-morbidly obese.

Influence of a Structured Microbiological Endotracheal Monitoring Program on the Outcome of Critically Ill COVID-19 Patients: An Observational Study.

In past influenza pandemics and the current COVID-19 pandemic, bacterial endotracheal superinfections are a well-known risk factor for higher morbidity and mortality. The goal of this study was to investigate the influence of a structured, objective, microbiological monitoring program on the prognosis of COVID-19 patients with mechanical ventilation. A structured microbiological monitoring program (at intubation, then every 3 days) included collection of endotracheal material. Data analysis focused on the spectrum of bacterial pathogens, mortality, as well as intensive care unit (ICU), hospital, and mechanical ventilation duration. A total of 29% of the patients showed bacterial coinfection at the time of intubation, and within 48 h, 56% developed ventilator-associated pneumonia (VAP). Even though patients with VAP had significantly longer ICU, hospital, and mechanical ventilation durations, there was no significant difference in mortality between patients with VAP pneumonia and patients without bacterial infection. VAP is a common complication in COVID-19 patients. In contrast to already published studies, in our study implementing a structured microbiological monitoring program, COVID-19 patients with bacterial coinfection or VAP did not show higher mortality. Thus, a standardized, objective, microbiological screening can help detect coinfection and ventilator-associated infections, refining anti-infective therapy and positively influencing patient outcomes.

Sulbactam/Durlobactam: First Approval.

Sulbactam/durlobactam (XACDURO®), is a co-packaged antibacterial product that has been developed by Entasis Therapeutics Inc. for the treatment of infections caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Coadministration of durlobactam (a β-lactamase inhibitor with potent activity against a broad range of serine β-lactamases) with sulbactam (an established class A β-lactamase inhibitor with antibacterial activity against A. baumannii) prevents sulbactam degradation by ABC-produced β-lactamases. In May 2023, sulbactam/durlobactam was approved in the USA for use in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of ABC. This article summarizes the milestones in the development of sulbactam/durlobactam leading to this first approval for the treatment of infections caused by ABC.

Clinical and Microbiological Outcomes and Follow-Up of Secondary Bacterial and Fungal Infections among Critically Ill COVID-19 Adult Patients Treated with and without Immunomodulation: A Prospective Cohort Study.

Nearly 10% of COVID-19 cases will require admission to the intensive care unit (ICU). Our aim was to assess the clinical and microbiological outcomes of secondary infections among critically ill COVID-19 adult patients treated with/without immunomodulation. A prospective observational cohort study was performed between 2020 and 2022 at a single ICU. The diagnosis and severity classification were established by the ECDC and WHO criteria, respectively. Eligible patients were included consecutively at admission, and followed for +30 days post-inclusion. Bloodstream-infections (BSIs), ventilator-associated bacterial pneumonia (VAP), and COVID-19-associated invasive pulmonary aspergillosis (CAPA) were defined according to international guidelines. Patient stratification was performed by immunomodulatory therapy administration (dexamethasone, tocilizumab, baricitinib/ruxolitinib). The primary outcome was any microbiologically confirmed major infectious complication, secondary outcomes were invasive mechanical ventilation (IMV) requirement and all-cause mortality. Altogether, 379 adults were included. At baseline, 249/379 (65.7%) required IMV and 196/379 (51.7%) had a cytokine storm. At +30 days post-inclusion, the rate of any microbiologically confirmed major infectious complication was 151/379 (39.8%), IMV requirement and all-cause mortality were 303/379 (79.9%) and 203/379 (53.6%), respectively. There were no statistically significant outcome differences after stratification. BSI, VAP, and CAPA episodes were mostly caused by Enterococcus faecalis (27/124, 22.1%), Pseudomonas aeruginosa (26/91, 28.6%), and Aspergillus fumigatus (20/20, 100%), respectively. Concerning the primary outcome, Kaplan-Meier analysis showed similar probability distributions between the treatment subgroups (118/299, 39.5% vs. 33/80, 41.3%, log-rank p = 0.22), and immunomodulation was not retained as its independent predictor in multivariate logistic regression. Secondary infections among critically ill COVID-19 adult patients represent a relevant burden, probably irrespective of immunomodulatory treatment.

Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK)

An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a β-lactam-β-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. Entasis Therapeutics and Zai Lab.

New Antibiotics for Staphylococcus aureus Infection: An Update from the World Association of Infectious Diseases and Immunological Disorders (WAidid) and the Italian Society of Anti-Infective Therapy (SITA).

Staphylococcus aureus is an extremely virulent pathogen that is capable of quickly evolving and developing antibiotic resistance. To overcome this problem, new antibiotics have been developed. Some of these have been licenced for use in clinical practice, mainly for the treatment of adults with acute skin and soft tissue infections, in addition to both community-acquired pneumonia (CAP) and nosocomial pneumonia (hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia). In this paper, the main characteristics and clinical use of new licenced anti-staphylococcal drugs have been discussed. In vitro studies have demonstrated that some new anti-staphylococcal antibiotics have better antimicrobial activity and, at least in certain cases, more favourable pharmacokinetic properties and higher safety and tolerability than the presently available anti-staphylococcal drugs. This suggests that they may have a potential use in reducing the risk of failure of S. aureus therapy. However, an in-depth analysis of microbiological and clinical studies carried out with these new drugs seems to indicate that further studies need to be conducted before the problem of resistance of S. aureus to the antibiotics available today can be completely solved. Considering the overall available research, the drugs that are active against S. aureus appear to present a great therapeutic opportunity for overcoming resistance to traditional therapy. There are advantages in the pharmacokinetic characteristics of some of these drugs and they have the potential to reduce hospital stays and economic costs associated with their use.