Sunny Kaul

Background: Patients with cystic fibrosis (CF) experience recurrent infections requiring repeated antimicrobial therapy, leading to high rates of multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa) and contributing substantially to disease-related mortality. Ceftolozane/tazobactam (C/T) is an innovative therapy used to treat resistant Gram-negative infections, with enhanced activity against P. aeruginosa infections. Methods: The Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam Real-world Analysis (SPECTRA) was a multicenter, retrospective real-world study of hospitalized adults who received ≥48 h of C/T across seven countries. Medical record data were collected for up to 6 months before treatment and 30 days after the final C/T dose (or death). This subgroup analysis describes clinical outcomes and healthcare resource utilization (HCRU) among hospitalized adults with CF who received C/T for an index infection. Results: Of 64 patients with CF, 53.1% had MDR P. aeruginosa. Clinical success was achieved in 78.1% of patients, with highest and lowest success rates in patients treated with C/T as second (100%) and sixth or later (40.0%) treatment. Microbial eradication was reported in 10.9% of patients. In-hospital mortality occurred in 14.1% of patients, with the lowest percentage in patients treated with C/T as first or second line treatment (0.0%) and the highest in patients treated with C/T sixth or later (40.0%). Median LOS was 31.5 days. Readmission (30-day all-cause) occurred in 10.9% of patients. Conclusions: In this SPECTRA subgroup analysis, C/T was associated with favorable real-world clinical outcomes among hospitalized adults with CF treated for an index infection. Interpretation is limited by the retrospective design, heterogeneous infection indications/sites, and limited interpretability of microbiologic endpoints in CF.

Background: Ceftolozane/tazobactam (C/T) has demonstrated activity against ESBL-producing Enterobacterales (ESBL-E) and provides a carbapenem-sparing option. Broader use of C/T alongside other carbapenem/inhibitor combinations may expand therapeutic choices and reduce selection pressure for carbapenem resistance, supporting antimicrobial stewardship and limiting the spread of carbapenem-resistant Enterobacterales. Methods: SPECTRA was a multicenter, retrospective real-world study of hospitalized adults (≥18 years) who received ≥48 h of C/T across seven countries (Australia, Austria, Germany, Italy, Mexico, Spain, and the UK) from January 2016 to November 2020. Medical-record data were collected for up to 6 months before treatment and 30 days after the final C/T dose (or until death). This sub-analysis describes clinical outcomes and healthcare utilization in patients with laboratory-confirmed ESBL-E (n = 39). Results: Thirty-nine ESBL-E patients were included (mean age 59.3 years; 56.4% male); 79.5% had ≥1 comorbidity (mean 2.2 per patient). Common pathogens were Escherichia coli (n = 23) and Klebsiella spp. (n = 12). Investigator-assessed clinical success was 64.9%, microbial eradication was 27.0%, in-hospital mortality was 20.5%, and 30-day readmission was 5.1%. ICU admission during the index hospitalization occurred for 38.5% of patients (mean ICU stay: 16.0 days). The median treatment duration was 11 days while the mean hospital stay after C/T initiation was 13.5 days. Conclusions: In this real-world multi-country cohort, C/T showed clinical effectiveness in ESBL-E infections, with outcomes consistent with the overall SPECTRA population. C/T offers a carbapenem-sparing strategy that broadens treatment options and may help reduce reliance on carbapenems, supporting efforts to limit carbapenem-resistant Enterobacterales. The findings warrant evaluation in larger and comparative studies.

Background: Antimicrobial resistance is a global health crisis associated with high mortality and economic burden. Patients with renal dysfunction and obesity have increased susceptibility to infections and may experience different real-world outcomes, including clinical success and mortality, but are often under-represented in clinical trials. Ceftolozane/tazobactam (C/T) is an innovative therapy used to treat resistant Gram-negative infections. We aimed to describe real-world clinical outcomes in hospitalized adults treated with C/T across categories of renal function and BMI in the SPECTRA study. Methods: SPECTRA was a multi-national observational study on 617 patients who received C/T for ≥48 h. Outcomes included clinical success, all-cause in-hospital mortality, readmission, and ICU admission and length of stay (LOS), with sub-analysis of patients across BMI and renal function strata. Results: Renal function and weight were reported in 597 and 469 patients, respectively, of which 51.9% had lower creatine clearance (<80 mL/min) and 50.7% were overweight. Clinical success and all-cause in-hospital mortality ranged at 59.1–77.8% and 11.1–29.2% across renal function strata and 64.6–68.6% and 18.6–21.4% across weight subgroups. Across renal function and weight subgroups, 38.9–54.2% and 45.9–53.5% of patients were admitted to ICU. Median ICU LOS was 8–21.5 and 14–20 days, respectively. Readmission (30-day all-cause) occurred in 4.5–11.8% and 8.2–11.9% of patients across renal function and weight strata. Conclusions: Results from this sub-analysis suggest real-world clinical effectiveness of C/T across patients with renal impairment and obesity, highlighting C/T as a component within treatment guidelines for resistant Gram-negative infections.

Background: Ceftolozane/tazobactam (C/T) has demonstrated activity against ESBL-producing Enterobacterales (ESBL-E) and provides a carbapenem-sparing option. Broader use of C/T alongside other carbapenem/inhibitor combinations may expand therapeutic choices and reduce selection pressure for carbapenem resistance, supporting antimicrobial stewardship and limiting the spread of carbapenem-resistant Enterobacterales. Methods: SPECTRA was a multicentre, retrospective real-world study of hospitalized adults (≥18 years) who received ≥48 hours of C/T across seven countries (Australia, Austria, Germany, Italy, Mexico, Spain, UK) from January 2016 to November 2020. Medical-record data were collected for up to 6 months before treatment and 30 days after the final C/T dose (or until death). This sub-analysis describes clinical outcomes and healthcare utilization in patients with laboratory-confirmed ESBL-E (n=39). Results: Thirty-nine ESBL-E patients were included (mean age 59.3 years; 56.4% male); 79.5% had ≥1 comorbidity (mean 2.2 per patient). Common pathogens were Escherichia coli (n=23) and Klebsiella spp (n=12). Investigator-assessed clinical success was 64.9%, microbial eradication was 27.0%, in-hospital mortality was 20.5%, and 30-day readmission was 5.1%. ICU admission during the index hospitalisation occurred in for 38.5% of patients (mean ICU stay 16.0 days). Median treatment duration was 11 days while mean hospital stay after C/T initiation was 13.5 days. Conclusions: In this real-world multi-country cohort, C/T showed clinical effectiveness in ESBL-E infections, with outcomes consistent with the overall SPECTRA population. C/T offers a carbapenem-sparing strategy that broadens treatment options and may help reduce reliance on carbapenems, supporting efforts to limit carbapenem-resistant Enterobacterales. Findings warrant evaluation in larger and comparative studies.

Background: AMR is a public health concern which leads to high global morbidity and mortality. Immunocompromised patients, who are more susceptible to contracting potentially life-threatening infections, are faced with reduced treatment options due to emerging AMR. Ceftolozane/tazobactam is a novel β-lactam/β-lactamase inhibitor which displays effectiveness against resistant Gram-negative infections. Methods: SPECTRA was a multinational, observational study conducted in seven countries including 617 patients who received ≥48 h of ceftolozane/tazobactam. Medical-record data were collected up to 6 months before treatment and 30 days after the final dose or until death. This analysis describes clinical outcomes and healthcare resource use in patients with sepsis or who were immunocompromised, specifically in patients with hematologic malignancy with and without solid tumor, febrile neutropenia, and solid organ transplant patients. Results: Clinical success ranged from 50.0% in patients with hematologic malignancy and solid tumor to 69.4% in 38 patients with febrile neutropenia. All-cause in-hospital mortality was 23.1–42.9%, with the lowest rates in patients with solid organ transplant. ICU admission was 46.4–68.2% across subpopulations (excluding febrile neutropenia) with the lowest rates in patients with hematologic malignancy. ICU length of stay was lowest within transplant patients (9 days) and highest within the hematologic malignancy and solid tumor population (32 days). Conclusions: The results from this sub analysis of SPECTRA showed that ceftolozane/tazobactam was associated with clinical success in the selected immunocompromised and sepsis patient populations and may lead to reduced morbidity, mortality, and healthcare-resource use. Further research is required to standardize treatment protocols and improve patient outcomes.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

The aim of this exploratory study was to investigate gastrointestinal tolerance and protein absorption markers with a new enteral peptide formula (PF) compared to an isocaloric enteral intact protein standard formula (SF) containing the same amount of protein in ICU patients. Patients admitted to a cardio-thoracic intensive care unit expected to receive tube feeding for ≥5 days were randomized to receive either PF (1.5 kcal/mL) or SF in a double-blind manner for ≤14 days. Twenty-six patients were randomized (13 SF and 13 PF) and 23 (12 SF and 11 PF) completed at least 5 days of product administration. There were no statistically significant differences between the feeds during the first 5 days of intervention for diarrhea (SF:3 (23%); PF:5 (39%), p = 0.388), vomiting (SF:1 (8%); PF:2 (15%), p = 0.549), constipation (SF:7 (54%), PF:3 (23%), p = 0.115), and high gastric residual volume (>500 mL: SF:1 (8%); PF: 2 (15%), p = 0.535). There were no differences in plasma amino acids or urinary markers of protein absorption and metabolism. In conclusion, no major differences were found in tolerability and protein absorption markers between the standard intact protein formula and the peptide formula.