Patient-Reported Outcomes in Patients With Advanced Urothelial Cancer Who Are Ineligible for Cisplatin and Treated With First-Line Enfortumab Vedotin Alone or With Pembrolizumab.

PURPOSE: Locally advanced/metastatic urothelial cancer (la/mUC) affects patients' quality of life (QOL) and functioning. We describe the impact of first-line (1L) enfortumab vedotin (EV) alone or with pembrolizumab (P) on QOL/functioning/symptoms in patients with la/mUC who were cisplatin-ineligible from EV-103 Cohort K. METHODS: In this phase Ib/II trial, patients were randomly assigned 1:1 to EV + P or EV monotherapy (mono). Exploratory patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Brief Pain Inventory Short Form (BPI-SF) at baseline, once per week for cycles 1-3, and then in every cycle through the end of treatment. Changes in scores from baseline to week 24, reported as least squares mean (standard error), were assessed by mixed models for repeated measures. There were no formal statistical comparisons between treatment arms. RESULTS: Of 149 patients treated, 65 (EV + P) and 63 (EV mono) comprised the PRO analysis set. For EV + P, EORTC QLQ-C30 QOL was maintained through week 24 with improvements in emotional functioning, pain, and insomnia. Clinically meaningful improvements were seen in EORTC QLQ-C30 pain after EV + P at weeks 12 (-14.41 [3.14]) and 24 (-14.99 [3.56]) and BPI-SF worst pain at week 24 (-2.07 [0.37]). For EV mono, EORTC QLQ-C30 QOL remained stable with clinically meaningful improvements in EORTC QLQ-C30 pain (-12.55 [4.27]), insomnia (-14.46 [4.69]), and constipation (-10.09 [4.35]) at week 24. There were small-to-moderate improvements in BPI-SF worst pain at week 24. CONCLUSION: EV + P in patients with la/mUC who were cisplatin-ineligible was associated with preservation or improvement of QOL/functioning/symptoms. Improvement in pain was seen in both PRO instruments and treatment arms. These data complement clinical outcomes of 1L EV + P.

Evaluation of inpatient medication guidance from an artificial intelligence chatbot.

PURPOSE: To analyze the clinical completeness, correctness, usefulness, and safety of chatbot and medication database responses to everyday inpatient medication-use questions. METHODS: We evaluated the responses from an artificial intelligence chatbot, a medication database, and clinical pharmacists to 200 real-world medication-use questions. Answer quality was rated by a blinded group of pharmacists, providers, and nurses. Chatbot and medication database responses were deemed "acceptable" if the mean reviewer rating was within 3 points of the mean rating for pharmacists' answers. We used descriptive statistics for reviewer ratings and Kendall's coefficient to evaluate interrater agreement. RESULTS: The medication database generated responses to 194 (97%) questions, with 88% considered acceptable for clinical correctness, 76% considered acceptable for completeness, 83% considered acceptable for safety, and 81% considered acceptable for usefulness compared to pharmacists' answers. The chatbot responded to only 160 (80%) questions, with 85% considered acceptable for clinical correctness, 65% considered acceptable for completeness, 71% considered acceptable for safety, and 68% considered acceptable for usefulness. CONCLUSION: Traditional search methods using a drug database provide more clinically correct, complete, safe, and useful answers than a chatbot. When the chatbot generated a response, the clinical correctness was similar to that of a drug database; however, it was not rated as favorably for clinical completeness, safety, or usefulness. Our results highlight the need for ongoing training and continued improvements to artificial intelligence chatbots for them to be incorporated reliably into the clinical workflow. With continued improvement in chatbot functionality, chatbots could be a useful pharmacist adjunct, providing healthcare providers with quick and reliable answers to medication-use questions.

Risk of relapse and readmission among hospitalized adults with carbapenem non-susceptible gram-negative infections.

BACKGROUND: Infections caused by carbapenem-nonsusceptible gram-negative (C-NS) pathogens are associated with increased mortality and high treatment costs. Identification of potentially modifiable factors that may improve patient outcomes is important for better management of C-NS GN infections. METHODS: This was a retrospective study of hospitalized adults with electronic health record evidence of complicated urinary tract infection (cUTI), bacterial pneumonia (BP), complicated intra-abdominal infection (cIAI), or bacteremia (BAC) due to C-NS GN organisms from January 2013 to March 2018. Treatment patterns and clinical characteristics during the index hospitalization were analyzed descriptively and stratified by infection site(s). The effect of patient characteristics on index infection relapse during the postdischarge period and on readmission with 30 days was modeled using logistic regression. RESULTS: The study included 2,862 hospitalized patients with C-NS GN infections. Index infection sites were 38.4% cUTI ± BAC, 21.5% BP ± BAC, 18.7% cUTI + BP ± BAC, 14.7% any cIAI, and 6.7% BAC only. The majority of patients (83.6%) received an antibiotic during their index hospitalization; among these, the most common classes given were penicillins (52.9%), fluoroquinolones (50.7%), and carbapenems (38.9%). During the postdischarge period, 21.7% of patients had a relapse of the index infection and 63.9% of patients were readmitted to the hospital. Factors associated with increased adjusted odds ratio (OR) for relapse or readmission included Charlson comorbidity score of ≥3 relative to 0 (relapse: OR [95% CI] = 1.34 [1.01-1.76], p = .040; readmission: OR [95% CI] 1.92 [1.50-2.46], p < .001), preindex immunocompromised status (relapse: OR [95% CI] 1.37 [1.05-1.79], p = .019; readmission: OR [95% CI] = 1.60 [1.27-2.02], p < .001), and preindex carbapenem use (relapse: OR [95% CI] = 1.35 [1.07-1.72], p = .013; readmission: OR [95% CI] = 1.25 [1.00-1.57], p = .048). CONCLUSIONS: Adverse postdischarge outcomes were common among hospitalized patients with C-NS GN infections and were significantly associated with previous carbapenem use and patient clinical characteristics such as higher comorbidity burden and immunocompromised status. Adoption of antimicrobial stewardship and consideration of individual patient risk factors in making treatment decisions may help improve clinical outcomes.

Methods to appraise available evidence and adequacy of data from a systematic literature review to conduct a robust network meta-analysis of treatment options for patients with hospital-acquired or ventilator-associated bacterial pneumonia.

We aimed to determine if available evidence from a previously conducted systematic literature review was sufficient to conduct a robust network meta-analysis (NMA) using the International Society for Pharmacoeconomics and Outcomes Research Good Practice Task Force NMA study questionnaire to evaluate suitability, relevance, and credibility of available randomized-controlled trials (RCT) of antibacterial therapies for treatment of patients with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). We assessed feasibility and reliability of an NMA for a connected network of RCTs, and then relevance and credibility of the connected network for informing decision-making. This previously conducted systematic literature review using Cochrane dual-reviewer methodology, Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and PICOTS (population, interventions, comparators, outcomes, timing, and setting) criteria identified 25 citations between 2001 and 2018; 18 were unique RCTs. Trial design characteristics, outcome definitions, assessment time points, and analyses populations varied across studies. Using "clinical response," an efficacy end point to health technology assessment agencies, we assessed potential network credibility, which collapsed from the overall data set to four studies and five interventions. This did not include closed loop(s) needed to assess consistency. Of the studies reporting clinical response, >70% of patients were ventilated at baseline with mean Acute Physiologic Assessment and Chronic Health Evaluation II scores from 14.7 to 17.5. Pseudomonas aeruginosa (range, 18.4-64.1%) and Klebsiella spp. (range, 1.6-49%) were the most common causative pathogens. We identified relevant RCTs for most standard-of-care agents approved for HABP/VABP, which provided a comprehensive evidence base. In summary, our appraisal of available evidence for the clinical response outcome among adult patients with HABP/VABP does not support the conduct of a scientifically robust and clinically meaningful NMA. Although this data is vital to registration, there are significant limitations in these trials for health technology assessments, payor decisions, guidelines, and protocol decisions.

Clinical characteristics, microbiology and outcomes of a cohort of patients treated with ceftolozane/tazobactam in acute care inpatient facilities, Houston, Texas, USA.

Background: Ceftolozane/tazobactam is a ß-lactam/ß-lactamase inhibitor combination with activity against a variety of Gram-negative bacteria, including MDR Pseudomonas aeruginosa. This agent is approved for hospital-acquired and ventilator-associated bacterial pneumonia. However, most real-world outcome data come from small observational cohorts. Thus, we sought to evaluate the utilization of ceftolozane/tazobactam at multiple tertiary hospitals in Houston, TX, USA. Methods: We conducted a multicentre retrospective study of patients receiving at least 48 h of ceftolozane/tazobactam therapy from January 2016 through to September 2019 at two hospital systems in Houston. Demographic, clinical and microbiological data were collected, including the infecting bacterial isolate, when available. The primary outcome was composite clinical success at hospital discharge. Secondary outcomes included in-hospital mortality and clinical disposition at 14 and 30 days post ceftolozane/tazobactam initiation. Multivariable logistic regression analysis was used to identify predictors of the primary outcome and mortality. Recovered isolates were tested for susceptibility to ceftolozane/tazobactam and underwent WGS. Results: A total of 263 patients were enrolled, and composite clinical success was achieved in 185 patients (70.3%). Severity of illness was the most consistent predictor of clinical success. Combination therapy with ceftolozane/tazobactam and another Gram-negative-active agent was associated with reduced odds of clinical success (OR 0.32, 95% CI 0.16-0.63). Resistance to ceftolozane/tazobactam was noted in 15.4% of isolates available for WGS; mutations in ampC and ftsI were common but did not cluster with a particular ST. Conclusions: Clinical success rate among this patient cohort treated with ceftolozane/tazobactam was similar compared with previous experiences. Ceftolozane/tazobactam remains an alternative agent for treatment of susceptible isolates of P. aeruginosa.

Cost-effectiveness of imipenem/cilastatin/relebactam for hospital-acquired and ventilator-associated bacterial pneumonia.

Aim: This study evaluates the cost-effectiveness of imipenem/cilastatin/relebactam (IMI/REL) for treating hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in an 'early adjustment prescribing scenario'. Methods: An economic model was constructed to compare two strategies: continuation of empiric piperacillin/tazobactam (PIP/TAZ) versus early adjustment to IMI/REL. A decision tree was used to depict the hospitalization period, and a Markov model used to capture long-term outcomes. Results: IMI/REL generated more quality-adjusted life years than PIP/TAZ, at an increased cost per patient. The incremental cost-effectiveness ratio of $17,529 per QALY is below the typical US willingness-to-pay threshold. Conclusion: IMI/REL may represent a cost-effective treatment for payers and a valuable option for clinicians, when considered alongside patient risk factors, local epidemiology, and susceptibility data.

Patterns, Predictors, and Intercenter Variability in Empiric Gram-Negative Antibiotic Use Across 928 United States Hospitals.

BACKGROUND: Empiric antibiotic use among hospitalized adults in the United States (US) is largely undescribed. Identifying factors associated with broad-spectrum empiric therapy may inform antibiotic stewardship interventions and facilitate benchmarking. METHODS: We performed a retrospective cohort study of adults discharged in 2019 from 928 hospitals in the Premier Healthcare Database. "Empiric" gram-negative antibiotics were defined by administration before day 3 of hospitalization. Multivariable logistic regression models with random effects by hospital were used to evaluate associations between patient and hospital characteristics and empiric receipt of broad-spectrum, compared to narrow-spectrum, gram-negative antibiotics. RESULTS: Of 8 017 740 hospitalized adults, 2 928 657 (37%) received empiric gram-negative antibiotics. Among 1 781 306 who received broad-spectrum therapy, 30% did not have a common infectious syndrome present on admission (pneumonia, urinary tract infection, sepsis, or bacteremia), surgery, or an intensive care unit stay in the empiric window. Holding other factors constant, males were 22% more likely (adjusted odds ratio [aOR], 1.22 [95% confidence interval, 1.22-1.23]), and all non-White racial groups 6%-13% less likely (aOR range, 0.87-0.94), to receive broad-spectrum therapy. There were significant prescribing differences by region, with the highest adjusted odds of broad-spectrum therapy in the US West South Central division. Even after model adjustment, there remained substantial interhospital variability: Among patients receiving empiric therapy, the probability of receiving broad-spectrum antibiotics varied as much as 34+ percentage points due solely to the admitting hospital (95% interval of probabilities: 43%-77%). CONCLUSIONS: Empiric gram-negative antibiotic use is highly variable across US regions, and there is high, unexplained interhospital variability. Sex and racial disparities in the receipt of broad-spectrum therapy warrant further investigation.

Risk Factors Associated with Severe Clostridioides difficile Infection in Patients with Cancer.

INTRODUCTION: Antibiotic use is a risk factor for Clostridioides difficile infection (CDI). Few studies have correlated use of prior antibiotic classes with CDI, microbiome composition, and disease severity in patients with cancer. We hypothesized that previous antibiotic exposure and fecal microbiome composition at time of presentation are risk factors for severe CDI in patients with cancer. METHODS: This non-interventional, prospective, cohort study examined 200 patients with cancer who had their first episode or first recurrence of CDI. C. difficile was identified using nucleic acid amplification testing. Univariate analysis was used to determine significant risk factors for severe CDI. Fecal microbiome composition was determined by sequencing the V3/V4 region of 16 s rDNA encoding gene. Differential abundance analyses were used to single out significant microbial features which differed across severity levels. RESULTS: On univariate analysis, factors associated with severe CDI included the presence of toxin A/B in stools (odds ratio [OR] 2.14 [1.05-4.36] p = 0.04 and prior 90-day metronidazole use (OR 2.66 [1.09-6.50] p = 0.03). Although alpha and beta diversity was similar between disease severity groups and toxin A/B in stools, increased abundance of Bacteroides uniformis, Ruminococcaceae, and Citrobacter koseri were associated with protection from severe CDI (p < 0.05) and depletion of anaerobes was higher in patients with prior metronidazole exposure. CONCLUSION: Use of metronidazole for non-CDI indications within 90 days prior to diagnosis and presence of toxin A/B in stools were associated with severe CDI. Findings provide valuable insights into risk factors for severe CDI in an underserved population with cancer that warrants further exploration.

The risk of inappropriate empiric treatment and its outcomes based on pathogens in non-ventilated (nvHABP), ventilated (vHABP) hospital-acquired and ventilator-associated (VABP) bacterial pneumonia in the US, 2012-2019.

BACKGROUND: Inappropriate empiric antimicrobial treatment (IET) contributes to worsened outcomes. While IET's differential impact across types of nosocomial pneumonia (NP: non-ventilated [nvHABP], ventilated [vHABP] hospital-acquired and ventilator-associated [VABP] bacterial pneumonia) is established, its potential interaction with the bacterial etiology is less clear. METHODS: We conducted a multicenter retrospective cohort study in the Premier Healthcare Database using an administrative algorithm to identify NP. We paired respective pathogens with empiric treatments. Antimicrobial coverage was appropriate if a drug administered within 2 days of infection onset covered the recovered organism(s). All other treatment was IET. RESULTS: Among 17,819 patients with NP, 26.5% had nvHABP, 25.6% vHABP, and 47.9% VABP. Gram-negative (GN) organisms accounted for > 50% of all infections. GN pathogens were ~ 2 × as likely (7.4% vHABP to 10.7% nvHABP) to engender IET than Gram-positive (GP, 2.9% vHABP to 4.9% nvHABP) pathogens. Although rare (5.6% nvHABP to 8.3% VABP), GN + GP infections had the highest rates of IET (6.7% vHABP to 12.9% nvHABP). Carbapenem-resistant GNs were highly likely to receive IET (33.8% nvHABP to 40.2% VABP). Hospital mortality trended higher in the IET group, reaching statistical significance in GN + GP vHABP (47.8% IET vs. 29.3% non-IET, p = 0.016). 30-day readmission was more common with IET (16.0%) than non-IET (12.6%, p = 0.024) in GN VABP. Generally post-infection onset hospital length of stay and costs were higher with IET than non-IET. CONCLUSIONS: IET is ~ 2 × more common in GN than GP infections. Although the magnitude of its impact varies by NP type, IET contributes to worsened clinical and economic outcomes.

Evaluation of Peripheral Administration of 10% Calcium Chloride in a Retrospective, Single-Center Electronic Health Record Cohort.

BACKGROUND: Calcium chloride is commonly used in emergency departments in the treatment of a variety of emergencies. Historically, administration via central venous catheters has been preferred owing to its high osmolarity and vesicant properties. Although preferred, central access may not always be available in time-sensitive, emergent situations leading to many instances of peripheral administration. The objective of this analysis was to evaluate the charted safety of peripheral venous administration of 10% calcium chloride. METHODS: A single-center retrospective chart review was performed in patients who received 10% calcium chloride in the adult emergency department evaluating for the incidence of infusion-related adverse events. Patients were excluded if they were less than 18 years of age or had a lack of catheter documentation during 10% calcium chloride administration or if the 10% calcium chloride was documented as given through a central venous catheter. RESULTS: A total of 72 administrations were evaluated. Patients were predominantly male (67%), with a median age of 55 years and body mass index of 29.2. The primary outcome demonstrated that 4 infusion-related adverse events occurred (6%) with grade 1 (n = 1) and grade 0 (n = 3) documented incidence of infusion-related adverse events. None of the documented incidence of infusion-related adverse events resulted in permanent tissue injury, and all patients had conservative management. DISCUSSION: This study demonstrated that administration of 10% calcium chloride via peripheral venous catheters may be feasible and seemed to carry a low incidence of documented complications. Further prospective studies are needed to confirm study observations.

The Comparative Effectiveness of Ceftolozane/Tazobactam versus Aminoglycoside- or Polymyxin-Based Regimens in Multi-Drug-Resistant Pseudomonas aeruginosa Infections.

Pseudomonas aeruginosa infections are challenging to treat due to multi-drug resistance (MDR) and the complexity of the patients affected by these serious infections. As new antibiotic therapies come on the market, limited data exist about the effectiveness of such treatments in clinical practice. In this comparative effectiveness study of ceftolozane/tazobactam versus aminoglycoside- or polymyxin-based therapies among hospitalized patients with positive MDR P. aeruginosa cultures, we identified 57 patients treated with ceftolozane/tazobactam compared with 155 patients treated with aminoglycoside- or polymyxin-based regimens. Patients treated with ceftolozane/tazobactam were younger (mean age 67.5 vs. 71.1, p = 0.03) and had a higher comorbidity burden prior to hospitalization (median Charlson 5 vs. 3, p = 0.01) as well as higher rates of spinal cord injury (38.6% vs. 21.9%, p = 0.02) and P. aeruginosa-positive bone/joint cultures (12.3% vs. 0.7%, p < 0.0001). Inpatient mortality was significantly lower in the ceftolozane/tazobactam group compared with aminoglycosides or polymyxins (15.8% vs. 27.7%, adjusted odds ratio 0.39, 95% confidence interval 0.16−0.93). There were no significant differences observed for the other outcomes assessed. In hospitalized patients with MDR P. aeruginosa, inpatient mortality was 61% lower among patients treated with ceftolozane/tazobactam compared to those treated with aminoglycoside- or polymyxin-based regimens.

Recurrent Clostridioides difficile infection worsens anxiety-related patient-reported quality of life.

BACKGROUND: Clostridioides difficile infection (CDI) is associated with high recurrence rates impacting health-related quality of life (HrQOL). However, patient-reported data are lacking particularly in the outpatient setting. We assessed changes in HrQOL over time in patients treated with bezlotoxumab at US infusion centers and determined clinical factors associated with HrQOL changes. METHODS: The HrQOL survey was conducted in adult patients with CDI, who received bezlotoxumab in 25 US outpatient infusion centers. The survey was adapted from the Cdiff32 instrument to assess anxiety-related changes to HrQOL and completed on the day of infusion (baseline) and at 90 days post bezlotoxumab (follow-up). Demographics, disease history, CDI risk factors, and recurrence of CDI (rCDI) at 90-day follow-up were collected. Changes in HrQOL scores were calculated and outcomes assessed using a multivariable linear regression model with P < 0.05 defined as statistically significant. RESULTS: A total of 144 patients (mean age: 68 ± 15 years, 63% female, median Charlson index: 4, 15.9% rCDI) were included. The overall mean baseline and follow-up HrQOL scores were 26.4 ± 11.5 and 56.4 ± 25.0, respectively. At follow-up, this score was significantly higher for patients who had primary CDI (34.5 ± 21.7) compared to those with multiple rCDI (24.7 ± 21.0; P = 0.039). The mean HrQOL change at follow-up was significantly higher for patients without rCDI (34.1 ± 28.8 increase) compared to patients with rCDI (6.7 ± 19.5 increase; P < 0.001), indicating improvement in anxiety. CONCLUSIONS: Using the Cdiff32 instrument, we demonstrated that HrQOL worsened significantly in patients with further rCDI. These findings support the use of Cdiff32 in assessing CDI-related humanistic outcomes.

Cost-Effectiveness of Imipenem/Cilastatin/Relebactam Compared with Colistin in Treatment of Gram-Negative Infections Caused by Carbapenem-Non-Susceptible Organisms.

INTRODUCTION: Imipenem/cilastatin/relebactam (IMI/REL), a combination ß-lactam antibiotic (imipenem) with a novel ß-lactamase inhibitor (relebactam), is an efficacious and well-tolerated option for the treatment of hospitalized patients with gram-negative (GN) bacterial infections caused by carbapenem-non-susceptible (CNS) pathogens. This study examines cost-effectiveness of IMI/REL vs. colistin plus imipenem (CMS + IMI) for the treatment of infection(s) caused by confirmed CNS pathogens. METHODS: We developed an economic model comprised of a decision-tree depicting initial hospitalization, and a Markov model projecting long-term health and economic impacts following discharge. The decision tree, informed by clinical data from RESTORE-IMI 1 trial, modeled clinical outcomes (mortality, cure rate, and adverse events including nephrotoxicity) in the two comparison scenarios of IMI/REL versus CMS + IMI for patients with CNS GN infection. Subsequently, a Markov model translated these hospitalization stage outcomes (i.e., death or uncured infection) to long-term consequences such as quality-adjusted life years (QALYs). Sensitivity analyses were conducted to test the model robustness. RESULTS: IMI/REL compared to CMS + IMI demonstrated a higher cure rate (79.0% vs. 52.0%), lower mortality (15.2% vs. 39.0%), and reduced nephrotoxicity (14.6% vs. 56.4%). On average a patient treated with IMI/REL vs. CMS + IMI gained additional 3.7 QALYs over a lifetime. Higher drug acquisition costs for IMI/REL were offset by shorter hospital length of stay and lower AE-related costs, which result in net savings of $11,015 per patient. Sensitivity analyses suggested that IMI/REL has a high likelihood (greater than 95%) of being cost-effective at a US willingness-to-pay threshold of $100,000-150,000 per QALY. CONCLUSIONS: For patients with confirmed CNS GN infection, IMI/REL could yield favorable clinical outcomes and may be cost-saving-as the higher IMI/REL drug acquisition cost is offset by reduced nephrotoxicity-related cost-for the US payer compared to CMS + IMI.

5 versus 10 Units of Intravenous Insulin for Hyperkalemia in Patients With Moderate Renal Dysfunction.

BACKGROUND: A reduced dose of 5 units of intravenous (i.v.) insulin has been widely accepted for treatment of hyperkalemia in those with end-stage renal dysfunction. However, there remains a dearth of data for patients with moderate renal dysfunction (estimated glomerular filtration rate 15-59 mL/min/m2). OBJECTIVE: Describe the incidence of hypoglycemia and relative change in serum potassium when using 5 vs. 10 units of insulin for hyperkalemia in patients with moderate renal dysfunction. METHODS: This was a single-center, retrospective study evaluating adult patients with moderate renal dysfunction who received i.v. insulin for treatment of hyperkalemia. Patients were analyzed based on whether they received 5 or 10 units of i.v. insulin. The primary outcome was the rate of hypoglycemia in each group. Secondary outcomes included rate of relative potassium-lowering effect and incidence of severe hypoglycemia. RESULTS: Hypoglycemia occurred in 12 patients who received 5 units of i.v. insulin and 16 patients who received 10 units of i.v. insulin (6.5% vs. 8.4%, p = 0.476). Serum potassium was significantly reduced when utilizing 10 units over 5 units of i.v. insulin (-0.9 mmol/L vs. -0.63 mmol/L, p = 0.001). Severe hypoglycemia was seen in two encounters in both the 5-unit and 10-unit groups (1.1% vs. 1.0%, p = 0.979). CONCLUSION: There was no difference in hypoglycemic events among patients with moderate renal dysfunction receiving 5 vs. 10 units of i.v. insulin for hyperkalemia. However, 10 units of i.v. insulin lowered serum potassium significantly more than 5 units of i.v. insulin.

Antibacterial data synthesis challenges: a systematic review of treatments for complicated Gram-negative urinary tract infections.

Aim: To determine the suitability of network meta-analysis (NMA) using antibacterial treatment evidence in complicated urinary tract infection. Materials & methods: We conducted a systematic literature review to identify published clinical trial data for complicated urinary tract infection treatments. We performed a feasibility assessment to determine whether the available evidence would support the creation of a robust NMA, considering key assumptions of homogeneity, similarity and consistency. Results: Twenty-five trials met eligibility criteria. Risk of bias was low, and individual studies met their primary end point(s). Assumptions central to the conduct of a robust NMA were not met. Heterogeneity was ubiquitous, including baseline pathogen, treatment and patient characteristics. Conclusion: Limited and heterogeneous data identified make the use of NMA to compare novel antibacterial agents impractical and likely unreliable.

Systematic Literature Review of Real-world Evidence of Ceftolozane/Tazobactam for the Treatment of Respiratory Infections.

INTRODUCTION: Gram-negative nosocomial pneumonia (NP), including hospital-acquired bacterial pneumonia (HABP), ventilated HABP (vHABP), and ventilator-associated bacterial pneumonia (VABP), is a significant cause of morbidity and mortality. Common pathogens, including Enterobacterales and Pseudomonas aeruginosa, are prevalent in healthcare settings and have few effective treatment options due to high rates of antibacterial resistance. Resistant pathogens are associated with significantly worse outcomes, relative to patients with susceptible infections. Ceftolozane/tazobactam (C/T) has established efficacy in clinical trials of patients with NP. This review aims to collate data on C/T use for HABP/vHABP/VABP infections in real-world clinical practice. METHODS: This systematic literature review searched online biomedical databases for real-world studies of C/T used to treat Gram-negative respiratory tract infections (RTIs) between January 2009 and June 2020. RESULTS: Thirty-three studies comprising 658 patients were identified. Pneumonia was the most common infection treated with C/T (85%), with a smaller number of unspecified RTIs (9%) and tracheobronchitis (5%) reported. The majority of patients had respiratory infections caused by P. aeruginosa (92.8%), of which 88.1% were multidrug-resistant. Examination of these studies demonstrated an increase in the percentage of patients receiving the recommended dose of C/T for respiratory infections (3 g q8h or renal impairment-adjusted) over time (36.8% of patients in 2017 to 71.5% in 2020). Clinical success rates ranged from 51.4 to 100%, with 10 studies (55.6% of studies reporting clinical success) reporting clinical success rates of > 70%; microbiological success rates ranged from 57.0 to 100.0%, with three studies (60.0% of studies reporting microbiological success) reporting microbiological success rates of > 70%. Thirty-day mortality ranged from 0.0 to 33.0%, with nine studies (90% of studies reporting mortality) reporting 30-day mortality of < 30%. CONCLUSIONS: The studies identified in this review demonstrate that C/T shows similar outcomes as those seen in clinical trials, despite the higher frequency of multidrug-resistant pathogens, and comorbidities that may have been excluded from the trials.

Real-world use of ceftolozane/tazobactam: a systematic literature review.

BACKGROUND: Antibacterial-resistant gram-negative infections are a serious risk to global public health. Resistant Enterobacterales and Pseudomonas aeruginosa are highly prevalent, particularly in healthcare settings, and there are limited effective treatment options. Patients with infections caused by resistant pathogens have considerably worse outcomes, and incur significantly higher costs, relative to patients with susceptible infections. Ceftolozane/tazobactam (C/T) has established efficacy in clinical trials. This review aimed to collate data on C/T use in clinical practice. METHODS: This systematic literature review searched online biomedical databases for real-world studies of C/T for gram-negative infections up to June 2020. Relevant study, patient, and treatment characteristics, microbiology, and efficacy outcomes were captured. RESULTS: There were 83 studies comprising 3,701 patients were identified. The most common infections were respiratory infections (52.9% of reported infections), urinary tract infections (UTIs; 14.9%), and intra-abdominal infections (IAIs; 10.1%). Most patients included were seriously ill and had multiple comorbidities. The majority of patients had infections caused by P. aeruginosa (90.7%), of which 86.0% were antimicrobial-resistant. C/T was used as both a 1.5 g q8h and 3 g q8h dose, for a median duration of 7-56 days (varying between studies). Outcome rates were comparable between studies: clinical success rates ranged from 45.7 to 100.0%, with 27 studies (69%) reporting clinical success rates of > 70%; microbiological success rates ranged from 31 to 100%, with 14 studies (74%) reporting microbiological success rates of > 70%. Mortality rates ranged from 0 to 50%, with 31 studies (69%) reporting mortality rates of ≤ 20%. In comparative studies, C/T was as effective as aminoglycoside- or polymyxin-based regimens, and in some instances, significantly more effective. CONCLUSIONS: The studies identified in this review demonstrate that C/T is effective in clinical practice, despite the diverse group of seriously ill patients, different levels of resistance of the pathogens treated, and varying dosing regimens used. Furthermore, comparative studies suggest that C/T offers a successful alternative to standard of care (SoC).

Cost Effectiveness of Ceftolozane/Tazobactam Compared with Meropenem for the Treatment of Patients with Ventilated Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

INTRODUCTION: The clinical efficacy and safety of ceftolozane/tazobactam for the treatment of ventilated hospital-acquired bacterial pneumonia (vHABP) and ventilator-associated bacterial pneumonia (VABP) has been demonstrated in the phase III randomised controlled trial ASPECT-NP. However, there are no published data on the cost-effectiveness of ceftolozane/tazobactam for vHABP/VABP. These nosocomial infections are associated with high rates of morbidity and mortality, and are increasingly complicated by growing rates of resistance and the inappropriate use of antimicrobials. This study is to assess the cost-effectiveness of ceftolozane/tazobactam compared with meropenem for the treatment of vHABP/VABP in a US hospital setting. METHODS: A short-term decision tree followed by a long-term Markov model was developed to estimate lifetime costs and quality-adjusted life-years associated with ceftolozane/tazobactam and meropenem in the treatment of patients with vHABP/VABP. Pathogen susceptibility and clinical efficacy were informed by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database and ASPECT-NP, respectively. A US healthcare sector perspective was adopted, capturing direct costs borne by third-party payers or integrated health systems, and direct health effects for patients. RESULTS: In the confirmed treatment setting (post-susceptibility results), the incremental cost-effectiveness ratio for ceftolozane/tazobactam compared to meropenem was US$12,126 per quality-adjusted life-year (QALY); this reduced when used in the early treatment setting (before susceptibility results) at $4775/QALY. CONCLUSION: Ceftolozane/tazobactam represents a highly cost-effective treatment option for patients with vHABP/VABP versus meropenem when used in either the confirmed or early treatment setting; with increased cost-effectiveness shown in the early setting.

Healthcare Resource Utilization of Ceftolozane/Tazobactam Versus Meropenem for Ventilated Nosocomial Pneumonia from the Randomized, Controlled, Double-Blind ASPECT-NP Trial.

INTRODUCTION: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP) are associated with significant healthcare resource utilization (HCRU). This a priori, exploratory, secondary analysis from the ASPECT-NP clinical trial evaluated resource utilization among patients with ventilated HABP (vHABP)/VABP treated with ceftolozane/tazobactam or meropenem. METHODS: This analysis used data from the randomized, double-blind, noninferiority phase 3 ASPECT-NP trial of patients with vHABP/VABP randomized to receive ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) or meropenem 1 g for 8-14 days. Day 28 outcomes included hospital length of stay (LOS), intensive care unit (ICU) LOS, and time to mechanical ventilation extubation in the microbiological intention-to-treat (mITT) population and in an HCRU population. The HCRU population, a subset of patients from the mITT population that were alive at day 28, was used to remove resource use bias influenced by mortality rates. RESULTS: Ceftolozane/tazobactam-treated versus meropenem-treated patients, respectively, had fewer deaths (20.1% vs. 25.5%), fewer hospital discharges (30.7% vs. 32.4%), and higher ICU discharges (60.0% vs. 58.3%) and extubations (51.9% vs. 48.2%) by day 28. In the HCRU population, adjusted LOS differences (95% confidence intervals) for ceftolozane/tazobactam compared with meropenem were 0.1 (- 1.4 to 1.6) hospitalization days, - 1.4 (- 2.9 to 0.2) ICU days, and - 0.9 (- 2.4 to 0.7) mechanical ventilation days. Patterns were similar among the VABP and Pseudomonas aeruginosa subgroups. CONCLUSION: Similar 28-day resource utilization outcomes were observed between ceftolozane/tazobactam and meropenem in the mITT population of patients from ASPECT-NP with vHABP/VABP due to gram-negative pathogens. ASPECT-NP was not powered to detect differences in resource utilization outcomes between treatment groups; however, numerical differences in ICU LOS and duration of mechanical ventilation were noted. Further study is needed to assess resource utilization in the real-world practice setting, especially among patients excluded from ASPECT-NP, including those with resistant P. aeruginosa infections. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.