Recent Research

Treatment for complicated UTIs and abdominal infections, age-adjusted D-dimer results, ticagrelor vs. aspirin after cerebral ischemic events, and more.

Ceftazidime-avibactam works for complicated UTIs and abdominal infections, industry study finds

Ceftazidime-avibactam may provide a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa, an industry-funded study found.

The FDA approved ceftazidime-avibactam (Avycaz) in February for adults with complicated intra-abdominal infection, in combination with metronidazole, and complicated urinary tract infection (UTI), including kidney infections, if they have limited or no alternative treatment options.

The REPRISE trial, funded by AstraZeneca, was a pathogen-directed, international, randomized, open-label, phase 3 trial that recruited 333 patients from hospitals across 16 countries worldwide who had complicated UTI or intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Study results were published in the June The Lancet Infectious Diseases.

Patients were randomized to 5 to 21 days of treatment with either a combination of 2,000 mg ceftazidime plus 500 mg avibactam, administered via a 2-hour IV infusion every 8 hours (n=165), or to best available therapy (n=168). The primary endpoint was clinical response at the test-of-cure visit, 7 to 10 days after last infusion of study therapy, analyzed in all patients who had at least 1 ceftazidime-resistant gram-negative pathogen, as confirmed by the central laboratory, and who received at least 1 dose of study drug.

Of the cohort, 154 assigned to ceftazidime-avibactam (144 with complicated UTI and 10 with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated UTI and 11 with complicated intra-abdominal infection) were analyzed for the primary outcome; 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy.

The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 of 154 patients [91%; 95% CI, 85.6% to 94.7%]) and best available therapy (135 of 148 patients [91%; 95% CI, 85.9% to 95.0%]). Fifty-one of 164 patients in the ceftazidime-avibactam group (31%) and 66 of 168 in the best available therapy group (39%) had an adverse event, most of which were mild or moderate. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 of 164 patients [13%]) and best available therapy (30 of 168 patients [18%]). No new safety concerns were identified for the drug.

The authors concluded that the results support the use of ceftazidime-avibactam as a potential alternative to carbapenems, noting that in UTI patients, clinical cure rates were similar and microbiological responses favored the new drug. “In complicated intra-abdominal infection, the proportion of patients with a clinical and microbiological response was also high for ceftazidime-avibactam and in line with that observed with best available therapy. However, the number of patients with complicated intra-abdominal infection in this study was small, limiting the interpretation of the findings in this population,” the authors added.

Ticagrelor not superior to aspirin after cerebral ischemic events, industry study finds

Ticagrelor was not superior to aspirin in reducing the rates of stroke, myocardial infarction, or death at 90 days in patients who had an acute ischemic stroke or transient ischemic attack, an industry-funded study found.

Researchers conducted an international, double-blind, randomized controlled trial at 674 centers in 33 countries. In the trial, 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intra-arterial thrombolysis and were not considered to have had a cardioembolic stroke were assigned in a 1:1 ratio within 24 hours after symptom onset.

Patients received either ticagrelor (a loading dose of 180 mg given as two 90-mg tablets on day 1, followed by 90 mg twice daily) or aspirin (a loading dose of 300 mg given as three 100-mg tablets on day 1, followed by 100 mg daily given orally). Both groups also received placebo versions of the drug they weren't taking. After 90 days, patients were treated at the discretion of the investigator and followed for an additional 30 days. The study was sponsored by AstraZeneca. Results were published online May 10 by the New England Journal of Medicine.

The primary composite endpoint event of stroke, myocardial infarction, or death within 90 days occurred in 442 of the 6,589 patients (6.7%) in the ticagrelor group and in 497 of the 6,610 patients (7.5%) in the aspirin group (hazard ratio [HR], 0.89; 95% CI, 0.78 to 1.01; P=0.07). All analyses of secondary endpoints were considered exploratory. The main secondary endpoint, ischemic stroke, occurred in 385 patients (5.8%) in the ticagrelor group and 441 patients (6.7%) in the aspirin group (HR, 0.87; 95% CI, 0.76 to 1.00; nominal P=0.046).

A primary safety endpoint event, major bleeding, occurred in 31 patients (0.5%) in the ticagrelor group and 38 patients (0.6%) in the aspirin group (HR, 0.83; 95% CI, 0.52 to 1.34). There were no significant differences in any of the major safety outcomes. “Although the rate of serious adverse events did not differ significantly between the ticagrelor and aspirin groups, discontinuation of study treatment was more common among patients who received ticagrelor,” the study authors noted. “This difference was primarily due to dyspnea, which is a known adverse effect of ticagrelor treatment. Other causes of the higher rate of discontinuation in the ticagrelor group were minor and minimal bleeding events.”

In other news affecting poststroke care, the American Heart Association/American Stroke Association released their first-ever guidelines on stroke rehabilitation and recovery. The guidelines describe “comprehensive rehabilitation programs with adequate resources, dose, and duration” as an essential aspect of care and offer specifics on the roles of all clinicians, including physicians, in providing the programs. The guidelines were published in the June Stroke.

Poor outcomes, inappropriate treatment more likely in CAP due to Pseudomonas aeruginosa

Community-acquired pneumonia (CAP) due to Pseudomonas aeruginosa is associated with higher mortality rates than CAP due to other forms of bacteria and is more likely to be treated inappropriately, according to a recent study.

Researchers performed an observational cohort study to examine prevalence, risk factors, and outcomes for CAP due to P. aeruginosa in a sample of consecutive patients admitted to a Spanish hospital with CAP between January 1999 and December 2014. Rates, risk factors, and outcomes of multidrug-resistant P. aeruginosa were also examined. CAP was defined as a new pulmonary infiltrate found on chest X-ray at hospital admission, with signs and symptoms of lower respiratory tract infection, in patients who had not been recently hospitalized and who had not been regularly exposed to the health care system. P. aeruginosa pneumonia was defined as pneumonia in which P. aeruginosa was isolated in blood or a valid respiratory sample, while polymicrobial pneumonia was defined as pneumonia with more than 1 pathogen identified as the causative agent. CAP was considered severe when patients met at least 1 major or 3 minor criteria from the Infectious Diseases Society of America/American Thoracic Society guidelines. Study results were published in the April CHEST.

A total of 2,023 CAP patients for whom microbial etiology was available (62% men, mean age 65 years) were included in the study. P. aeruginosa was found in 77 CAP patients (4%). Of these, 68 cases had antibiogram data available, and 22 (32%) were found to be multidrug-resistant. Inappropriate antibiotic therapy was prescribed for 65% of patients with P. aeruginosa CAP versus 11% of patients with CAP due to other pathogens (P<0.001). Patients with P. aeruginosa CAP had a significantly higher mortality rate than those with CAP due to other organisms (18% vs. 6%; P<0.001). An independent association was seen between P. aeruginosa CAP and male sex, chronic respiratory disease, a C-reactive protein level below 12.35 mg/dL, and a Pneumonia Severity Risk class of IV to V. Patients with multidrug-resistant P. aeruginosa CAP were more likely to have previously been treated with antibiotics than those with non-multidrug-resistant CAP (58% vs. 29%; P=0.029). Factors associated with 30-day mortality in multivariate analysis were age 65 years or older, P. aeruginosa CAP, chronic liver disease, neurologic disease, nursing home status, acute respiratory distress syndrome criteria, acute renal failure, ICU admission, and inappropriate empirical treatment.

The authors noted that their study was done in only a single facility and took place over 12 years. However, they concluded that although P. aeruginosa CAP is not common, it is often treated inappropriately and is associated with higher mortality rates than CAP due to other organisms. They pointed out that 32% of P. aeruginosa cases in their study were multidrug-resistant and that P. aeruginosa CAP was associated with more severe disease. “Although this organism is uncommon, awareness of it is important because the presence of P. aeruginosa was an independent predictor for mortality among patients with CAP,” they wrote.

Age-adjusting D-dimer results improves predictive ability with Wells rule

For patients with suspected pulmonary embolism (PE), an age-adjusted D-dimer test combined with the Wells score safely reduced the need for imaging compared to a Wells score and fixed D-dimer cutoff, a recent analysis found.

The systematic review and meta-analysis used individual data on 7,268 patients, gathered from 6 prospective studies in which diagnosis of PE was guided by the Wells rule and D-dimer testing. Researchers looked at patients who were unlikely to have a PE based on their Wells score, then compared the efficiency of ruling out PE based on a fixed D-dimer cutoff (≤500 µg/L) or an age-adjusted one (age × 10 µg/L in patients age >50 years). Results were published by Annals of Internal Medicine on May 17.

The percentage of patients in whom PE could be ruled out without imaging was increased with use of the age-adjusted cutoff (33% vs. 28%), the analysis found. The rate of symptomatic venous thromboembolism within 3 months, which researchers considered failure of the diagnostic algorithm, was not significantly different and was under 3% in all subgroups. Certain subgroups did see greater gains in efficiency, or the ability to rule out PE without imaging, from the age adjustment than others: 12% more elderly were ruled out, while inpatients only gained 2.6%.

Based on the results, the researchers recommended using age-adjusted, rather than fixed, D-dimer testing with the Wells rule “because it increases efficiency without jeopardizing safety in all studied subgroups.” However, they noted that physicians will have to use their judgment on whether to proceed directly to imaging in inpatients, who in this study had PE ruled out only 7% or 10% of the time with age-adjusted and fixed cutoffs, respectively. “It may still be valuable to avoid the risk for contrast-induced nephropathy in ill patients who often already have comorbidities,” the authors wrote.

In addition to elderly patients, those with COPD also had significantly increased efficiency from the age-adjusted algorithm, while patients with cancer, previous venous thromboembolism, or a delayed presentation gained less, the analysis found. Study authors noted that there was considerable heterogeneity among the included studies, likely due to differences in patient populations.