HealthDay News — The NoMicro classifier appears accurate for evaluating urine cultures in cases of suspected urinary tract infection in the primary care setting without the need for microscopy, according to a study published in the January/February issue of the Annals of Family Medicine.

Gurpreet Dhanda, MD, from the University of Kansas Medical Center in Kansas City, and colleagues redesigned a classifier (NoMicro) that does not depend on urine microscopy and retrospectively validated a machine learning prediction model for urine cultures internally (emergency department data set) and externally (primary care data set). Pathogenic urine culture growing 100,000 or greater colony-forming units was the primary outcome, while predictor variables were: age; gender; dipstick urinalysis nitrites, leukocytes, clarity, glucose, protein, and blood; dysuria; abdominal pain; and history of urinary tract infection.

The researchers found that removal of microscopy features did not severely compromise performance under internal validation (receiver operating characteristic area under the curve [ROC-AUC], 0.86 and 0.88 for NoMicro/XGBoost and NeedMicro, respectively). In external validation, excellent performance was also achieved (NoMicro/random forests ROC-AUC, 0.85).

“Retrospective simulation suggested that NoMicro/random forests can be used to safely withhold antibiotics for low-risk patients, thereby avoiding antibiotic overuse,” the authors write. “The NoMicro classifier appears appropriate for primary care. Prospective trials to adjudicate the balance of benefits and harms of using the NoMicro classifier are appropriate.”

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Previously, Avycaz had only been approved for adults and pediatric patients 3 months of age and older. The expanded approval was based on data from an open-label, single-arm, multicenter, phase 2 study (ClinicalTrials.gov Identifier: NCT04126031) that evaluated the pharmacokinetics, safety, and tolerability of Avycaz in 46 pediatric patients from birth (gestational age ≥31 weeks) to less than 3 months; the median age was 24 days. 

The overall safety profile of Avycaz in this pediatric population was similar to that seen in adults with cIAI, cUTI, and HABP/VABP. There was 1 death reported in the trial and no treatment discontinuations due to adverse reactions. The most common adverse reactions (incidence ≥3%) were vomiting and increased transaminases.

In this trial, 25 patients with suspected or confirmed bacterial infection received a single dose of Avycaz, while 21 patients with suspected or confirmed serious gram-negative infections received multiple doses. Among patients who received multiple Avycaz doses, the mean treatment duration was 6 days and the maximum treatment duration was 12 days.

Avycaz is supplied as ceftazidime 2g/avibactam 0.5g strength powder for IV injection in single-use vials.

Florian M. Wagenlehner, M.D., from Justus Liebig University in Giessen, Germany, and colleagues conducted a phase 3 randomized trial involving hospitalized adults with complicated UTI, including acute pyelonephritis. Participants were randomly assigned to receive intravenous cefepime-taniborbactam (2.5g) or meropenem (1g) every 8 hours for seven days in a 2:1 ratio; in the case of bacteremia, this duration could be extended up to 14 days.

The researchers found that composite success (microbiologic and clinical success on trial days 19 to 23) occurred in 70.6 and 58.0% of patients in the cefepime-taniborbactam and meropenem groups, respectively, with cefepime-taniborbactam superior to meropenem (treatment difference, 12.6 percentage points). At late follow-up (days 28 to 35), differences in treatment response were sustained, with higher composite success and clinical success seen for cefepime-taniborbactam. Adverse events occurred in 35.5 and 29.0% of patients in the cefepime-taniborbactam and meropenem groups, respectively; the 2 groups had a similar frequency of serious adverse events.

“Cefepime-taniborbactam was shown to be a potential treatment option for patients with complicated UTI and acute pyelonephritis caused by Enterobacterales species and P. aeruginosa, including antimicrobial-resistant strains,” the authors write.

The study was funded by VenatoRx Pharmaceuticals, the developer of cefepime-taniborbactam.

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Shruti K. Gohil, MD, MPH, from the University of California Irvine School of Medicine, and colleagues examined whether CPOE prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI in a cluster-randomized trial in 59 US community hospitals. The effect of a CPOE stewardship bundle vs routine stewardship (29 and 30 hospitals, respectively) on antibiotic selection during the first three hospital days in noncritically ill adults hospitalized with UTI was compared for a 15-month intervention period and an 18-month baseline period. Participants had low estimated absolute risk for MDRO UTI.

Data were included for 127,403 adults: 71,991 at baseline and 55,412 during the intervention periods. The researchers observed a 17.4% reduction in empiric extended-spectrum days of therapy in the group using CPOE prompts compared with routine stewardship (rate ratio, 0.83). No significant difference was seen between the CPOE prompt and routine groups in terms of the safety outcomes of mean days to intensive care unit transfer and hospital length of stay.

“This intervention could be a viable strategy to reduce extended-spectrum antibiotics in up to 200,000 adults hospitalized in the US who receive unnecessarily broad antibiotics for UTI annually,” the authors write.

Two authors disclosed ties to the pharmaceutical industry.

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HealthDay News — Cranberry products reduce the risk for symptomatic, culture-verified urinary tract infections (UTIs), especially in specific populations, according to a review published online April 17 in the Cochrane Library.

Gabrielle Williams, PhD, MPH, from The Children’s Hospital at Westmead in Australia, and colleagues examined the effectiveness of cranberry products in preventing UTI in susceptible populations. Twenty-six studies were added for this update, resulting in 50 included studies with 8857 randomly assigned participants. A total of 45 studies compared cranberry products to placebo or no specific treatment; 26 of these could be meta-analyzed.

The researchers found that cranberry products reduced the risk for UTIs based on moderate-certainty evidence (risk ratio, 0.70). When studies were categorized according to treatment indication, cranberry products reduced the risk for symptomatic, culture-verified UTIs in women with recurrent UTIs, children, and those with a susceptibility to UTIs due to an intervention (risk ratios, 0.74, 0.46, and 0.47, respectively). Little or no benefit was seen in elderly institutionalized men and women, pregnant women, or adults with neuromuscular bladder dysfunction with incomplete bladder emptying (based on low-certainty evidence).

“This is a review of the totality of the evidence and as new evidence emerges, new findings might occur,” a coauthor said in a statement. “In this case, the new evidence shows a very positive finding that cranberry juice can prevent UTI in susceptible people.”

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In the INSPIRE trial (Intelligent Stewardship Prompts to Improve Real-time Empiric antibiotic selection; ClinicalTrials.gov Identifier: NCT03697096), investigators compared a novel antibiotic stewardship including computerized provider order entry (CPOE) prompts with routine antibiotic stewardship among 127,403 adults admitted with UTI to 59 private community hospitals. Prompts were tailored to the specific extended-spectrum antibiotic ordered: cefepime orders triggered evaluation for low risk of Pseudomonas UTI; carbapenem orders triggered evaluated for low risk of extended-spectrum β-lactamase-producing Enterobacterales (ESBLs) or resistant Pseudomonas. Although uncommon, prompts were also generated for vancomycin orders for gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus for UTI. The automated approach included each hospital’s prevalence of syndrome-specific multidrug-resistant organism (MDRO). Mean age of the cohort was 69.4 years, 30.5% were male, and the median Elixhauser Comorbidity Index was 4.

The intervention group experienced a significant 17.4% reduction in the number of days on empiric extended-spectrum antibiotics compared with the routine stewardship group, Shruti K. Gohil, MD, MPH, of the University of California Irvine, and colleagues reported in JAMA. The empiric extended-spectrum days of therapy (per 1000 empiric days) for the CPOE bundle group decreased from a mean 392.2 to 326.0 days, whereas it increased from a mean 431.1 to 446.0 days for the routine stewardship group. Use of antipseudomonal antibiotics decreased by one-fifth.

Only 3.4% or less of urine cultures were positive for Pseudomonas and 8.0% or less for ESBL. Antibiotic escalation was comparable between the intervention and control groups (10.0% vs 10.2%). Less than 6% of patients deemed low risk in the intervention group were found to have a MDRO. ICU transfers (6.6 vs 7.0 days) and hospital length of stay (6.3 vs 6.5 days) did not increase in the intervention vs control group.

In an accompanying editorial, Anurag N. Malani, MD, and Preeti N. Malani, MD, MSJ, of University of Michigan Health in Ann Arbor, noted the hurdles in implementing the complex system and commented:

“Even with the CPOE bundle and significant reductions, extended-spectrum antibiotic use remained high in both the pneumonia and UTI studies, while the rate of multidrug-resistant organisms isolated in cultures was low. Future studies should also consider cost savings, effects on local antibiograms, the nuances surrounding diagnostic certainty (for both pneumonia and UTI), and how to develop policy that incentivizes this type of innovation.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Irinotecan Liposome Injection (Onivyde^®) Regimen for Pancreatic Ductal Adenocarcinoma

PDUFA date: February 13, 2024

The FDA is reviewing the supplemental NDA (sNDA) for irinotecan liposome injection (Onivyde) plus 5 fluorouracil/leucovorin and oxaliplatin (NALIRIFOX regimen) for the first-line treatment for metastatic pancreatic ductal adenocarcinoma. Irinotecan liposome injection is a topoisomerase 1 inhibitor encapsulated in a lipid bilayer vesicle or liposome.The sNDA is supported by data from the phase 3 NAPOLI 3 trial (ClinicalTrials.gov Identifier: NCT04083235). Results showed a statistically significant improvement in overall survival and progression free survival in patients treated with NALIRIFOX compared with those who received nab-paclitaxel and gemcitabine.

Cefepime-Taniborbactam for Complicated Urinary Tract Infections, Including Pyelonephritis

PDUFA date: February 22, 2024

Cefepime-taniborbactam is an investigational intravenous beta-lactam/beta-lactamase inhibitor antibiotic. The combination has demonstrated in vitro activity against clinically significant gram-negative bacteria, including carbapenem-resistant Enterobacterales, multidrug-resistant Pseudomonas aeruginosa and extended spectrum beta-lactamase-producing Enterobacterales. The NDA is supported by data from the phase 3 CERTAIN-1 study (ClinicalTrials.gov Identifier: NCT03840148), which compared the efficacy and safety of cefepime-taniborbactam to meropenem in 661 adults with cUTI, including acute pyelonephritis. Findings showed treatment with cefepime-taniborbactam was noninferior to meropenem at the test of cure visit.

Lifileucel for the Treatment of Advanced Melanoma

PDUFA date: February 24, 2024

Lifileucel is a one-time autologous adoptive cell transfer therapy that utilizes a tumor infiltrating lymphocyte manufacturing process. The BLA is supported by data from the C-144-01 study (ClinicalTrials.gov Identifier: NCT02360579), which evaluated lifileucel in adults with advanced melanoma. The efficacy analysis included 153 patients, all of whom had progressed on or after immune checkpoint inhibitor therapy and targeted BRAF/MEK inhibitor therapy where appropriate. Findings showed lifileucel was associated with clinically meaningful and durable responses.

Roluperidone for the Treatment of Negative Symptoms in Schizophrenia

PDUFA date: February 26, 2024

Roluperidone is an investigational 5-HT2_A, sigma₂ and α _1A-adrenergic receptor antagonist. The NDA submission included data from phase 3 MIN-101 study (ClinicalTrials.gov Identifier: NCT03397134), which evaluated the efficacy and safety of roluperidone in 513 adult patients with moderate to severe negative symptoms of schizophrenia. Findings showed an improvement in negative symptoms (as measured by the Positive and Negative Syndrome Scale PANSS Marder Negative Symptoms Factor Score) in patients receiving roluperidone 64mg compared with placebo. 

Visit our Drugs in the Pipeline news section to stay up-to-date on the latest drugs in development.

Sulopenem etzadroxil is an investigational oral penem anti-infective that has been combined with probenecid in a bilayer tablet. The REASSURE trial was conducted to support the approval of the product following a letter from the Food and Drug Administration (FDA) requesting additional study data. 

The phase 3 trial (ClinicalTrials.gov Identifier: NCT05584657) included adult female patients with uUTI; participants were randomly assigned to receive sulopenem etzadroxil 500mg/probenecid 500mg (n=480) or amoxicillin 875mg/clavulanate 125mg (n=442) twice daily for 5 days. The primary endpoint was overall success, defined as clinical success (resolution of uUTI symptoms present at study entry and no new symptoms) and microbiologic success (eradication of the baseline pathogen) at the test of cure visit (day 12 +/- 1 day).

Findings showed treatment with sulopenem/probenecid was statistically superior to amoxicillin/clavulanate; overall success was achieved by 61.7% of the sulopenem/probenecid group and 55% of the amoxicillin/clavulanate group (treatment difference, 6.7%; 95% CI, 0.3-13). In the sulopenem/probenecid arm, 77.3% and 75.2% of patients had clinical success and microbiological success, compared with 76.7% and 66.7% of those in the amoxicillin/clavulanate arm. No new safety signals were reported in the trial. 

“These results bring us one step closer to delivering a much-needed oral treatment option for women suffering from uUTIs,” said Sailaja Puttagunta, MD, Iterum’s Chief Medical Officer. “In addition, we believe these results, along with evidence from our prior phase 3 studies, support the potential of sulopenem in other indications, such as complicated urinary tract infections.” 

The Company is expected to resubmit the New Drug Application for oral sulopenem with this new data in the second quarter of 2024.

HealthDay News — For children with urinary tract infection (UTI), standard-course therapy is associated with lower rates of treatment failure, according to a study published online June 26 in JAMA Pediatrics.

Theoklis Zaoutis, MD, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues compared the efficacy of standard-course and short-course therapy for children with UTI in a randomized clinical noninferiority trial. Data were included for 664 children aged 2 months to 10 years with UTI exhibiting clinical improvement after 5 days of antimicrobials who were randomly assigned to another five days of antimicrobials (standard-course therapy) or 5 days of placebo (short-course therapy; 328 and 336 children, respectively).

The researchers found that 0.6 and 4.2% of those assigned to standard-course and short-course therapy had treatment failure, defined as symptomatic UTI at or before the first follow-up visit (days 11 to 14; absolute difference, 3.6%; upper bound of 95% CI, 5.5%). The likelihood of having asymptomatic bacteriuria or a positive urine culture at or by the first follow-up visit was increased for children receiving short-course therapy. No between-group differences were seen in the rates of UTI after the first follow-up visit, incidence of adverse events, or incidence of gastrointestinal colonization with resistant organisms.

“The slightly increased risk of treatment failure with the added benefit of convenience and potentially less adverse events should be discussed with parents; in this way, they can contribute to conversations surrounding the ultimate duration of therapy prescribed,” write the authors of an accompanying editorial.

Several authors disclosed ties to the pharmaceutical industry.

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HealthDay News — For men with lower urinary tract symptoms, treatment is associated with a reduced risk for death, according to a study published in the October 1 issue of The Journal of Urology.

Blayne Welk, MD, and J. Andrew McClure, from Western University in London, Ontario, Canada, conducted a secondary analysis of the Medical Treatment of Prostate Symptoms randomized trial of placebo, doxazosin, finasteride, or a combination of doxazosin and finasteride involving 3046 men aged older than 50 years with moderate-to-severe lower urinary tract symptoms. The relationship between the American Urology Association (AUA) Symptom Score and death was examined.

The researchers found that the hazard ratio for death was 0.96 for each 1-point improvement in the AUA Symptom Score. A similar significant reduction in the hazard ratio for death was seen for men who had active treatment, but not for those randomly assigned to the placebo arm. The results were unchanged when men were censored at the time of transurethral prostate resection, after adjustment for potential confounding variables, or with a shorter observation period after the last study visit. With 1-point improvements in the storage and voiding subscales individually, comparable significant reductions in death were seen (hazard ratios, 0.94 and 0.95, respectively).

“We found a small but significant decrease in mortality risk for older men who received medications for treatment of lower urinary tract symptoms,” Welk said in a statement. “The findings suggest that we may need to view urinary symptoms differently, possibly with an emphasis on earlier treatment.”

One author is a consultant for Becton, Dickinson, and Company.

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HealthDay News — Uncomplicated urinary tract infections (uUTIs) pose a substantial burden on US women, according to a study published online February 1 in PLOS ONE.

Jeffrey Thompson, PhD, from Cerner Enviza in Malvern, Pennsylvania, and colleagues assessed the impact of uUTIs from the patient perspective. The analysis included data from 375 US women who self-reported a uUTI in the prior 60 days and were treated with one or more oral antibiotic.

The researchers found that impaired activities included sexual intercourse (66.9%), sleep (60.8%), and exercise (52.3%). Compared with a matched control population, health-related quality of life (HRQoL) was worse, as measured with the physical component score, the mental component score, and health utility index. Further, Work Productivity and Activity Impairment assessments were worse for the uUTI cohort vs controls. For participants receiving two or more antibiotics, adjusted direct costs were significantly higher than for women receiving one antibiotic ($2090 vs $776). Increased activity impairment, worse HRQoL, and higher costs were seen for recurrent uUTI vs nonrecurrent uUTI.

“While uUTIs are common, their impact on patients should not be underestimated; appropriate treatment is crucial in preventing adverse impacts on quality-of-life and health care resource utilization,” conclude the authors.

Two authors disclosed employment histories with Cerner Enviza, which received funding from GlaxoSmithKline to conduct this study. Three authors are employees of GlaxoSmithKline.

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