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      Safety and Efficacy of Ceftolozane/Tazobactam Versus Meropenem in Neonates and Children With Complicated Urinary Tract Infection, Including Pyelonephritis: A Phase 2, Randomized Clinical Trial

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          Background:

          Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, active against multidrug-resistant Gram-negative pathogens, is approved for treatment of adults with complicated urinary tract infections (cUTI). Safety and efficacy of ceftolozane/tazobactam in pediatric participants with cUTI, including pyelonephritis, were assessed.

          Methods:

          This phase 2 study (NCT03230838) compared ceftolozane/tazobactam with meropenem for treatment of cUTI in participants from birth to <18 years of age. The primary objective was safety and tolerability. Key secondary end points included clinical cure and per-participant microbiologic response rates at end of treatment (EOT) and test of cure (TOC) visits.

          Results:

          The microbiologic modified intent-to-treat (mMITT) population included 95 participants (ceftolozane/tazobactam, n = 71; meropenem, n = 24). The most common diagnosis and pathogen were pyelonephritis (ceftolozane/tazobactam, 84.5%; meropenem, 79.2%) and Escherichia coli (ceftolozane/tazobactam, 74.6%; meropenem, 87.5%); 5.7% (ceftolozane/tazobactam) and 4.8% (meropenem) of E. coli isolates were extended-spectrum β-lactamase-producers. Rates of adverse events were similar between treatment groups (any: ceftolozane/tazobactam, 59.0% vs. meropenem, 60.6%; drug-related: ceftolozane/tazobactam, 14.0% vs. meropenem, 15.2%; serious: ceftolozane/tazobactam, 3.0% vs. meropenem, 6.1%). Rates of clinical cure for ceftolozane/tazobactam and meropenem at EOT were 94.4% and 100% and at TOC were 88.7% and 95.8%, respectively. Rates of microbiologic eradication for ceftolozane/tazobactam and meropenem at EOT were 93.0% and 95.8%, and at TOC were 84.5% and 87.5%, respectively.

          Conclusions:

          Ceftolozane/tazobactam had a favorable safety profile in pediatric participants with cUTI; rates of clinical cure and microbiologic eradication were high and similar to meropenem. Ceftolozane/tazobactam is a safe and effective new treatment option for children with cUTI, especially due to antibacterial-resistant Gram-negative pathogens.

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          Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis

          (2022)
          Summary Background Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date. Methods We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level. Findings On the basis of our predictive statistical models, there were an estimated 4·95 million (3·62–6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27·3 deaths per 100 000 (20·9–35·3), and lowest in Australasia, at 6·5 deaths (4·3–9·4) per 100 000. Lower respiratory infections accounted for more than 1·5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000–1 270 000) deaths attributable to AMR and 3·57 million (2·62–4·78) deaths associated with AMR in 2019. One pathogen–drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000–100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistant E coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae. Interpretation To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen–drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programmes, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasising the need to expand microbiology laboratory capacity and data collection systems to improve our understanding of this important human health threat. Funding Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.
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            Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations.

            David van Duin, Robert Bonomo, Louis Saravolatz (2016)
            Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both ceftolozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of complicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumonia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.
            Article 0 comments Cited 203 times – based on 0 reviews     Review now
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              Prevalence of urinary tract infection in childhood: a meta-analysis.

              Max H Farrell, James E. Bost, Nader Shaikh … (2008)
              Knowledge of baseline risk of urinary tract infection can help clinicians make informed diagnostic and therapeutic decisions. We conducted a meta-analysis to determine the pooled prevalence of urinary tract infection (UTI) in children by age, gender, race, and circumcision status. MEDLINE and EMBASE databases were searched for articles about pediatric urinary tract infection. Search terms included urinary tract infection, cystitis, pyelonephritis, prevalence and incidence. We included articles in our review if they contained data on the prevalence of UTI in children 0-19 years of age presenting with symptoms of UTI. Of the 51 articles with data on UTI prevalence, 18 met all inclusion criteria. Two evaluators independently reviewed, rated, and abstracted data from each article. Among infants presenting with fever, the overall prevalence (and 95% confidence interval) of UTI was 7.0% (CI: 5.5-8.4). The pooled prevalence rates of febrile UTIs in females aged 0-3 months, 3-6 months, 6-12 months, and >12 months was 7.5%, 5.7%, 8.3%, and 2.1% respectively. Among febrile male infants less than 3 months of age, 2.4% (CI: 1.4-3.5) of circumcised males and 20.1% (CI: 16.8-23.4) of uncircumcised males had a UTI. For the 4 studies that reported UTI prevalence by race, UTI rates were higher among white infants 8.0% (CI: 5.1-11.0) than among black infants 4.7% (CI: 2.1-7.3). Among older children (<19 years) with urinary symptoms, the pooled prevalence of UTI (both febrile and afebrile) was 7.8% (CI: 6.6-8.9). Prevalence rates of UTI varied by age, gender, race, and circumcision status. Uncircumcised male infants less than 3 months of age and females less than 12 months of age had the highest baseline prevalence of UTI. Prevalence estimates can help clinicians make informed decisions regarding diagnostic testing in children presenting with signs and symptoms of urinary tract infection.
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                Author and article information

                Contributors
                Emmanuel Roilides
                Negar Ashouri
                John S. Bradley
                Julia Lonchar
                Feng-Hsiu Su
                Jennifer A. Huntington
                Myra W. Popejoy
                Mekki Bensaci
                Carisa De Anda
                Elizabeth G. Rhee
                Christopher J. Bruno
                Journal
                Journal ID (nlm-ta): Pediatr Infect Dis J
                Journal ID (iso-abbrev): Pediatr Infect Dis J
                Journal ID (publisher-id): INF
                Title: The Pediatric Infectious Disease Journal
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0891-3668
                ISSN (Electronic): 1532-0987
                Publication date (Electronic): 23 January 2023
                Publication date (Print): April 2023
                Volume: 42
                Issue: 4
                Pages: 292-298
                Affiliations
                From the [* ]Third Department of Pediatrics, Infectious Diseases Unit, School of Medicine, Aristotle University and Hippokration General Hospital, Thessaloniki, Greece
                [† ]Division of Infectious Diseases, CHOC Children’s Hospital, Orange, California
                [‡ ]Department of Pediatrics, University of California San Diego School of Medicine and Rady Children’s Hospital of San Diego, San Diego, California
                [§ ]Merck & Co., Inc., Rahway, New Jersey.
                Author notes
                Address for correspondence: Matthew G. Johnson, MD, Merck & Co., Inc., 126 E. Lincoln Ave, Rahway, NJ 07065. E-mail: matthew.johnson1@ 123456merck.com .
                Article
                Accession ID: 00005
                DOI: 10.1097/INF.0000000000003832
                PMC ID: 9990597
                PubMed ID: 36689671
                SO-VID: 6b198b27-23cf-47bd-8951-e76e12a75ea5
                Copyright © Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                Date accepted : 29 November 2022
                Categories
                Subject: Antimicrobial Reports
                Custom metadata
                OPEN-ACCESS TRUE
                SDC T

                Keywords: cuti,antibacterial,pyelonephritis,escherichia coli
                Data availability:
                Keywords: cuti, antibacterial, pyelonephritis, escherichia coli

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