Antibiotics

Background/Objectives: Phages show efficacy against multidrug-resistant Pseudomonas aeruginosa, but limited host ranges require combining them in cocktails. In this work, we characterized 25 P. aeruginosa phages, developed therapeutic cocktails active against diverse clinical isolates, and tested phage efficacy in a mouse incisional wound model. Methods/Results: These phages represent seven genera, and genomic and phenotypic analyses indicate that 24/25 are lytic and suitable for phage therapy. Phage host ranges on a diversity panel of 156 P. aeruginosa strains that included 106 sequence types varied from 8% to 54%, and together the 24 lytic phages were active against 133 strains (85%). All of the phages reduced bacterial counts in biofilms. A cocktail of five lytic phages, WRAIR_PAM1, covered 56% of the strain panel, protected 100% of mice from lethal systemic infection (vs. 20% survival in the saline-treated group), and accelerated healing of infected wounds. An improved five-phage cocktail, WRAIR_PAM2, was formulated by a rational design approach (using phages with broader host ranges, more complementing activity, relatively low resistance background, and compatibility in mixes). Conclusions: WRAIR_PAM2 covered 76% of highly diverse clinical isolates and demonstrated significant efficacy against topical and systemic P. aeruginosa infection, indicating that it is a promising therapeutic candidate.

Introduction: The appropriate use of antibiotic prophylaxis (AP) in surgical procedures is an ongoing debate. There is a lack of evidence, and urological guidelines provide limited, procedure-specific recommendations. Our aim was to develop a generic model of an audit to define the need for AP in urological procedures, as well as in other surgical specialties. Material and Methods: Based on our experience with the Global Prevalence of Infections in Urology (GPIU) study and a literature review, we defined benchmark standards for 30-day infection rates, including sepsis, and estimated the number of patients needed to be included in a comparative study of AP versus no AP for a surgical procedure within one year. The generic study model was developed during a modified consensus process within the UTISOLVE research group. Urology departments giving and not giving AP were invited to join our development project as an extension of GPIU. Results: Radical prostatectomy was used as a model procedure. Ca. 60 urology centers performing more than 50 radical prostatectomies per year signed up. There was variation in AP practice among sites. Our own review showed that infection rates were ca. 5%, with severe infections, including sepsis, occurring in <0.5% of cases. A sample of 1825 patients would be required to achieve a 95% confidence interval half-width of ±1.0% for general infections. For sepsis, assuming an incidence of 0.5%, a sample of 2124 patients would be needed to reach a 95% confidence interval precision of ±0.30%. Enrollment of 2070 consecutive procedures would be needed to yield precisions of ±0.94% for infection and ±0.30% for sepsis. Based on the number of procedures performed and the number of interested study sites, we agreed on a prospective, multi-center, non-interventional service evaluation, expected to collect standardized data over a 3-month period. The primary outcome was defined as the 30-day incidence of infectious complications. All patients will undergo 30-day post-procedure follow-up through routine clinical care pathways. Conclusions: Our audit model is based on benchmarking of relevant outcomes. It defines how to assess AP in surgical procedures and clarifies a series of issues necessary to defend the status of a generic study model. We regard DEEP-URO to be a comprehensive, multi-center-based initiative that will help balance infection prevention with antimicrobial stewardship and improve the quality of clinical practice and personalized medicine.

Invasive Candida infections in the neonatal intensive care unit (NICU) are associated with significant morbidity and mortality, particularly among extremely preterm neonates. Early treatment with antifungals is critical to improve survival rates and avoid long-term adverse outcomes. Prevention with antifungal prophylaxis in high-risk neonates has been shown to reduce the prevalence of invasive Candida infections effectively. However, the irrational and/or inappropriate use of antifungals has been documented. This narrative review aims to provide an overview of the rationales for the inappropriate use of antifungals in the NICU, the consequences that ensue, and the promising strategy of antifungal stewardship programs to optimize antifungal use. The nonspecific clinical presentation of systemic Candida infections and the lack of rapid, accurate diagnostic techniques for Candida identification and specification in most settings lead to a high rate of empirical treatment in neonates without a proven infection. Moreover, evidence on the optimal dosing of antifungal agents and the treatment duration in the neonatal population is lacking, which may result in excessive or subtherapeutic drug exposure. Antifungal misuse is associated with microbiological consequences, including the emergence of antifungal-resistant Candida strains, and clinical consequences, such as drug toxicities and alterations in the intestinal mycobiome. It is therefore imperative to optimize antifungal use in the NICU. The implementation of antifungal stewardship programs, which, through a multidisciplinary approach, aim to improve diagnosis and guide clinicians on antifungal selection, dosing, and duration for both prevention and treatment according to the local epidemiology, represents a promising strategy for antifungal optimization in the NICU.