According to the latest reports from WHO, the incidence of antibiotic-resistant bacterial infections is increasing worldwide, resulting in increased morbidity and mortality and a rising pressure on ...health-care systems. However, the development of new antibiotics is an expensive and time-consuming process, urging scientists to seek alternative antimicrobial strategies. Over the past few decades, the concept of therapeutic administration of bacteriophages (also known as phages) has gained popularity worldwide. Although conceptually promising, the widespread implementation of phage therapy in routine clinical practice is restricted by the scarcity of safety and efficacy data obtained according to the strict standards of the applicable clinical trial regulations. In this systematic review, we list clinical data published between Jan 1, 2000 and Aug 14, 2021 on the safety and efficacy of phage therapy for difficult-to-treat bacterial infections, and provide an overview of trials and case studies on the use of phage therapy in several medical disciplines.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options ...available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2–infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.
Model-informed precision dosing (MIPD) software tools are used to optimize dosage regimens in individual patients, aiming to achieve drug exposure targets associated with desirable clinical outcomes. ...Over the last few decades, numerous MIPD software tools have been developed. However, they have still not been widely integrated into clinical practice. This study focuses on identifying the requirements for and evaluating the performance of the currently available MIPD software tools. First, a total of 22 experts in the field of precision dosing completed a web survey to assess the importance (from 0; do not agree at all, to 10; completely agree) of 103 pre-established software tool criteria organized in eight categories: user-friendliness and utilization, user support, computational aspects, population models, quality and validation, output generation, privacy and data security, and cost. Category mean ± pooled standard deviation importance scores ranged from 7.2 ± 2.1 (user-friendliness and utilization) to 8.5 ± 1.8 (privacy and data security). The relative importance score of each criterion within a category was used as a weighting factor in the subsequent evaluation of the software tools. Ten software tools were identified through literature and internet searches: four software tools were provided by companies (DoseMeRx, InsightRX Nova, MwPharm++, and PrecisePK) and six were provided by non-company owners (AutoKinetics, BestDose, ID-ODS, NextDose, TDMx, and Tucuxi). All software tools performed well in all categories, although there were differences in terms of in-built software features, user interface design, the number of drug modules and populations, user support, quality control, and cost. Therefore, the choice for a certain software tool should be made based on these differences and personal preferences. However, there are still improvements to be made in terms of electronic health record integration, standardization of software and model validation strategies, and prospective evidence for the software tools' clinical and cost benefits.
Given that antibiotic use is associated with externalities, standard economic evaluation which considers costs and health gains accruing to patients under-values antibiotics. Informed by a scoping ...review, this discussion paper aims to identify the societal value elements of antibiotics and to provide guidance on how these value elements can be incorporated in economic evaluation. With a view to appropriately quantify the societal value of antibiotics, there is a need for good practice guidelines on the methodology of economic evaluation for such products. We argue that it is important to assess antibiotics at population level to account for their transmission, diversity, insurance, spectrum, novel action and enablement values. In addition to the value of antibiotics to infected patients, economic evaluations need to use modeling approaches to explore the impact of different modes of employing new and existing antibiotics (for example, as last resort treatment) on disease transmission and resistance development in current and future patients. Hence, assessing the value of antibiotics also involves an ethical dimension. Further work is required about how the multiple value elements of antibiotics are linked to each other and how they can be aggregated.
Estimators of glomerular filtration rate (GFR) have been shown to be flawed in critically ill patients, especially for augmented renal clearance (ARC), commonly defined as a measured urinary ...creatinine clearance (CrCl) ≥ 130 ml/min/1.73 m2 1. ...measuring CrCl should be performed in daily practice on the intensive care unit (ICU). ...the aim of this study is to define the most precise GFR estimator, which can then be used to detect ARC when measured CrCl is unavailable. ...the performance of these cut-offs was evaluated in an external single-center (Leuven, January 2016–December 2016) validation set by receiver-operating characteristics (ROC) curve analysis, using 2000 bootstrap replicates.
Purpose
Early diagnosis of acute kidney injury (AKI) remains a major challenge. We developed and validated AKI prediction models in adult ICU patients and made these models available via an online ...prognostic calculator. We compared predictive performance against serum neutrophil gelatinase-associated lipocalin (NGAL) levels at ICU admission.
Methods
Analysis of the large multicenter EPaNIC database. Model development (
n
= 2123) and validation (
n
= 2367) were based on clinical information available (1) before and (2) upon ICU admission, (3) after 1 day in ICU and (4) including additional monitoring data from the first 24 h. The primary outcome was a comparison of the predictive performance between models and NGAL for the development of any AKI (AKI-123) and AKI stages 2 or 3 (AKI-23) during the first week of ICU stay.
Results
Validation cohort prevalence was 29% for AKI-123 and 15% for AKI-23. The AKI-123 model before ICU admission included age, baseline serum creatinine, diabetes and type of admission (medical/surgical, emergency/planned) and had an AUC of 0.75 (95% CI 0.75–0.75). The AKI-23 model additionally included height and weight (AUC 0.77 (95% CI 0.77–0.77)). Performance consistently improved with progressive data availability to AUCs of 0.82 (95% CI 0.82–0.82) for AKI-123 and 0.84 (95% CI 0.83–0.84) for AKI-23 after 24 h. NGAL was less discriminant with AUCs of 0.74 (95% CI 0.74–0.74) for AKI-123 and 0.79 (95% CI 0.79–0.79) for AKI-23.
Conclusions
AKI can be predicted early with models that only use routinely collected clinical information and outperform NGAL measured at ICU admission. The AKI-123 models are available at
http://akipredictor.com/
.
Trial registration
Clinical Trials.gov NCT00512122
Bacteriophage therapy has recently attracted increased interest, particularly in difficult-to-treat infections. Although it is not a novel concept, standardized treatment guidelines are currently ...lacking. We present the first steps towards the establishment of a “multidisciplinary phage task force” (MPTF) and a standardized treatment pathway, based on our experience of four patients with severe musculoskeletal infections. After review of their medical history and current clinical status, a multidisciplinary team found four patients with musculoskeletal infections eligible for bacteriophage therapy within the scope of Article 37 of the Declaration of Helsinki. Treatment protocols were set up in collaboration with phage scientists and specialists. Based on the isolated pathogens, phage cocktails were selected and applied intraoperatively. A draining system allowed postoperative administration for a maximum of 10 days, 3 times per day. All patients received concomitant antibiotics and their clinical status was followed daily during phage therapy. No severe side-effects related to the phage application protocol were noted. After a single course of phage therapy with concomitant antibiotics, no recurrence of infection with the causative strains occurred, with follow-up periods ranging from 8 to 16 months. This study presents the successful outcome of bacteriophage therapy using a standardized treatment pathway for patients with severe musculoskeletal infection. A multidisciplinary team approach in the form of an MPTF is paramount in this process.
Vancomycin pharmacokinetic (PK) and pharmacodynamic (PD) data in neonates are based on total concentrations. However, only unbound vancomycin is pharmacologically active. The objective was to ...determine vancomycin protein binding and the covariates impacting unbound vancomycin concentration in neonates and young infants. In neonates and young infants to whom vancomycin was administered intermittently for medical indications, total and unbound vancomycin plasma concentrations were determined using LC-MS/MS. Sampling occurred randomly during vancomycin exposure, covering a broad range of concentrations. Impact of covariates on unbound vancomycin concentration was determined using linear regression. Significant results of the univariate regressions were entered in a stepwise multiple regression. Passing-Bablok regression and Bland-Altman were used to assess the difference between measured and calculated unbound vancomycin concentration. Thirty-seven samples in 33 patients (median (interquartile range) gestational age 35 (29–39) weeks) were collected. Median total and unbound vancomycin concentrations were 14.2 (7.4–20.6) and 13.6 (7.2–22.5) mg/L, respectively. Median unbound fraction was 0.90 (0.77–0.98). Multiple regression revealed total vancomycin concentration (
β
= 0.884,
p
< 0.001) and albumin (
β
= − 0.323,
p
= 0.007) as most important covariates of unbound vancomycin concentrations, with an
R
2
adjusted of 0.953 (
p
< 0.0001). Mean absolute difference between calculated and measured unbound vancomycin was − 0.008 (95% CI − 0.92–0.91) mg/L. The unbound vancomycin fraction in neonates is higher compared to that in children and adults, and total vancomycin concentration and albumin were the most important covariates of unbound vancomycin concentration. Integration of protein binding in future PK/PD analyses is appropriate to optimize vancomycin dosing and to determine population-specific vancomycin PD targets for neonates.
Summary Background and aims Catheter-related infection (CRI) is the most common and serious complication for adult patients receiving home parenteral nutrition (HPN). Our aim is to provide ...epidemiological data on infection incidence, infecting pathogens and contributing risk factors.- Methods Four electronic databases (Embase, Medline, IPA, CINAHL) were screened for eligible studies published between 1970 and March 2012. Methodological quality was evaluated and terminology/definitions were re-categorized. Results Thirty-nine studies were included. Extensive variability was observed in terminology/definitions as well as in expression of CRI rate. After correct interpretation of definitions, overall catheter-related bloodstream infection rate (CRBSI) ranged between 0.38 and 4.58 episodes/1000 catheter days (median 1.31). Gram-positive bacteria of human skin flora caused more than half of infections. An analysis of the reported risk factors showed that the origin of a CRBSI is often multifactorial. The risk factors were related to the patient, the venous access device, the education, HPN therapy and follow-up. Conclusions This review on CRI in adult HPN patients revealed that included studies are of low quality and used poorly described risk factors and different definitions. The human skin flora caused most of infections; therefore, hand hygiene and training remain essential.
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