Head-to-head comparison of multi-dose oritavancin and dalbavancin for complicated infections: a propensity score-matched analysis.

BACKGROUND: Oritavancin and dalbavancin are long-acting lipoglycopeptide antibiotics approved for the treatment of skin and skin structure infections. Recently, they have been used for outpatient antimicrobial therapy for complicated infections. No head-to-head studies exist for this purpose. OBJECTIVE: To compare outcomes of patients treated with multiple doses of oritavancin or dalbavancin for complicated infections. PATIENTS AND METHODS: This was a single-center, retrospective cohort study evaluating adult patients who received 2 or more doses of lipoglycopeptides for complicated infections from February 2019 through December 2022. Patients receiving oritavancin were compared to dalbavancin after propensity score-matching. The primary endpoint was clinical success at 90 days. Other endpoints included: 30-day re-admission, 30-day mortality, adverse drug reactions (ADRs), and changes in white blood cell count and inflammatory markers after the first dose. RESULTS: After exclusions and propensity score-matching, 131 matched pairs (N=262) were included in the analysis. Most patients were receiving lipoglycopeptide therapy for osteomyelitis. There was no significant difference in clinical success at 90 days in patients who received oritavancin compared to those who received dalbavancin (99 [76%] vs 103 [79%], respectively; p=0.556). There was no significant difference in secondary endpoints, however, there was a trend towards higher incidence of ADRs oritavancin compared to dalbavancin (9 [7%] vs 2 [2%], respectively; p=0.060) which led to more treatment discontinuation. CONCLUSION: There was no significant difference in efficacy between multi-dose oritavancin and dalbavancin for the treatment of complicated infections. Both agents were generally well tolerated; however, dalbavancin may be better tolerated when long-term treatment is warranted.

Clinical characteristics and antimicrobial therapy of healthcare-associated carbapenem-non-susceptible gram-negative bacterial meningitis: a 16-year retrospective cohort study.

OBJECTIVE: Healthcare-associated Gram-negative bacterial meningitis is a substantial clinical issue with poor outcomes, especially for neurosurgical patients. Here, we aimed to study the characteristics and treatment options of patients with healthcare-associated carbapenem-non-susceptible (Carba-NS) Gram-negative bacterial meningitis. METHODS: This observational cohort study was conducted at a teaching hospital from 2004 to 2019. The clinical characteristics of patients with meningitis with Carba-NS and carbapenem-susceptible (Carba-S) bacilli were compared, and the antimicrobial chemotherapy regimens and outcomes for Carba-NS Gram-negative bacterial meningitis were analyzed. RESULTS: A total of 505 patients were included, of whom 83.8% were post-neurosurgical patients. The most common isolates were Acinetobacter spp. and Klebsiella spp., which had meropenem-resistance rates of 50.6% and 42.5%, respectively, and showed a markedly growing carbapenem-resistance trend. Kaplan-Meier curve analysis revealed that Carba-NS Gram-negative bacilli were associated with a significantly higher in-hospital mortality rate (18.8%, 35/186) compared to the Carba-S group (7.4%, 9/122; P = 0.001). For Carba-NS Enterobacterales meningitis, aminoglycoside-based and trimethoprim-sulfamethoxazole-based regimens yielded significantly higher clinical efficacy rates than non-aminoglycoside-based and non-trimethoprim-sulfamethoxazole-based regimens (69.0% vs. 38.7%, P = 0.019 and 81.8% vs. 46.9%, P = 0.036, respectively). For Carba-NS A. baumannii complex meningitis, tetracycline-based (including doxycycline, minocycline, or tigecycline) therapy achieved a significantly higher clinical efficacy rate (62.9%, 22/35) than the non-tetracycline-based therapy group (40.4%, 19/47; P = 0.044). CONCLUSIONS: Our findings revealed that Carba-NS Gram-negative bacilli are associated with higher in-hospital mortality in patients with healthcare-associated meningitis. The combination therapies involving particular old antibiotics may improve patients' outcome. TRIAL REGISTRATION: This study was registered on the Chinese Clinical Trial Register under ChiCTR2000036572 (08/2020).

Invasive Candida Infection in Patients With Bacterial Infective Endocarditis.

Over 21 months, 12 patients with invasive Candida infections detected during the course of treatment of bacterial endocarditis, including 11 with candidemia, were identified. Invasive Candida infections can occur as a complication of bacterial endocarditis and may occur more frequently in patients with injection drug use and broad-spectrum antibiotic exposure.

Expert opinion on antimicrobial therapies: is there enough scientific evidence to state that targeted therapies outperform non-targeted ones?

INTRODUCTION: Different active and passive strategies have been developed to fight against pathogenic bacteria. Those actions are undertaken to reduce the bacterial burden while minimizing the possibilities to develop not only antimicrobial resistance but also antimicrobial side-effects such as allergic or hypersensitivity reactions. AREAS COVERED: We have reviewed preclinical results that evidence that targeted antimicrobial therapies outperform non-targeted ones. Active selective targeting against pathogenic bacteria has been achieved through the functionalization of antimicrobials, either alone or encapsulated within micro- or nanocarriers, with various recognition moieties. These moieties include peptides, aptamers, antibodies, carbohydrates, extracellular vesicles, cell membranes, infective agents, and other affinity ligands with specific bacterial tropism. Those selective ligands increase retention and enhance effectiveness reducing the side-effects and the required dose to exert the antimicrobial action at the site of infection. EXPERT OPINION: When using targeted antimicrobial therapies not only reduced side-effects are observed, but also, compared to the administration of equivalent doses of the non-targeted drugs, a superior efficacy has been demonstrated against planktonic, sessile, and intracellular pathogenic bacterial persisters. The translation of those targeted therapies to subsequent phases of clinical development still requires the demonstration of a reduction in the probabilities for the pathogen to develop resistance when using targeted approaches.

Osteomyelitis Masquerading as Cellulitis: A Case Report.

Osteomyelitis, a significant global healthcare issue, often results from infections related to open fractures, surgery, or conditions like diabetic foot ulcers. This report describes a case of osteomyelitis in a 62-year-old female with various pre-existing health conditions. The patient initially presented with swelling, pain, and difficulty walking in the right lower extremity, accompanied by systemic symptoms. Despite an initial diagnosis of cellulitis and treatment with ceftriaxone, a subsequent CT scan revealed a pretibial abscess and confirmed osteomyelitis caused by pan-sensitive Escherichia coli. Surgical debridement was performed, and the patient received six weeks of intravenous antibiotics. Hence, a heightened level of suspicion is essential to facilitate a timely diagnosis of osteomyelitis and enhance long-term prognosis. The case underscores the importance of a multidisciplinary approach, including meticulous surgical intervention and tailored antimicrobial therapy, in achieving positive outcomes for osteomyelitis patients.

Outpatient parenteral antimicrobial therapy (OPAT) in Germany: insights and clinical outcomes from the K-APAT cohort study.

PURPOSE: Outpatient parenteral antimicrobial therapy (OPAT) offers several key advantages, including enhanced patient quality of life, reduced healthcare costs, and a potential reduction of nosocomial infections. It is acknowledged for its safety and effectiveness. This study provides the first systematic clinical data for Germany, where OPAT has not yet been widely adopted. The aim is to establish a foundational reference point for further research and integration of OPAT into the German healthcare system. METHODS: This prospective observational study descriptively analyses data obtained from a cohort of patients receiving OPAT. Both in- and outpatients from all medical specialties could be recruited. Patients administered the anti-infective medications themselves at home using elastomeric pumps. RESULTS: 77 patients received OPAT, with a median duration of 15 days and saving 1782 inpatient days. The most frequently treated entities were orthopaedic infections (n = 20, 26%), S. aureus bloodstream infection (n = 16, 21%) and infectious endocarditis (n = 11, 14%). The most frequently applied drugs were flucloxacillin (n = 18, 23%), penicillin G (n = 13, 17%) and ceftriaxone (n = 10; 13%). Only 5% of patients (n = 4) reported to have missed more than one outpatient dose (max. 3 per patient). Only one catheter-related adverse event required medical intervention, and there were no catheter-related infections. CONCLUSION: The study demonstrates that OPAT can be safely conducted in Germany. In preparation for its broader implementation, crucial next steps include creating medical guidelines, fostering interdisciplinary and inter-sectoral communication, as well as creating financial and structural regulations that facilitate and encourage the adoption of OPAT. TRIAL REGISTRATION NUMBER: NCT04002453.

Antimicrobial therapy and outcome of methicillin-resistant Staphylococcus aureus endocarditis: A retrospective multicenter study in Japan.

BACKGROUND: MRSA (methicillin-resistant Staphylococcus aureus)-infective endocarditis (IE) is associated with high morbidity and mortality. This study aimed to assess data from patients with MRSA-IE across multiple facilities in Japan, with a specific focus on antimicrobial therapy and prognosis. METHODS: This retrospective study enrolled patients with a confirmed diagnosis of IE attributed to MRSA, spanning the period from January 2015 to April 2019. RESULTS: Sixty-four patients from 19 centers were included, with a median age of 67 years. The overall mortality rate was 28.1% at 30 days, with an in-hospital mortality of 45.3%. The most frequently chosen initial anti-MRSA agents were glycopeptide in 67.2% of cases. Daptomycin and linezolid were selected as initial therapy in 23.4% and 17.2% of cases, respectively. Approximately 40% of all patients underwent medication changes due to difficulty in controlling infection or drug-related side effects. Significant prognostic factors by multivariable analysis were DIC for 30-day mortality and surgical treatment for 30-day and in-hospital mortality. For vancomycin as initial monotherapy, there was a trend toward a worse prognosis for 30-day and in-hospital mortality (OR, 6.29; 95%CI, 1.00-39.65; p = 0.050, OR, 3.61; 95%CI, 0.93-14.00; p = 0.064). Regarding the choice of initial antibiotic therapy, statistical analysis did not show significant differences in prognosis. CONCLUSION: Glycopeptide and daptomycin were the preferred antibiotics for the initial therapy of MRSA-IE. Antimicrobial regimens were changed for various reasons. Prognosis was not significantly affected by choice of antibiotic therapy (glycopeptide, daptomycin, linezolid), but further studies are needed to determine which antimicrobials are optimal as first-line agents.

Impact of Immunosuppressed Status on Prognosis of Carbapenem-Resistant Organisms Bloodstream Infections.

INTRODUCTION: The impact of immunosuppression on prognosis of carbapenem-resistant organism (CRO) bloodstream infection (BSI) remains unclear. The aim of this study was to clarify the relationship between immunosuppression and mortality of CRO-BSI and to identify the risk factors associated with mortality in immunosuppressed patients. METHODS: This retrospective study included 279 patients with CRO-BSI from January 2018 to March 2023. Clinical characteristics and outcomes were compared between the immunosuppressed and immunocompetent patients. The relationship between immunosuppression and 30-day mortality after BSI onset was assessed through logistic-regression analysis, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Factors associated with mortality in immunosuppressed patients were analyzed using multivariable logistic regression analysis. RESULTS: A total of 88 immunocompetent and 191 immunosuppressed patients were included, with 30-day all-cause mortality of 58.8%. Although the 30-day mortality in immunosuppressed patients was significantly higher than in immunocompetent patients (46.6% vs. 64.4%, P = 0.007), immunosuppression was not an independent risk factor for mortality in multivariate logistic regression analysis (odds ratio [OR] 3.53, 95% confidence interval [CI] 0.74-18.89; P = 0.123), PSM (OR 1.38, 95% CI 0.60-3.18; P = 0.449,) or IPTW (OR 1.40, 95% CI 0.58-3.36; P = 0.447). For patients with CRO-BSI, regardless of immune status, appropriate antibiotic therapy was associated with decreased 30-day mortality, while Charlson comorbidity index (CCI), intensive care unit (ICU)-acquired infection and thrombocytopenia at CRO-BSI onset were associated with increased mortality. CONCLUSION: Despite the high mortality rate of CRO-BSI, immunosuppression did not affect the mortality. Appropriate antibiotic therapy is crucial for improving the prognosis of CRO-BSI, regardless of the immune status.

Desirability of Outcome Ranking and Response Adjusted for Antibiotic Risk (DOOR/RADAR) Post Hoc Analysis Supports Equipoise for Antibiotic Initiation Strategies in Intensive Care Unit-Acquired Pneumonia.

Background: Pneumonia is the most common intensive care unit (ICU)-acquired infection and source of potential sepsis in ICU populations but can be difficult to diagnose in real-time. Despite limited data, rapid initiation of antibiotic agents is endorsed by society guidelines. We hypothesized that a post hoc analysis of a recent randomized pilot study would show no difference between two antibiotic initiation strategies. Patients and Methods: The recent Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP) was a pragmatic cluster-randomized pilot of antibiotic initiation strategies for patients with suspected ICU-acquired pneumonia. Participating ICUs were cluster-randomized to either an immediate initiation protocol or a specimen-initiated protocol where a gram stain was required for initiation of antibiotics. Patients in the study were divided into one of seven mutually exclusive outcome rankings (desirability of outcome ranking; DOOR): (1) Survival, No Pneumonia, No adverse events; (2) Survival, Pneumonia, No adverse events; (3) Survival, No Pneumonia, ventilator-free-alive days ≤14; (4) Survival, Pneumonia, ventilator-free-alive days ≤14; (5) Survival, No Pneumonia, Subsequent episode of suspected pneumonia; (6) Survival, Pneumonia, Subsequent episode of suspected pneumonia; and (7) Death. These rankings were further refined using the duration of antibiotics prescribed for pneumonia (response adjusted for antibiotic risk; RADAR). Results: There were 186 patients enrolled in the study. After applying the DOOR analysis, a randomly selected patient was equally likely to have a better outcome in specimen-initiated arm as in the immediate initiation arm (DOOR probability: 50.8%; 95% confidence interval [CI], 42.7%-58.9%). Outcome probabilities were similar after applying the RADAR analysis (52.5%; 95% CI, 44.2%-60.6%; p = 0.31). Conclusions: We found that patients for whom antibiotic agents were withheld until there was objective evidence (specimen-initiated group) had similar outcome rankings to patients for whom antibiotic agents were started immediately. This supports the findings of the TARPP pilot trial and provides further evidence for equipoise between these two treatment strategies.

Antimicrobial susceptibility prediction from genomes: a dream come true?

Genome-based diagnostics provides relevant information to guide patient treatment and support pathogen and resistance surveillance. Recently, Coll et al. introduced a curated database for predicting antimicrobial resistance (AMR) from Enterococcus faecium genomics data, offering excellent predictive values for susceptibility to important antimicrobials. Challenges to predict resistance to last-resort antimicrobials remain.

Risk factors for mortality in Stenotrophomonas maltophilia bacteremia - a meta-analysis.

BACKGROUND: Stenotrophomonas maltophilia (S. maltophilia) is a nosocomial pathogen causing life-threatening invasive infections with a high mortality rate in some patient populations, especially those who are severely ill or immunocompromised. There is a need for data on mortality in patients with S. maltophilia bacteremia. OBJECTIVE: In this meta-analysis, we aimed to investigate risk factors for mortality in S. maltophilia bacteremia. METHODS: Studies comparing patients who died from S. maltophilia bacteremia with patients who survived were considered for inclusion. Studies were included if they reported one or more risk factors for mortality. Mortality risk factors included clinical predisposing factors, predisposing comorbidities and appropriateness of antibiotic therapy. RESULTS: Nineteen studies with 1248 patients were included in the meta-analysis. Five hundred and six (40.5%) patients died. The following risk factors for mortality were identified: ICU admission, septic shock, need for mechanical ventilation, indwelling central venous catheter, neutropenia, comorbid hematological malignancies, chronic kidney disease, inappropriate antimicrobial therapy and prior antibiotic use. CONCLUSIONS: Appropriate antimicrobial therapy had a protective effect against mortality in S. maltophilia bacteremia. Indwelling central venous catheter, neutropenia, hematological malignancies and chronic kidney disease were also risk factors for mortality.

In vitro and in silico studies of enterobactin-inspired Ciprofloxacin and Fosfomycin first generation conjugates on the antibiotic resistant E. coli OQ866153.

BACKGROUND: The emergence of antimicrobial resistance in bacterial pathogens is a growing concern worldwide due to its impact on the treatment of bacterial infections. The "Trojan Horse" strategy has been proposed as a potential solution to overcome drug resistance caused by permeability issues. OBJECTIVE: The objective of our research was to investigate the bactericidal activity and mechanism of action of the "Trojan Horse" strategy using enterobactin conjugated with Ciprofloxacin and Fosfomycin against the antibiotic-resistant Escherichia coli strain OQ866153. METHODOLOGY: Enterobactin, a mixed ligand of E. coli OQ866153, was conjugated with Ciprofloxacin and Fosfomycin individually to aid active absorption via specific enterobactin binding proteins (FepABCDG). The effectiveness of the conjugates was assessed by measuring their bactericidal activity against E. coli OQ866153, as well as their ability to inhibit DNA gyrase enzyme and biofilm formation. RESULTS: The Fe+3-enterobactin-Ciprofloxacin conjugate effectively inhibited the DNA gyrase enzyme (Docking score = -8.597 kcal/mol) and resulted in a lower concentration (25 µg/ml) required to eliminate supercoiled DNA plasmids compared to the parent drug (35 µg/ml; Docking score = -6.264 kcal/mol). The Fe+3-Enterobactin-Fosfomycin conjugate showed a higher inhibition percentage (100%) of biofilm formation compared to Fosfomycin (21.58%) at a concentration of 2 mg/ml, with docking scores of -5.481 and -3.756 kcal/mol against UDP-N acetylglucosamine 1-carboxyvinyltransferase MurA. CONCLUSION: The findings of this study suggest that the "Trojan Horse" strategy using enterobactin conjugated with Ciprofloxacin and Fosfomycin can effectively overcome permeability issues caused by efflux proteins and enhance the bactericidal activity of these drugs against antibiotic-resistant strains of E. coli.

Evaluation of health-related quality of life in patients receiving outpatient parenteral antimicrobial therapy (OPAT) in a UK setting.

BACKGROUND: Studies assessing the benefits of outpatient parenteral antimicrobial therapy (OPAT) have paid less attention to patient-centered factors such as patients' experiences and their health-related quality of life (HRQoL). RESEARCH DESIGN AND METHODS: Prospective before-and-after quasi-experimental study enrolled adult patients receiving OPAT at a tertiary hospital in Derbyshire, UK, between October 2022 and October 2023. Consenting patients completed paired EQ-5D-3 L questionnaires before OPAT initiation and upon completion of therapy or 30 days after its commencement (whichever occurred first). Changes and predictors of change in HRQoL indicators and associations with clinical outcomes (treatment failure, adverse events, and 30-day unplanned readmission) were examined. RESULTS: Health state index and visual analogue scale (EQ VAS) scores of 162 enrolled patients at baseline were significantly lower than the UK population averages, but the patients experienced significant improvements in both scores and in four EQ-5D dimensions (mobility, self-care, usual activities, and pain/discomfort). Baseline health index and EQ VAS scores were significant independent predictors of positive changes in HRQoL scores. CONCLUSIONS: OPAT is associated with improved patient-reported quality of life and facilitates early return to work or school. Nevertheless, it is crucial to closely monitor patients with a lower baseline quality of life to optimize their overall OPAT experience.

Knowledge, Perception, and Self-Confidence of Antibiotic Resistance, Appropriate Antibiotic Therapy, and Antibiotic Stewardship Among Undergraduate Pharmacy Students in Sudan.

Background: Adequate training in infectious diseases and antibiotic resistance is crucial for pharmacy students to participate in antibiotic stewardship programs and understand microbiology careers. Aim: The study was carried out to assess the knowledge and self-reported confidence in antibiotic resistance, antibiotic therapy, and antimicrobial stewardship (AMS) among final-year undergraduate pharmacy students in Sudan. Methods: A cross-sectional study was conducted in three universities using a 57-item online questionnaire between April and May 2022. Results: A total of 109 students (response rate 36%) participated and showed average knowledge scores of 5.6±1.7 (out of 10.0) for antibiotic resistance, 4.9±2.0 (out of 5.0) for appropriate antibiotic therapy, and 3.1±1.4 (out of 5.0) for AMS. No significant differences were observed among schools. Some students reported poor knowledge about antibiotic therapy and the consequences of resistance. One-third of students lacked confidence in interpreting microbiological results. Knowledge of antibiotic resistance among students' practice area after graduation was higher (p=0.017) and those interested in ID careers (5.8 vs 4.8) (p=0.037). Male students (5.6 vs 4.5) and those interested in ID careers (4.3 vs 3.4) (p<0.001) had higher scores of appropriate antibiotic therapy. Students attended antibiotic resistance courses (51.5 vs 45.2), and those interested in ID significantly had higher self-confidence (55.3 vs 45.8) (p=0.008). Conclusion: Pharmacy students in Sudan have substantial knowledge of AMS and antibiotic resistance with poor knowledge of antibiotic therapy. Adequate training about infectious diseases and related topics is recommended to improve pharmacy students' understanding of microbiological findings, other competencies, and skills to incorporate in antimicrobial stewardship.

Exploration of a Potential DOOR Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

BACKGROUND: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here, we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). METHODS: Through comprehensive examination of data from nearly 4,000 participants enrolled in six registrational trials for HABP/VABP submitted to the FDA between 2005-2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator. RESULTS: DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Though infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar. CONCLUSIONS: Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design.

A retrospective study of the detection of sepsis pathogens comparing blood culture and culture-independent digital PCR.

Fast and precise identification of microorganisms in the early diagnosis of sepsis is crucial for enhancing patient outcomes. Digital PCR (dPCR) is a highly sensitive approach for absolute quantification that can be utilized as a culture-independent molecular technique for diagnosing sepsis pathogens. We performed a retrospective investigation on 69 ICU patients suspected of sepsis. Our findings showed that a multiplex dPCR diagnostic kit outperformed blood culture in detecting the 15 most frequent bacteria that cause sepsis. Ninety-two bacterial strains were identified using dPCR at concentrations varying from 34 copies/mL to 105,800 copies/mL. The detection rate of dPCR was much greater than that of BC, with 27.53% (19/69) versus 73.91% (51/69). The sensitivity of dPCR was 63.2%. Our research indicated that dPCR outperforms blood culture in the early detection of sepsis-causing microorganisms. The diagnostic kit can detect a greater variety of pathogens with quantitative data, including polymicrobial infections, and has a quicker processing time. DPCR is a valuable technique that could aid in the proper management of sepsis.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Barriers and facilitators for the implementation and expansion of outpatient parenteral antimicrobial therapy: a systematic review.

Outpatient parenteral antimicrobial therapy (OPAT) has been expanding in recent years and serves as a viable solution in reducing the shortage of hospital beds. However, the wider implementation of OPAT faces numerous challenges. This review aimed to assess implementation barriers and facilitators of OPAT services. Studies describing barriers and facilitators of the OPAT service were retrieved from PubMed, Scopus, MEDLINE, EMBASE, CINAHL, Cochrane Library, Web of Science Proceedings, International Pharmaceutical Abstracts and PsycINFO. All types of study designs published in the English language were included. Studies that did not mention any barrier or facilitator, did not differentiate OPAT and inpatient, focused on specific antimicrobials or diseases, and made no distinction between parenteral and other treatments were excluded. Qualitative analysis was performed using the 'best-fit' framework approach and the Consolidated Framework for Implementation Research (CFIR). The review was PROSPERO registered (CRD42023441083). A total of 8761 studies were screened for eligibility and 147 studies were included. Problems in patient selection, lack of awareness, poor communication and co-ordination, lack of support, lack of structured service and inappropriate prescriptions were identified. OPAT provides safe, effective and efficient treatment while maintaining patients' privacy and comfort, resulting in less daily life disruption, and reducing the risk of infection. Satisfaction and preference for OPAT were very high. Initiatives in strengthening OPAT such as antimicrobial stewardship and telemedicine are beneficial. Challenges to and facilitators of OPAT were identified among patients, health professionals, OPAT service providers and healthcare administrators. Understanding them is crucial to designing targeted initiatives for successful OPAT service implementation.