Doses Of Antibiotics Research Articles

Effect of Blood Product Resuscitation on Cefazolin Pharmacokinetics in Trauma Patients.

Background: Antibiotics are frequently administered prophylactically to trauma patients with various injury patterns to prevent infectious complications. Trauma patients may also require large volume resuscitation with blood products. Limited data are available to support antibiotic dosing recommendations in this population. We hypothesized that we would be able to develop a population pharmacokinetic model of cefazolin, a frequently used antibiotic in the trauma scenario, from remnant blood samples by pharmacokinetic analysis of trauma patients. Methods: Remnant plasma from standard of care chemistry/hematology assessments was retrieved within 48 h of collection and assayed to determine cefazolin concentrations. Population pharmacokinetic analyses were conducted in Pmetrics using R. Linear regression was conducted to assess the effect of blood product resuscitation volume on cefazolin pharmacokinetic parameters. Results: Cefazolin concentrations best fitted a two-compartment model (Akaike information criterion: 443.9). The mean ± standard deviation parameters were total body clearance (4.3 ± 1.9L), volume of the central compartment (Vc: 7.7 ± 6.9L), and intercompartment transfer constants (k12: 1.3 ± 0.98 h-1, k21: 0.6 ± 0.45 h-1). No statistical relationships were observed between blood products, volume of blood products, and cefazolin clearance or Vc (R2: 0.0004-0.21, p = 0.08-0.95). Using a 5,000-patient Monte Carlo simulation, 2 g with repeated dosing every 2 h until end of surgery was required to achieve 93.2% probability of 100% free time above the minimum inhibitory concentration (MIC) (fT > MIC) at the ECOFF value for Staphylococcus aureus (2 mg/L). Conclusions: In these 15 trauma patients receiving blood transfusion, no relationship with blood volume resuscitation and cefazolin pharmacokinetics was observed. On the basis of this pharmacokinetic model, frequent cefazolin doses are required to maintain 100% fT > MIC.

Are Nurses Aware of Their Contribution to the Antibiotic Stewardship Programme? A Mixed-Method Study from Qatar.

The antibiotic stewardship programme (ASP) is a new concept initiated by WHO, but nurses are not yet ready to adopt the program. The training and empowerment of nurses are the best strategies for enhancing their knowledge and engagement in ASP. This mixed-method study was used to assess perceived roles and barriers of nurses' involvement in ASP. An online survey was conducted among 420 clinical nurses to identify their role, and 23 individual interviews were performed among nurses and infection control practitioners to explore the barriers and recommendations to overcome the identified barriers. The majority of the nurses agreed with the sixteen identified roles in ASP, of which 'antibiotic dosing and de-escalation' (82.61%), 'IV to PO conversion of antibiotic, outpatient antibiotic therapy' (85.23%), and 'outpatient management, long-term care, readmission' of the patients (81.19%) had the lowest agreement from the participants. The major themes generated through the qualitative interviews were a lack of knowledge about ASP, poor communication between multidisciplinary teams, lack of opportunity and multidisciplinary engagement, lack of formal education and training about ASP, lack of ASP competency and defined roles in policy, role conflict or power/position, availability of resources, and lack of protected time. Nurses play an integral role in the successful implementation of antibiotic stewardship programs. The empowerment of nurses will help them to adopt the unique role in ASP. Nurses can significantly contribute to antibiotic stewardship efforts and improve patient outcomes through addressing these challenges.

Frequency of surgical site infection after single dose of preoperative antibiotics in children with uncomplicated acute appendicitis: a cross-sectional study

Background: Hyperaemic suppurative appendicitis, or uncomplicated appendicitis, often requires an appendectomy. Surgical Site Infection (SSI) is common post-surgery, and prophylactic studies show ceftriaxone and metronidazole effectively protect against most causative organisms. Methods: Ninety patients were included through non-probability convenience sampling. Acute appendicitis was diagnosed using the Alvarado score, with surgery for scores of 7 or higher. A single preoperative dose of ceftriaxone and metronidazole was administered. Follow-up visits included stitch removal on the seventh postoperative day and monitoring up to the tenth postoperative day using the Southampton criteria for wound infection. Results: Of the 90 patients, 64 (71.1%) were male and 26 (28.9%) were female. Fifty (55.6%) scored 7-8 on the Alvarado score, and 40 (44.4%) scored 9-10. Using the Southampton criteria, 5 (5.6%) developed grade I SSI. Infection rates showed no significant difference between male (3.1%) and female (11.5%) patients (p value >0.05) or by Alvarado score and symptom duration. No cases of SSI beyond grade II were observed. Conclusions: Administering a single preoperative antibiotic dose effectively minimizes surgical site infection in children with uncomplicated acute appendicitis, demonstrating clear management advantages.

Antibiotic delivery in the presence of green AgNPs using multifunctional bilayer carrageenan nanofiber/sodium alginate nanohydrogel for rapid control of wound infections

This study constructed bilayer nano-hydrogels using solvent casting and electrospinning techniques. The first layer consisted of a hydrogel containing sodium alginate and gellan gum, while the second layer was a carrageenan/polyvinyl alcohol nanofibrous membrane. The nanohydrogels were prepared with different doses of doxycycline antibiotic (0.12, 0.06, 0.03 g) and a fixed amount of silver nanoparticles (0.012 g), which were synthesized using the green method including Capparis spinosa leaf extract. The films were tested for their mechanical properties, swelling behavior, XRD, and FTIR, and their morphology was characterized using SEM. The biological properties of the nanohydrogels were also extensively assayed. X-ray diffraction analysis showed peak 111 for silver nanoparticles. Incorporating silver nanoparticles significantly enhanced nanohydrogels' mechanical and antibacterial properties and improved their ability to heal wounds. Nanohydrogels exhibited biodegradability, biocompatibility, anti-inflammatory properties (57.63 %), and high cell viability (>85 %) in laboratory conditions. The study confirmed that wound dressings containing doxycycline with controlled release are highly effective against pathogenic bacteria and prevent the formation of biofilms (92 %). The rats in-vivo study demonstrated that 100 % wound closure was achieved in nanohydrogels containing SA/GG/PVA/CAR/AgNPs/DOX0.12 after 14 days. The films could potentially lead to the development of new treatments against bacterial infections and inflammatory conditions of wounds.

Optimizing preoperative antibiotic use through improved penicillin allergy documentation.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Penicillin allergy documentation in the electronic health record (EHR) lacks detail with regard to type of reaction, history of reaction, and other tolerated β-lactams. Because of concern for penicillin allergy cross-reactivity with cefazolin, patients with a reported penicillin allergy are frequently prescribed suboptimal preoperative antibiotics, which have been associated with negative patient outcomes, including increased risk of surgical site infection. The purpose of this study was to increase preoperative use of cefazolin via improvement to the documentation of penicillin allergies in the EHR. This single-center, quasi-experimental quality improvement study compared patients with a self-reported penicillin allergy admitted for select elective surgeries before and after implementation of a penicillin allergy questionnaire. The primary outcome was receipt of cefazolin for surgical prophylaxis. Secondary outcomes were the proportion of patients with detailed penicillin allergy documentation, the proportion of patients with surgical site infections occurring within 30 days of surgery, and the proportion of patients who received the full antibiotic dose before the first surgical incision. A total of 100 patients were included in the preintervention group, while 85 patients were included in the postintervention group. Cefazolin use was higher in the postintervention group (13.0% vs 41.2%; P < 0.001). The postintervention group also had a larger proportion of patients with detailed allergy documentation (2.0% vs 50.6%; P < 0.001) and who received the full preoperative antibiotic dose before the first incision (25.0% vs 48.2%; P = 0.001). There was no statistical difference between the groups in the incidence of surgical site infection at 30 days after surgery (3.0% vs 1.2%; P = 0.63). Preoperative cefazolin use was higher in patients with a reported penicillin allergy after implementation of a penicillin allergy questionnaire and EHR documentation tool.

Exploring the Therapeutic Potential of High Dose Co-amoxiclav (1 gm) in Different Clinical Conditions: A Review.

Amoxicillin/clavulanate (co-amoxiclav) is a widely used antibiotic in community healthcare settings, combining amoxicillin and clavulanate potassium to combat β-lactamase-producing bacteria. Despite its extensive use, limited pharmacokinetic/pharmacodynamic data support current dosing guidelines. This review explores the significance of high-dose co-amoxiclav (875 mg/125 mg) in treating various infections amidst rising antibiotic resistance. A comprehensive narrative literature review was conducted using MEDLINE, PubMed, and Google Scholar, focusing on co-amoxiclav 875 mg/125 mg from 1992 to 2024. Keywords included "Co-amoxiclav 875mg/125mg," "amoxicillin 875mg," "Co-amoxiclav dosing," "pharmacology," "PK," and "safety." Studies on non-safety aspects, those on cost-effectiveness, non-English articles, and those without full-text access were excluded. Clinical efficacy studies demonstrate the effectiveness of co-amoxiclav (875 mg/125 mg) in treating conditions such as cutaneous actinomycosis, actinomycetoma, lower respiratory tract infections, acute bacterial maxillary sinusitis, and community-acquired pneumonia. Comparative studies reveal similar or superior efficacy of co-amoxiclav (875 mg/125 mg) compared to other dosing regimens and antibiotics such as clindamycin, cefaclor, cefuroxime, and ciprofloxacin. Safety and tolerability assessments indicate that co-amoxiclav is generally well-tolerated, with common mild-to-moderate gastrointestinal side effects. In summary, co-amoxiclav 1 gm remains a crucial antibiotic with optimized dosing regimens enhancing clinical outcomes while addressing resistance challenges.

What Is the Risk of Irrigation and Debridement Following Foot and Ankle Surgery? Development of a Risk Severity Scoring System.

Surgical site infection (SSI) after foot and ankle surgery has serious negative effects on patient health and quality of life. While previous studies have looked at predisposing factors for SSI, to our knowledge, no study has proposed a risk severity score. Can a risk severity score, based on patient demographic characteristics and surgical variables, be developed for preoperative use in patients undergoing foot and ankle surgery that will calculate the risk of an irrigation and debridement (I&D) procedure within 90 days of surgery utilizing data from previous surgeries? A retrospective chart study was performed on patients undergoing foot and ankle surgery. Data on demographic characteristics including age, sex, and BMI were recorded. Data on patient factors including diabetes and smoking history were also recorded. Surgical details including length of surgery, procedure type, surgeon, antibiotic delivery time, antibiotic type, and antibiotic dose were analyzed. Of 2979 procedures, 1% (36) of I&Ds were performed within 90 days. The mean age at surgery was 49 ± 17 years, and 57% (1702) of patients were female. The mean BMI was 28 ± 6 kg/m2. The primary outcome was I&D within 90 days postoperatively. Descriptive statistics of differences in patient characteristics between those who underwent I&D and those who did not were examined using chi-square tests and t-tests (p < 0.05 was taken as significant). Significant variables from a simple regression analysis were included in a multiple logistic regression model with a forward stepwise procedure for variable selection. We required all data in the model to be categorical; thus, continuous variables such as time were dichotomized. We factored odds ratios determined by multiple regression for significant variables into the final risk severity score, and an easy-to-use tool based on this risk severity score was created in Excel (Microsoft). Current tobacco use, diabetes, and longer operative times were the only factors associated with I&D within 90 days postoperatively. A risk severity score was developed using current tobacco use, diabetes, and length of surgery greater than 60 minutes as factors. A patient with a severity score of 0 (no risk factors) had a 0.6% chance of I&D within 90 days, while a severity score of 1 indicated a 1.1% chance, a score of 2 indicated a 2.1% chance, a score of 3 indicated a 4.0% chance, and a score of 4 (all risk factors) indicated a 7.5% chance of I&D within 90 days. A spreadsheet that can be used at the point of care was created based on these findings. Our risk severity score may help inform preoperative patient guidance and operative planning. Calculating the score in the office setting during preoperative visits can also improve communication between physician and patient. Future research should focus on validation of this risk severity score at multiple institutions. Level III, prognostic study.

Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark

Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. Innovation Fund Denmark and Rigshospitalets Forskningsfond.

Molecular Genetic Analysis of Perioperative Colonization by Infection-Related Microorganisms in Patients Receiving Intraoral Microvascular Grafts.

Background/Objectives: In oral and maxillofacial surgery, the reconstruction of defects often involves the transfer of skin tissue into the oral cavity utilizing microvascular grafts. This study investigates postoperative changes in microbial colonization following intraoral microvascular transplantation, as well as potential influencing factors. Methods: In 37 patients undergoing intraoral reconstructions, pre- and postoperative swabs were taken from the donor and recipient regions to quantify the seven selected marker bacteria using TaqMan PCRs. Patient-specific factors and clinical data were also recorded. Results: The infection-associated Acinetobacter baumannii tended to decrease postoperatively, while the infectious pathogens Pseudomonas aeruginosa, Enterococcus faecalis and the family of Enterobacteriaceae showed a postoperative increase without being directly associated with a clinical infection. Streptococcus mitis showed a significant postoperative decrease on buccal mucosa and increase on the graft surface (oral dysbiosis) and was significantly reduced or displaced by other bacteria (e.g., Mycoplasma salivarium, positive selection) when treated with ampicillin/sulbactam. Conclusions: The cutaneous microbiome of the graft adapts to the local intraoral environment. Postoperative shifts in oral bacterial colonization and an increase in infection-relevant bacteria were observed. These perioperative changes in colonization are also influenced by the administration of ampicillin/sulbactam. Consequently, single doses of antibiotics appear to be more beneficial compared to longer-term preventive use.

Pneumococcal competence is a populational health sensor driving multilevel heterogeneity in response to antibiotics

Competence for natural transformation is a central driver of genetic diversity in bacteria. In the human pathogen Streptococcus pneumoniae, competence exhibits a populational character mediated by the stress-induced ComABCDE quorum-sensing (QS) system. Here, we explore how this cell-to-cell communication mechanism proceeds and the functional properties acquired by competent cells grown under lethal stress. We show that populational competence development depends on self-induced cells stochastically emerging in response to stresses, including antibiotics. Competence then propagates through the population from a low threshold density of self-induced cells, defining a biphasic Self-Induction and Propagation (SI&P) QS mechanism. We also reveal that a competent population displays either increased sensitivity or improved tolerance to lethal doses of antibiotics, dependent in the latter case on the competence-induced ComM division inhibitor. Remarkably, these surviving competent cells also display an altered transformation potential. Thus, the unveiled SI&P QS mechanism shapes pneumococcal competence as a health sensor of the clonal population, promoting a bet-hedging strategy that both responds to and drives cells towards heterogeneity.

Evaluation of the adherence to surgical antibiotic prophylaxis recommendations and associated factors in a University Hospital: A cross-sectional study

Surgical antibiotic prophylaxis (SAP) is an important preventive measure, aiming to minimize surgical site infections. However, despite evidence-based guidelines, adherence to SAP protocols remains suboptimal in clinical practice. The aim of this study was to assess the adequacy of SAP in a high-complexity hospital and investigate associated factors. A cross-sectional design was conducted, involving surgeries performed by expert teams in cardiology, urology, neurology, and gastrointestinal. SAP prescriptions were evaluated based on indication, antibiotic choice, dosage, and duration, according to the hospital protocol. Data analysis included descriptive statistics and association tests between protocol adherence and patient demographics, clinical variables, surgical teams, and types of surgeries. Out of 1,864 surgeries, only 20.7% adhered to SAP protocols. Lower adherence rates were observed for antibiotic choice and duration of prophylaxis. Neurological surgeries exhibited significantly lower adherence, particularly concerning antibiotic choice and duration. Factors associated with nonadherence included elevated preoperative blood glucose levels, prolonged hospitalization, and extended surgical duration. Logistic regression analysis identified surgical teams as significant factors influencing protocol adherence. Despite the relatively high adherence to antibiotic dosage, challenges persist in antibiotic choice and duration adjustment. Poor glycemic control, prolonged surgery, and surgical teams were variables associated with inappropriate practice.

Detailed regimens for the prolonged β-lactam infusion therapy

A recent systematic review and meta-analysis of randomized controlled trials (RCTs) evaluated the efficacy and safety of prolonged versus intermittent β-lactam infusion in adult sepsis patients. The findings revealed a significant decrease in all-cause mortality and marked clinical success in the prolonged infusion group. Unfortunately, however, the manuscript lacked data and discussion for the specific regimens of prolonged β-lactam infusion defined in the included 15 RCT studies, which are herein additionally provided. Excluding one RCT, all protocols adopted a continuous infusion for the prolonged treatment. Except for three RCTs, dosages and timings of bolus injection were clearly defined. The total daily antibiotic dose for the continuous therapy was equivalent to those recommended for intermittent therapy. We believe this supplementary data aids clinicians in providing prolonged β-lactam infusions, contributing to enhanced treatment outcomes for patients suffering from severe sepsis or septic shock.

Antibiotic dose optimisation in the critically ill: targets, evidence and future strategies.

To highlight the recent evidence for antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in enhancing patient outcomes in sepsis and septic shock. We also summarise the limitations of available data and describe future directions for research to support translation of antibiotic dose optimisation to the clinical setting. Sepsis and septic shock are associated with poor outcomes and require antibiotic dose optimisation, mostly due to significantly altered pharmacokinetics. Many studies, including some randomised controlled trials have been conducted to measure the clinical outcome effects of antibiotic dose optimisation interventions including use of therapeutic drug monitoring. Current data support antibiotic dose optimisation for the critically ill. Further investigation is required to evolve more timely and robust precision antibiotic dose optimisation approaches, and to clearly quantify whether any clinical and health-economic benefits support expanded use of this treatment intervention. Antibiotic dose optimisation appears to improve outcomes in critically ill patients with sepsis and septic shock, however further research is required to quantify the level of benefit and develop a stronger knowledge of the role of new technologies to facilitate optimised dosing.

Repurposing of dibucaine and niflumic acid as antimicrobial agents in combination with antibiotics against Staphylococcus aureus.

The versatile human commensal bacteria and pathogen Staphylococcus aureus cause several community and hospital-acquired illnesses associated with significant morbidity and death. Antibiotic therapy for S. aureus infections has grown increasingly difficult as the organism has developed a wide spectrum of antibiotic resistance mechanisms. This situation emphasizes the significance of developing and advocating new antimicrobials for preventative and therapeutic measures. Our study aimed to identify and evaluate new therapeutic options against S. aureus. We investigated the efficacy of two drugs, dibucaine, and niflumic acid, as potential adjuvant for anti-staphylococcal therapeutics. Dibucaine and niflumic acid found to have bactericidal activity against S. aureus. These drugs acted synergistically with antibiotics reducing the required dose of antibiotics up to 4 times. In combination with antibiotics, they were effectively and synergistically inhibited the formation of biofilms of S. aureus. The best synergistic partner of dibucaine was with kanamycin and tetracycline, whereas niflumic acid was with streptomycin and ampicillin. Both the drugs showed significant efflux inhibition in the bacteria. Moreover, the drugs are found to be safe at synergistic doses. Our findings suggest that dibucaine and niflumic acid could be potential adjuvant with antibiotics for the treatment of S. aureus infections. Their ability to significantly enhance the efficacy of antibiotics highlights their potential clinical significance as adjunct therapies.

Adherence to Antimicrobial Prophylaxis Guidelines in Endourologic Procedures: Frequency and Related Outcomes.

Background: Surgical antimicrobial prophylaxis (SAP), when used appropriately based on evidence-based guidelines, can reduce the rate of infectious complications following endourologic procedures without compromising patient outcomes. Objectives: To investigate the appropriateness of the current SAP used in endourologic surgeries based on international guidelines and report their associated outcomes (urinary tract infection [UTI] and blood stream infection [BSI]). Design: Prospective cross-sectional study. Methodology: The medical records of patients undergoing endourologic procedures were reviewed to assess healthcare providers' adherence to international guideline recommendations. Assessed parameters included indication, duration, choice, and dose of the antibiotics used in endourologic procedures in two medical centers in Amman/Jordan. Furthermore, patients were asked to conduct laboratory urine tests to determine the rate of infectious complications within one month post-procedure. Results: Three hundred and sixty-one patients were recruited for the study. The adherence rates to guidelines regarding indication, choice, and dose of pre-operative antibiotics were 90.3%, 2.8%, and 77.8%, respectively. The duration was concordant with guidelines in only 3.4% of participants. A total of 41.8% of patients completed follow-up. Among those, 4.6% developed bacterial UTIs, and 0.7% developed BSI. Conclusion: Adherence to SAP guidelines in endourologic procedures was far from optimal. Primary deviations in the implementation of guidelines' recommendations were pinpointed. These results are crucial for planning interventions that optimize SAP utilization.

Population pharmacokinetics of flucloxacillin as intermittent bolus infusion in patients with Staphylococcus aureus bloodstream infection.

Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics, which may be influenced by various patient-related factors, particularly in critically ill patients. To describe the population pharmacokinetics (PopPK) of the antibiotic flucloxacillin in patients with S. aureus BSI. Subsequently, we sought to translate the model into a user-friendly app for generating a priori and a posteriori time-concentration curves and dose recommendations to optimize dosing regimens. Total and unbound flucloxacillin concentrations were included from 49 patients from a prospective cohort study conducted during clinical routine, including non-critically ill and critically ill individuals who received intermittent bolus applications. These data were analysed using non-linear mixed-effects modelling. Most patients (98%) were treated with 2 g of flucloxacillin every 4 h. We developed a joint model that simultaneously described total and unbound concentrations. The model included an allometric effect of glomerular filtration rate on clearance and albumin on the albumin dissociation constant. The latter was especially important, as in our population the unbound fraction was higher at 11.5% (16.7% for critically ill patients) compared with reported values of approximately 5%. Based on our joint model, we developed a web-based app for optimizing dosing regimens of flucloxacillin. By utilizing data from clinical routine, we were able to create a predictive PopPK model of flucloxacillin and identify influential covariates. The web-based app is currently being validated in a clinical trial.

Pharmacist review of discharge antibiotics for urinary tract infections in the emergency department

AbstractEmergency medicine (EM) pharmacists provide high‐quality patient care in a fast‐paced environment by optimizing pharmacotherapy regimens and reducing medication errors. Current literature demonstrates higher rates of medication errors with antibiotics compared with other medication classes. The aim of this quality improvement (QI) project was to reduce medication errors by 25% from baseline for antibiotic discharge prescriptions for urinary tract infections (UTIs). This QI initiative utilized the Institute for Healthcare Improvement Model for Improvement to implement a UTI stewardship intervention and prospective pharmacist review of discharge prescriptions. Patients discharged from the adult ED with an electronic prescription for UTI treatment with select antibiotics were included. The primary outcome metric was the percent of medication errors, defined as a composite of appropriate antibiotic agent, dose, frequency, and treatment duration based on our local treatment algorithm. The balancing metric was time spent per order reviewed. Data over time were assessed using statistical process control charts. A total of 534 antibiotic prescriptions were reviewed from January 9, 2022 to May 31, 2023. The most common indication was cystitis (70%), followed by pyelonephritis (17.4%) and asymptomatic bacteriuria (12.5%). Composite error rate decreased from 64.2% to 5%. Duration of therapy was the most common baseline error and was reduced from 45.3% to 11.6%. Errors in agent, dose and frequency decreased from 19.7% to 3.5%, 10.3% to 0.8% and from 5.7% to 0%, respectively. The aim of this QI initiative was achieved through a series of interventions, including prospective review of discharge antibiotics for UTIs by EM pharmacists, which reduced medication errors. This project demonstrates EM pharmacists have a positive impact in optimization of antimicrobial therapy for the treatment of UTIs.

A 30-year perspective of low-dose dexamethasone, a single dose of mannitol and antiseizures prophylaxis on the prognosis of pneumococcal meningitis

Objectives This study details the accumulated experience of more than 31 years using a low-dose systematic dexamethasone protocol with mannitol and antiseizure prophylaxis for the treatment of suspected pneumococcal meningitis. Methods Data have been prospectively collected for the period1977–2018. From 1987, patients with suspected pneumococcal meningitis received 12 mg dexamethasone followed by 4 mg/6 h for 48 h, started before or with the first antibiotic dose. They also received (1) a single intravenous dose of 0.5–1 g/Kg mannitol, and (2) antiseizure prophylaxis with phenytoin. Results In total, 363 episodes of pneumococcal meningitis were recorded. Of these, 242 were treated with the dexamethasone protocol after 1987 and 121 were treated without the protocol. Overall mortality was 11.6% (28/242) among patients treated with dexamethasone and 35% (43/121) among those treated without dexamethasone (p = 0.000). Early mortality was significantly lower at 5.8% (14/242) with dexamethasone and 24% (29/121) without dexamethasone (p = 0.000). Finally, neurological mortality was significantly lower at 7.4% (18/242) with dexamethasone and 23% (28/121) without dexamethasone (p = 0.000). Conclusions A low dose of dexamethasone along with a single dose of mannitol and antiseizures prophylaxis might be useful for reducing both overall and early mortality in pneumococcal meningitis in adult patients.

Optimal use of β-lactams in neonates: machine learning-based clinical decision support system

BackgroundAccurate prediction of the optimal dose for β-lactam antibiotics in neonatal sepsis is challenging. We aimed to evaluate whether a reliable clinical decision support system (CDSS) based on machine learning (ML) can assist clinicians in making optimal dose selections. MethodsFive β-lactam antibiotics (amoxicillin, ceftazidime, cefotaxime, meropenem and latamoxef), commonly used to treat neonatal sepsis, were selected. The CDSS was constructed by incorporating the drug, patient, dosage, pharmacodynamic, and microbiological factors. The CatBoost ML algorithm was used to build the CDSS. Real-world studies were used to evaluate the CDSS performance. Virtual trials were used to compare the CDSS-optimized doses with guideline-recommended doses. FindingsFor a specific drug, by entering the patient characteristics and pharmacodynamic (PD) target (50%/70%/100% fraction of time that the free drug concentration is above the minimal inhibitory concentration [fT>MIC]), the CDSS can determine whether the planned dosing regimen will achieve the PD target and suggest an optimal dose. The prediction accuracy of all five drugs was > 80.0% in the real-world validation. Compared with the PopPK model, the overall accuracy, precision, recall, and F1-Score improved by 10.7%, 22.1%, 64.2%, and 43.1%, respectively. Using the CDSS-optimized doses, the average probability of target concentration attainment increased by 58.2% compared to the guideline-recommended doses. InterpretationAn ML-based CDSS was successfully constructed to assist clinicians in selecting optimal β-lactam antibiotic doses. FundingThis work was supported by the National Natural Science Foundation of China; Distinguished Young and Middle-aged Scholar of Shandong University; National Key Research and Development Program of China.

Guiding antibiotics towards their target using bacteriophage proteins

Novel therapeutic strategies against difficult-to-treat bacterial infections are desperately needed, and the faster and cheaper way to get them might be by repurposing existing antibiotics. Nanodelivery systems enhance the efficacy of antibiotics by guiding them to their targets, increasing the local concentration at the site of infection. While recently described nanodelivery systems are promising, they are generally not easy to adapt to different targets, and lack biocompatibility or specificity. Here, nanodelivery systems are created that source their targeting proteins from bacteriophages. Bacteriophage receptor-binding proteins and cell-wall binding domains are conjugated to nanoparticles, for the targeted delivery of rifampicin, imipenem, and ampicillin against bacterial pathogens. They show excellent specificity against their targets, and accumulate at the site of infection to deliver their antibiotic payload. Moreover, the nanodelivery systems suppress pathogen infections more effectively than 16 to 32-fold higher doses of free antibiotics. This study demonstrates that bacteriophage sourced targeting proteins are promising candidates to guide nanodelivery systems. Their specificity, availability, and biocompatibility make them great options to guide the antibiotic nanodelivery systems that are desperately needed to combat difficult-to-treat infections.