Machine Learning To Stratify Methicillin-Resistant Staphylococcus aureus Risk among Hospitalized Patients with Community-Acquired Pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is an uncommon but serious cause of community-acquired pneumonia (CAP). A lack of validated MRSA CAP risk factors can result in overuse of empirical broad-spectrum antibiotics. We sought to develop robust models predicting the risk of MRSA CAP using machine learning using a population-based sample of hospitalized patients with CAP admitted to either a tertiary academic center or a community teaching hospital. Data were evaluated using a machine learning approach. Cases were CAP patients with MRSA isolated from blood or respiratory cultures within 72 h of admission; controls did not have MRSA CAP. The Classification Tree Analysis algorithm was used for model development. Model predictions were evaluated in sensitivity analyses. A total of 21 of 1,823 patients (1.2%) developed MRSA within 72 h of admission. MRSA risk was higher among patients admitted to the intensive care unit (ICU) in the first 24 h who required mechanical ventilation than among ICU patients who did not require ventilatory support (odds ratio [OR], 8.3; 95% confidence interval [CI], 2.4 to 32). MRSA risk was lower among patients admitted to ward units than among those admitted to the ICU (OR, 0.21; 95% CI, 0.07 to 0.56) and lower among ICU patients without a history of antibiotic use in the last 90 days than among ICU patients with antibiotic use in the last 90 days (OR, 0.03; 95% CI, 0.002 to 0.59). The final machine learning model was highly accurate (receiver operating characteristic [ROC] area = 0.775) in training and jackknife validity analyses. We identified a relatively simple machine learning model that predicted MRSA risk in hospitalized patients with CAP within 72 h postadmission.

Individual meropenem epithelial lining fluid and plasma PK/PD target attainment.

It is unclear whether plasma is a reliable surrogate for target attainment in the epithelial lining fluid (ELF). The objective of this study was to characterize meropenem target attainment in plasma and ELF using prospective samples. The first 24-hour T>MIC was evaluated vs 1xMIC and 4xMIC targets at the patient (i.e., fixed MIC of 2 mg/L) and population [i.e., cumulative fraction of response (CFR) according to EUCAST MIC distributions] levels for both plasma and ELF. Among 65 patients receiving ≥24 hours of treatment, 40% of patients failed to achieve >50% T>4xMIC in plasma and ELF, and 30% of patients who achieved >50% T>4xMIC in plasma had <50% T>4xMIC in ELF. At 1xMIC and 4xMIC targets, 3% and 25% of patients with >95% T>MIC in plasma had <50% T>MIC in ELF, respectively. Those with a CRCL >115 mL/min were less likely to achieve >50%T>4xMIC in ELF (P < 0.025). In the population, CFR for Escherichia coli at 1xMIC and 4xMIC was >97%. For Pseudomonas aeruginosa, CFR was ≥90% in plasma and ranged 80%-85% in ELF at 1xMIC when a loading dose was applied. CFR was reduced in plasma (range: 75%-81%) and ELF (range: 44%-60%) in the absence of a loading dose at 1xMIC. At 4xMIC, CFR for P. aeruginosa was 60%-86% with a loading dose and 18%-62% without a loading dose. We found that plasma overestimated ELF target attainment inup to 30% of meropenem-treated patients, CRCL >115 mL/min decreased target attainment in ELF, and loading doses increased CFR in the population.

Pharmacological and Behavioral Interventions to Mitigate Premature Aging in Patients with HIV.

PURPOSE OF REVIEW: We sought to review pharmacological and behavioral interventions that have been publicly presented, published, or are currently ongoing to prevent or mitigate the effect of premature HIV-associated comorbidities. RECENT FINDINGS: Multiple studies have been conducted in hopes of finding an effective intervention. While the choice of antiretroviral regimen influences recovery of immune function, several drugs used as adjunct treatments have proven effective to mitigate premature aging. Additionally, few behavioral interventions have exhibited some efficacy. Statins, angiotensin-receptor blockers, and anti-hyperglycemic agents as well as optimal adherence, exercise, and intermittent fasting among others have had beneficial impact on markers of immune activation and levels of inflammatory biomarkers. However, several investigations had inconclusive outcomes so further studies with larger sample sizes are warranted.

Individual target pharmacokinetic/pharmacodynamic attainment rates among meropenem-treated patients admitted to the ICU with hospital-acquired pneumonia.

OBJECTIVES: Critical illness reduces ß-lactam pharmacokinetic/pharmacodynamic (PK/PD) attainment. We sought to quantify PK/PD attainment in patients with hospital-acquired pneumonia. METHODS: Meropenem plasma PK data (n = 70 patients) were modelled, PK/PD attainment rates were calculated for empirical and definitive targets, and between-patient variability was quantified [as a coefficient of variation (CV%)]. RESULTS: Attainment of 100% T>4×MIC was variable for both empirical (CV% = 92) and directed (CV% = 33%) treatment. CONCLUSIONS: Individualization is required to achieve suggested PK/PD targets in critically ill patients.

Optimizing Aminoglycoside Dosing Regimens for Critically Ill Pediatric Patients with Augmented Renal Clearance: a Convergence of Parametric and Nonparametric Population Approaches.

Augmented renal clearance (ARC) can occur in critically ill pediatric patients receiving aminoglycosides such as gentamicin and tobramycin, yet optimal dosing strategies for ARC are undefined. We evaluated the probability of achieving efficacious or toxic exposures in pediatrics. Parallel population modeling of concentration strategies were pursued using Pmetrics v1.5.2 (nonparametric) and Monolix v2019R2 (parametric). Bayesian exposures were used to classify ARC based on total clearance (CL). The effects of serum creatinine (SCR), creatinine clearance (CRCL), total body weight (TBW), postnatal age (PNA), and ARC were explored as covariates. The probabilities of target attainment (PTA) (i.e., maximum concentration [Cmax]/MIC, area under the concentration-time curve [AUC]/MIC) and of toxic exposure (PTE) (i.e., minimum concentration [Cmin] > 2 µg/ml) were calculated according to PNA and ARC. A total of 123 patients (1 to 21 years old, 56% female) contributed 304 concentrations. A two-compartment model was superior to a one-compartment model in both approaches. Bayesian posterior predicted concentrations from the nonparametric base model fit the data well (R2 = 0.96) and classified 34 patients as having ARC (28%). Both the nonparametric and parametric approaches resulted in allometrically scaling of TBW on volume (V) and clearance (CL). ARC modified CL and central V. CRCL and a maturation function modified CL. ARC was associated with a 1.49- versus 1.66-fold increase in CL and a 1.56- versus 1.66-fold increase in the central V (nonparametric versus parametric). A high dose of 12 mg/kg of body weight/day was required to achieve adequate PTA when MICs were 1 to 2 µg/ml; ARC lowered achievable MICs. When PNA was <2 years, PTE was increased. Aminoglycoside monotherapy should be avoided in critically ill pediatric patients with ARC when MICs exceed 1 µg/ml, as optimal exposures are unachievable with standard dosing.

Expanding expedited partner therapy and HIV prophylaxis in the emergency department.

PURPOSE: Sexually transmitted infections (STIs) continue to have a disproportionate impact on individuals belonging to sexual, gender, and racial minorities. Across the nation, many emergency medicine pharmacists (EMPs) possess the skills and knowledge to expand the provision of expedited partner therapy (EPT) for STIs and provide HIV prophylaxis within existing practice frameworks. This report serves as a call to action for expanded provision of EPT and HIV prophylaxis by EMPs and highlights current barriers and solutions to increase pharmacist involvement in these practice areas. SUMMARY: Emergency medicine pharmacy practice continues to expand to allow for limited prescribing authority through collaborative practice agreements (CPAs). In recent years, CPA restrictions have been changed to facilitate treatment of more patients with less bureaucracy. This report addresses the unique challenges and opportunities for expanding EPT and HIV pre- and postexposure prophylaxis provision by pharmacists in emergency departments (EDs). Furthermore, current strategies and treatments for EPT, such as patient-delivered partner therapy and HIV prophylaxis, are discussed. Pharmacist involvement in STI treatment and HIV prevention is a key strategy to increase access to high-risk populations with high ED utilization and help close current gaps in care. CONCLUSION: Expanding EMP provision of EPT and HIV prophylaxis may be beneficial to reducing the incidence of STIs and HIV infection in the community. CPAs offer a feasible solution to increase pharmacist involvement in the provision of these treatments. Legislative efforts to expand pharmacist scope of practice can also contribute to increasing access to EPT and HIV prophylaxis. With these efforts, EMPs can play an essential role in the fight against STIs and HIV.

Flucloxacillin worsens while imipenem-cilastatin protects against vancomycin-induced kidney injury in a translational rat model.

BACKGROUND AND PURPOSE: Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem-cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. KEY RESULTS: Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem-cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. CONCLUSIONS AND IMPLICATIONS: Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem-cilastatin in a translational rat model. The combination of vancomycin + imipenem-cilastatin was nephroprotective.

Defining the Importance of Age-Related Changes in Drug Clearance to Optimizing Aminoglycoside Dosing Regimens for Adult Patients with Cystic Fibrosis.

BACKGROUND AND OBJECTIVE: The number of adults living with cystic fibrosis (CF) has increased and will continue to do so with the approval of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Because systemic aminoglycosides are commonly administered for CF pulmonary exacerbations, we sought to define optimized dosing regimens using a population pharmacokinetic modeling and simulation approach. METHODS: Adult CF patients admitted for pulmonary exacerbation, receiving at least 72 h of systemic gentamicin, tobramycin, or amikacin, with measured concentrations were included. Covariates [e.g., age, weight, creatinine clearance (CRCL)] were screened. Population modeling was completed using Monolix, and simulations were conducted in R. Simulated exposures were calculated using noncompartmental analysis. Once-daily fixed (10 mg/kg) and exposure-matched dosing (i.e., 15, 10, 7.5, 6 mg/kg for ages 20, 30, 40, and 50 years, respectively) strategies were compared. First-24 h exposures were evaluated for each strategy according to the probability of target attainment (PTA) (ratio of peak plasma concentrations relative to the minimum inhibitory concentration [Cmax/MIC] or ratio of the area under the concentration-time curve to MIC [AUC/MIC]) and the probability of toxic exposure (PTE) (trough concentration, Ctrough > 2 mg/l). RESULTS: Forty-eight adult patients (55% female) were included. A one-compartment model best fit the data. Estimates for volume of distribution (V) and clearance (CL) were 22 l and 5.57 l/h, respectively. Weight significantly modified CL and V. Age significantly modified CL and was more influential than CRCL. PTA was > 90% at MICs ≤ 1 mg/l for fixed doses of 10 mg/kg and for exposure-matched doses at MIC ≤ 1 mg/l. Exposure-matched dosing reduced PTE roughly 50% in patients aged 40 and 50 years vs. fixed dosing. CONCLUSIONS: Exposure-matching maintained PTA at MICs ≤ 1 mg/l while reducing toxicity risk in older patients compared to fixed dosing. Confirmatory studies are needed.

Adherence to Antiretroviral Therapy Among Iranian HIV/AIDS Patients

PURPOSE: Treatment adherence of 95% or higher is recommended for appropriate therapeutic response and improving the function of immune system in HIV positive patients. To the best of our knowledge, there was report of adherence to HAART regimen from Iran. In the present study, we have reported the HAART adherence rate of Iranian HIV positive patients. METHOD: In a twelve-month period, all patients older than 18 years old who referred to HIV clinic were on HAART regimen enrolled in the study. Beside demographic and clinical characteristics of Iranian HIV positive patients, Adherence to HAART was assessed by self-report and pill count methods at during the three consecutive months of the patients' visits. RESULTS: The mean of patients' adherence to HAART regimen based on the self-report method was 69.4%, 64.6% and 62.8% in the first, second and third month of follow up, respectively. The mean of adherence rates in three months followup assessed by self-report (65.5%) and pill count (60.4%) methods were correlated significantly (r=0.93 and p<0.001). Living with family members, changing the HAART regimen and stage of disease had a significant relationship with adherence rates. CONCLUSION: Although the adherence level of Iranian HIV infected patients is acceptable compared to other countries, the available antiretroviral medications are limited in our country, therefore, encouraging patients to have higher levels of adherence is more important.