Developing Parametric and Nonparametric Models for Model-Informed Precision Dosing: A Quality Improvement Effort in Vancomycin for Patients With Obesity.

BACKGROUND: Both parametric and nonparametric methods have been proposed to support model-informed precision dosing (MIPD). However, which approach leads to better models remains uncertain. Using open-source software, these 2 statistical approaches for model development were compared using the pharmacokinetics of vancomycin in a challenging subpopulation of class 3 obesity. METHODS: Patients on vancomycin at the University of Vermont Medical Center from November 1, 2021, to February 14, 2023, were entered into the MIPD software. The inclusion criteria were body mass index (BMI) of at least 40 kg/m2 and 1 or more vancomycin levels. A parametric model was created using nlmixr2/NONMEM, and a nonparametric model was created using metrics. Then, a priori and a posteriori predictions were evaluated using the normalized root mean squared error (nRMSE) for precision and the mean percentage error (MPE) for bias. The parametric model was evaluated in a simulated MIPD context using an external validation dataset. RESULTS: In total, 83 patients were included in the model development, with a median age of 56.6 years (range: 24-89 years), and a median BMI of 46.3 kg/m2 (range: 40-70.3 kg/m2). Both parametric and nonparametric models were 2-compartmental, with creatinine clearance and fat-free mass as covariates to c clearance and volume parameters, respectively. The a priori MPE and nRMSE for the parametric versus nonparametric models were -6.3% versus 2.69% and 27.2% versus 30.7%, respectively. The a posteriori MPE and RMSE were 0.16% and 0.84%, and 13.8% and 13.1%. The parametric model matched or outperformed previously published models on an external validation dataset (n = 576 patients). CONCLUSIONS: Minimal differences were found in the model structure and predictive error between the parametric and nonparametric approaches for modeling vancomycin class 3 obesity. However, the parametric model outperformed several other models, suggesting that institution-specific models may improve pharmacokinetics management.

An AUC Target Simulation for Vancomycin in Patients With Class III Obesity.

OBJECTIVE: The objective of this simulation is to compare 24-hour vancomycin (Vanc24) dosage requirements between a target area under the curve (AUC) versus a target trough approach in patients with class III obesity. METHODS: Adult patients were included if they received vancomycin in accordance with the University of Vermont Medical Center's class III obesity dosage protocol from June 2016 through December 2018. Patient-specific pharmacokinetic parameters were calculated for each patient using the Sawchuck-Zaske method. For this simulation, Vanc24 dosages were calculated to achieve an AUC of 400 mg/L h and a trough concentration of 15 mg/L. RESULTS: Sixty-three patients had Vanc24 dosage requirements calculated. The median age was 59 years (interquartile range [IQR]: 51.5-68), body mass index (BMI): 45.7 kg/m2 (IQR: 42.4-51.5), and 50.7% were male. The mean Vanc24 dosage requirements were 3995 mg (standard deviation [SD] ±1673) in the target trough approach versus 2783 mg (SD ±1149) in the target AUC approach (P < .0001). CONCLUSION: A target AUC approach required less vancomycin over a 24-hour time period relative to a target trough approach. Vancomycin therapeutic drug monitoring that explicitly targets AUC may reduce vancomycin exposure and potentially decrease the risk of nephrotoxicity in patients with class III obesity.

Establishing Antibiotic Stewardship Programs in Rural Hospitals to Decrease Fluoroquinolone Prescribing: The Vermont Experience.

Critical access and rural community hospitals struggle to develop effective antimicrobial stewardship programs (ASPs). We assisted six Vermont hospitals in developing their antimicrobial stewardship programs to meet the Centers for Disease Control and Prevention's core elements of antibiotic stewardship. We show that rural hospitals in Vermont can (1) extract antimicrobial use data from their electronic medical record; (2) develop interventions to decrease high use antimicrobial agents, such as fluoroquinolones; and (3) successfully develop sustained ASPs meeting the CDC core elements in less than 2 years.

Utility of ampicillin-sulbactam for empiric treatment of ventilator-associated pneumonia in a trauma population.

BACKGROUND: Ampicillin-sulbactam is guideline-recommended treatment for early-onset ventilator-associated pneumonia (VAP). However, intensive care unit clinicians are encountering increasing resistance to ampicillin-sulbactam. We sought to analyze the time period for early-onset VAP in our trauma population by using daily evaluation of resistance to ampicillin-sulbactam. METHODS: A retrospective cohort study was completed on all mechanically ventilated trauma patients admitted to a rural level-1 trauma center from January 2003 to December 2008 who were diagnosed with VAP. Daily bacterial resistance to ampicillin-sulbactam > 15% was defined as the threshold for early empiric antibiotic failure for the first episode of VAP. A univariate analysis of risk factors for multi-drug resistant pathogens (MDRPs) and comorbidities was completed to assess for predisposing factors for ampicillin-sulbactam resistance. RESULTS: One hundred sixty-three pathogens were identified in 121 trauma patients diagnosed with VAP. Of these isolates, 71% were gram-negative, 28% were gram-positive, and 1% was fungal. Methicillin-susceptible Staphylococcus aureus (23.9%), H aemophilus influenzae (20.9%), and Pseudomonas aeruginosa (11.7%) were the most common infecting organisms. Daily ampicillin-sulbactam resistance was 40%, 26%, 32%, 43%, 50%, and 60% on days 3 to 7 and ≥ 8 days, respectively. Only the presence of MDRP risk factors (89% vs. 65%, p < 0.01) and hospital LOS (36.8 [22.8-49.0] vs. 25.7 days [19.0-32.5], p < 0.01) was different between ampicillin- sulbactam resistant and ampicillin-sulbactam susceptible VAP groups. On univariate analysis, hospital length of stay >4 days and antibiotic use within 90 days were associated with ampicillin-sulbactam resistant VAP (p < 0.01). CONCLUSIONS: Ampicillin-sulbactam is not an effective empiric therapy for early-onset VAP in our rural trauma population. The utility of ampicillin-sulbactam should be reviewed at other institutions to assess for appropriate empiricism.

When are Oral Antibiotics a Safe and Effective Choice for Bacterial Bloodstream Infections? An Evidence-Based Narrative Review.

Bacterial bloodstream infections (BSIs) are a major cause of morbidity and mortality in the United States. Traditionally, BSIs have been managed with intravenous antimicrobials. However, whether intravenous antimicrobials are necessary for the entirety of the treatment course in BSIs, especially for uncomplicated episodes, is a more controversial matter. Patients that are clinically stable, without signs of shock, or have been stabilized after an initial septic presentation, may be appropriate candidates for treatment of BSIs with oral antimicrobials. There are risks and costs associated with extended courses of intravenous agents, such as the necessity for long-term intravenous catheters, which entail risks for procedural complications, secondary infections, and thrombosis. Oral antimicrobial therapy for bacterial BSIs offers several potential benefits. When selected appropriately, oral antibiotics offer lower cost, fewer side effects, promote antimicrobial stewardship, and are easier for patients. The decision to use oral versus intravenous antibiotics must consider the characteristics of the pathogen, the patient, and the drug. In this narrative review, the authors highlight areas where oral therapy is a safe and effective choice to treat bloodstream infection, and offer guidance and cautions to clinicians managing patients experiencing BSI.

Enhancing compliance with Medicare guidelines for surgical infection prevention: experience with a cross-disciplinary quality improvement team.

HYPOTHESIS: The Center for Medicare and Medicaid Services instituted standardized reporting of measures aimed at surgical infection prevention (SIP). The complexity and number of medical personnel involved in antibiotic administration requires multiple disciplines to successfully improve compliance. DESIGN: Survey study. SETTING: Tertiary care university hospital. PATIENTS: All patients undergoing the following operations from July 2004 through December 2005 were monitored for compliance with SIP: (1) coronary artery bypass graft, (2) other cardiac, (3) vascular, (4) hysterectomy, (5) colon resection, (6) hip arthroplasty, and (7) knee arthroplasty. INTERVENTION: A team including a surgeon, an anesthesiologist, nurses (preoperative, operating room, and floor), a pharmacist, a hospital infection control committee member, and quality improvement and operations specialists was created in July 2004. Hospital guidelines for SIP were defined, personnel roles defined and processes standardized, and communication/education for health care professionals was enhanced. MAIN OUTCOME MEASURES: Compliance with 3 SIP measures over 3 consecutive periods of 6 months each: (1) percentage of patients receiving antibiotics within 1 hour of incision, (2) percentage of patients with appropriately selected antibiotics, and (3) percentage of patients with antibiotics discontinued within 24 hours of operation end time. RESULTS: One thousand seventy-two patients were monitored. Measure 1 compliance improved from 72.25% to 83.78% (P<.001, Cochran-Armitage trend test); improvement or high performance (>90% compliance) was demonstrated in 5 of 7 services. Measure 2 compliance remained uniformly high (approximately 98%). Measure 3 compliance improved from 54.5% to 87.16% (P<.001); improvement was seen in 5 of 7 services. CONCLUSIONS: The clearly defined roles of a cross-disciplinary team and the process improvements discussed in this article can easily be implemented in other institutions. These elements were integral to our success in improving the timely delivery and discontinuation of prophylactic surgical antibiotics.

Daily evaluation of macroaspiration in the critically ill post-trauma patient.

BACKGROUND: Although critically ill trauma patients represent a high-risk population for macroaspiration, studies of trauma patients have not been explored. The study aims were to quantify rate and associated risks of macroaspiration and explore the pattern of antibiotic use and incidence of aspiration pneumonia within this patient group. METHODS: Consecutive trauma patients admitted to the intensive care unit (ICU) were prospectively observed for development of macroaspiration and subsequent aspiration pneumonia. Daily monitoring included chart review, laboratory and radiography results, and nurse inquiries for witnessed macroaspiration events. RESULTS: Seven of 60 patients included experienced a clinically confirmed macroaspiration event (11.7%). The incidence of pneumonia was similar, regardless of macroaspiration occurrence (28.6%: macroaspiration cases vs 17.0%: controls, p > or = 0.05). Patients with macroaspiration required a longer duration of mechanical ventilation (15 vs 9.5 days, p = 0.021) and intensive care unit stay (28 vs 7 days, p = 0.015). Paralytic agent utilization was associated with an increased risk for aspiration (p = 0.045). CONCLUSIONS: The incidence of macroaspiration within a critically ill trauma population may be less frequent compared with studies performed in other patient populations. Although macroaspiration was associated with a longer duration of mechanical ventilation and intensive care unit stay, this condition may not be associated with an increased rate of pulmonary infection.

Use of longitudinal surveillance data to assess the effectiveness of infection control in critical care.

A simple method for quantifying nosocomial infection and colonization with multidrug-resistant organisms is described. This method is applied to the intensive care unit of an academic medical center where longitudinal surveillance data have been used to assess the impact of infection control interventions and antibiotic use.

A survey of once-daily dosage tobramycin therapy in patients with cystic fibrosis.

The purpose of this study was to quantify the prevalence of once-daily dosage of tobramycin (ODDT) among Cystic Fibrosis Foundation-accredited care centers and affiliated programs (CFFACCs) and characterize the ODDT approaches used by these institutions. An anonymous cross-sectional survey of CFFACCs was performed using an electronic survey tool. This tool was electronically mailed to the program directors. Eighty-four out of 195 institutions completed the survey (response rate = 43%). Fifty-one (61%) of 84 centers reported using ODDT. Of those 51 institutions, 34 (67%) use a dosage of 10 mg/kg/dose. Serum creatinine was measured routinely in 51 centers (100%) with weekly monitoring being used in 40 centers (78%). Audiometric evaluation was performed routinely in 22 (43%) centers with annual assessment performed in 14 (64%) of these 22 centers. In conclusion, a majority of responding institutions use ODDT. The most common reported dosage is 10 mg/kg. Serum creatinine was routinely measured in all institutions with weekly assessment being the most common frequency. Audiometic assessment is routinely performed in <50% of centers. Of the institutions performing audiograms routinely, annual assessment is the most common frequency.