Challenges Facing Antimicrobial Stewardship Programs in the Endemic Region for Coccidioidomycosis.

Coccidioidomycosis poses a significant cost and morbidity burden in the United States. Additionally, coccidioidomycosis requires constant decision-making related to prevention, diagnosis, and management. Delays in diagnosis lead to significant consequences, including unnecessary diagnostic workup and antibacterial therapy. Antifungal stewardship considerations regarding empiric, prophylactic, and targeted management of coccidioidomycosis are also complex. In this review, the problems facing antimicrobial stewardship programs (ASPs) in the endemic region for coccidioidomycosis, consequences due to delayed or missed diagnoses of coccidioidomycosis on antibacterial prescribing, and excess antifungal prescribing for prevention and treatment of coccidioidomycosis are elucidated. Finally, our recommendations and research priorities for ASPs in the endemic region for coccidioidomycosis are outlined.

Trends of Azole Antifungal Prescription in the United States: Medicare Part D Provider Utilization and Payment Data Analysis.

Background: Invasive fungal infections carry a substantial risk of mortality and morbidity. Azole antifungals are used in the treatment of such infections; however, their extensive use can lead to the emergence of antifungal resistance and increased costs to patients and healthcare systems. The aim of this study is to evaluate trends in these antifungals use and costs. Methods: The secular and regional trends of outpatient azole antifungals were analyzed using Medicare Part D Prescriber Public Use Files for the years 2013-2020. The total days supply (TDS), total drug cost (TDC) per 100 000 enrollees, and cost per day (CPD) were evaluated. Results: The azole antifungal TDS for Medicare Part D enrollees increased by 12% between 2013 and 2020, and increases were noted for each azole. Southern US regions had the highest TDS, with Arizona having the highest TDS among US states in 2020. Cost analysis showed that TDC of all azoles has increased by 93% over the years, going up from $123 316 in 2013 to $238 336 per 100 000 enrollees in 2020. However, CPD showed an increase only for fluconazole and isavuconazole, with CPD of $1.62 per day and $188.30 per day, respectively. Conclusions: Combined azole antifungal prescriptions TDS increased among Medicare Part D enrollees. The trend in CPD was mixed, whereas overall costs consistently increased over the same period. Such findings provide an insight into the impact of azole antifungal prescriptions, and increasing use could foreshadow more antifungal resistance. Continued studies to evaluate different prescribers' trends are warranted.

Risk for primary cephalosporin resistance in Gram-negative bacteremia.

Objective: This study aimed to examine the clinical risk factors for cephalosporin resistance in patients with Gram-negative bacteremia caused by Escherichia coli (EC), Klebsiella pneumoniae (KP), Enterobacter cloacae (ENC), and Pseudomonas aeruginosa (PS). Methods: This retrospective cohort study included 400 adults with Gram-negative bacteremia. The goal was to review 100 cases involving each species and approximately half resistant and half susceptible to first-line cephalosporins, ceftriaxone (EC or KP), or cefepime (ENC or PS). Logistic regression was used to identify factors predictive of resistance. Results: A total of 378 cases of Gram-negative bacteremia were included in the analysis. Multivariate analysis identified significant risk factors for resistance, including admission from a chronic care hospital, skilled nursing facility, or having a history of infection within the prior 6 months (OR 3.00, P < .0001), requirement for mechanical ventilation (OR 3.76, P < .0001), presence of hemiplegia (OR 3.54, P = .0304), and presence of a connective tissue disease (OR 3.77, P = .0291). Conclusions: Patients without the identified risk factors should be strongly considered for receiving ceftriaxone or cefepime rather than carbapenems and newer broad-spectrum agents.

Performance of Bayesian Area Under the Concentration-Time Curve-Based Pharmacokinetic Dosing Based on a One-Compartment Model and Trough-Only Monitoring for Vancomycin.

A novel Bayesian method was developed to interpret serum vancomycin concentrations (SVCs) following the administration of one or more vancomycin doses with potential varying doses and intervals based on superposition principles. The method was evaluated using retrospective data from 442 subjects from three hospitals. The patients were required to receive vancomycin for more than 3 days, have stable renal function (fluctuation in serum creatinine of ≤0.3 mg/dL), and have at least 2 trough concentrations reported. Pharmacokinetic parameters were predicted using the first SVC, and the fitted parameters were then used to predict subsequent SVCs. Using only covariate-adjusted population prior estimates, the first two SVC prediction errors were 47.3 to 54.7% for the scaled mean absolute error (sMAE) and 62.1 to 67.8% for the scaled root mean squared error (sRMSE). "Scaled" refers to the division of the MAE or RMSE by the mean value. The Bayesian method had minimal errors for the first SVC (by design), and for the second SVC, the sMAE was 8.95%, and the sRMSE was 36.5%. The predictive performance of the Bayesian method did degrade with subsequent SVCs, which we attributed to time-dependent pharmacokinetics. The 24-h area under the concentration-time curve (AUC) was determined from simulated concentrations before and after the first SVC was reported. Prior to the first SVC, 170 (38.4%) patients had a 24-h AUC of <400 mg · h/L, 186 (42.1%) had a 24-h AUC within the target range, and 86 (19.5%) had a 24-h AUC of >600 mg · h/L. After the first SVC was reported, 322 (72.9%) had a 24-h AUC within the target range, 68 (15.4%) had low values, and 52 (11.8%) had high values based on the model simulation. Target attainments were 38% before the first SVC and 73% after the first SVC. The hospitals had no policies or procedures in place for targeting 24-h AUCs, although the trough target was typically 13 to 17 mg/L. Our data provide evidence of time-dependent pharmacokinetics, which will require regular therapeutic drug monitoring regardless of the method used to interpret SVCs.

Medication dosing in adult patients with reduced lean body mass and kidney injury: A focus on cystatin C.

PURPOSE: Creatinine-based estimates of glomerular filtration rate (GFR) have been the standard for classifying kidney function and guiding drug dosing for over 5 decades. There have been many efforts to compare and improve different methods to estimate GFR. The National Kidney Foundation recently updated the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without race for creatinine (CKD-EPIcr_R) and creatinine and cystatin C (CKD-EPIcr-cys_R), and the 2012 CKD-EPI equation based on cystatin C (CKD-EPIcys) remains. The focus of this review is to highlight the importance of muscle atrophy as a cause for overestimation of GFR when using creatinine-based methods. SUMMARY: Patients with liver disease, protein malnutrition, inactivity, denervation, or extensive weight loss may exhibit markedly lower creatinine excretion and serum creatinine concentration, leading to overestimation of GFR or creatinine clearance when using the Cockcroft-Gault equation or CKD-EPIcr (deindexed). In some cases, estimated GFR appears to exceed the physiological normal range (eg, >150 mL/min/1.73 m2). Use of cystatin C is recommended when low muscle mass is suspected. One would expect discordance between the estimates such that CKD-EPIcys < CKD-EPIcr-cys < CKD-EPIcr ≈ Cockcroft-Gault creatinine clearance. Clinical evaluation can then occur to determine which estimate is likely accurate and should be used for drug dosing. CONCLUSION: In the setting of significant muscle atrophy and stable serum creatinine levels, use of cystatin C is recommended, and the resulting estimate can be used to calibrate interpretation of future serum creatinine measurements.

The relationship of vancomycin 24-hour AUC and trough concentration.

PURPOSE: Prior to the 2020 release of a joint consensus guideline on monitoring of vancomycin therapy for serious methicillin-resistant Staphylococcus aureus (MRSA) infections, clinicians had escalated vancomycin doses for 2 decades while targeting trough concentrations of 15 to 20 µg/mL, leading to an increased frequency of nephrotoxicity. For MRSA infections, the 2020 guideline recommends adjusting doses to achieve a 24-hour area under the concentration-time curve (AUC) of 400 to 600 µg · h/mL; however, monitoring of trough concentrations has been entrenched for 3 decades. Calculating dose regimens based on AUC will require obtaining an increased number of vancomycin serum concentrations and, possibly, advanced software. The aim of this investigation was to determine the relationship between AUC and trough concentration and the influence of dosing regimen on goal achievement. METHODS: The relationship between trough concentration and AUC was explored through derivation of an equation based on a 1-compartment model and simulations. RESULTS: 24-hour AUC is related to dosing interval divided by half-life in a nonlinear fashion. The target trough concentration can be individualized to achieve a desired AUC range, and limiting use of large doses (>15-20 mg/kg) can protect against excessive 24-hour AUC with trough-only monitoring. CONCLUSION: After initially determining pharmacokinetic parameters, subsequent monitoring of AUC can be accomplished using trough concentrations only. Trough concentration may be used as a surrogate for AUC, although the acceptable target trough concentration will vary depending on dosing interval and elimination rate constant. This work included development of an AUC-trough equation to establish a patient-specific target for steady-state trough concentration.

A preliminary study of the plasma concentrations of orally administered fluconazole in alpacas (Vicugna pacos).

Alpacas residing in the region endemic for Coccidioides spp. are susceptible to serious, disseminated coccidioidomycosis that may result in death. There is currently no oral antifungal dose recommendation for this species. We used a steady-state study design to assess the pharmacokinetics of oral generic fluconazole in alpacas dosed q 24 h for 14 days. Cohorts of 2-3 animals received fluconazole from 6 to 15 mg/kg/day, and pharmacokinetic analysis was performed after each group of animals in order to make dose adjustments for the next group. The final three animals were used as confirmation of our dose recommendation. The median Tmax was 7 h, and the median Cmax was 1.25 µg/ml per mg/kg dose. The mean dose-normalized 24-h AUC was 41.7 µg h/ml per mg/kg dose (CV = 72%). Based on these results, we recommend alpacas receive a starting dose of oral fluconazole at 10-15 mg/kg/day based on the fluconazole AUC in humans (313-625 µg h/ml). Testing to ascertain putative therapeutic plasma concentrations and monitoring of serum transaminases should be performed.

Efficacy of personal pharmacogenomic testing as an educational tool in the pharmacy curriculum: A nonblinded, randomized controlled trial.

Personal genomic educational testing (PGET) has been suggested as a strategy to improve student learning for pharmacogenomics (PGx), but no randomized studies have evaluated PGET's educational benefit. We investigated the effect of PGET on student knowledge, comfort, and attitudes related to PGx in a nonblinded, randomized controlled trial. Consenting participants were randomized to receive PGET or no PGET (NPGET) during 4 subsequent years of a PGx course. All participants completed a pre-survey and post-survey designed to assess (1) PGx knowledge, (2) comfort with PGx patient education and clinical skills, and (3) attitudes toward PGx. Instructors were blinded to PGET assignment. The Wilcoxon Rank Sum test was used to compare pre-survey and post-survey PGx knowledge, comfort, and attitudes. No differences in baseline characteristics were observed between PGET (n = 117) and NPGET (n = 116) participants. Among all participants, significant improvement was observed in PGx knowledge (mean 57% vs. 39% correct responses; p < 0.001) with similar results for student comfort and attitudes. Change in pre/post-PGx knowledge, comfort, and attitudes were not significantly different between PGET and NPGET groups (mean 19.5% vs. 16.7% knowledge improvement, respectively; p = 0.41). Similar results were observed for PGET participants carrying a highly actionable PGx variant versus PGET participants without an actionable variant. Significant improvement in Likert scale responses were observed in PGET versus NPGET for questions that assessed student engagement (p = 0.020) and reinforcement of course concepts (p = 0.006). Although some evidence of improved engagement and participation was observed, the results of this study suggest that PGET does not directly improve student PGx knowledge, comfort, and attitudes.

Creatinine Assessment in Non-Steady-State Conditions: A Critical Review.

OBJECTIVES: To discuss methods for the assessment of creatinine clearance (Clcr) when serum creatinine (SCr) is not at steady state in order to estimate kidney function and apply the estimate to kidney function staging for clinical assessment or drug dosing. DATA SOURCES: A PubMed search was conducted from 1976 to mid-January 2021 with other articles identified through review of bibliographies of retrieved articles and citations in Scopus. STUDY SELECTION AND DATA EXTRACTION: Articles assessing Clcr under non-steady-state conditions and studies evaluating predictive equations were selected. DATA SYNTHESIS: When SCr is systematically changing (ie, trending up or down), kinetic methods to estimate Clcr are appropriate. Estimates from kinetic methods should be individual based and not indexed to body surface area, and careful monitoring is required to confirm predictions as the situation evolves. Standard methods intended for steady-state conditions should not be used to estimate Clcr in patients with unstable SCr. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Creatinine continues to be a monitoring parameter of choice and is an important variable in all the commonly used equations for estimating Clcr and most important for estimating glomerular filtration rate. However, standard methods of estimating Clcr for medication dosing are not accurate under non-steady-state conditions. CONCLUSION: The methods for kinetic clearance estimation and standards methods for clearance estimation, such as the Cockcroft-Gault equation, are mutually exclusive. There are no benefits of using the kinetic method in patients with stable SCr concentrations, and standard equations are not appropriate with unstable SCr concentrations.

Clinical and Economic Burden of Valley Fever in Arizona: An Incidence-Based Cost-of-Illness Analysis.

BACKGROUND: Coccidioidomycosis, ie, Valley fever, is an important fungal infection in the Southwest, with half to two thirds of all cases occurring in Arizona. This endemic respiratory disease can range from primary uncomplicated pneumonia to disseminated infection such as meningitis with chronic pulmonary complications. Valley fever diagnoses have risen over recent years and cause substantial morbidity and economic burden in Arizona. METHODS: We estimated the lifetime cost-of-illness associated with all cases of Valley fever diagnosed in 2019 in Arizona. Natural history of the disease was determined from literature and expert opinion and assigned costs from national data sources to determine lifetime direct and indirect costs (work loss). RESULTS: Total lifetime costs of $736 million were estimated for the 10 359 cases of Valley fever diagnosed in Arizona in 2019. Direct costs of $671 million accounted for over 90% of expenditures, with $65 million in indirect costs. Disseminated infection produces the highest economic burden at $1.26 million direct and $137 400 indirect costs per person. The lowest Valley fever lifetime costs were for cases of primary uncomplicated pneumonia with $23 200 in direct costs and $1300 in lost wages. The average lifetime direct costs across all Valley fever manifestations are $64 800 per person diagnosed in Arizona in 2019 and $6300 for indirect costs. CONCLUSIONS: Valley fever is responsible for substantial economic burden in Arizona. Our estimates underscore the value of supporting research into developing more rapid diagnostic tests, better therapies, and ultimately a preventative vaccine to address this important public health problem in Arizona.

Assessment of Kidney Function in Patients With Extreme Obesity: A Narrative Review.

OBJECTIVES: To discuss the evidence and caveats associated with estimated and measured creatinine clearance (eClCr and mClCr) and glomerular filtration rate (eGFR and mGFR) assessments of kidney function in patients with more extreme forms of obesity. DATA SOURCES: PubMed (1976 to mid-May 2020) was used, with bibliographies of retrieved articles searched for additional articles. STUDY SELECTION AND DATA EXTRACTION: Articles using gold standard mGFR to evaluate eClCr, mClCr, and eGFR assessments of kidney function in patients with more extreme forms of obesity were included. DATA SYNTHESIS: The overestimation of GFR by mClCr is well established, but mClCr is an alternative to mGFR assessments for determining medication dosing in patients with extremes of body size or muscle mass, or in patients receiving narrow therapeutic index medications when eGFR is likely to be inaccurate. The vast majority of studies comparing eGFR assessments with gold standard indicators of kidney function were attempts to validate eGFR equations for diagnosing and staging chronic kidney disease (CKD). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: For dosing medications in patients with stable kidney function and extreme obesity, a deindexed 4-variable Modification of Diet in Renal Disease or CKD Epidemiology Collaboration equation is an alternative to Cockcroft-Gault. Consistent use of the same equation by provider and between providers within any given setting is of paramount importance. CONCLUSIONS: In patients with extreme obesity and stable kidney function, eClCr or eGFR using deindexed values provides estimates of function for dosing adjustments of medications with elimination by the kidneys, but more research is needed with respect to the best size descriptor to use with estimating equations.

A Critical Evaluation of Newer ß-Lactam Antibiotics for Treatment of Pseudomonas aeruginosa Infections.

OBJECTIVE: This article critically evaluates common Pseudomonas aeruginosa resistance mechanisms and the properties newer ß-lactam antimicrobials possess to evade these mechanisms. DATA SOURCES: An extensive PubMed, Google Scholar, and ClinicalTrials.gov search was conducted (January 1995 to July 2020) to identify relevant literature on epidemiology, resistance mechanisms, antipseudomonal agents, newer ß-lactam agents, and clinical data available pertaining to P aeruginosa. STUDY SELECTION AND DATA EXTRACTION: Relevant published articles and package inserts were reviewed for inclusion. DATA SYNTHESIS: Therapeutic options to treat P aeruginosa infections are limited because of its intrinsic and acquired resistance mechanisms. The goal was to identify advances with newer ß-lactams and characterize improvements in therapeutic potential for P aeruginosa infections. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Multidrug-resistant (MDR) P aeruginosa isolates are increasingly encountered from a variety of infections. This review highlights potential activity gains of newer ß-lactam antibacterial drugs and the current clinical data to support their use. Pharmacists will be asked to recommend or evaluate the use of these agents and need to be aware of information specific to P aeruginosa, which differs from experience derived from Enterobacterales infections. CONCLUSIONS: Newer agents, including ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and cefiderocol, are useful for the treatment of MDR P aeruginosa infections. These agents offer improved efficacy and less toxicity compared with aminoglycosides and polymyxins and can be used for pathogens that are resistant to first-line antipseudomonal ß-lactams. Selection of one agent over another should consider availability, turnaround of susceptibility testing, and product cost. Efficacy data specific for pseudomonal infections are limited, and there are no direct comparisons between the newer agents.