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.

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.

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.

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.

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.

Current Concepts and Future Directions in the Pharmacology and Treatment of Coccidioidomycosis.

Coccidioidomycosis remains a significant clinical problem with substantial morbidity and mortality. The vast majority of infections are asymptomatic and the need for early primary therapy remains controversial. The use of triazole antifungals has improved tolerability of therapy but concerns about acute and long-term toxicities among available agents limit their use. In addition, recent findings of decreased in vitro fluconazole susceptibility to as many as 37% of Coccidioides spp. isolates raises concerns regarding optimal therapy for these infections as fluconazole is commonly used for therapy including central nervous system disease. Thus, new agents from novel antifungal classes are currently in preclinical and clinical development aimed at reducing toxicity and improving outcomes of these serious infections.

Cefazolin Monotherapy Versus Cefazolin Plus Aminoglycosides for Antimicrobial Prophylaxis of Type III Open Fractures.

BACKGROUND: There are conflicting recommendations between organizations regarding aminoglycoside use for the prophylaxis of type III open fractures. STUDY QUESTION: To compare cefazolin monotherapy versus cefazolin plus aminoglycoside therapy for prophylaxis of type III open fractures in trauma patients. STUDY DESIGN: This was a multicenter, retrospective, cohort study conducted in 3 academic medical centers in the United States. Consecutive adult trauma patients with type III open fractures between January 2014 and September 2016 were included. Patients were divided into 2 groups: (1) cefazolin monotherapy versus (2) cefazolin plus aminoglycoside. MEASURES AND OUTCOMES: The primary outcome measure was the occurrence of infection at the open fracture site. The secondary outcome measure was the occurrence of acute kidney injury. RESULTS: There were 134 patients included in the study cohort. Of these, 39 received cefazolin monotherapy and 95 received cefazolin plus aminoglycoside. Overall, the mean age was 39 ± 15 years, 105 (78%) were male, and the most common fracture location was tibia/fibula (n = 74, 56%). Infection at the open fracture site occurred in 6 of 39 patients (15%) in the cefazolin monotherapy group and 15 of 95 patients (16%) in the cefazolin plus aminoglycoside group (P = 1.000). Acute kidney injury occurred in 0 of 39 (0%) in the cefazolin monotherapy group and 1 of 95 (1%) in the cefazolin plus aminoglycoside group (P = 1.000). CONCLUSIONS: Cefazolin monotherapy may be appropriate for antimicrobial prophylaxis of type III open fractures in trauma patients.

Impact of requiring re-authorization of restricted antibiotics on day 3 of therapy.

Background: Pre-authorization of restricted antibiotics is a core component of an antibiotic stewardship programme (ASP). On day 3, information about culture results and clinical status is typically available. Our objective was to compare an ASP that requires initial authorization alone with one requiring initial authorization and re-authorization on day 3 of therapy. Methods: A single-centre, retrospective, before and after study was conducted. Randomly selected adults were eligible if receiving a restricted antibiotic for ≥3 days during April to June in 2012 (pre-intervention) and during the same months in 2013 (post-intervention). The target sample size was 166 patients. The intervention required re-authorization of restricted antibiotics that were continuing on day 3. The days of therapy of restricted antibiotic(s), length of hospital stay (LOS) and hospital mortality were compared between pre- and post-intervention periods. Results: The ASP intervention was associated with a decrease in median days of therapy from 5 (4-9) to 4 (3-5) days (P < 0.001) for all restricted agents, from 5 (3-6) to 3 (3-5) days for broad-spectrum Gram-negative agents (P < 0.001) and from 6.5 (6-7) to 3 (3-4.5) days for oral vancomycin. The proportion of subjects receiving restricted agents for >4 days decreased from 57.8% to 30.1% (P < 0.001). LOS decreased from 8 (5-17) to 6 (5-9) days (P = 0.005) without a significant change in hospital mortality. Conclusions: Requiring re-authorization of restricted antibiotics on day 3 of therapy in addition to initial authorization was associated with reduction in overall consumption of restricted antibiotics and LOS without adversely affecting hospital mortality.

Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: a systematic review and meta-analysis.

BACKGROUND: Both typical and atypical bacteria can cause community-acquired pneumonia (CAP); however, the need for empiric atypical coverage remains controversial. Our objective was to evaluate the impact of antibiotic regimens with atypical coverage (a fluoroquinolone or combination of a macrolide/doxycycline with a ß-lactam) to a regimen without atypical antibiotic coverage (ß-lactam monotherapy) on rates of clinical failure (primary endpoint), mortality, bacteriologic failure, and adverse events, (secondary endpoints). METHODS: We searched the PubMed, EMBASE and Cochrane Library databases for relevant RCTs of hospitalized CAP adults. We estimated risk ratios (RRs) with 95% confidence intervals (CIs) using a fixed-effect model, but used a random-effects model if significant heterogeneity (I 2 ) was observed. RESULTS: Five RCTs with a total of 2011 patients were retained. A statistically significant lower clinical failure rate was observed with empiric atypical coverage (RR, 0.851 [95% CI, 0.732-0.99; P = 0.037]; I 2  = 0%). The secondary outcomes did not differ between the two study groups: mortality (RR = 0.549 [95% CI, 0.259-1.165, P = 0.118], I 2  = 61.434%) bacteriologic failure (RR = 0.816 [95% CI, 0.523-1.272, P = 0.369], I 2  = 0%), diarrhea (RR = 0.746 [95% CI, 0.311-1.790, P = 0.512], I 2  = 65.048%), and adverse events requiring antibiotic discontinuation (RR = 0.83 [95% CI, 0.542-1.270, P = 0.39], I 2  = 0%). CONCLUSIONS: Empiric atypical coverage was associated with a significant reduction in clinical failure in hospitalized adults with CAP. Reduction in mortality, bacterial failure, diarrhea, and discontinuation due to adverse effects were not significantly different between groups, but all estimates favored atypical coverage. Our findings provide support for the current guidelines recommendations to include empiric atypical coverage.

Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis.

Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii. This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.

Modeling nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials.

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Coccidioides species that is being developed as a first-in-class orphan product for treatment of coccidioidomycosis. It has previously been shown to reduce lethal respiratory infections in mice to undetectable levels when treatment is begun 48 hours after infection. The studies described here focus on bracketing NikZ doses for phase 2 and 3 clinical trials, using an established mouse respiratory infection as a model and starting treatment 120 hours after infection. A dose of 80 mg/kg/day, divided into 2 doses, nearly eradicated infection, and larger doses did not improve fungal clearance. Increasing the duration of treatment from 1 week to 3 weeks resulted in a greater percentage of culture-negative mice. Comparative data show that plasma levels of NikZ that nearly eradicate Coccidioides in mice are achievable in patients and provide a plausibly effective dose range for initial phase 2 clinical studies.

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.

Efficacy of Nikkomycin Z for respiratory coccidioidomycosis in naturally infected dogs.

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with antifungal efficacy against Coccidioides spp. and other endemic fungi. Dogs suffer a rate and range of natural coccidioidomycosis similar to humans and were considered an excellent model for initially testing NikZ against naturally acquired disease. Twelve dogs with coccidioidal pneumonia that had been present for an average of three months were treated with 250 mg (5-15 kg) or 500 mg (> 15-30 kg) twice daily for 60 days. Nine dogs completed the course of treatment and seven dogs had improvement in disease based on radiographs, clinicopathological parameters, physical examination findings, and subjective assessment by owners; three dogs had resolution or near resolution of disease. Based on this small study, NikZ shows efficacy to treat naturally acquired coccidioidomycosis and merits further development for trials in humans.

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.

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.