Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

Animal Models in Regulatory Breakpoint Determination: Review of New Drug Applications of Approved Antibiotics from 2014-2022.

We sought to better understand the utility and role of animal models of infection for Food and Drug Administration (FDA)-approved antibiotics for the indications of community-, hospital-acquired-, and ventilator-associated bacterial pneumonia (CABP, HABP, VABP), complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), and acute bacterial skin and structural infections (ABSSSIs). We reviewed relevant documents from new drug applications (NDA) of FDA-approved antibiotics from 2014-2019 for the above indications. Murine neutropenic thigh infection models supported the choice of a pharmacokinetic-pharmacodynamic (PKPD) target in 11/12 NDAs reviewed. PKPD targets associated with at least a 1-log bacterial decrease were commonly considered ideal (10/12 NDAs) to support breakpoints. Plasma PK, as opposed to organ specific PK, was generally considered most reliable for PKPD correlation. Breakpoint determination was multi-disciplinary, accounting at minimum for epidemiologic cutoffs, non-clinical PKPD, clinical exposure-response and clinical efficacy. Non-clinical PKPD targets in combination with probability of target attainment (PTA) analyses generated breakpoints that were consistent with epidemiologic cutoffs and clinically derived breakpoints. In 6/12 NDAs, there was limited data to support clinically derived breakpoints, and hence the non-clinical PKPD targets in combination with PTA analyses played a heightened role in the final breakpoint determination. Sponsor and FDA breakpoint decisions were in general agreement. Disagreement may have arisen from differences in the definition of the optimal PKPD index or the ability to extrapolate protein binding from animals to humans. Overall, murine neutropenic thigh infection models supported the reviewed NDAs by providing evidence of pre-clinical efficacy and PKPD target determination, and played, in combination with PTA analysis, a significant role in breakpoint determination for labeling purposes.

Seraph 100 Microbind Affinity Blood Filter Does Not Clear Antibiotics: An Analysis of Antibiotic Concentration Data from PURIFY-OBS.

INTRODUCTION: Novel hemoperfusion systems are emerging for the treatment of sepsis. These devices can directly remove pathogens, pathogen-associated molecular patterns, cytokines, and other inflammatory markers from circulation. However, significant safety concerns such as potential antibiotic clearance need to be addressed prior to these devices being used in large clinical studies. METHODS: Prospective, observational study of 34 participants undergoing treatment with the Seraph 100® Microbind Affinity Blood Filter (Seraph 100) device at 6 participating sites in the USA. Patients were included for analysis if they had a record of receiving an antibiotic concurrent with Seraph 100 treatment. Patients were excluded if there was missing information for blood flow rate. Blood samples were drawn pre- and post-filter at 1 h and 4 h after treatment initiation. These average pre- and post-filter time-concentration observations were then used to estimate antibiotic clearance in L/h (CLSeraph) due to the Seraph 100 device. RESULTS: Of the 34 participants in the study, 17 met inclusion and exclusion criteria for the antibiotic analysis. Data were obtained for 7 antibiotics (azithromycin, cefazolin, cefepime, ceftriaxone, linezolid, piperacillin, and vancomycin) and one beta-lactamase inhibitor. Mean CLSeraph for the antibiotics investigated ranged from -0.57 to 0.47 L/h. No antibiotic had a CLSeraph statistically significant from 0. DISCUSSION/CONCLUSION: The Seraph 100 did not significantly clear any measured antibiotic in clinical samples. These data give further evidence to suggest that these therapies may be safely administered to critically ill patients and will not impact concentrations of administered antibiotics.

Daily Naltrexone Use Does Not Adversely Affect Physical, Cognitive or Marksmanship Performance in U.S. Army Soldiers.

INTRODUCTION: Considering the potential of weaponized opioids, evaluating how prophylactic countermeasures affect military-relevant performance is necessary. Naltrexone is a commercially available Food and Drug Administration-approved medication that blocks the effects of opioids with minimal side effects. However, the effects of naltrexone on the health and performance of non-substance abusing military personnel are not well described in the existing literature. METHODS: Active duty U.S. Army Soldiers (n = 16, mean ± SD, age: 23.1 ± 5.3 y) completed a series of physical, cognitive, and marksmanship tasks during a 4-day pretrial, a 7-day active trial, and a 4-day post-trial phase. During the active trial, participants were administered 50 mg of oral naltrexone daily. Physiological and biological processes were monitored with a daily review of systems, sleep monitoring, biochemistry, and hematology blood panels. RESULTS: Naltrexone did not negatively affect physical performance, cognitive functioning, marksmanship, or sleep duration (P > 0.05). Improvements were observed during the active trial compared to the pretrial phase in cognitive tasks measuring logical relations (P = 0.05), matching to sample (P = 0.04), math speed (P < 0.01), math percent correct (P = 0.04), and spatial processing (P < 0.01). Results from biochemistry and hematology blood panels remained within clinically normative ranges throughout all phases of the study. No participants were medically withdrawn; however, one participant voluntarily withdrew due to nausea and reduced appetite. CONCLUSIONS: Temporary (7-day) daily use of naltrexone was safe and did not negatively affect physical performance, cognitive functioning, marksmanship ability, or sleep in a healthy cohort of U.S. Army Soldiers.

Impact of Blast Overpressure on the Pharmacokinetics of Various Antibiotics in Sprague Dawley Rats.

INTRODUCTION: Combat injuries are complex and multimodal. Most injuries to the extremities occur because of explosive devices such as improvised explosive devices. Blast exposure dramatically increases the risk of infection in combat wounds, and there is limited available information on the best antibiotic treatments for these injuries. We previously demonstrated that mice exposed to blast displayed a delayed clearance of cefazolin from the plasma and liver; further semi-mechanistic modeling determined that cefazolin concentrations in the skin of these mice were reduced. Our objective was to investigate the effects of blast on the pharmacokinetics of antibiotics of different types used for the treatment of combat wounds in the rat model. MATERIALS AND METHODS: Male Sprague Dawley rats were exposed to blast overpressure followed by injection of a bolus of animal equivalent doses of an antibiotic (cefazolin, cefepime, ertapenem, or clindamycin) into the tail vein at 1-hour post-blast exposure. Blood was collected at predetermined time points via repeated sampling from the tail vein. Animals were also euthanized at predetermined time points, at which time liver, kidney, skin, and blood via cardiac puncture were collected. Antibiotic concentrations were determined by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Blast-exposed rats exhibited a similar rate of clearance compared to non-blasted rats in the blood, liver, kidney, and skin, which is inconsistent with the data regarding cefazolin in blast-exposed mice. CONCLUSIONS: Our results in rats do not recapitulate our previous observation of delayed cefazolin clearance in mice following the blast overpressure exposure. Although using rats permitted us to collect multiple blood samples from the same animals, rats may not be a suitable model for measuring the pharmacokinetics of antibiotics following blast. The interpretation of the results may be challenging because of variation in data among rat subjects in the same sample groups.

Systematic Review and Meta-Analysis of the Effect of Loop Diuretics on Antibiotic Pharmacokinetics.

Loop diuretics and antibiotics are commonly co-prescribed across many clinical care settings. Loop diuretics may alter antibiotic pharmacokinetics (PK) via several potential drug interactions. A systematic review of the literature was performed to investigate the impact of loop diuretics on antibiotic PK. The primary outcome metric was the ratio of means (ROM) of antibiotic PK parameters such as area under the curve (AUC) and volume of distribution (Vd) on and off loop diuretics. Twelve crossover studies were amenable for metanalysis. Coadministration of diuretics was associated with a mean 17% increase in plasma antibiotic AUC (ROM 1.17, 95% CI 1.09-1.25, I2 = 0%) and a mean decrease in antibiotic Vd by 11% (ROM 0.89, 95% CI 0.81-0.97, I2 = 0%). However, the half-life was not significantly different (ROM 1.06, 95% CI 0.99-1.13, I2 = 26%). The remaining 13 observational and population PK studies were heterogeneous in design and population, as well as prone to bias. No large trends were collectively observed in these studies. There is currently not enough evidence to support antibiotic dosing changes based on the presence or absence of loop diuretics alone. Further studies designed and powered to detect the effect of loop diuretics on antibiotic PK are warranted in applicable patient populations.

Systematic Review of Safety of Selective Androgen Receptor Modulators in Healthy Adults: Implications for Recreational Users.

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI.

Beta-Lactam Probability of Target Attainment Success: Cefepime as a Case Study.

INTRODUCTION: Probability of target attainment (PTA) analysis using Monte Carlo simulations has become a mainstay of dose optimization. We highlight the technical and clinical factors that may affect PTA for beta-lactams. METHODS: We performed a mini review in adults to explore factors relating to cefepime PTA success and how researchers incorporate PTA into dosing decisions. In addition, we investigated, via simulations with a population pharmacokinetic (PK) model, factors that may affect cefepime PTA success. RESULTS: The mini review included 14 articles. PTA results were generally consistent, given the differences in patient populations. However, dosing recommendations were more varied and appeared to depend on the definition of pharmacodynamic (PD) target, definition of PTA success and specific clinical considerations. Only 3 of 14 articles performed formal toxicological analysis. Simulations demonstrated that the largest determinants of cefepime PTA were the choice of PD target, continuous vs. intermittent infusion and creatinine clearance. Assumptions for protein binding, steady state vs. first dose, and simulating different sampling schemes may impact PTA success under certain conditions. The choice of one or two compartments had a minimal effect on PTA. CONCLUSIONS: PTA results may be similar with different assumptions and techniques. However, dose recommendation may differ significantly based on the selection of PD target, definition of PTA success and considerations specific to a patient population. Demographics and the PK parameters used to simulate time-concentration profiles should be derived from patient data applicable to the purpose of the PTA. There should be strong clinical rationale for dose selection. When possible, safety and toxicity should be considered in addition to PTA success.

Hemoperfusion with Seraph 100 Microbind Affinity Blood Filter Unlikely to Require Increased Antibiotic Dosing: A Simulations Study Using a Pharmacokinetic/Pharmacodynamic Approach.

INTRODUCTION: The Seraph® 100 Microbind® Affinity Blood Filter (Seraph 100) is a hemoperfusion device that can remove pathogens from central circulation. However, the effect of Seraph 100 on achieving pharmacodynamic (PD) targets is not well described. We sought to determine the impact of Seraph 100 on ability to achieve PD targets for commonly used antibiotics. METHODS: Estimates of Seraph 100 antibiotic clearance were obtained via literature. For vancomycin and gentamicin, published pharmacokinetic models were used to explore the effect of Seraph 100 on ability to achieve probability of target attainment (PTA). For meropenem and imipenem, the reported effect of continuous kidney replacement therapy (CKRT) on achieving PTA was used to extrapolate decisions for Seraph 100. RESULTS: Seraph 100 antibiotic clearance is likely less than 0.5 L/h for most antibiotics. Theoretical Seraph 100 clearance up to 0.5 L/h and 2 L/h had a negligible effect on vancomycin PTA in virtual patients with creatinine clearance (CrCl) = 14 mL/min and CrCl >14 mL/min, respectively. Theoretical Seraph 100 clearance up to 0.5 L/h and 2 L/h had a negligible effect on gentamicin PTA in virtual patients with CrCl = 120 mL/min and CrCl <60 mL/min, respectively. CKRT intensity resulting in antibiotic clearance up to 2 L/h generally does not require dose increases for meropenem or imipenem. As Seraph 100 is prescribed intermittently and likely contributes far less to antibiotic clearance, dose increases would also not be required. CONCLUSION: Seraph 100 clearance of vancomycin, gentamicin, meropenem, and imipenem is likely clinically insignificant. There is insufficient evidence to recommend increased doses. For aminoglycosides, we recommend extended interval dosing and initiating Seraph 100 at least 30 min to 1 h after completion of infusion to avoid the possibility of interference with maximum concentrations.

Comparison of Piperacillin and Tazobactam Pharmacokinetics in Critically Ill Patients with Trauma or with Burn.

Critical illness caused by burn and sepsis is associated with pathophysiologic changes that may result in the alteration of pharmacokinetics (PK) of antibiotics. However, it is unclear if one mechanism of critical illness alters PK more significantly than another. We developed a population PK model for piperacillin and tazobactam (pip-tazo) using data from 19 critically ill patients (14 non-burn trauma and 5 burn) treated in the Military Health System. A two-compartment model best described pip-tazo data. There were no significant differences found in the volume of distribution or clearance of pip-tazo in burn and non-burn patients. Although exploratory in nature, our data suggest that after accounting for creatinine clearance (CrCl), doses would not need to be increased for burn patients compared to trauma patients on consideration of PK alone. However, there is a high reported incidence of augmented renal clearance (ARC) in burn patients and pharmacodynamic (PD) considerations may lead clinicians to choose higher doses. For critically ill patients with normal kidney function, continuous infusions of 13.5-18 g pip-tazo per day are preferable. If ARC is suspected or the most stringent PD targets are desired, then continuous infusions of 31.5 g pip-tazo or higher may be required. This approach may be reasonable provided that therapeutic drug monitoring is enacted to ensure pip-tazo levels are not supra-therapeutic.

Pharmacokinetics, safety and efficacy of intra-articular non-steroidal anti-inflammatory drug injections for the treatment of osteoarthritis: A narrative review.

WHAT IS KNOWN AND OBJECTIVE: Osteoarthritis (OA) is a common cause of joint disease and activity limitation in adults. Common therapies to treat OA-related pain are oral and topical non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular (IA) corticosteroids. However, prolonged courses of oral NSAIDs are associated with systemic adverse effects and repeat IA corticosteroid injections may cause cartilage degeneration. IA NSAIDs may be an alternative therapy possibly minimizing systemic side effects while maintaining efficacy. Therefore, we sought to summarize the pharmacokinetics, safety and efficacy of IA NSAIDs to help providers make a more informed decision on the use of IA NSAIDs. METHODS: We searched the National Library of Medicine Database with terms "intraarticular and nsaid", yielding 1032 results. Only traditional formulations of NSAIDs were considered for inclusion. Animal studies were included if animals were healthy or if the method of arthritis induction was a reasonable model of osteoarthritis. Human studies were included if humans were healthy or if the primary disease studied was osteoarthritis of a large joint. Of 1032 results, 31 research articles met the inclusion criteria and were summarized in this review. RESULTS AND DISCUSSION: We found that single doses of IA NSAIDs provided far less total systemic and synovial exposure compared to a one week course of oral NSAIDs, but maximum concentrations to the synovium with IA administration were much higher. IA NSAIDs had an excellent safety profile in small animals, large animals and humans, although these injections were associated with non-specific cartilage inflammation in healthy animals. In animal models, IA NSAIDs had similar efficacy to PO NSAIDs in treating OA-related pain. In humans, IA NSAIDs had similar efficacy to PO NSAIDS and IA corticosteroids in treating OA-related pain; however, many trials did not have a placebo control and outcome measures were heterogeneous. WHAT IS NEW AND CONCLUSION: Overall, single doses of IA NSAIDs appear safe and efficacious across animals and humans. The optimal use of IA NSAIDs is still to be determined and further research is needed. However IA NSAIDs may be an additional beneficial therapy to treat OA-related pain. Potential uses may be to augment IA corticosteroids injections, to interrupt multiple IA corticosteroid injections or as an alternative in patients that are high risk for corticosteroid-related adverse events.

Pharmacokinetics of piperacillin and tazobactam in critically Ill patients treated with continuous kidney replacement therapy: A mini-review and population pharmacokinetic analysis.

WHAT IS KNOWN AND OBJECTIVE: Timely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement therapy (CKRT) often have physiologic derangements that affect pharmacokinetics (PK) of antibiotics and dosing may be challenging. We sought to aggregate previously published piperacillin and tazobactam (pip-tazo) pharmacokinetic data in critically ill patients undergoing CKRT to better understand pharmacokinetics of pip-tazo in this population and better inform dosing. METHODS: The National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn. RESULTS AND DISCUSSION: Median and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA. WHAT IS NEW AND CONCLUSION: Pip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.

Applying Pharmacogenomic Guidelines to Combat Medical Care.

Pharmacogenomics is a pillar of personalized medicine that has the potential to deliver optimized treatment in many medical settings. Military medicine in the deployed setting is unique and therefore warrants separate assessment pertaining to its potential capabilities and impact. Pharmacogenomics for United States Active Duty Service Members medical care in the deployed setting has not, to our knowledge, been previously reviewed. We present potential applications of pharmacogenomics to forward medical care through two comprehensive references for deployed medical care, the Tactical Combat Casualty Care Guidelines (TCCC) and Emergency War Surgery (EWS) fifth edition. All drugs within the deployment manuals, TCCC guidelines and EWS book, were identified and the list was cross-referenced to the Clinical Pharmacogenetics Implementation Consortium guidelines and genes-drugs interactions list as well as the Food and Drug Administration Table of Pharmacogenomics Biomarkers in Drug Labeling. Ten pharmacologic categories were identified, consisting of 15 drugs, along with the classes, aminogylcosides, beta-blockers, and volatile anesthetics. Drugs and pharmacogenomics liabilities were tabulated. Eight specific drugs or classes are expounded upon given the belief of the authors of their potential for impacting future treatment on the battlefield in the setting of prolonged field care. This review outlines several genes with liabilities in the prolonged field care setting and areas that may produce improved care with further study.

Evaluation of Pharmacogenomics Testing of Cytochrome P450 Enzymes in the Military Health System From 2015 to 2020.

Pharmacogenomics (PGx) plays a fundamental role in personalized medicine, providing an evidence-based treatment approach centered on the relationship between genomic variations and their effect on drug metabolism. Cytochrome P450 (CYP450) enzymes are responsible for the metabolism of most clinically prescribed drugs and a major source of variability in drug pharmacokinetics and pharmacodynamics. To assess the prevalence of PGx testing within the Military Health System (MHS), testing of specific CYP450 enzymes was evaluated. Data were retrospectively obtained from the Military Health System Management Analysis and Reporting Tool (M2) database. Patient demographics were identified for each test, along with TRICARE status, military treatment facility, clinic, and National Provider Identifier. A total of 929 patients received 1,833 PGx tests, predominantly composed of active duty/guard service members (N = 460; 49.5%), with highest testing rates in the army (51.5%). An even distribution in testing was observed among gender, with the highest rates in Caucasians (41.7%). Of the CYP enzymes assessed, CYP2C19 and CYP2D6 accounted for 87.8% of all PGx CYP testing. The majority of patients were tested in psychiatry clinics (N = 496; 53.4%) and primary care clinics (N = 233; 25.1%), accounting for 56.4% and 24.8% of all tests, respectively. Testing was found to be provider driven, suggesting a lack of a standardized approach to PGx and its application in patient care within the MHS. We initially recommend targeted education and revising testing labels to be more uniform and informative. Long-term recommendations include establishing pharmacy-driven protocols and point-of-care PGx testing to optimize patient outcomes.

Prescription Patterns and Relationship to Pharmacogenomics Testing in the Military Health System.

INTRODUCTION: Clinical utilization of pharmacogenomics (PGx) testing is highly institutionally dependent, and little information is known about provider practices of PGx testing in the Military Health System (MHS). In this study, we aimed to characterize Clinical Pharmacogenetics Implementation Consortium (CPIC) actionable prescription (Rx) patterns and their temporal relationship with PGx testing in the MHS. METHODS: Using data from the Military Health System Management Analysis and Reporting Tool (M2) database, this retrospective cohort study included all patients receiving at least one PGx test and at least one CPIC actionable Rx from January 2015 to August 2020 (845 patients, 1,471 PGx, 7,725 index CPIC actionable Rxs). Rx patterns and temporal relationships with PGx testing were characterized via descriptive statistics. Binomial regression was used to determine which patient and provider characteristics were associated with a patient receiving a PGx test within 30 days of an index Rx. RESULTS: Patients had a median of 9 index CPIC actionable Rx's (range 1-26). Pain medications were most commonly prescribed (N = 794, 94% patients with at least 1 Rx). However, pain medication had the lowest Rx-PGx match rate (40%) compared to an average of 62% Rx-PGx match rate for all CPIC drugs. Antidepressants were also commonly prescribed (N = 668, 79.1% patients with at least 1 Rx), and antidepressants had the highest Rx-PGx match rate of 86.7%. A minority of providers (20%, N = 249) ordered the majority of PGx tests (86.1%, N = 1,266) and only 8.3% of PGx tests (N = 398) matched to a CPIC actionable drug within 30 days of the test (defined by Rxs ordered within 30 days before or after the PGx test). However, approximately 39.8% of patients (N = 317) had at least one drug match to a PGx test within 30 days. The largest predictor of whether a patient received a PGx test within 30 days of any index Rx was whether or not a specific psychiatry provider ordered the PGx test (odds ratio; OR 3.7, 95% CI 2.13-6.54, P < 0.001). Neither the CPIC level of evidence nor FDA PGx actionable or informative labels had a significant effect on PGx test timing. CONCLUSIONS: PGx testing was generally limited to high Rx-drug users and was found to be an under-utilized resource. PGx testing did not typically follow CPIC guidelines. Implementing PGx testing protocols, simplifying PGx test-ordering by incorporating at minimum CYP2D6, CYP2C19, and CYP2C9 into PGx-testing panels, and unifying providers' PGx knowledgebase in the MHS are feasible and would improve the clinical utilization of PGx tests in the MHS.

Semimechanistic Modeling of the Effects of Blast Overpressure Exposure on Cefazolin Pharmacokinetics in Mice.

Cefazolin is a first-line antibiotic to treat infection related to deployment-associated blast injuries. Prior literature demonstrated a 331% increase cefazolin liver area under the curve (AUC) in mice exposed to a survivable blast compared with controls. We repeated the experiment, validated the findings, and established a semimechanistic two-compartment pharmacokinetic (PK) model with effect compartments representing the liver and skin. We found that blast statistically significantly increased the pseudo-partition coefficient to the liver by 326% (95% confidence interval: 76-737%), which corresponds to the observed 331% increase in cefazolin liver AUC described previously. To a lesser extent, plasma AUC in blasted mice increased 14-45% compared with controls. Nevertheless, the effects of blast on cefazolin PK were transient, normalizing by 10 hours after the dose. It is unclear as to how this blast effect t emporally translates to humans; however, given the short-lived effect on PK, there is insufficient evidence to recommend cefazolin dosing changes based on blast overpressure injury alone. Clinicians should be aware that cefazolin may cause drug-induced liver injury with a single dose and the risk may be higher in patients with blast overpressure injury based on our findings. SIGNIFICANCE STATEMENT: Blast exposure significantly, but transiently, alters cefazolin pharmacokinetics in mice. The questions of whether other medications or potential long-term consequences in humans need further exploration.

An open label study of the safety and efficacy of a single dose of weekly chloroquine and azithromycin administered for malaria prophylaxis in healthy adults challenged with 7G8 chloroquine-resistant Plasmodium falciparum in a controlled human malaria infection model.

BACKGROUND: Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro. METHODS: In this open label study, 18 healthy volunteers, aged 18-50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge. RESULTS: All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28-41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did. CONCLUSION: Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808.

Risk of type 2 diabetes mellitus by antimuscarinic agents among adult females receiving care in the military health system.

PURPOSE: To explore patterns of antimuscarinic medication as a risk factor for type 2 diabetes mellitus (T2DM). METHODS: This is a retrospective cohort study of females 18 years or older within the Military Health System from 2006 to 2016. Administrative and claims data were used to select patients who initiated therapy with tolterodine, fesoterodine, oxybutynin, darifenacin, solifenacin, or trospium. Patients with no documented history of T2DM were followed for the occurrence of T2DM, the end of the study or loss of eligibility. Rates of T2DM were calculated for the overall population, by duration of therapy and by individual drugs. Crude and adjusted Cox proportional hazards were calculated to assess differences by duration of use and specific muscarinic antagonist. RESULTS: Over 2.6 million antimuscarinic prescriptions were dispensed to 241 829 females (mean age/SD, 62 ± 18 years). Patients exposed to M3 selective antagonists had highest risk of developing T2DM compared to those exposed to nonselective antagonists. Using oxybutynin, a nonselective antagonist as a comparator, adjusted rate ratios of T2DM were 57% (HR 1.57, 95%CI 1.48-1.67) and 29% (HR 1.29, 95%CI 1.24-1.35) significantly higher for darifenacin and solifenacin, respectively (both M3 selective). CONCLUSIONS: We found exposure to M3 selective antagonists darifenacin and solifenacin had the highest risk of developing T2DM compared to nonselective antagonist oxybutynin. This is supported by well described physiologic mechanisms and may allow for more informed prescribing decisions, particularly if minimizing risk of T2DM is a priority.

Saccharomyces boulardii CNCM I-745 probiotic does not alter the pharmacokinetics of amoxicillin.

Background Probiotics are live microbial organisms that provide benefit to the host while co-habitating in the gastrointestinal tract. Probiotics are safe, available over the counter, and have clinical benefit by reducing the number of antibiotic-associated diarrhea days. Prescriptions from providers and direct consumer demand of probiotics appear to be on the rise. Several recent animal studies have demonstrated that probiotics may have significant effect on absorption of co-administered drugs. However, to date, most probiotic-drug interaction studies in animal models have been limited to bacterial probiotics and nonantibiotic drugs. Methods We performed a traditional pharmacokinetic mouse study examining the interactions between a common commercially available yeast probiotic, Saccharomyces boulardii CNCM I-745 (Florastor®) and an orally administered amoxicillin. Results We showed that there were no significant differences in pharmacokinetic parameters (half-life, area under the curve, peak concentrations, time to reach maximum concentration, elimination rate constant) of amoxicillin between the probiotic treated and untreated control groups. Conclusions Altogether, our findings suggest that coadministration or concurrent use of S. boulardii probiotic and amoxicillin would not likely alter the efficacy of amoxicillin therapy.

Toward Personalized Medicine Implementation: Survey of Military Medicine Providers in the Area of Pharmacogenomics.

INTRODUCTION: Personalized medicine is the right treatment, to the right patient, at the right dose. Knowledge of genetic predisposition to variable metabolism and distribution of drugs within the body is currently available as pharmacogenomic testing and is one of the pillars of personalized medicine. Pharmacogenomic testing is growing. It has become part of guidelines for dosing on FDA labels and has been used by health care organizations to improve outcomes and reduce adverse events. Additionally, it has been FDA approved for direct-to-consumer purchase and has been cause of concern of patient self-dosing and medication changes. Presumably in the near future, pharmacogenomics will be impressed upon the military health system (MHS) provider from either a top-down, command requested, or from a bottom-up, patient requested, approach. To date, widespread implementation of pharmacogenomic testing does not seem to be established within the MHS. This survey sheds light on the knowledge, exposure, use, comfort, and interest among family medicine providers in the MHS. It compares similar results in other national and international surveys and compares results among a small subset of residents to staff. MATERIALS AND METHODS: The questions were part of a larger survey conducted by the Clinical Investigations Committee of the Uniformed Services Academy of Family Physicians (USAFP) at the USAFP 2019 annual meeting. The study received approval from the Uniformed Services University Institutional Review Board. Submitted questions were written using multiple choice, fill-in, five-point Likert scale, and best answer. Direct results are reported as well as chi-square statistics for categorical data with statistical significance to attain a P-value of < 0.05. RESULTS: Among the 532 USAFP-registered conference attendees eligible to complete the survey, 387 attendees responded to the survey, for a response rate of 72.7%. Some results included were a knowledge question in which 37% of respondents answered correctly. Less than half of respondents agreed that they could define pharmacogenomics, and resident respondents were more likely to have received teaching in graduate medical education. Additionally, 12% of providers responded to being exposed to direct-to-consumer results, and 28% of those exposed were influenced to change medications, while 14% were influenced to change medications on multiple occasions. Chi-square comparisons resulted in statistically significant direct relationships to exposure to direct to consumer testing, previous training, and confidence of those that answered the knowledge question correctly. CONCLUSIONS: This survey establishes a baseline for the possible needs associated with implementation of a pharmacogenomic program, and it argues an actionable level for the use of pharmacogenomics among the patient population within the MHS.