Plerixafor is a CXCR4 antagonist approved in 2008 by the FDA for hematopoietic stem cell collection. Subsequently, plerixafor has shown promise as a potential pathogen-agnostic immunomodulator in a variety of preclinical animal models. Additionally, investigator-led studies demonstrated plerixafor prevents viral and bacterial infections in patients with WHIM syndrome, a rare immunodeficiency with aberrant CXCR4 signaling.
View Article and Find Full Text PDFWe 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.
View Article and Find Full Text PDFIntroduction: 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.
View Article and Find Full Text PDFIntroduction: 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.
View Article and Find Full Text PDFIntroduction: 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.
View Article and Find Full Text PDFLoop 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.
View Article and Find Full Text PDFSelective 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.
View Article and Find Full Text PDFAntibiotics (Basel)
February 2023
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.
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.
View Article and Find Full Text PDFIntroduction: 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.
View Article and Find Full Text PDFWhat 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.
View Article and Find Full Text PDFWhat 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.
View Article and Find Full Text PDFIntroduction: 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).
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.
View Article and Find Full Text PDFPharmacogenomics 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.
View Article and Find Full Text PDFIntroduction: Severe burn injury involves widespread skin and tissue damage leading to systemic inflammation, hypermetabolism and multi-organ failure. The hypermetabolic phase of burn injury has been associated with increased systemic antibiotic clearance; however, critical illness in the absence of burn may also induce similar physiologic changes. Continuous renal replacement therapy (CRRT) is often implemented in critically ill patients and may also affect antibiotic clearance.
View Article and Find Full Text PDFCefazolin 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.
View Article and Find Full Text PDFContinuous venovenous hemofiltration (CVVH) is a life-sustaining procedure in patients with severe burns and acute kidney injury. Physiologic changes from burn injury and use of CVVH may alter imipenem pharmacokinetics (PK). We aimed to compare imipenem clearance (CL) in burn patients with and without CVVH, determine the effect of burn on imipenem volume of distribution (CVVH, n = 12; no CVVH, n = 11), in combination with previously published models.
View Article and Find Full Text PDFBackground: Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments.
View Article and Find Full Text PDFPurpose: 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.
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.
View Article and Find Full Text PDFIntroduction: 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.
View Article and Find Full Text PDFObjective: Abiraterone is a relatively noncytotoxic drug approved by the US Food and Drug Administration in 2011 for the treatment of metastatic prostate cancer (MPC). As an inhibitor of 17α-hydroxylase and C17,20-lyase (CYP17), abiraterone blocks androgen synthesis and glucocorticoid production. Decreased cortisol levels result in an increased ACTH release, which can lead to increased mineralocorticoid levels.
View Article and Find Full Text PDFIntroduction: The United States Military Health System provides healthcare to a diverse patient population throughout the world. There are three distinct challenges that the Military Health System faces. (1) Providers have varying degrees of clinical training expertise and may be called upon to practice outside their usual scope of care.
View Article and Find Full Text PDFThe authors present a case of an elderly man with a history of Waldenstrom macroglobulinaemia in remission who presented with progressively worsening gait abnormalities and falls for several months. His examination was notable for bilateral lower extremity weakness and an unsteady gait. Brain and spinal MRI showed focal leptomeningeal enhancement in the brain and spinal column.
View Article and Find Full Text PDF