Animal pharmacokinetics/pharmacodynamics (PK/PD) infection models for clinical development of antibacterial drugs: lessons from selected cases.

In the wake of emerging antimicrobial resistance, antibacterial drug development has become more critical. At the same time, development of antibacterial drugs targeting specific pathogens or resistance phenotypes that may have low prevalence presents challenges because it is difficult to conduct large, randomized controlled trials for such drugs. Animal models have increasingly supported clinical development of antibacterials; however, more work is needed to optimize the design and application of these animal models to ensure clear and actionable translation to further human investigation. This review discusses recent case studies of animal infection models used to support antibacterial drug development in order to illuminate considerations for future development of novel antibacterial drugs.

A Review of Genome-Based Precision Medicine Efforts Within the Department of Defense.

INTRODUCTION: Providing patient-specific clinical care is an expanding focus for medical professionals and researchers, more commonly referred to as personalized or precision medicine. The goal of using a patient-centric approach is to provide safer care while also increasing the probability of therapeutic success through careful consideration of the influence of certain extrinsic and intrinsic human factors in developing the patient care plan. Of increasing influence on patient care is the phenotype and genotype information gathered from employing various next-generation sequencing methods. Guided by and partnered with our civilian colleagues, clinical components within the DoD are embracing and advancing genomic medicine in many facets-from the bench to the bedside-and in many therapeutic areas, from Psychiatry to Oncology. In this PubMed-based review, we describe published clinical research and interventions within the DoD using genome-informed data and emphasize precision medicine efforts in earlier stages of development with the potential to revolutionize the approach to therapeutics. MATERIALS AND METHODS: The new PubMed database was searched for articles published between 2015 and 2020 with the following key search terms: precision medicine, genomic, pharmacogenetic, pharmacogenomic, US military, and Department of Defense. RESULTS: Eighty-one articles were retrieved in our initial search. After screening the abstracts for studies that only involved direct testing of (or clinical interaction with) active duty, Reserve, National Guard, or civilian personnel working within the DoD and excluding any epidemiological or microbial isolation studies, seven were included in this review. CONCLUSION: There are several programs and studies within the DoD, which investigate or use gene-based biomarkers or gene variants to deliver more precise clinical assessment and treatment. These genome-based precision medicine efforts aim to optimize the clinical care of DoD beneficiaries, particularly service members in the operational environment.

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.

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.