Female-Specific Health Care of Military Female-Designated Service Members and Veterans: A Systematic Overview of Reviews.

INTRODUCTION: Since the War in Afghanistan began in 2001, service members have faced significant health effects related to service during war, with female-designated service members facing unique challenges. Numerous high-quality review articles have been published on the health and care of female-designated service members and veterans. Given the increasing volume of literature, we completed an overview of reviews on the health and health care of female-designated military populations. Our objective was to conduct an overview of reviews on the obstetrics and gynecologic health and health care of female-designated military populations since 2000 to understand female-specific health consequences of military service during war and make clinical recommendations. MATERIALS AND METHODS: On May 10, 2022, a medical librarian performed a comprehensive search across five databases (Ovid Medline, Embase, CINAHL, PsycINFO, Ovid All EBM Reviews, and Web of Science) for all relevant reviews published from 2000 to May 10, 2022. Results were limited to English language. After the removal of duplicates, 2,438 records were reviewed, and 69 studies were included in the final review. The search strategy and methods were registered with PROSPERO and are reported according to the Preferred Reporting Items for Overviews of Reviews (PRIOR) guidelines. Two independent reviewers conducted title and abstract screening and subsequent full text review using Covidence Systematic Review Software. Reviews addressing female-specific and obstetrics and gynecologic health of female-designated service members or veterans, utilizing a clear and systematic methodology, were eligible for inclusion. Quality assessment was conducted by teams of two reviewers. RESULTS: A total of 69 studies were included in the final review. Themes included mental health and impact of sexual assault on service members or veterans, veteran health care, issues of menstruation, pregnancy, and urogenital concerns. Areas with few reviews included occupational risks of military service and impact on obstetric outcomes, eating disorders, and menopause. There were insufficient or no reviews on the impact of military service on fertility, access to abortion care, reproductive health outcomes of lesbian, bisexual and transgender service members, surgical treatment of gynecologic conditions, and screening and treatment for breast, gynecologic, and non-pelvic organ cancers. CONCLUSIONS: Female-designated military populations serving during periods of war face unique health challenges that should be considered in screening practices and the delivery of trauma informed care. Further research and reviews are needed for female-specific oncology, fertility, abortion access, and sexual and non-binary and expansive gender identities to better capture female-designated service member and veteran health during wartime and beyond.

"Primum Non Nocere"-First, Do No Harm: A Retrospective Review of the Impact of Curricular Reform on USUHS Graduates' Performance During Their PGY-1 Year.

PURPOSE: To determine whether medical school curricular change impacted the assessment of graduates in their first year of postgraduate training. METHODS: The authors examined for differences in the survey of postgraduate year one (PGY-1) program directors for Uniformed Services University (USU) medical school graduates from the Classes of 2011 and 2012 (pre-curriculum reform, pre-CR), Classes of 2015, 2016, and 2017 (curriculum transition), and Classes of 2017, 2018, and 2019 (post-curriculum reform, post-CR). Multivariate analysis of variance was used to explore for differences among the cohorts in the 5 previously identified factors on the PGY-1 survey (Medical Expertise; Professionalism; Military Unique Practice, Deployments and Humanitarian Missions; System-Based Practice and Practiced-Based Learning; Communication and Interpersonal Skills). Nonparametric tests were used when the error variance between cohorts was found to be unequal across samples. Kruskal-Wallis (a rank ordered analysis of variance) and Tamhan's T2 were used to characterize specific differences. RESULTS: There were 801 students included: 245 (pre-CR); 298 (curricular transition); and 212 (post-CR). Multivariate analysis of variance demonstrated significant differences in all survey factors among the comparison groups. From pre-CR to the curricular transition, ratings in all factors declined, but none reached the level of a statistical significance. Ratings of all 5 factors showed significant improvement from the curricular transition to post-CR, and scores from pre-CR to post-CR trended in the positive direction with Practice-Based Learning (effect size 0.77), showing significant gains. CONCLUSION: Ratings by PGY-1 program directors of USU graduates over time demonstrated a very small decline soon after curriculum reform but later showed a large improvement in domains reflecting areas of emphasis in the curriculum. In the eyes of a key stakeholder, the USU curriculum reform did no harm and led to improved PGY-1 assessments.

Evaluating a Competency-Based Blended Health Professions Education Program: A Programmatic Approach.

INTRODUCTION: Competency-based education (CBE) programs usually evaluate student learning outcomes at a course level. However, a more comprehensive evaluation of student achievement of competencies requires evaluation at a programmatic level across all courses. There is currently insufficient literature on accomplishing this type of evaluation. In this article, we present an evaluation strategy adopted by the competency-based master's degree program at the Center for Health Professions Education at the Uniformed Services University of Health Sciences to assess student achievement of competencies. We hypothesized that (1) learners would grow in the competencies through their time in the program and (2) learners would exhibit a behavioristic change as a result of their participation in the program. MATERIALS AND METHODS: The degree program at the Center for Health Professions Education conducts an annual student self-assessment of competencies using a competency survey. The competency survey data from graduated master's students were collected, providing data from three time points: initial (pre-program survey), middle, and final (end-of-program survey). Open-ended responses from these three surveys were also analyzed. A general linear model for repeated measures was conducted. Significant effects were followed by post hoc tests across time. We also conducted post hoc analysis across domains to better understand the comparative levels of the domains at each time point. The responses to the open-ended prompt were thematically analyzed. RESULTS: Analysis of the quantitative data revealed that (1) learners reported significant growth across time, (2) learners had different perceptions of their competencies in each of the domains, and (3) not all domains experienced similar changes over time. Analysis of the free responses highlighted the impact of coursework on competency attainment and the behavioristic change in learners. CONCLUSIONS: This study presents a strategic evaluation tool for course-based CBE programs that follow a traditional credit hour model. Programmatic evaluation of CBE programs should enable the inclusion of the learner's voice and provide evaluation data that go beyond individual course evaluations.

Successful Surgical Airway Performance in the Combat Prehospital Setting: A Qualitative Study of Experienced Military Prehospital Providers.

INTRODUCTION: Military first responders are in a unique category of the healthcare delivery system. They range in skill sets from combat medic and corpsman to nurses, physician assistants, and occasionally, doctors. Airway obstruction is the second leading cause of preventable battlefield death, and the decision for intervention to obtain an airway depends on the casualty's presentation, the provider's comfort level, and the available equipment, among many other variables. In the civilian prehospital setting cricothyroidotomy (cric) success rates are over 90%, but in the US military combat environment success rates range from 0-82%. This discrepancy in success rates may be due to training, environment, equipment, patient factors and/or a combination of these. Many presumed causes have been assumed to be the root of the variability, but no research has been conducted evaluating the first-person point of view. This research study is focused on interviewing military first responders with real-life combat placement of a surgical airway to identify the underlying influences which contribute to their perception of success or failure. MATERIALS AND METHODS: We conducted a qualitative study with in-depth semi-structured interviews to understand participants' real-life cric experiences. The interview questions were developed based on the Critical Incident Questionnaire. In total, there were 11 participants-4 retired military and 7 active-duty service members. RESULTS: Nine themes were generated from the 11 interviews conducted. These themes can be categorized into 2 groups: factors internal to the provider, which we have called intrinsic influences, and factors external to the provider, which we call extrinsic influences. Intrinsic influences include personal well-being, confidence, experience, and decision-making. Extrinsic influences include training, equipment, assistance, environment, and patient factors. CONCLUSIONS: This study revealed practitioners in combat settings felt the need to train more frequently in a stepwise fashion while following a well-understood airway management algorithm. More focus must be on utilizing live tissue with biological feedback, but only after anatomy and geospatial orientation are well understood on models, mannequins, and cadavers. The equipment utilized in training must be the equipment available in the field. Lastly, the focus of the training should be on scenarios which stress the physical and mental capabilities of the providers. A true test of both self-efficacy and deliberate practice is forced through the intrinsic and extrinsic findings from the qualitative data. All of these steps must be overseen by expert practitioners. Another key is providing more time to focus on medical skills development, which is critical to overall confidence and overcoming hesitation in the decision-making process. This is even more specific to those who are least medically trained and the most likely to encounter the casualty first, EMT-Basic level providers. If possible, increasing the number of medical providers at the point of injury would achieve multiple goals under the self-efficacy learning theory. Assistance would instill confidence in the practitioner, help with the ability to prioritize patients quickly, decrease anxiety, and decrease hesitation to perform in the combat environment.

A Critical Review of Professional Identity Formation Interventions in Medical Education.

PURPOSE: Professional identity formation (PIF) can be defined as the integration of the knowledge, skills, values, and behaviors of a profession with one's preexisting identity and values. Several different, and sometimes conflicting, conceptualizations and theories about PIF populate the literature; applying these different theories in PIF curricula and pedagogic strategies can profoundly impact the PIF of future physicians. The authors conducted a critical review of the recent literature on PIF interventions in medical education to explore the conceptualizations of and theoretical approaches to PIF that underlie them. METHOD: The authors searched articles on PIF educational interventions published in 5 major medical education journals between 2010 and March 2021. The articles' context and findings were extracted, analyzed, and summarized to identify conceptualizations and theoretical approaches to PIF. RESULTS: The authors identified 43 studies examining medical education interventions aimed at influencing PIF. The majority of the studies (n = 31) focused on undergraduate medical education. Reflective writing and the use of narrative reflections were the dominant modes of student activity in PIF interventions, supporting the dominant individualist approach to PIF. Less commonly PIF was understood as a socialization process or as an active process with both individually and socially focused influences. CONCLUSIONS: Relying on reflective writing as the intervention of choice to impact PIF feeds the dominant individualist perspective on PIF. An unintended consequence of this individualist orientation is that cultural problems embedded in the profession can become burdens for individual physicians to personally bear. Future education and research into PIF should account for theoretical preferences and the impact of these preferences.

Leading the Military Health System Transformation: From Military Treatment Facility to Market Construct.

The transition of authority to manage and administer all DoD Medical Treatment Facilities from the Military Department Services to the Defense Health Agency is an extremely complex challenge involving multiple stakeholders and systems in an effort to achieve greater force readiness while reducing cost. Womack Army Medical Center at Fort Bragg served as the U.S. Army's sole prototype for the initial phase of the transition of authority. Starting with a foundational shift to an organizational outward mindset was essential in building effective relationships to exercise Mission Command at echelon to manage risks to mission during this period of uncertainty and ambiguity. This shift in mindset set the conditions for mobilizing Army Doctrine, elicited, and invited collaborative behaviors, and resulted in the improved organizational performance accomplished with velocity to successfully lead the transformation to Defense Health Agency.

Synergistic activity of ceftobiprole and vancomycin in a rat model of infective endocarditis caused by methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus.

The therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) or glycopeptide-intermediate Staphylococcus aureus (GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 µg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 µg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log(10) CFU/g MRSA or 6 log(10) CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. In in vitro time-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, and in vivo synergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.

Characterization and developmental expression of genes encoding the early carotenoid biosynthetic enzymes in Citrus paradisi Macf.

In the present study, the full-length cDNA sequences of PSY, PDS, and ZDS, encoding the early carotenoid biosynthetic enzymes in the carotenoid pathway of grapefruit (Citrus paradisi), were isolated and characterized for the first time. CpPSY contained a 1311-bp open reading frame (ORF) encoding a polypeptide of 436 amino acids, CpPDS contained a 1659-bp ORF encoding a polypeptide of 552 amino acids, and CpZDS contained a 1713-bp ORF encoding a polypeptide of 570 amino acids. Phylogenetic analysis indicated that CpPSY shares homology with PSYs from Citrus, tomato, pepper, Arabidopsis, and the monocot PSY1 group, while CpPDS and CpZDS are most closely related to orthologs from Citrus and tomato. Expression analysis revealed fluctuations in CpPSY, CpPDS, and CpZDS transcript abundance and a non-coordinated regulation between the former and the two latter genes during fruit development in albedo and juice vesicles of white ('Duncan') and red ('Flame') grapefruits. A 3× higher upregulation of CpPSY expression in juice vesicles of red-fleshed 'Flame' as compared to white-fruited 'Duncan' was observed in the middle stages of fruit development, which correlates with the well documented accumulation pattern of lycopene in red grapefruit. Together with previous data, our results suggest that the primary mechanism controlling lycopene accumulation in red grapefruit involves the transcriptional upregulation of CpPSY, which controls the flux into the carotenoid pathway, and the downregulated expression of CpLCYB2, which controls the step of cyclization of lycopene in chromoplasts during fruit ripening. A correlation between CpPSY expression and fruit color evolution in red grapefruit is demonstrated.

Efficacy of a new fluoroquinolone, JNJ-Q2, in murine models of Staphylococcus aureus and Streptococcus pneumoniae skin, respiratory, and systemic infections.

The in vivo efficacy of JNJ-Q2, a new broad-spectrum fluoroquinolone (FQ), was evaluated in a murine septicemia model with methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) and in a Streptococcus pneumoniae lower respiratory tract infection model. JNJ-Q2 and comparators were also evaluated in an acute murine skin infection model using a community-acquired MRSA strain and in an established skin infection (ESI) model using a hospital-acquired strain, for which the selection of resistant mutants was also determined. JNJ-Q2 demonstrated activity in the MSSA septicemia model that was comparable to that moxifloxacin (JNJ-Q2 50% effective dose [ED(50)], 0.2 mg/kg of body weight administered subcutaneously [s.c.] and 2 mg/kg administered orally [p.o.]) and activity in the MRSA septicemia model that was superior to that of vancomycin (JNJ-Q2 ED(50), 1.6 mg/kg administered s.c.). In an S. pneumoniae lower respiratory tract infection model, JNJ-Q2 displayed activity (ED(50), 1.9 mg/kg administered s.c. and 7.4 mg/kg administered p.o.) that was comparable to that of gemifloxacin and superior to that of moxifloxacin. In both MRSA skin infection models, treatment with JNJ-Q2 resulted in dose-dependent reductions in bacterial titers in the skin, with the response to JNJ-Q2 at each dose exceeding the responses of the comparators ciprofloxacin, moxifloxacin, linezolid, and vancomycin. Additionally, in the ESI model, JNJ-Q2 showed a low or nondetectable propensity for ciprofloxacin resistance selection, in contrast to the selection of ciprofloxacin-resistant mutants observed for both ciprofloxacin and moxifloxacin. JNJ-Q2 demonstrated activity that was comparable or superior to the activity of fluoroquinolone or antistaphylococcal comparators in several local and systemic skin infection models performed with both S. aureus and S. pneumoniae and is currently being evaluated in phase II human clinical trials.

Comparative effects of carbapenems on bacterial load and host immune response in a Klebsiella pneumoniae murine pneumonia model.

Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum ß-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.

Recovery of Candida dubliniensis and other Candida species from the oral cavity of subjects with periodontitis who had well-controlled and poorly controlled type 2 diabetes: a pilot study.

The goal of this study was to determine the prevalence of Candida dubliniensis and other Candida species from saliva samples and from subgingival plaque samples at periodontally healthy and periodontally diseased sites in subjects who had type 2 diabetes and periodontitis. Saliva and subgingival samples were obtained from 30 subjects with periodontitis: 15 with poorly controlled and 15 with well-controlled type 2 diabetes. Samples were analyzed for the presence of C. dubliniensis and other Candida species. Among subjects with poorly controlled diabetes, 53% were positive for C. albicans, 20% for C. glabrata, 6% for C. tropicalis, and 6% for C. parapsilosis. Among well-controlled subjects, 33% were positive for C. albicans and 13% for C. glabrata; none had C. tropicalis or C. parapsilosis. No samples were positive for C. dubliniensis in either group of subjects.

In vivo activity of ceftobiprole in murine skin infections due to Staphylococcus aureus and Pseudomonas aeruginosa.

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (methicillin-susceptible S. aureus [MSSA]), S. aureus OC 8525 (MRSA), Pseudomonas aeruginosa OC 4351 (having an inducible AmpC beta-lactamase), and P. aeruginosa OC 4354 (overproducing AmpC beta-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC beta-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.

In vivo activity of the pyrrolopyrazolyl-substituted oxazolidinone RWJ-416457.

RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibiotic-susceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two- to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log(10) at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log(10) (MSSA) and 2 log(10) (CA-MRSA). In the pneumococcal model, RWJ-416457 was two- to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC(24)) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC(24)/MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.

A methodology for identifying human error in U.S. Navy diving accidents.

OBJECTIVE: To better understand how human error contributes to U.S. Navy diving accidents. BACKGROUND: An analysis of 263 U.S. Navy diving accident and mishap reports revealed that the human factors classifications were not informative for further analysis, and 70% of mishaps were attributed to unknown causes; only 23% were attributed to human factors. METHOD: Five diving fatality reports were examined using the consensual qualitative research (CQR) method to develop a taxonomy of six categories and 21 subcategories for classifying human errors in diving. In addition, 15 critical incident technique (CIT) interviews were conducted with U.S. Navy divers who had been involved in a diving accident or near miss and analyzed using the dive team error taxonomy. RESULTS: Overall, failures in situation awareness and leadership were the most common human errors made by the dive team. CONCLUSION: The dive team human error taxonomy could aid in accident investigation and in the training and evaluation of U.S. Navy divers. APPLICATION: The development of the dive team human error taxonomy has generated a number of considerations that researchers should take into account when developing, or adapting, an error taxonomy from one industry to another.

The synthesis and antimicrobial evaluation of a new series of isoxazolinyl oxazolidinones.

A series of oxazolidinone antibacterial agents containing a 5-substituted isoxazol-3-yl moiety were synthesized via a nitrile oxide [3+2] dipolar cycloaddition reaction. These compounds were screened against a panel of susceptible and resistant Gram-positive organisms. Several analogs from this series were comparable to or more potent than linezolid in vitro.

In-vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp.

The in-vitro biotransformation of the anxiolytic agent, RWJ-50172 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH-generating system, and incubating with Cunninghamella echinulata in soy-bean medium. Unchanged RWJ-50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1-M6) were profiled, quantified and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-50172 are proposed, and the four metabolic pathways are: pyrido-oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy-pyrido-RWJ-50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro-RWJ-50172 in trace quantities in rat. Pathway B produced hydroxyphenyl-RWJ-50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy-RWJ-50172 as a trace metabolite in rat. Step D produced a minor benzimidazole-reduced metabolite in fungi. RWJ-50172 is substantially metabolized by this rat hepatic S9 fraction and fungi.

Novel piperidinyloxy oxazolidinone antibacterial agents. Diversification of the N-Substituent.

Oxazolidinone antibacterial agents, where the morpholino group of linezolid was replaced with an N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The functionality attached to the piperidine nitrogen was varied extensively to determine the SAR for this series. One of the most potent compounds, 11, showed in vivo efficacy upon subcutaneous administration in a Staphylococcus aureus Smith murine systemic infection.