Randomized controlled trial of the relative efficacy of high-dose intravenous ceftriaxone and oral cefixime combined with doxycycline for the treatment of Chlamydia trachomatis and Neisseria gonorrhoeae co-infection.

OBJECTIVES: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the commonest bacterial causes of sexually transmitted infections in humans with high incidence of co-infection. Treatment with high doses of ceftriaxone (CRO) and cefixime (CFM) is strongly recommended due to the reduced drug susceptibility of NG. However, their safety and efficacy have not been confirmed. We compared the safety and efficacy of a single 1 g intravenous (IV) dose of ceftriaxone (CRO) plus doxycycline (DOX) versus a single 800 mg oral dose of cefixime (CFM) plus DOX for the treatment of NG-CT co-infection. METHODS: An open-label randomized controlled trial was conducted on 125 individuals aged > 18 years with untreated gonorrhea and chlamydia to compare a single 1 g intravenous dose of CRO + DOX and a single 800 mg oral dose of CFM + DOX. The primary outcome was the clearance of NG from all the initially infected sites. Secondary outcomes included symptom resolution, changes in the serum clearance levels, glomerular filtration rate, and antibiotic minimum inhibitory concentrations. RESULTS: Both regimens were highly effective in treating gonorrhea with success rates of 96.7% (95% confidence interval [CI] 88.8-99.1%) for CRO and 95.3% (95% CI 87.1-98.4%) for CFM. However, CRO + DOX was superior to CFM + DOX for the treatment of NG-CT co-infection (odds ratio 4.41, 95% CI 1.11-25.7). The safety profiles of the two regimens were similar. CONCLUSIONS: CRO + DOX was superior to CFM + DOX for the treatment of NG-CT co-infection. CFM + DOX may be indicated in patients with CRO allergy and in settings where CRO is unavailable. Trial registration ClinicalTrials.gov (NCT05216744) on 31/01/22.

Para-aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research.

AIMS: Tenofovir and para-aminosalicylic acid (PAS) may be coprescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the 2 drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics (PK). METHODS: Initially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (OAT1 and OAT3). Later, we estimated clinical drug interactions using static and physiologically based PK modelling. Finally, we investigated the effects of PAS-calcium formulation (PAS-Ca) on tenofovir disoproxil fumarate PK in healthy male Korean subjects. RESULTS: PAS inhibited OAT1- and OAT3-mediated tenofovir uptake in vitro. The physiologically based PK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when coadministered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir PK showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (Cmax ) and area under the curve (AUC0-inf ) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively. CONCLUSION: Our study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.

A Multiple Logistic Regression Model Based on Gamma-Glutamyl Transferase as a Biomarker for Early Prediction of Drug-Induced Liver Injury in Vietnamese Patients.

The discovery of new biomarkers and the causality of drug-induced liver injury (DILI) is a major focus in modern medicine. Alcoholism is considered a risk factor for DILI. However, the extraction and assessment of alcohol history are difficult due to noncooperation by patients and intermittent management. Therefore, we conducted a case-control study of 1277 patients diagnosed with DILI according to the Roussel Uclaf Causality Assessment Method scale to evaluate gamma-glutamyl transferase (GGT) as a biomarker for predicting DILI in Vietnamese patients, where the proportion of alcoholism is quite high. Further, we built and validated a logistic regression model to predict the risk of DILI in hospitalized patients. The risk of DILI increased by 10% for 1 UI/L higher levels of GGT before prescription (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.01). A history of alcoholism was not a risk factor for DILI occurrence (OR, 1.83; 95%CI, 0.99-3.04; P = .057). A logistic regression model was successfully built and validated based on age; sex; initial levels of alanine aminotransferase, alkaline phosphatate, GGT, likelihood score of the suspected drug, and history of liver disease; the area under the receiver operating characteristic curve of the model was 0.883 (95%CI, 0.868-0.897). Our results thus suggest the necessity of exercising caution when prescribing to patients without a history of alcoholism but having high GGT levels. This model can be applied clinically to assess the risk of DILI before prescribing to reduce the risk of DILI in the patient.

mHealth Messaging to Motivate Quitline Use and Quitting: Protocol for a Community-Based Randomized Controlled Trial in Rural Vietnam.

BACKGROUND: Tobacco kills more than 8 million people each year, mostly in low- and middle-income countries. In Vietnam, 1 in every 2 male adults smokes tobacco. Vietnam has set up telephone Quitline counseling that is available to all smokers, but it is underused. We previously developed an automated and effective motivational text messaging system to support smoking cessation among US smokers. OBJECTIVE: The aim of this study is to adapt the aforementioned system for rural Vietnamese smokers to promote cessation of tobacco use, both directly and by increasing the use of telephone Quitline counseling services and nicotine replacement therapy. Moreover, we seek to enhance research and health service capacity in Vietnam. METHODS: We are testing the effectiveness of our culturally adapted motivational text messaging system by using a community-based randomized controlled trial design (N=600). Participants were randomly allocated to the intervention (regular motivational and assessment text messages) or control condition (assessment text messages only) for a period of 6 months. Trial recruitment took place in four communes in the Hung Yen province in the Red River Delta region of Vietnam. Recruitment events were advertised to the local community, facilitated by community health workers, and occurred in the commune health center. We are assessing the impact of the texting system on 6-month self-reported and biochemically verified smoking cessation, as well as smoking self-efficacy, uptake of the Quitline, and use of nicotine replacement therapy. In addition to conducting the trial, the research team also provided ongoing training and consultation with the Quitline during the study period. RESULTS: Site preparation, staff training, intervention adaptation, participant recruitment, and baseline data collection were completed. The study was funded in August 2017; it was reviewed and approved by the University of Massachusetts Medical School Institutional Review Board in 2017. Recruitment began in November 2018. A total of 750 participants were recruited from four communes, and 700 (93.3%) participants completed follow-up by March 2021. An analysis of the trial results is in progress; results are expected to be published in late 2022. CONCLUSIONS: This study examines the effectiveness of mobile health interventions for smoking in rural areas in low- and middle-income countries, which can be implemented nationwide if proven effective. In addition, it also facilitates significant collaboration and capacity building among a variety of international partners, including researchers, policy makers, Quitline counselors, and community health workers. TRIAL REGISTRATION: ClinicalTrials.gov NCT03567993; https://clinicaltrials.gov/ct2/show/NCT03567993. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30947.

Early essential newborn care is associated with improved newborn outcomes following caesarean section births in a tertiary hospital in Da Nang, Vietnam: a pre/post-intervention study.

BACKGROUND: To improve maternal and neonatal outcomes, Vietnam implemented early essential newborn care (EENC) using clinical coaching and quality improvement self-assessments in hospitals to introduce policy, practice and environmental changes. Da Nang Hospital for Women and Children began EENC with caesarean section births to inform development of national guidelines. This study compared newborn outcomes after caesarean sections pre/post-EENC introduction. METHODS: Maternity records of all live in-born hospital caesarean births and separate case records of the subpopulation admitted to the neonatal intensive care unit (NICU) were reviewed pre-EENC (November 2013-October 2014) and post-EENC (November 2014-October 2015) implementation. NICU admissions and adverse outcomes on NICU admission were compared using descriptive statistics. FINDINGS: A total of 16 927 newborns were delivered by caesarean section: 7928 (46.8%) pre-EENC and 8999 post-EENC (53.2%). Total NICU admissions decreased from 16.7% to 11.8% (relative risk 0.71; 95% CI 0.66 to 0.76) after introduction of EENC. Compared with the pre-EENC period, babies with hypothermia on admission to the NICU declined from 5.0% to 3.7% (relative risk 0.73; 95% CI 0.63 to 0.84) and cases of sepsis from 3.2% to 0.8% (relative risk 0.26; 95% CI 0.20 to 0.33) post-EENC implementation. While more than half of all newborns in the NICU were fed something other than breastmilk pre-EENC introduction, 85.8% were exclusively breast fed post-EENC (relative risk 1.86; 95% CI 1.75 to 1.98). Preterm newborns <2000 g receiving kangaroo mother care (KMC) increased from 50% to 67% (relative risk 1.33; 95% CI 1.12 to 1.59). CONCLUSION: The EENC quality improvement approach with caesarean section births was associated with reduced NICU admissions, admissions with hypothermia and sepsis, and increased rates of exclusive breast feeding and KMC in the NICU.

Early Essential Newborn Care can still be used with mothers who have COVID-19 if effective infection control measures are applied.

We describe the first infant born to a woman with COVID-19 in Vietnam, by Caesarean section at 36 weeks and 5 days of gestation. The mother and baby remained together during their hospital stay and prolonged skin-to-skin contact and early and exclusive breastfeeding were achieved. This was in line with the World Health Organization's Early Essential Newborn Care (EENC) recommendations, the national Vietnamese standard of care since 2014. The baby remained virus-free throughout the 34-day postpartum follow-up. CONCLUSION: The EENC approach can still be used with mothers who have COVID-19 if effective infection control measures are applied.

Appropriate care for neonates born to mothers with COVID-19 disease.

The global COVID-19 pandemic has been associated with high rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, morbidity and mortality in the general population. Evidence-based guidance on caring for babies born to mothers with COVID-19 is needed. There is currently insufficient evidence to suggest vertical transmission between mothers and their newborn infants. However, transmission can happen after birth from mothers or other carers. Based on the currently available data, prolonged skin-to-skin contact and early and exclusive breastfeeding remain the best strategies to reduce the risks of morbidity and mortality for both the mother with COVID-19 and her baby.

Physiologically Based Pharmacokinetic Modeling Approach to Predict Drug-Drug Interactions With Ethionamide Involving Impact of Genetic Polymorphism on FMO3.

The widely used second-line antituberculosis drug ethionamide shows wide interindividual variability in its disposition; however, the relevant factors affecting this phenomenon have not been characterized. We previously reported the major contribution of flavin-containing monooxygenase 3 (FMO3) in the reductive elimination pathway of ethionamide. In this study, ethionamide metabolism was potentially inhibited by methimazole in vitro. The drug-drug interaction leading to methimazole affecting the disposition of ethionamide mediated by FMO3 was then quantitated using a bottom-up approach with a physiologically based pharmacokinetic framework. The maximum concentration (Cmax ) and area under the curve (AUC) of ethionamide were estimated to increase by 13% and 16%, respectively, when coadministered with methimazole. Subsequently, we explored the effect of FMO3 genetic polymorphism on metabolic capacity, by constructing 2 common functional variants, Lys158 -FMO3 and Gly308 -FMO3. Compared to the wild type, recombinant Lys158 -FMO3 and Gly308 -FMO3 variants significantly decreased the intrinsic clearance of ethionamide by 2% and 24%, respectively. Two prevalent functional variants of FMO3 were predicted to affect ethionamide disposition, with mean ratios of Cmax and AUC of up to 1.5 and 1.7, respectively, in comparison with the wild type. In comparing single ethionamide administration with the wild type, simulations of the combined effects of comedications and FMO3 genetic polymorphism estimated that the Cmax and AUC ratios of ethionamide increased up to 1.7 and 2.0, respectively. These findings suggested that FMO3-mediated drug-drug interaction and genetic polymorphism could be important determinants of interindividual heterogeneity in ethionamide disposition that need to be considered comprehensively to optimize the personalized dosing of ethionamide.

What Does it Take to Make Model-Informed Precision Dosing Common Practice? Report from the 1st Asian Symposium on Precision Dosing.

Model-informed precision dosing (MIPD) is modeling and simulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity in comparison to traditional dosing. This paper describes the background and status of MIPD and the activities at the 1st Asian Symposium of Precision Dosing. The theme of the meeting was the question, "What does it take to make MIPD common practice?" Formal presentations highlighted the distinction between genetic and non-genetic sources of variability in drug exposure and response, the use of modeling and simulation as decision support tools, and the facilitators to MIPD implementation. A panel discussion addressed the types of models used for MIPD, how the pharmaceutical industry views MIPD, ways to upscale MIPD beyond academic hospital centers, and the essential role of healthcare professional education as a way to progress. The meeting concluded with an ongoing commitment to use MIPD to improve patient care.

Effect of rifampin on enantioselective disposition and anti-hypertensive effect of benidipine.

AIMS: In vitro study showed that benidipine is exclusively metabolized by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti-hypertensive effect of benidipine. METHODS: Benidipine (8 mg) was administered to healthy subjects with or without repeated rifampin dosing, in a crossover design. Plasma concentrations of (S)-(S)-(+)-α and (R)-(R)-(-)-α isomers of benidipine and blood pressure were measured for up to 24 h after dosing. In addition, CYP3A metabolic capacity was evaluated in each subject using oral clearance of midazolam. RESULTS: The exposure of (S)-(S)-(+)-α-benidipine was greater than that of (R)-(R)-(-)-α-benidipine by approximately three-fold following single dose of benidipine. Repeated doses of rifampin significantly decreased the exposure of both isomers. Geometric mean ratios (GMRs) (95% CI) of Cmax and AUC∞ for (S)-(S)-(+)-α-benidipine were 0.14 (0.10-0.18) and 0.12 (0.08-0.18), respectively. GMRs (95% CI) of Cmax and AUC∞ for (R)-(R)-(-)-α-benidipine were 0.10 (0.06-0.17) and 0.10 (0.06-0.17), respectively. Oral clearances of both isomers were increased equally by approximately 10-fold. There were no significant differences in cardiovascular effect following benidipine administration between control and rifampin treatment. CYP3A activity using midazolam did not appear to correlate with oral clearance of benidipine. CONCLUSIONS: After single administration of racemic benidipine, enantioselective disposition of (S)-(S)-(+)-α- and (R)-(R)-(-)-α-benidipine was observed. Treatments with rifampin significantly decreased the exposure of both isomers but appeared to marginally affect its blood pressure-lowering effect in healthy subjects. Impact of coadministration of rifampin on the treatment effects of benidipine should be assessed in hypertensive patients.

Knowledge, experience and attitudes towards skin-to-skin contact following Caesarean sections among health professionals in Vietnam.

AIM: This study explored knowledge, experience and attitudes of health professionals towards early essential newborn care and skin-to-skin contact following Caesarean sections in a tertiary hospital in Central Vietnam. METHOD: We conducted a cross-sectional descriptive study using an anonymous questionnaire in March 2016. Health professionals from obstetrics, anaesthesiology and neonatology departments were surveyed. RESULTS: All of the 204 surveys were returned, accounting for 82% of total staff involved in the care for women and newborns with Caesarean sections. Correct knowledge of early essential newborn care was lowest among anaesthesiology staff. Health professionals reported that ≥90% of Caesarean section births they attended in the preceding week had skin-to-skin contact. Approximately 16% obstetricians, 71% midwives, 49% anaesthesiology and 76% neonatology staff considered the current frequency of skin-to-skin contact to be about right. The remainder considered the current rate too high. All professional groups identified the main difficulties of conducting skin-to-skin contact as the temperature in the operating theatre and the need for additional staff. Other concerns included increasing the risk of the baby of falling off, prolonging the operation and difficulty to monitor mothers. CONCLUSION: The study identifies issues where improvements can be made in the implementation of skin-to-skin contact following Caesarean sections.

Development of a Physiologically Based Pharmacokinetic Model of Ethionamide in the Pediatric Population by Integrating Flavin-Containing Monooxygenase 3 Maturational Changes Over Time.

Currently, ethionamide is the most frequently prescribed second-line antituberculosis drug in children. After extensive metabolism by flavin-containing monooxygenase (FMO) isoform 3 in the liver, the drug may exert cytotoxic effects. The comparison of children in different age groups revealed a significant age-related increase in ethionamide elimination in vivo. However, to date, the exact mechanism underlying this dynamic increase in ethionamide elimination has not been elucidated. We hypothesized that the age-dependent changes in ethionamide elimination were predominantly a result of the progressive increases in the expression and metabolic capacity of FMO3 during childhood. To test this hypothesis, a full physiologically based pharmacokinetic (PBPK) model of ethionamide was established and validated in adults through incorporation of comprehensive metabolism and transporter profiles, then expanded to the pediatric population through integration of FMO3 maturational changes over time. Thus, a good prediction PBPK model was validated successfully both in adults and children and applied to demonstrate the critical contribution of FMO3 in the mechanistic elimination pathway of ethionamide. In addition, a significant correlation between clearance and age was observed in children by accounting for ethionamide maturation, which could offer a mechanistic understanding of the age-associated changes in ethionamide elimination. In conclusion, this study underlines the benefits of in vitro-in vivo extrapolation and a quantitative PBPK approach for the investigation of transporter-enzyme interplay in ethionamide disposition and the demonstration of FMO3 ontogeny in children.

Early Essential Newborn Care Is Associated With Reduced Adverse Neonatal Outcomes in a Tertiary Hospital in Da Nang, Viet Nam: A Pre- Post- Intervention Study.

BACKGROUND: To accelerate reductions in neonatal mortality, Viet Nam rolled out early essential newborn care (EENC) using clinical coaching, quality improvement assessments in hospitals, and updated protocols. Da Nang Hospital for Women and Children, a tertiary referral hospital in central Viet Nam, compared outcomes pre- and post-EENC introduction. METHODS: Records of live births and NICU admissions were reviewed pre- (November 2013-October 2014) and post- (November 2014-October 2015) EENC implementation. Delivery room practices, NICU admissions and adverse outcomes on NICU admission were compared using descriptive statistics. FINDINGS: A total of 13,201 live births were delivered pre- and 14,180 live births post-EENC introduction. Post-EENC, delivery practice scores, rates of early and prolonged skin-to-skin contact and early breastfeeding rose significantly. There was a significant reduction in risk of NICU admissions (relative risk [RR] 0.68; 95% confidence interval [CI] 0.64-0.71; p < 0.0001), hypothermia on NICU admission (RR 0.72; 95% CI 0.65-0.81, p < 0.0001) and sepsis (RR 0.28; 95% CI 0.23-0.35, p < 0.0001). Exclusive breastfeeding rates in NICU increased from 49% to 88% (p < 0.0001) and of kangaroo mother care (KMC) from 52% to 67% (p < 0.0001). Reduced formula use resulted in decreased monthly costs. INTERPRETATION: EENC introduction, including staff coaching, quality improvement assessments and changes in hospital protocols and environments, were associated with improved clinical practices, reduced NICU admissions, admissions with hypothermia and sepsis and increased rates of exclusive breastfeeding and KMC in the NICU. FUNDING: Data collection was funded by the World Health Organization Western Pacific Regional Office and Newborns Vietnam. OUTSTANDING QUESTIONS: •What is the impact of the package of early essential newborn care interventions on newborn mortality?•What are the total direct and indirect cost savings of early essential newborn care implementation?•What is the cost effectiveness of kangaroo mother care for preterm and low birth weight babies?•What strategies can help reduce unnecessary cesarean sections in hospitals?