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Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

IntroductionMaternal antiretroviral therapy (ART) with viral suppression prior to conception, during pregnancy and throughout the breastfeeding period accompanied by infant postnatal prophylaxis (PNP) forms the foundation of current approaches to preventing vertical HIV transmission. Unfortunately, infants continue to acquire HIV infections, with half of these infections occurring during breastfeeding. A consultative meeting of stakeholders was held to review the current state of PNP globally, including the implementation of WHO PNP guidelines in different settings and identifying the key factors affecting PNP uptake and impact, with an aim to optimize future innovative strategies.DiscussionWHO PNP guidelines have been widely implemented with adaptations to the programme context. Some programmes with low rates of antenatal care attendance, maternal HIV testing, maternal ART coverage and viral load testing capacity have opted against risk-stratification and provide an enhanced PNP regimen for all infants exposed to HIV, while other programmes provide infant daily nevirapine antiretroviral (ARV) prophylaxis for an extended duration to cover transmission risk throughout the breastfeeding period. A simplified risk stratification approach may be more relevant for high-performing vertical transmission prevention programmes, while a simplified non-risk stratified approach may be more appropriate for sub-optimally performing programmes given implementation challenges. In settings with concentrated epidemics, where the epidemic is often driven by key populations, infants who are found to be exposed to HIV should be considered at high risk for HIV acquisition. All settings could benefit from newer technologies that promote retention during pregnancy and throughout the breastfeeding period. There are several challenges in enhanced and extended PNP implementation, including ARV stockouts, lack of appropriate formulations, lack of guidance on alternative ARV options for prophylaxis, poor adherence, poor documentation, inconsistent infant feeding practices and in inadequate retention throughout the duration of breastfeeding.ConclusionsTailoring PNP strategies to a programmatic context may improve access, adherence, retention and HIV-free outcomes of infants exposed to HIV. Newer ARV options and technologies that enable simplification of regimens, non-toxic potent agents and convenient administration, including longer-acting formulations, should be prioritized to optimize the effect of PNP in the prevention of vertical HIV transmission.

BackgroundIsoniazid (INH) metabolism depends on the N-acetyl transferase 2 (NAT2) enzyme, whose maturation process remains unknown in low birth weight (LBW) and preterm infants. We aimed to assess INH exposure and safety in infants receiving oral tuberculosis prevention.MethodsThis population pharmacokinetics (PK) analysis used INH and N-acetyl-isoniazid (ACL) concentrations in infants (BW ≤ 4 kg), including preterm, with follow-up for 6 months. PK parameters were described using nonlinear mixed effects modeling. Simulations were performed to assess INH exposure and optimal dosing regimens, using 2 targets: Cmax at 3-6 mg/L and area under the curve (AUC) ≥ 10.52 mg h/L.ResultsWe included 57 infants (79% preterm, 84% LBW) in the PK analysis, with a median (range) gestational age of 34 (28.7-39.4) weeks. At the time of sampling, postnatal age was 2.3 (0.2-7.3) months and weight (WT) was 3.7 (0.9-9.3) kg. NAT2 genotype was available in 43 (75.4%) patients (10 slow, 26 intermediate, and 7 fast metabolizers). Ninety percent of NAT2 maturation was attained by 4.4 post-natal months. WT, postmenstrual age, and NAT2 genotype significantly influenced INH exposure, with a 5-fold difference in AUC between slow and fast metabolizers for the same dose. INH appeared safe across the broad range of exposure for 61 infants included in the safety analysis.ConclusionsIn LBW/preterm infants, INH dosing needs frequent adjustment to account for growth and maturation. Pharmacogenetics-based dosing regimens is the most powerful approach to deliver safe and equalized exposures for all infants, because NAT2 genotype highly impacts INH pharmacokinetic variability.

Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network and the World Health Organization (WHO)-convened Pediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low-income and middle-income countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy pharmacokinetic/pharmacodynamic (PK/PD) studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical.

Background There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. Methods and findings Hospitalized infants A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-'Low' Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-'Medium' Watch), 18.0% (n = 566) started a carbapenem (Group 4-'High' Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. Conclusion Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. Trial registration ClinicalTrials.gov, (NCT03721302)., Author(s): Neal J. Russell 1,*, Wolfgang Stöhr 2, Nishad Plakkal 3, Aislinn Cook 1, James A. Berkley 4,5,6, Bethou Adhisivam 3, Ramesh Agarwal 7, Nawshad Uddin Ahmed 8, Manica Balasegaram [...]

Background: The smallest dolutegravir (DTG) dose approved is 5 mg once-daily in infants ≥4 weeks and weighing ≥3 to <6 kg using a dispersible tablet (DT). Neonates (<28 days of life) may require a lower dose due to immature organ development. We evaluated the aqueous dispersibility of the generic DTG-DT 10-mg scored tablets (Viatris Inc.) to determine the possibility of uniform concentrations that could allow for lower daily doses in neonates. Methods: Each 5-mL polypropylene tube had DTG-DT 5 mg dissolved in 5-mL ultrapure water. Tubes were labeled with 3 "zones" (bottom: 0–1 mL; middle: 1–3 mL; top: 3–5 mL). Suspensions were mixed by swirling or swirling with a syringe pump, vortexing, or sonication. DTG concentration in each zone was determined using high-performance liquid chromatography. Tubes were rinsed with 1-mL acetonitrile to determine the residual drug. Acceptable criterion for percentage difference was set at ≤20% according to the European Medicines Agency guidelines. Results: Dispersion of DTG-DT in water did not remain homogeneous, resulting in DTG concentrations that varied by over 50% across the 3 zones within the tubes. Rapid sedimentation was observed shortly after mixing. Furthermore, it was found that 24%–35% of the DTG residue remained adhered to the tube after the aqueous dispersion had been eluted, highlighting the importance of the rinse step. Conclusions: Aqueous dispersion of the DTG-DT is not uniform and displays a high degree of sedimentation. It is therefore not possible to administer a fraction of the dispersion (lower DTG dose) to neonates by using this formulation. [ABSTRACT FROM AUTHOR]

Background Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice. Methods We conducted a 6-country retrospective cohort study among hospitalized women of childbearing age between 1 March 2020 and 31 March 2021. Exposures were (1) pregnancy and (2) a positive SARS-CoV-2 RT-PCR test. The primary outcome for both analyses was intensive care unit (ICU) admission. Secondary outcomes included supplemental oxygen requirement, mechanical ventilation, adverse birth outcomes, and in-hospital mortality. We used log-binomial regression to estimate the effect between pregnancy and SARS-CoV-2 infection. Factors associated with mortality were evaluated using competing-risk proportional subdistribution hazards models. Results Our analyses included 1315 hospitalized women: 510 pregnant women with SARS-CoV-2, 403 nonpregnant women with SARS-CoV-2, and 402 pregnant women without SARS-CoV-2 infection. Among women with SARS-CoV-2 infection, pregnancy was associated with increased risk for ICU admission (adjusted risk ratio [aRR]: 2.38; 95% CI: 1.42–4.01), oxygen supplementation (aRR: 1.86; 95% CI: 1.44–2.42), and hazard of in-hospital death (adjusted sub-hazard ratio [aSHR]: 2.00; 95% CI: 1.08–3.70). Among pregnant women, SARS-CoV-2 infection increased the risk of ICU admission (aRR: 2.0; 95% CI: 1.20–3.35), oxygen supplementation (aRR: 1.57; 95% CI: 1.17–2.11), and hazard of in-hospital death (aSHR: 5.03; 95% CI: 1.79–14.13). Conclusions Among hospitalized women in SSA, both SARS-CoV-2 infection and pregnancy independently increased risks of ICU admission, oxygen supplementation, and death. These data support international recommendations to prioritize COVID-19 vaccination among pregnant women. [ABSTRACT FROM AUTHOR]

Background In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7–72.9), isoniazid (11.6–26.3), and pyrazinamide (233–429 mg ∙ h/L). Results In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22–12] years; weight 10.7 [3.20–28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4–8, 8–12, 12–16, and 16–25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6–13, 13–20. and 20–25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. Conclusions Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands. [ABSTRACT FROM AUTHOR]