Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis.

BACKGROUND: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF), as well as, following its co-administration with high-dose rifampicin. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In the LASER-TBM pharmacokinetic substudy, the intervention groups received high-dose rifampicin (35 mg/kg) plus 1200 mg/day of linezolid for 28 days, which was then reduced to 600 mg/day. Plasma sampling was done on day 3 (intensive) and day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: Thirty participants contributed 247 plasma and 28 CSF observations. Their median age and weight were 40 years (range, 27-56) and 58 kg (range, 30-96). Plasma pharmacokinetics was described by a 1-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25 L/h, and the Michaelis-Menten constant was 27.2 mg/L. Rifampicin cotreatment duration did not affect linezolid pharmacokinetics. CSF-plasma partitioning correlated with CSF total protein up to 1.2 g/L, where the partition coefficient reached a maximal value of 37%. The plasma-CSF equilibration half-life was ∼3.5 hours. CONCLUSIONS: Linezolid was readily detected in CSF despite high-dose rifampicin coadministration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults. Clinical Trials Registration. ClinicalTrials.gov (NCT03927313).

Gestational Weight Gain and Neonatal Biometry during the COVID-19 Pandemic: A Multicenter Observational Cohort.

OBJECTIVE: This study aimed to test the hypothesis that being pregnant and delivering during the coronavirus disease 2019 (COVID-19) pandemic was associated with changes in gestational weight gain (GWG) or frequency of small- (SGA) or large-for-gestational-age (LGA) neonates. STUDY DESIGN: Secondary analysis of a multicenter observational cohort comparing pregnant people who delivered during the COVID-19 pandemic (June-December 2020) to people who delivered prior to the pandemic (March-December 2019). Those with multiple gestations, fetuses with major congenital anomalies, implausible GWG values, unavailable body mass index (BMI), or who were severe acute respiratory syndrome coronavirus-2-positive were excluded. The primary outcome was frequency of optimal recommended GWG based on prepregnancy BMI. Neonatal outcomes included birth weight, ponderal index, and frequency of SGA, LGA, and small head circumference for live births. Multivariable regression analysis was used to assess associations between exposure to the pandemic and outcomes. RESULTS: A total of 10,717 pregnant people were included in our analysis. A total of 4,225 pregnant people were exposed to the pandemic and 6,492 pregnant people delivered prior to the COVID-19 pandemic. Pregnant people exposed to the pandemic were older and more likely to have gestational diabetes. The frequency of appropriate GWG was 28.0% during the pandemic and 27.6% before the pandemic (adjusted odds ratio [aOR]: 1.02, 95% confidence interval [CI]: 0.93-1.11). Excessive GWG was more likely (54.9 vs. 53.1%; aOR: 1.08, 95% CI: 1.001-1.17), and inadequate GWG was less likely during the pandemic (17.0 vs. 19.3%; aOR: 0.86, 95% CI: 0.77-0.95). The frequency of SGA was 5.4% during the pandemic and 6.1% before the pandemic (aOR: 0.90, 95% CI: 0.76-1.06), and the frequency of LGA was 16.0% during the pandemic versus 15.0% before the pandemic (aOR: 1.06, 95% CI: 0.95-1.18). Other neonatal outcomes including birth weight percentile (62.1 [35.8-83.2] vs. 60.2 [34.4-82.2]; adjusted mean difference (aMD) = 1.50, 95% CI: -0.28 to 3.29), ponderal index (2.6 g/cm3 [2.4-2.8] in both groups; aMD = 0.01, 95% CI: 0.00-0.02), and small head circumference for livebirths (<10th percentile [8.2 vs. 8.1%; aOR: 1.03, 95% CI: 0.89-1.19], <3rd percentile [3.5 vs. 3.1%; aOR: 1.16, 95% CI: 0.93-1.44]) were similar between groups as well. CONCLUSION: Being pregnant and delivering during the COVID-19 pandemic was associated with a higher likelihood of excessive GWG and a lower likelihood of inadequate GWG. KEY POINTS: · Delivering during the COVID-19 pandemic was associated with higher likelihood of excessive GWG.. · Delivering during the COVID-19 pandemic was associated with lower likelihood of inadequate GWG.. · COVID-19 pandemic was not associated with changes in frequency of SGA or LGA..

Optimizing dosing of the cycloserine pro-drug terizidone in children with rifampicin-resistant tuberculosis.

There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine. We included 107 children with median (interquartile range) age and weight of 3.33 (1.55, 5.07) years and 13.0 (10.1, 17.0) kg, respectively. The pharmacokinetics of cycloserine was described with a one-compartment model with first-order elimination and parallel transit compartment absorption. Allometric scaling using fat-free mass best accounted for the effect of body size, and clearance displayed maturation with age. The clearance in a typical 13 kg child was estimated at 0.474 L/h. The mean absorption transit time when capsules were opened and administered as powder was significantly faster compared to when capsules were swallowed whole (10.1 vs 72.6 min) but with no effect on bioavailability. Lower bioavailability (-16%) was observed in children with weight-for-age z-score below -2. Compared to adults given 500 mg daily terizidone, 2022 WHO-recommended pediatric doses result in lower exposures in weight bands 3-10 kg and 36-46 kg. We developed a population pharmacokinetic model in children for cycloserine dosed as terizidone and characterized the effects of body size, age, formulation manipulation, and underweight-for-age. With current terizidone dosing, pediatric cycloserine exposures are lower than adult values for several weight groups. New optimized dosing is suggested for prospective evaluation.

Population Pharmacokinetic Analysis of Rifampicin in Plasma, Cerebrospinal Fluid, and Brain Extracellular Fluid in South African Children with Tuberculous Meningitis.

Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this analysis, we characterize the distribution of rifampicin in cerebrospinal fluid (CSF), lumbar (LCSF) and ventricular (VCSF), and brain extracellular fluid (ECF). Children with TBM were included in this pharmacokinetic analysis. Sparse plasma, LCSF, and VCSF samples were collected opportunistically, as clinically indicated. Brain ECF was sampled using microdialysis (MD). Rifampicin was quantified with liquid chromatography with tandem mass spectrometry in all samples, and 25-desacetyl rifampicin in the plasma samples. The data were interpreted with nonlinear mixed-effects modeling, with the CSF and brain ECF modeled as "effect compartments." Data were available from 61 children, with median (min-max) age of 2 (0.3 to 10) years and weight of 11.0 (4.8 to 49.0) kg. A one-compartment model for parent and metabolite with first-order absorption and elimination via saturable hepatic clearance described the data well. Allometric scaling, maturation, and auto-induction of clearance were included. The pseudopartition coefficient between plasma and LCSF/VCSF was ~5%, while the value for ECF was only ~0.5%, possibly reflecting low recovery of rifampicin using MD. The equilibration half-life between plasma and LCSF/VCSF was ~4 h and between plasma and ECF ~2 h. Our study confirms previous reports showing that rifampicin concentrations in the LCSF are lower than in plasma and provides novel knowledge about rifampicin in the VCSF and the brain tissue. Despite MD being semiquantitative because the relative recovery cannot be quantified, our study presents a proof-of-concept that rifampicin reaches the brain tissue and that MD is an attractive technique to study site-of-disease pharmacokinetics in TBM.

Placenta Accreta Spectrum and Postpartum Hemorrhage.

Placenta accreta spectrum is a group of disorders involving abnormal trophoblastic invasion to the deep layers of endometrium and myometrium. Placenta accrete spectrum is one of the major causes of severe maternal morbidity, with increasing incidence in the past decade mainly secondary to an increase in cesarean deliveries. Severity varies depending on the depth of invasion, with the most severe form, known as percreta, invading uterine serosa or surrounding pelvic organs. Diagnosis is usually achieved by ultrasound, and MRI is sometimes used to assess invasion. Management usually involves a hysterectomy at the time of delivery. Other strategies include delayed hysterectomy or expectant management.

Association between Individual versus Community-level Social Vulnerability and Neonatal Opioid Withdrawal Syndrome among Pregnant Individuals Receiving Buprenorphine for Opioid Use Disorder.

OBJECTIVE: Individual patient-level measures of adverse social determinants of health are associated with neonatal opioid withdrawal syndrome (NOWS), but the relative impact of community-level adverse social determinants of health remains to be defined. We examined the association between community-level social vulnerability and NOWS among pregnant individuals receiving buprenorphine for opioid use disorder. STUDY DESIGN: We conducted a secondary analysis of an established cohort of pregnant individuals and their infants participating in a multidisciplinary prenatal/addiction care program from 2013 to 2021. Addresses were geocoded using ArcGIS and linked at the census tract to the Centers for Disease Control and Prevention 2018 Social Vulnerability Index (SVI), incorporating 15 census variables. The primary exposure was the SVI as a composite measure of community-level social vulnerability, and secondarily, individual scores for four thematic domains (socioeconomic status, household composition and disability, minority status and language, and housing type and transportation). The primary outcome was a clinical diagnosis of NOWS defined as withdrawal requiring pharmacological treatment following buprenorphine exposure. RESULTS: Among 703 pregnant individuals receiving buprenorphine, 39.8% (280/703) of infants were diagnosed with NOWS. Among our patinets, those who were nulliparous, had post-traumatic stress disorder, a term birth (≥ 37 weeks) and had a male infant were more likely to have an infant diagnosed with NOWS. Individuals with and without an infant diagnosed with NOWS had similarly high community-level social vulnerability per composite SVI scores (mean [standard deviation]: 0.6 [0.4-0.7] vs. 0.6 [0.4-0.7], p = 0.2]. In adjusted analyses, SVI, as a composite measure as well as the four domains, was not associated with NOWS diagnosis. CONCLUSION: Among pregnant persons receiving buprenorphine enrolled in a multidisciplinary prenatal and addition care program, while individual risk factors that measure adverse social determinants of health were associated with an NOWS diagnosis in the infant, community-level social vulnerability as measured by the SVI was not associated with the outcome. KEY POINTS: · Community-level SVI was not associated with neonatal opioid use disorder.. · Certain individual risk factors were identified as being associated with NOWS.. · Homogeneity of composite SVI scores may have led to lack of significant findings..

Association between Diabetes in Pregnancy and Shoulder Dystocia by Infant Birth Weight in an Era of Cesarean Delivery for Suspected Macrosomia.

OBJECTIVE: We estimated the association between diabetes and shoulder dystocia by infant birth weight subgroups (<4,000, 4,000-4,500, and >4,500 g) in an era of prophylactic cesarean delivery for suspected macrosomia. STUDY DESIGN: A secondary analysis from the National Institute of Child Health and Human Development U.S. Consortium for Safe Labor of deliveries at ≥24 weeks with a nonanomalous, singleton fetus with vertex presentation undergoing a trial of labor. The exposure was either pregestational or gestational diabetes compared with no diabetes. The primary outcome was shoulder dystocia and secondarily, birth trauma with a shoulder dystocia. We calculated adjusted risk ratios (aRRs) with modified Poison's regression between diabetes and shoulder dystocia and the number needed to treat (NNT) to prevent a shoulder dystocia with cesarean delivery. RESULTS: Among 167,589 assessed deliveries (6% with diabetes), pregnant individuals with diabetes had a higher risk of shoulder dystocia at birth weight <4,000 g (aRR: 1.95; 95% confidence interval [CI]: 1.66-2.31) and 4,000 to 4,500 g (aRR: 1.57; 95% CI: 1.24-1.99), albeit not significantly at birth weight >4,500 g (aRR: 1.26; 95% CI: 0.87-1.82) versus those without diabetes. The risk of birth trauma with shoulder dystocia was higher with diabetes (aRR: 2.29; 95% CI: 1.54-3.45). The NNT to prevent a shoulder dystocia with diabetes was 11 and 6 at ≥4,000 and >4,500 g, versus without diabetes, 17 and 8 at ≥4,000 and >4,500 g, respectively. CONCLUSION: Diabetes increased the risk of shoulder dystocia, even at lower birth weight thresholds than at which cesarean delivery is currently offered. Guidelines providing the option of cesarean delivery for suspected macrosomia may have decreased the risk of shoulder dystocia at higher birth weights. KEY POINTS: · >Diabetes increased the risk of shoulder dystocia, even at lower birth weight thresholds than at which cesarean delivery is currently offered.. · Cesarean delivery for suspected macrosomia may have decreased the risk of shoulder dystocia at higher birth weights.. · These findings can inform delivery planning for providers and pregnant individuals with diabetes..

Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa.

BACKGROUND: Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa. METHODS: Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models. RESULTS: Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5∗3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5∗3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 × 10-7) and CNTN5 rs75285763 (P = 2.9 × 10-8), respectively. CONCLUSIONS: Among South Africans treated for drug-resistant tuberculosis, CYP3A5∗3 was associated with slower bedaquiline clearance. Different CYP3A5∗3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.

Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study.

BACKGROUND: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescribers but have not been systematically studied at the standard dose, and the relationship between linezolid exposure and clinical toxicity is not completely elucidated. PATIENTS AND METHODS: We conducted an observational cohort study to describe the incidence and determinants of linezolid toxicity, and to determine a drug exposure threshold for toxicity, among patients with rifampicin-resistant TB in South Africa. Linezolid exposures were estimated from a population pharmacokinetic model. Mixed-effects modelling was used to analyse toxicity outcomes. RESULTS: One hundred and fifty-one participants, 63% HIV positive, were enrolled and followed for a median of 86 weeks. Linezolid was permanently discontinued for toxicity in 32 (21%) participants. Grade 3 or 4 linezolid-associated adverse events occurred in 21 (14%) participants. Mean haemoglobin concentrations increased with time on treatment (0.03 g/dL per week; 95% CI 0.02-0.03). Linezolid trough concentration, male sex and age (but not HIV positivity) were independently associated with a decrease in haemoglobin >2 g/dL. Trough linezolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemoglobin and treatment-emergent anaemia (adjusted OR 2.9; 95% CI 1.3-6.8). SNPs 2706A > G and 3010G > A in mitochondrial DNA were not associated with linezolid toxicity. CONCLUSIONS: Permanent discontinuation of linezolid was common, but linezolid-containing therapy was associated with average improvement in toxicity measures. HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring.

Population pharmacokinetics of ethambutol in African children: a pooled analysis.

OBJECTIVES: Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population. METHODS: We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3-12.6) years and 9.6 (3.9-34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92%). RESULTS: Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2 months after birth and 99% by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax = 0.882 (0.669-1.28) versus 1.66 (1.21-2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16 years or older. CONCLUSIONS: To obtain exposure within the 2-6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.

Association between Prenatal Marijuana and Tobacco Smoke Exposures and Small for Gestational Age at Birth.

OBJECTIVE: The aim of this study was to determine the association of prenatal marijuana exposure with and without tobacco smoke exposure and small for gestational age (SGA) at birth. STUDY DESIGN: We conducted a secondary analysis of the prospective Lifestyle and Early Achievement in Families (LEAF) cohort enrolled from 2010 to 2015. We included singleton nonanomalous liveborn pregnancies. We assessed marijuana use inclusive of any pregnancy urine specimen with a Δ9-THC-COOH concentration of more than 15 ng/mL by mass spectrometry, self-report on questionnaire, and/or electronic health record; and self-reported maternal tobacco use. Because of the high co-frequency of marijuana with tobacco exposure in pregnancy and the known association between tobacco and fetal growth restriction, we modeled the exposure as: both marijuana and tobacco (hereafter "co-use"), only marijuana, only tobacco, and neither (reference). Incidence of SGA in each group was compared with the neither group. The primary outcome was SGA less than 10th percentile, and secondarily less than 5th percentile, using parity-specific definitions per 2017 US natality reference data. RESULTS: Among 325 assessed mothers, 46% had neither exposure, 11% had only prenatal marijuana exposure, 20% only tobacco exposure, and 23% co-use exposure. A third (33%) of infants were SGA less than 10th percentile and 20% SGA less than 5th percentile. Marijuana exposure only was associated with an increased risk of SGA less than 10th percentile (43 vs. 26%; adjusted relative risk [aRR]: 1.66; 95% confidence interval [CI]: 1.02-2.69), and SGA less than5th percentile (30 vs. 13%; aRR: 2.26; 95% CI: 1.15-4.47). Tobacco was not associated with SGA less than 10th percentile, but was with SGA less than 5th percentile (26 vs. 13%; aRR: 2.01; 95% CI: 1.13, 3.56). Co-use was not associated with increased SGA risk in multivariate analysis, but was in sensitivity analysis when tobacco use was defined using a cotinine assay rather than self-report (SGA <10th percentile, aRR: 1.97; 95% CI: 1.24-3.15) and (SGA <5th percentile, aRR: 2.03; 95% CI: 1.09-3.78). CONCLUSION: Prenatal marijuana exposure in addition to tobacco may increase the risk of SGA. Given the rising prevalence of marijuana use in pregnancy, further research is warranted to understand how in utero marijuana exposure may impact fetal growth and birth weight with and without tobacco exposure. KEY POINTS: · Marijuana and tobacco are commonly used together in pregnancy.. · Prenatal marijuana and tobacco exposure may increase the risk of a small for gestational age infant.. · Further research is warranted to understand how in utero marijuana exposure impacts fetal growth..

Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis.

Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300 mg daily for 3 days, followed by 100 mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300 mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (ΔQTcF > 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with ΔQTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300 mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.

Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis.

Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid. Pretomanid may also have benefit as a treatment-shortening agent for drug-sensitive tuberculosis. It is unclear how and whether it can be used together with rifamycins, which are key sterilizing first-line drugs. In this analysis, data were pooled from two studies: the Assessing Pretomanid for Tuberculosis (APT) trial, in which patients with drug-sensitive pulmonary TB received pretomanid, isoniazid, and pyrazinamide plus either rifampin or rifabutin versus standard of care under fed conditions, and the AIDS Clinical Trials Group 5306 (A5306) trial, a phase I study in healthy volunteers receiving pretomanid alone or in combination with rifampin under fasting conditions. In our population pharmacokinetic (PK) model, participants taking rifampin had 44.4 and 59.3% reductions in pretomanid AUC (area under the concentration-time curve) compared to those taking rifabutin or pretomanid alone (due to 80 or 146% faster clearance) in the APT and A5306 trials, respectively. Median maximum concentrations (Cmax) in the rifampin and rifabutin arms were 2.14 and 3.35 mg/liter, while median AUC0-24 values were 30.1 and 59.5 mg·h/liter, respectively. Though pretomanid exposure in APT was significantly reduced with rifampin, AUC0-24 values were similar to those associated with effective treatment in registrational trials, likely because APT participants were fed with dosing, enhancing pretomanid relative bioavailability and exposures. Pretomanid concentrations with rifabutin were high but in range with prior observations. While pretomanid exposures with rifampin are unlikely to impair efficacy, our data suggest that pretomanid should be taken with food if prescribed with rifampin. (This study has been registered at ClinicalTrials.gov under identifier NCT02256696.).

Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis.

Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimization, we aimed to characterize the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV coinfection, on drug exposure. Data were obtained from pharmacokinetic substudies in a randomized controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis. Participants underwent intensive and sparse plasma sampling. We analyzed linezolid concentration data using nonlinear mixed-effects modeling and performed simulations to estimate attainment of putative efficacy and toxicity targets. A total of 124 participants provided 444 plasma samples; 116 were on the standard daily dose of 600 mg, while 19 had dose reduction to 300 mg due to adverse events. Sixty-one participants were female, 71 were HIV-positive, and their median weight was 56 kg (interquartile range [IQR], 50 to 63). In the final model, typical values for clearance and central volume were 3.57 liters/h and 40.2 liters, respectively. HIV coinfection had no significant effect on linezolid exposure. Simulations showed that 600-mg dosing achieved the efficacy target (area under the concentration-time curve for the free, unbound fraction of the drug [[Formula: see text] at a MIC level of 0.5 mg/liter) with 96% probability but had 56% probability of exceeding safety target ([Formula: see text]. The 300-mg dose did not achieve adequate efficacy exposures. Our model characterized population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600-mg daily dose with safety monitoring.

Population Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Pregnant South African Women with Tuberculosis and HIV.

Tuberculosis is an important cause of maternal morbidity, but little is known about the effects of pregnancy on antituberculosis drug concentrations. We developed population pharmacokinetic models to describe drug dispositions of isoniazid, pyrazinamide, and ethambutol in pregnant women with tuberculosis and HIV. HIV-positive pregnant women with tuberculosis receiving standard first-line tuberculosis treatment and participating in Tshepiso, a prospective cohort study in Soweto, South Africa, underwent sparse pharmacokinetic sampling at >36 weeks of gestation and 7 weeks postpartum. The effects of pregnancy on the pharmacokinetics of isoniazid, pyrazinamide, and ethambutol were investigated via population pharmacokinetic modeling. Isoniazid, pyrazinamide, and ethambutol concentrations were available for 29, 18, and 18 women, respectively. Their median weight was 66 kg while pregnant and 64 kg postpartum. No significant differences were observed in drug clearance, volume of distribution, or bioavailability during and after pregnancy. The model-estimated isoniazid, pyrazinamide, and ethambutol area under the concentration-time curve from 0 to 24 h (AUC0-24) medians were, respectively, 6.88, 419, and 16.5 mg · h/liter during pregnancy versus 5.01, 407, and 19.0 mg · h/liter postpartum. The model-estimated maximum concentration (Cmax) medians for isoniazid, pyrazinamide, and ethambutol were, respectively, 1.39, 35.9, and 1.82 mg/liter during pregnancy versus 1.43, 34.5, and 2.11 mg/liter postpartum. A posteriori power calculations determined that our analysis was powered 91.8%, 59.2%, and 90.1% at a P of <0.01 to detect a 40% decrease in the AUCs of isoniazid, pyrazinamide, and ethambutol, respectively. Pregnancy does not appear to cause relevant changes in the exposure to isoniazid, pyrazinamide, and ethambutol. Additional studies of antituberculosis drugs in pregnancy are needed.

Clofazimine pharmacokinetics in patients with TB: dosing implications.

BACKGROUND: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. OBJECTIVES: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. PATIENTS AND METHODS: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. RESULTS: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. CONCLUSIONS: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

The impact of low-dose versus high-dose antibiotic prophylaxis regimens on surgical site infection rates after cesarean delivery.

OBJECTIVE: The objective of this study was to determine if high-dose antibiotic prophylaxis with cefazolin decreases the risk of surgical site infection (SSI) after a cesarean delivery. METHODS: We performed a retrospective cohort study of women who underwent a cesarean section. Two preoperative antibiotic regimens were compared: low dose versus high dose. The primary outcome was SSI. A sample size of 343 patients per group was calculated for a 50% reduction in risk for SSI. RESULTS: Seven hundred and thirty women were included with an incidence of SSI of 5%. Women who received the high-dose antibiotic regimen had lower rates of risk factors for SSI. The only exception was skin incision closure with staples. The rate of SSI did not differ between the low-dose and high-dose groups, even after adjusting for confounding variables [aOR 1.78, 95% CI (0.82-3.9)]. CONCLUSIONS: Higher doses of antibiotic prophylaxis did not decrease the rates of SSI after cesarean delivery.

Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection.

The World Health Organization (WHO) recently recommended that linezolid be prioritized in treatment regimens for drug-resistant tuberculosis (TB), but there are limited data on its pharmacokinetics (PK) in patients with this disease. We conducted an observational study to explore covariate effects on linezolid PK and to estimate the probability of PK/pharmacodynamic target attainment in South African patients with drug-resistant TB. Consecutive adults on linezolid-based regimens were recruited in Cape Town and underwent intensive PK sampling at steady state. Noncompartmental analysis was performed. Thirty participants were included: 15 HIV positive, 26 on the initial dose of 600 mg daily, and 4 participants on 300 mg daily after dose reduction for linezolid-related toxicity. There was a negative correlation between body weight and exposure, with 17.4% (95% confidence interval [CI], 0.1 to 31.7) decrease in area under the concentration-time curve from 0 to 24 h (AUC0-24) per 10-kg weight increment after adjustment for other covariates. Age was an independent predictor of trough concentration, with an estimated 43.4% (95% CI, 5.9 to 94.2) increase per 10-year increment in age. The standard 600-mg dose achieved the efficacy target of free AUC/MIC of >119 at wild-type MIC values (≤0.5 mg/liter), but the probability of target attainment dropped to 61.5% (95% CI, 40.6 to 79.8) at the critical concentration of 1 mg/liter. When dosed at 600 mg daily, trough concentrations were above the toxicity threshold of 2 mg/liter in 57.7% (95% CI, 36.9 to 76.6). This confirms the narrow therapeutic index of linezolid, and alternative dosing strategies should be explored.

The Effect of Wearing White Coats on Patients' Appreciation of Physician Communication during Postpartum Rounds: A Randomized Controlled Trial.

OBJECTIVE: Wearing a white coat (WC) has been associated with risk of colonization and transmission of resistant pathogens. Also, studies have shown that physicians' attire in general affects patients' confidence in their physician and the patient-physician relationship. Our objective is to evaluate the hypothesis that not wearing a WC during physician postpartum rounds does not affect patient-physician communication scores. MATERIALS AND METHODS: This is an unblinded, randomized, parallel arms, controlled trial of postpartum women at a single university hospital. Women were randomly assigned to having their postpartum physicians' team wear a WC or not (no-WC) during rounds. Our primary outcome was "patient-physician communication" score. Univariable and multivariable analysis were used where appropriate. RESULTS: One hundred and seventy-eight patients were enrolled (87 in WC and 91 in no-WC groups). Note that 40.4% of patients did not remember whether the physicians wore a WC or not. There was no difference in the primary outcome (p = 0.64) even after adjusting for possible confounders. CONCLUSION: Not wearing a WC during postpartum rounds did not affect the patient-physician communication or patient satisfaction scores. In the setting of prior reports showing a risk of WC pathogen transmission between patients, our findings cannot support the routine wearing of WCs during postpartum rounds.

Sexual Health Outcomes in Adults with Complete Male Epispadias.

PURPOSE: Complete male epispadias is a rare congenital anomaly characterized by failed closure of the entire penopubic dorsal urethra. Epispadias repair is typically performed during infancy, and resultant genitourinary abnormalities can have a marked impact on adult life. We assess long-term post-reconstruction sexual health and fertility outcomes in adults with complete male epispadias. MATERIALS AND METHODS: A total of 132 patients 18 years or older with complete male epispadias who had undergone reconstruction were identified from a prospectively maintained, institutionally approved database. Patients who could be contacted were asked to complete a telephone survey regarding sexual function. Reconstructive history and clinical details were obtained by chart/database review. RESULTS: Of 132 patients with complete male epispadias 74 met inclusion criteria and 15 (20%) completed the questionnaire. Seven patients (47%) reported currently being in a relationship. Although 12 patients (80%) reported overall satisfactory sexual intercourse, 11 (73%) admitted to 1 or more problems with sexual function, including abnormal ejaculation (53%), diminished sensation (20%) and difficulty maintaining an erection (20%). When questioned regarding the importance of fertility on a scale of 0 to 5 using a Likert-type item the response of 10 patients (67%) was 4 points or greater. Five patients (33%) reported having impregnated a sexual partner. Although 4 patients (27%) had suspicion of fertility problems, only 2 (13%) reported having abnormal semen analyses. CONCLUSIONS: This is one of few studies examining post-reconstruction sexual health and function in adults with complete male epispadias. Although small, our study demonstrates that patients are able to engage in relationships, participate in sexual intercourse and impregnate their partners. These results highlight sexual concerns and outcomes that may be of use when counselling patients with complete male epispadias and their families.