Background Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen-drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date. MethodsWe estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drugresistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level. FindingsOn the basis of our predictive statistical models, there were an estimated 4•95 million (3•62-6•57) deaths associated with bacterial AMR in 2019, including 1•27 million (95% UI 0•911-1•71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27•3 deaths per 100 000 (20•9-35•3), and lowest in Australasia, at 6•5 deaths (4•3-9•4) per 100 000. Lower respiratory infections accounted for more than 1•5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000-1 270 000) deaths attributable to AMR and 3•57 million (2•62-4•78) deaths associated with AMR in 2019. One pathogen-drug combination, meticillinresistant S aureus, caused more than 100 000 deaths attributa...

In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822 .).

Objective We evaluated the pharmacokinetics (pk) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods IMPAACT 1026s is an on-going prospective study of antiretroviral pk during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady state 12-hour pk profiles performed during pregnancy and at 6–12 weeks postpartum. Targets were trough concentration above 0.035 µg/mL, the estimated tenth percentile in non-pregnant historical controls. Results Median raltegravir AUC was 6.6 µg*hr/mL for second trimester (n= 16), 5.4 µg*hr/mL for third trimester (n=41), and 11.6 µg*hr/mL postpartum (n= 38) (p=0.03 pp vs 2nd trimester, p=0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester and postpartum subjects respectively, with wide variability (<0.010–0.917 µg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were < 400 copies/mL in 92% of women at delivery. Adverse events included elevated liver transaminases in one woman and vomiting in one. All infants with known status are HIV-uninfected. Conclusions Median raltegravir AUC was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.

Background The impact of pregnancy on efavirenz pharmacokinetics is unknown. Methods International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg efavirenz once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6–12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile efavirenz AUC in non-pregnant historical controls (40.0 mcg.hr/mL) and a trough concentration of 1 mcg/mL. Results Twenty five women were enrolled during the third trimester: median (range) age was 29.3 (18.9–42.9) years, weight 69.0 (40–130) kg, gestational age 32.9 (30.1–38.7) weeks. Median (range) efavirenz AUC0-24, Cmax and C24hour were 55.4 mcg.hr/mL (13.5–220.3), 5.4 mcg/mL (1.9–12.2) and 1.6 mcg/ml (0.23–8.13), respectively. Efavirenz AUC and Cmax did not differ during pregnancy and postpartum but C24hour was lower during the third trimester (1.6 vs. 2.1 mcg/mL, p=0.01). During the third trimester, 5 of 25 (20%) women had an efavirenz AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. Efavirenz cord blood/maternal concentration ratio was 0.49 (0.37–0.74). All women had a HIV-1 RNA viral load less than 400 copies/mL at delivery and 19 (76%) had a viral load below 50 copies/mL. One child was perinatally HIV-infected. Three women were exposed to efavirenz throughout the first 6 weeks of pregnancy. EFV was well tolerated and among the 25 infants no congenital anomalies or newborn complications were reported. Conclusions Changes in efavirenz pharmacokinetics during pregnancy compared to postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.

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ObjectiveTo gain an understanding of the variation in available resources and clinical practices between neonatal units (NNUs) in the low-income and middle-income country (LMIC) setting to inform the design of an observational study on the burden of unit-level antimicrobial resistance (AMR).DesignA web-based survey using a REDCap database was circulated to NNUs participating in the Neonatal AMR research network. The survey included questions about NNU funding structure, size, admission rates, access to supportive therapies, empirical antimicrobial guidelines and period prevalence of neonatal blood culture isolates and their resistance patterns.Setting39 NNUs from 12 countries.PatientsAny neonate admitted to one of the participating NNUs.InterventionsThis was an observational cohort study.ResultsThe number of live births per unit ranged from 513 to 27 700 over the 12-month study period, with the number of neonatal cots ranging from 12 to 110. The proportion of preterm admissions <32 weeks ranged from 0% to 19%, and the majority of units (26/39, 66%) use Essential Medicines List ‘Access’ antimicrobials as their first-line treatment in neonatal sepsis. Cephalosporin resistance rates in Gram-negative isolates ranged from 26% to 84%, and carbapenem resistance rates ranged from 0% to 81%. Glycopeptide resistance rates among Gram-positive isolates ranged from 0% to 45%.ConclusionAMR is already a significant issue in NNUs worldwide. The apparent burden of AMR in a given NNU in the LMIC setting can be influenced by a range of factors which will vary substantially between NNUs. These variations must be considered when designing interventions to improve neonatal mortality globally.

Objective: HIV prevention and treatment studies demonstrate that pharmacologic adherence metrics are more accurate than self-report. Currently available metrics use liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS), which is expensive and laboratory-based. We developed a specific and sensitive antibody against tenofovir, the backbone of treatment and prevention, but conversion to a lateral flow assay (LFA) – analogous to a urine pregnancy test – is required for point-of-care testing. We describe the development of the first LFA to measure antiretroviral adherence in real-time. Methods: Previous work in a directly observed therapy study of providing tenofovir disoproxil fumarate (TDF) to HIV-noninfected volunteers at various simulated adherence patterns defined the appropriate cut-off for the LFA (1500 ng tenofovir/ml urine). We developed the LFA using a sample pad for urine; a conjugate pad coated with TFV-specific antibodies conjugated to colloidal gold nanoparticles; a nitrocellulose membrane striped with tenofovir-antigen (test line) and a control line; with an absorbent pad to draw urine across the reaction membrane. Results: We tested 300 urine samples collected from the directly observed therapy study by this LFA and the gold-standard method of LC-MS/MS. The LFA demonstrated 97% specificity (95% CI 93–99%) and 99% sensitivity (94–100%) compared with LC-MS/MS. The LFA accurately classified 98% of patients who took a dose within 24 h as adherent. Conclusion: We describe the development and validation of the first point-of-care assay to measure short-term adherence to HIV prevention and treatment in routine settings. The assay is low-cost, easy-to-perform and measures the breakdown product (tenofovir) of both TDF and tenofovir alafenamide (TAF). This assay has the potential to improve HIV and PrEP outcomes worldwide by triggering differentiated service delivery with further study merited.

Background: Current pharmacologic adherence monitoring for antiretrovirals involves expensive, labor-intensive liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS)-based methods. Antibody-based assays can monitor and support adherence in real-time. We developed a tenofovir (TFV)-based immunoassay and further validated it in a directly-observed-therapy (DOT) study.Design: Pharmacologic DOT study of TFV disoproxil fumarate (TDF)/emtricitabine (FTC) administered to HIV-noninfected volunteers Methods: The TARGET study provided directly-observed TDF 300mg/FTC 200mg 7 (high adherence), 4 (moderate) and 2 doses/week (low) to 30 volunteers (10/group) in Thailand, collecting a total of 637 urine samples over 6-weeks of administration and during wash-out. ELISA measured urine TFV levels by the immunoassay and LC-MS/MS-based concentrations served as the gold-standard. A mixed-effects regression model evaluated cut-offs for a point-ofcare (POC) assay. Performance characteristics of the immunoassay were compared to LC-MS/MS at a chosen cut-off.Results: Median TFV levels were 12,000ng/mL by the immunoassay 1-day after dosing; 5000ng/mL 2-days after dosing; 1500ng/mL 3-days after dosing and below the lower-limit-of-