Evaluation of Dose Adjustment in Patients With Renal Impairment at Muhimbili National Hospital in Tanzania.

Background: The burden of renal diseases is increasing in developing countries like Tanzania. Drug accumulation exposes patients with renal impairment to drug toxicity that may lead to adverse drug reactions, poor adherence to treatment, and increased healthcare costs. There is limited information on the appropriateness of dosage regimen adjustment for patients with renal impairment, particularly in developing countries such as Tanzania. This study aimed to investigate the appropriateness of drug dosing in hospitalized patients with renal impairment in Tanzania. Methods: This was a retrospective cross-sectional study. It was conducted between November 2019 and April 2020 amongst hospitalized patients at Muhimbili National Hospital. All enrolled patients had serum creatinine levels ≥1.2 mg/dL and taking at least one drug requiring dosage regimen adjustment. Creatinine clearance was calculated from patient serum creatinine using the Cockcroft-Gault equation. Drug dosing appropriateness was determined by comparing the current practice with tertiary references. The relationship between the patient's baseline characteristics and the rate of dosage regimen adjustment was determined using the X2 test. Univariate and multivariate logistic regression analysis evaluated the predictors of dosing adjustment. Results: Most of the enrolled patients, 269 (98.9%) had comorbidities. Of the medication orders included in the final analysis, 372 (27%) needed dosage regimen adjustment. Out of the 372 medication orders, not adjusted were 168 (45.2%), inappropriately adjusted 105 (28.2%), and appropriately adjusted were only 99 (26.6%). In this study, 212 (77.9%) patients received at least one drug with an incorrect dosage regimen. Females and those with level 4 renal impairment patients were more likely to have their doses appropriately adjusted compared to their counterparts. Conclusions: In this study, about three-quarters of the patients received at least one drug with an incorrect dosage regimen. Thus, appropriate measures such as the availability of national guidelines and clinical decision support systems for drug dosing adjustment in patients' renal impairment should be in place.

Incidence and determinants of adverse events in individuals with HIV commencing Dolutegravir-based antiretroviral therapy in mainland Tanzania.

Tanzania adopted a Dolutegravir (DTG)-based regimen as first-line treatment in 2019 following the World Health Organization recommendation. Data on the DTG safety profile from sub-Saharan Africa including Tanzania are limited. We investigated the incidence of DTG-related adverse events (AEs) and associated factors among people living with HIV (PLHIV) initiated on a DTG regimen. A prospective cohort study was conducted from 25 Care and Treatment Clinics in mainland Tanzania. PLHIV aged 12 years and above who were initiated on a DTG-based regimen were actively followed up for three months. The Cox regression model was used to determine the predictors of occurrence of AEs over time. A p-value of 0.05 was considered statistically significant. From January 2020 to June 2022, a cohort of 935 participants who were both newly diagnosed and ART-experienced who transitioned to a DTG-based regimen was enrolled. Out of 935 participants, 59 (6.3%) reported a total of 62 AEs. The most frequently experienced AE was skin itching and rashes (15/62; 24.2%). DTG-associated neuropsychiatric AEs were less common and included headache (6 [9.6%]) and sleep disturbances (3 [4.8%]). The overall incidence of occurrence of the first AEs was 96.7 per 1000 person-months [95% C.I: 74.4-125.7] with the highest incidence observed among the elderly (≥ 60 years). Individuals on WHO HIV Clinical Stage 2 had a 2.7 significantly higher risk of developing AEs (adjusted hazard ratio = 2.73, 95% CI = 1.46-5.12, p = 0.017). We report a low incidence of grade I (mild) and grade II (moderate) DTG-associated AEs suggesting that the regimen is generally safe in the population. Continued monitoring of DTG safety in the population is recommended.

Prevalence of urinary tract infection and antimicrobial resistance patterns of uropathogens with biofilm forming capacity among outpatients in morogoro, Tanzania: a cross-sectional study.

INTRODUCTION: Urinary tract infection (UTI) is the second most common infectious disease affecting more than 150 million people globally annually. Uropathogenic E. coli (UPEC), the predominant cause of UTI, can occur as a biofilm associated with antimicrobial resistance (AMR). There is a data gap on global AMR patterns from low-income settings, including Tanzania. Data on antimicrobial susceptibility patterns in relation to biofilm formation will help in the proper selection of antibiotics and the fight against AMR. METHODS: This analytical cross-sectional study was conducted among consecutively selected outpatients (n = 344) from January to May 2022 at Morogoro Regional Referal Hospital. Mid-stream urine samples were collected aseptically from symptomatic patients. A significant UTI was defined when more than 105 colonies/ml of urine were recorded. Kirby Bauer's disc diffusion method was used for antibiotics susceptibility patterns and a Congo Red Agar method was used to determine biofilm formation. Two-sided χ2 test or Fisher's exact test, Cohen's kappa coefficient and logistic regression were used for data analysis. A p-value < 0.05 was considered statistically significant. RESULTS: The prevalence of UTIs was 41% (141/344) and elders (>=60 years) had five times higher odds of having UTI as compared to adolescents (p < 0.001). E. coli was the most predominant bacteria (47%; 66/141), which displayed moderate susceptibility against ciprofloxacin (59.1%) and nitrofurantoin (57.6%). A total of 72 (51%) of all isolated bacteria were multi-drug resistant. All isolated bacteria demonstrated high resistance (> 85%) against ampicillin and co-trimoxazole. In this study, 51.5% (34/66) were biofilm-forming E. coli and demonstrated relatively higher antibiotic resistance as compared to non-biofilm forming bacteria (p < 0.05). CONCLUSION: We report high antibiotic resistance against commonly used antibiotics. Slightly more than half of the isolated bacteria were biofilm forming E. coli. A need to strengthen stewardship programs is urgently advocated.

Impact of COVID-19 on the supply chain of essential health commodities: a mixed method study, in Dar es Salaam, Tanzania.

BACKGROUND: The outbreak of COVID-19 in the late 2019 led to major global health crises, including morbidities and mortalities. The pandemic has adversely affected the supply chain of essential health commodities globally. However, such data from sub-Saharan Africa including Tanzania are largely limited. We assessed the impact of COVID-19 on the supply chain of essential health commodities in Tanzania. METHOD: A cross-sectional study with pragmatic mixed method design was conducted in Dar es Salaam region from January to June 2021. Grounded theory was adopted to purposeful select key informants (n = 15) from importers of essential health commodities and local pharmaceutical manufacturers. Community pharmacy dispensers (n = 242) were also recruited for the quantitative part of this study. The prices of selected tracer health commodities were extracted from the Tanzania Medicine and Medical Device Authority (TMDA) Regulatory Information Management system. The mean unit prices 1 year before the pandemic were compared with the mean prices 1 year during the pandemic using paired t test. Thematic analysis was used for qualitative data. RESULTS: The information regarding the impact of COVID-19 on the supply chain of essential health commodities was synthesized into three main themes namely, reduced availability of health commodities, increased price of health commodities and increased lead time for imported essential health commodities during COVID-19. Majority (90%) of community pharmacy dispensers reported that COVID-19 reduced the availability of essential health commodities. Azithromycin, Paracetamol, Multivitamin and Vitamin C tablets were the highly demanded products and their mean unit prices increased significantly during COVID-19 as compared to 1 year before the pandemic (p < 0.05). CONCLUSIONS: COVID-19 led to shortage, increased prices and delayed delivery of essential health commodities. This might happen in the future whenever unexpected crises causing disruption in the supply chain occur underscoring the need for the country preparedness measures.

Population pharmacokinetics of ivermectin after mass drug administration in lymphatic filariasis endemic communities of Tanzania.

Ivermectin (IVM) is a drug of choice used with albendazole for mass drug administration (MDA) to halt transmission of lymphatic filariasis. We investigated IVM pharmacokinetic (PK) variability for its dose optimization during MDA. PK samples were collected at 0, 2, 4, and 6 h from individuals weighing greater than 15 kg (n = 468) receiving IVM (3-, 6-, 9-, or 12 mg) and ALB (400 mg) during an MDA campaign in Tanzania. Individual characteristics, including demographics, laboratory/clinical parameters, and pharmacogenetic variations were assessed. IVM plasma concentrations were quantified by liquid-chromatography tandem mass spectrometry and analyzed using population-(PopPK) modeling. A two-compartment model with transit absorption kinetics, and allometrically scaled oral clearance (CL/F) and central volume (Vc /F) was adapted. Fitting of the model to the data identified 48% higher bioavailability for the 3 mg dose compared to higher doses and identified a subpopulation with 97% higher mean transit time (MTT). The final estimates for CL/F, Vc /F, intercompartment clearance, peripheral volume, MTT, and absorption rate constant for a 70 kg person (on dose other than 3 mg) were 7.7 L/h, 147 L, 20.4 L/h, 207 L, 1.5 h, and 0.71/h, respectively. Monte-Carlo simulations indicated that weight-based dosing provides comparable exposure across weight bands, but height-based dosing with capping IVM dose at 12 mg for individuals with height greater than 160 cm underdoses those weighing greater than 70 kg. Variability in IVM PKs is partly explained by body weight and dose. The established PopPK model can be used for IVM dose optimization. Height-based pole dosing results in varying IVM exposure in different weight bands, hence using weighing scales for IVM dosing during MDA is recommended.

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4ß-Hydroxycholesterol/Cholesterol Ratio.

Changes in cortisol and other hormones during pregnancy may alter CYP3A enzymes activity, but data from sub-Saharan Africa are sparse. We investigated the effect of pregnancy and CYP3A5 genotypes on CYP3A enzymes activity using the plasma 4ß-hydroxycholesterol (4ß-OHC)/cholesterol (Chol) ratio, a known endogenous biomarker. Tanzanian pregnant women (n = 110) and non-pregnant women (n = 59) controls were enrolled. Plasma 4ß-OHC and Chol were determined in the second and third trimesters for pregnant women and once for non-pregnant women using gas chromatography−mass spectrometry. Genotyping for CYP3A5 (*3, *6, *7) was performed. Wilcoxon Signed-Rank Test and Mann−Whitney U test were used to compare the median 4ß-OHC/Chol ratio between trimesters in pregnant women and between pregnant and non-pregnant women. Repeated-measure ANOVA was used to evaluate the effect of the CYP3A5 genotypes on the 4ß-OHC/Chol ratio in pregnant women. No significant effect of the pregnancy status or the CYP3A5 genotype on the cholesterol level was observed. The plasma 4ß-OHC/Chol ratio significantly increased by 7.3% from the second trimester to the third trimester (p = 0.02). Pregnant women had a significantly higher mean 4ß-OHC/Chol ratio than non-pregnant women, (p < 0.001). In non-pregnant women, the mean 4ß-OHC/Chol ratio was significantly lower in carriers of defective CYP3A5 alleles (*3, *6 or *7) as compared to women with the CYP3A5*1/*1 genotypes (p = 0.002). Pregnancy increases CYP3A enzymes activity in a gestational-stage manner. The CYP3A5 genotype predicts CYP3A enzymes activity in the black Tanzanian population, but not during pregnancy-mediated CYP3A enzyme induction.

Effectiveness of Intermittent Preventive Treatment With Dihydroartemisinin-Piperaqunine Against Malaria in Pregnancy in Tanzania: A Randomized Controlled Trial.

Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) to prevent malaria and adverse birth outcomes is threatened by Plasmodium falciparum resistance to sulfadoxine-pyrimethamine. We investigated the effectiveness of intermittent preventive treatment in pregnancy with monthly dihydroartemisinin-piperaquine (IPTp-DHP) as an alternative option to IPTp-SP. A total of 956 malaria-free (malaria rapid diagnostic test (MRDT) negative) pregnant women from moderate malaria transmission areas in Tanzania were enrolled and randomized to receive monthly IPTp-DHP (n = 478) or IPTp-SP (n = 478) and followed for maternal and birth outcomes. The primary outcome was the prevalence of histopathologically confirmed placental malaria (active or past infection). Secondary outcomes were overall malaria at delivery, symptomatic-malaria, parasitemia during pregnancy, and adverse birth outcomes as a composite of spontaneous-abortion, premature birth, stillbirth, and low birth weight (LBW) fetal anemia. Outcome differences between treatment groups were expressed as the protective efficacy (PE), defined as 1-prevalence ratios or 1-incidence rate ratio. The prevalence of histopathologically confirmed placental malaria was significantly lower in IPTp-DHP (2.5%, 12/478) than IPTp-SP (8.2%, 39/478); PE = 69% (95% confidence interval (CI): 42-84, P < 0.001). The prevalence of maternal malaria at delivery was significantly lower in IPTp-DHP (8.2%) than IPTp-SP (18.2%, P < 0.001). The incidence per person-years at risk for symptomatic-malaria (0.02 vs. 0.12, P = 0.002) and parasitemia during pregnancy (0.28 vs. 0.67, P < 0.001) were significantly lower in the IPTp-DHP group than in the IPTp-SP group. The prevalence of any adverse birth outcomes (composite) was not significantly (P = 0.06) different between IPTp-DHP (17.9%) and IPTp-SP (23.8%). However, the prevalence of LBW (4.6% vs. 9.6%, P = 0.003) was significantly lower in IPTp-DHP compared with IPTp-SP. We report superior protective efficacy of monthly IPTp-DHP against malaria in pregnancy and LBW than IPTp-SP.

Prevalence and Correlates of Asymptomatic Malaria and Anemia on First Antenatal Care Visit among Pregnant Women in Southeast, Tanzania.

Asymptomatic malaria and anemia during pregnancy increase the risk of negative birth outcomes. This cross-sectional study investigated the prevalence and correlates of asymptomatic malaria and anemia during first antenatal care (ANC) visit among pregnant women in a rural district, Tanzania. HIV-uninfected pregnant women without symptoms of malaria (n = 819) attending their first ANC at Kibiti Health Centre were enrolled from February 2017 to February 2018. Asymptomatic malaria was detected by malaria rapid-diagnostic tests (mRDT) and real-time PCR. Hemoglobin concentration was determined by HemoCue Hemoglobin 201+. The study outcomes were the prevalence of asymptomatic malaria and anemia (Hemoglobin level <11 g/dL). The overall prevalence of asymptomatic malaria was 36.4% (95% CI: 33.1, 39.8). The monthly prevalence of asymptomatic malaria remained >25% throughout the year, and the highest prevalence (40%) was recorded during the rainy season. Asymptomatic malaria was significantly associated with primigravida, younger maternal age, and anemia. The prevalence of anemia was 68.5% (95% CI: 65.2, 71.6). Asymptomatic malaria, primigravida, younger maternal age and low Body Mass Index were significant predictors of low hemoglobin concentration. We report high prevalence of asymptomatic malaria and anemia among pregnant women on the first ANC visit. Screening of malaria and anemia during the first ANC visit is recommended for targeted interventions.

Effect of sulfadoxine-pyrimethamine doses for prevention of malaria during pregnancy in hypoendemic area in Tanzania.

BACKGROUND: Malaria in pregnancy increases the risk of deleterious maternal and birth outcomes. The use of ≥ 3 doses of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria (IPTp-SP) is recommended for preventing the consequences of malaria during pregnancy. This study assessed the effect of IPTp-SP for prevention of malaria during pregnancy in low transmission settings. METHODS: A cross-sectional study that involved consecutively selected 1161 pregnant women was conducted at Mwananyamala regional referral hospital in Dar es Salaam. Assessment of the uptake of IPTp-SP was done by extracting information from antenatal clinic cards. Maternal venous blood, cord blood, placental blood and placental biopsy were collected for assessment of anaemia and malaria. High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used to detect and quantify sulfadoxine (SDX). Dried blood spots (DBS) of placental blood were collected for determination of sub-microscopic malaria using polymerase chain reaction (PCR). RESULTS: In total, 397 (34.2%) pregnant women reported to have used sub-optimal doses (≤ 2) while 764 (65.8%) used optimal doses (≥ 3) of IPTp-SP at the time of delivery. The prevalence of placental malaria as determined by histology was 3.6%. Submicroscopic placental malaria was detected in 1.4% of the study participants. Women with peripheral malaria had six times risk of maternal anaemia than those who were malaria negative (aOR, 5.83; 95% CI 1.10-30.92; p = 0.04). The geometric mean plasma SDX concentration was 10.76 ± 2.51 µg/mL. Sub-optimal IPTp-SP dose was not associated with placental malaria, premature delivery and fetal anaemia. The use of ≤ 2 doses of IPTp-SP increased the risk of maternal anaemia by 1.36-fold compared to ≥ 3 doses (aOR, 1.36; 95% CI 1.04-1.79; p = 0.02). CONCLUSION: The use of < 2 doses of IPTp-SP increased the risk of maternal anaemia. However, sub-optimal doses (≤ 2 doses) were not associated with increased the risk of malaria parasitaemia, fetal anaemia and preterm delivery among pregnant women in low malaria transmission setting. The use of optimal doses (≥ 3 doses) of IPTp-SP and complementary interventions should continue even in areas with low malaria transmission.

Effectiveness of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Malaria and Adverse Birth Outcomes in Pregnant Women.

Effectiveness of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) for prevention of malaria and adverse birth outcomes can be compromised by parasites-resistance to sulfadoxine-pyrimethamine. This study prospectively evaluated the effectiveness of IPTp-SP in Southeast Tanzania. From January 2017 to May 2019, HIV-negative and malaria-negative (mRDT) pregnant women attending their first antenatal-care visit in the second or third trimester (n = 500) were enrolled to receive monthly IPTp-SP and followed the protocol till delivery. The primary outcome was the prevalence of histopathological placental malaria. Secondary outcomes were anemia, malaria parasites detected during pregnancy and at delivery, adverse birth outcomes (low-birth-weight [LBW], premature birth, fetal anemia, still birth, and spontaneous abortion). Rates of histopathological placental malaria, any parasitemia at delivery (placental, cord or maternal), and any adverse birth outcome were 9.4%, 20.9%, and 26.5%, respectively. Rates of symptomatic malaria and parasitemia during pregnancy were 2.8% and 16%, respectively. Histopathological placental malaria significantly increased the odds of any adverse birth outcomes, particularly LBW. IPTp-SP with more than or equal to three doses significantly improved birth weight and reduced the risk of LBW by 56% compared to <3 SP doses (p = 0.009). IPTp-SP with more than or equal to three doses is still effective in improving birth weight. However, the detection of histopathological placental-malaria in one-tenth and parasitemia in one-fifth of pregnant women reflects the need to optimize the prevention of malaria during pregnancy.