Implementation research for promoting access and rational use of antibiotics for children: lessons learnt from Tanzania.

Implementation research (IR) has proved to be a potential catalyst in facilitating the uptake of evidence-based innovations into routine practices and thereby maximizing public health outcomes. IR not only focuses on the effectiveness of the innovations but also identifies and addresses the barriers and facilitators to maximize their uptake into routine practices. This article describes the processes undertaken to implement a research project aimed at promoting access and rational use of antibiotics for children (PARAC). It also provides an overview of the lessons learnt during its implementation in Tanzanian hospital and community settings.

Profiling of antimicrobial dispensing practices in accredited drug dispensing outlets in Tanzania: a mixed-method cross-sectional study focusing on pediatric patients.

BACKGROUND: The emergency of antimicrobial resistance due to irrational antimicrobial use has put public health under threat. Accredited Drug Dispensing Outlets (ADDOs) play an important role in enhancing availability and accessibility of antimicrobials, however, there is a scarcity of studies assessing antimicrobial dispensing practices in these outlets, focusing on children in Tanzania. OBJECTIVE: This study was conducted to assess the antimicrobial dispensing practices among ADDO dispensers and explore the factors influencing the use of antimicrobials for children in Tanzania. METHODS: A community-based cross-sectional study utilizing both qualitative (interviews) and quantitative (simulated clients) methods was conducted between June and September 2020 in seven zones and 14 regions in Tanzania. RESULTS: The study found inappropriate dispensing and use of antimicrobials for children, influenced by multiple factors such as patient's and dispenser's knowledge and attitude, financial constraints, and product-related factors. Only 8% (62/773) of dispensers asked for prescriptions, while the majority (90%) were willing to dispense without prescriptions. Most dispensers, 83% (426/513), supplied incomplete doses of antimicrobials and only 60.5% (345/570) of the dispensers gave proper instructions for antimicrobial use to clients. Over 75% of ADDO dispensers displayed poor practice in taking patient history. CONCLUSION: ADDO dispensers demonstrated poor practices in dispensing and promoting rational antimicrobial use for children. Training, support, and regulatory interventions are required to improve antimicrobial dispensing practices in community drug outlets.

Implementation of antibiotic stewardship programmes in paediatric patients in regional referral hospitals in Tanzania: experience from prescribers and dispensers.

Background: In 2017, Tanzania launched the National Action Plan for Antimicrobial Resistance (NAPAR), 2017-2022 and implementation of antibiotic stewardship programmes (ASPs) was one of the agendas. Since the launch of the National Action Plan, no study has been done to assess its implementation. Objectives: To explore the experiences of prescribers and dispensers on implementing ASPs among paediatric patients attending Regional Referral Hospitals (RRHs) in Tanzania. Methods: An exploratory qualitative study was conducted among key informants, in 14 RRHs in Tanzania between July and August 2020. A total of 28 key informants, 14 dispensers in charge of pharmacies and 14 medical doctors in charge of paediatric departments (prescribers), were interviewed. A hybrid thematic analysis was conducted on the gathered information. Results: Most of the study participants were not conversant with the term 'antibiotic stewardship'. Some had heard about the programmes but were not aware of the activities involved in the programme. Those who were knowledgeable on ASPs mentioned the lack of existence of such programmes in their settings. They further added that absence or limited knowledge of the stewardship concepts may have influenced the current poor practices. Barriers to the implementation of ASPs mentioned were lack of laboratory facilities to support culture and susceptibility tests, lack of materials and reagents, management pressure to prevent loss or to generate income, patients' influence and limited training opportunities. Conclusions: Despite launching the NAPAR in 2017, we found limited implementation of ASPs in the management of paediatric patients. This study highlighted some barriers and identified possible intervention points.

Effectiveness of a structured stimulated spontaneous safety monitoring of medicines reporting program in strengthening pharmacovigilance system in Tanzania.

Under-reporting of adverse drug events (ADEs) is a challenge facing developing countries including Tanzania. Given the high magnitude of under-reporting, it was necessary to develop and assess the effectiveness of a 'structured stimulated spontaneous safety monitoring' (SSSSM) reporting program of ADEs which aimed at strengthening pharmacovigilance system in Tanzania. A quasi-experimental design and data mining technique were used to assess the effect of intervention after the introduction of program in seven tertiary hospitals. ADEs reports were collected from a single group and compared for 18 months before (July 2017 to December, 2018) and after the program (January 2019 to June 2020). Out of 16,557 ADEs reports, 98.6% (16,332) were reported after intervention and 0.1% (23) death related to adverse drug reactions (ADRs) were reported. Reports increased from 20 to 11,637 after intervention in Dar es salaam, 49 to 316 in Kilimanjaro and 17 to 77 in Mbeya. The population-based reporting ratio per 1,000,000 inhabitants increased from 2 reports per million inhabitants in 2018 to 85 reports in 2019. The SSSSM program can increase the reporting rate of ADEs and was useful in detecting signals from all types of medicines. This was first effective developed spontaneous program to monitor medicine safety in Tanzania.

Drivers of irrational use of antibiotics among children: a mixed-method study among prescribers and dispensers in Tanzania.

BACKGROUND: Misuse of antibiotics has been associated with poor knowledge, attitude and practice (KAP). Therefore, this study aimed to assess if KAP of prescribers and dispensers could drive irrational use of antibiotics among children in Tanzania. METHODS: A convergent parallel mixed-methods study design that employed quantitative and qualitative approaches was conducted in 14 regional referral hospitals (RRHs). A total of 108 participants, prescribers [54] and dispensers [54] working with the pediatric population in the respective regions participated in a quantitative survey, by filling the standard questionnaire while 28 key informant interviews were conducted with in-charges of units from the pharmacy and pediatric departments. Two key informants (prescriber and dispenser) were selected from each RRH. RESULTS: Overall, among prescribers and dispensers, there was adequate knowledge; 81.5% and 79.6%, p = 0.53, those with positive attitudes were 31.5% and 81.5%, p < 0.001 and poor practices were among 70.4% and 48% p = 0.0312 respectively. Among prescribers, 14.8% agreed and strongly agreed that prescribing antibiotics that a patient did not need does not contribute to resistance. Moreover 19% disagreed to prescribe antibiotics according to local guidelines. Among dispensers, a-quarter of the dispensers thought individual efforts to implement antibiotic stewardship would not make a difference, 17% agreed and strongly agreed that antibiotics can treat viral infection and 7% agreed and strongly agreed antibiotics can be stopped upon resolution of symptoms. From qualitative interviews, both participants displayed an adequate understanding of multi-contributors of antibiotic resistance (AR) including polypharmacy, community self-medication, among others. Regardless, both professions declared to prescribed and dispensed antibiotics according to the antibiotics available in stock at the facility. Furthermore, prescribers perceived laboratory investigation took a long time, hence wasting their time. On the other hand, Dispensers reported not to provide adequate instruction to the patients, after dispensing antibiotics. CONCLUSIONS: Both prescribers and dispensers had adequate knowledge, few prescribers had positive attitudes and the majority had poor practices. Few dispensers had poor attitude and practice. These findings highlight the need to provide adequate training on antimicrobial stewardship and enforce regulation that foster appropriate medical practice.

Adherence, Effectiveness and Safety of Dolutegravir Based Antiretroviral Regimens among HIV Infected Children and Adolescents in Tanzania.

Objectives:This study aimed at assessing adherence, effectiveness, and safety of DTG-based HAART regimens among HIV-infected children and adolescents in Tanzania. Methods: This was a single-center prospective cohort study, conducted at the pediatric HIV Clinic in Mbeya, Tanzania. A binary logistic regression model was used to determine predictors of undetectable viral load at week 24. The results were significant when P-value was <0.05. Results: A total of 200 patients were enrolled with the majority (85.5%) being treatment experienced. High adherence levels (71%) were observed using the pharmacy refill method. At week 24, the overall proportion of patients with undetectable viral load was 70.2%. The predictors of undetectable viral load were age, World Health Organization (WHO) clinical stage, baseline VL and adherence to pharmacy refill. Conclusion: The majority of patients attained undetectable viral load 6 months after using DTG based regimen. DTG-based regimens were generally safe with few ADEs reported.

Post marketing surveillance of selected veterinary medicines in Tanzania mainland.

BACKGROUND: Veterinary medicines have been widely used for the prevention and treatment of animal diseases. Globally, the veterinary medicine industry is growing. However, there is a significant increase of concern on the quality of veterinary medicines in various developing countries' legal markets. Poor-quality medicines are associated with treatment failure, development of drug resistance, increased healthcare cost, and death. These reasons warrant a need for monitoring the quality of the medicines circulating in the Tanzania Mainland. METHODS: This was a survey study and veterinary medicines samples were collected from 9 out of 26 regions of Tanzania mainland between 2014 and 2017. Veterinary medicines were sampled from wholesale pharmacies, retail pharmacies, veterinary clinics and Veterinary Accredited Drug Dispensing Outlets (ADDO-vet). All sampled medicines were subjected to product information review and full quality control testing at the Tanzania Medicines and Medical Devices Authority-World Health Organization prequalified laboratory. RESULTS: A total of 238 samples of veterinary medicines were collected. Out of these, 97.1% (231/238) were subjected to full quality control testing and product information review. All sampled veterinary medicines conformed to visual appearance, clarity, pH, solubility and sterility tests. Also, of the sampled veterinary medicines 97.8% (226/231) and 89.2% (206/231) passed identification and assay tests, respectively. As well as, the majority of the collected samples 92% (219/238) failed to comply with product information requirements. The most observed deficiencies on product information were inadequate information on the package insert 94.1% (224/238), inappropriate storage conditions 55.5% (132/238) and lack of Tanzania registration number 27% (64/238). CONCLUSION: Veterinary medicines with poor quality were found circulating in the legal markets of Tanzania. This can potentiate treatment failure and the development of drug resistance in animals and humans. Post marketing surveillance program will continue to be implemented to ensure that only good quality, safe and efficacious medicines are circulating in the Tanzania Mainland market.

Determinants of misuse of antibiotics among parents of children attending clinics in regional referral hospitals in Tanzania.

Parents are the important implementers on appropriate/inappropriate use of antibiotics, especially in the pediatric population. Limited studies have associated poor knowledge, attitude, and practice (KAP) among parents with antibiotics misuse. Therefore, this study was conducted to determine the parents' KAP and factors associated with inappropriate use of antibiotics among Tanzanian children. A hospital-based cross-sectional study was conducted in 14 regional referral hospitals (RRHs) in Tanzania between June and September 2020. KAP was estimated using a Likert scale, whereas KAP factors were determined using logistic regression models. A total of 2802 parents were enrolled in the study. The median age (interquartile range) of parents was 30.0 (25-36) years where 82.4% (n = 2305) were female parents. The majority of the parents had primary education, 56.1% (n = 1567). Of 2802 parents, only 10.9% (n = 298) had good knowledge about antibiotics, 16.4% (n = 455) had positive attitude whereas 82.0% (n = 2275) had poor practice on the appropriate use of antibiotics. Parents' education level, i.e., having a university degree (aOR: 3.27 95% CI 1.62-6.63, p = 0.001), good knowledge (aOR: 1.70, 95% CI 1.19-2.23, p = 0.003) and positive attitudes (aOR: 5.56, 95% CI 4.09-7.56, p < 0.001) were significantly associated with the appropriate use of antibiotics in children. Most parents had poor knowledge, negative attitude, and poor practice towards antibiotics use in children. Parents' education level, employment status, knowledge on antibiotic use, and good attitude contributed to the appropriate use of antibiotics in children attending clinics at RRHs.

Quality of selected anti-retroviral medicines: Tanzania Mainland market as a case study.

BACKGROUND: Antiretroviral drugs (ARVs) have significantly reduced morbidity, mortality and improved the quality of life of people living with HIV infection. Poor quality ARVs may result in harmful consequences such as adverse drug reactions, treatment failure and development of drug resistant strains and sometimes death, which in turn may undermine the healthcare delivery system. To ensure optimal treatment outcomes, medicines quality control must be undertaken regularly. This study was aimed at evaluating the quality of ARVs circulating on the Tanzania Mainland market. METHODS: This was a survey study. ARVs samples were collected in 20 regions of Tanzania Mainland, between 2012 and 2018. All sampled ARVs were subjected to screening testing using the Global Pharma Health Fund® Mini-Lab kits. Sampled ARV's that failed screening test or yielded doubtful results and 10 % (10 %) of all that complied with the screening test requirements were selected for full quality control testing. Quality control testing was conducted at the Tanzania Medicines and Medical Devices Authority (TMDA) laboratory a World Health Organisation prequalified. Samples collected from the medicine distribution outlets were also, subjected to product information review. RESULTS: A total of 2,630 samples were collected, of which 83.7 % (2200/2630) were from port of entry (POEs). All sampled ARVs were screened and conformed to the specifications, except of the fixed dose combination (FDC) lopinavir/ritonavir 0.27 % (7/2630) and lamivudine/zidovudine/nevirapine 0.27 % (7/2630) that failed the disintegration test. Out of the 100 samples selected for full quality control testing, 3 % of them failed to comply with the specifications, of which FDC stavudine/lamivudine/nevirapine failed disintegration and assay tests 2 % (2/100) and 1 % (1/100), respectively. Samples failing the assay test had low content of stavudine (86.6 %) versus specification limits (90 -110 %). Out of the 430 samples which were subjected to product information review, 25.6 % (110/430) failed to comply with the TMDA packaging and labelling requirements. CONCLUSIONS: The quality of majority of ARVs circulating on the Tanzania Mainland market was good, even so, significant deficiencies on labelling and packaging were observed. These results call for continuous monitoring of quality of medicines circulating on the Tanzania Mainland market.

Clinical characteristics and treatment outcomes of patients with MDR tuberculosis in Dar Es Salaam region, Tanzania.

BACKGROUND: In Tanzania more than 28% of all multi-drug resistant tuberculosis (MDR-TB) cases occur in Dar es Salaam. However, information about management and clinical outcomes of patients with MDR-TB in the region is scarce, and hence the need for this study. METHODS: A 5-year retrospective cohort study was conducted in six centres in Dar es Salaam. Descriptive statistics were used to summarize social demographics and clinical characteristics. Associations between occurrence of adverse events, regimen change and cure were determined using the Chi-square test whereas factors associated with mortality were determined using the Log-ranking test and Cox regression model. RESULTS: Three-hundred patient files were found and reviewed. The majority were male 199 (66.3%), aged 25-44 years [176 (58.7%)] and 89 (30.1%) were HIV co-infected. 186 (62%) completed their treatment, 68 (22.0%) were on treatment and 9 (3.3%) were lost to follow-up. The majority, 152 (51.0%) were managed using long MDR-TB regimens. The overall mortality rate was 5.7 per 1000 MDR-TB patients. A higher mortality rate was associated with being ≥45 years [adjusted hazard ratio (AHR): 10.82, 95% CI: 1.14-102.74, P = 0.038), female (AHR: 5.92, 95% CI: 1.75-20.08, P = 0.004), on a short anti-TB regimen (AHR: 4.34, 95% CI: 1.41-13.35, P = 0.010), HIV co-infected [crude hazard ratio (CHR): 2.56, 95% CI: 1.01-6.50, P = 0.048), on concomitant long-term medication use (CHR: 2.99, 95% CI: 1.17-7.64, P = 0.022) and having other co-morbidities (CHR: 3.45, 95% CI: 1.32-9.02, P = 0.011). CONCLUSIONS: MDR-TB mortality was associated with short anti-TB regimens, sex, age, concomitant long-term medication use and HIV coinfection. In this population, use of long and individualized regimens is recommended.

Malaria prevalence, severity and treatment outcome in relation to day 7 lumefantrine plasma concentration in pregnant women.

BACKGROUND: Day 7 plasma concentrations of lumefantrine (LF) can serve as a marker to predict malaria treatment outcome in different study populations. Two main cut-off points (175 and 280 ng/ml) are used to indicate plasma concentrations of LF, below which treatment failure is anticipated. However, there is limited data on the cumulative risk of recurrent parasitaemia (RP) in relation to day 7 LF plasma concentrations in pregnant women. This study describes the prevalence, severity, factors influencing treatment outcome of malaria in pregnancy and day 7 LF plasma concentration therapeutic cut-off points that predicts treatment outcome in pregnant women. METHODS: This was a one-arm prospective cohort study whereby 89 pregnant women with uncomplicated Plasmodium falciparum malaria receiving artemether-lumefantrine (ALu) participated in pharmacokinetics and pharmacodynamics study. Blood samples were collected on days 0, 2, 7, 14, 21 and 28 for malaria parasite quantification. LF plasma concentrations were determined on day 7. The primary outcome measure was an adequate clinical and parasitological response (ACPR) after treatment with ALu. RESULTS: The prevalence of malaria in pregnant women was 8.1 % (95 % CI 6.85-9.35) of whom 3.4 % (95 % CI 1.49-8.51) had severe malaria. The overall PCR-uncorrected treatment failure rate was 11.7 % (95 % CI 0.54-13.46 %). Low baseline hemoglobin (<10 g/dl) and day 7 LF concentration <600 ng/ml were significant predictors of RP. The median day 7 LF concentration was significantly lower in pregnant women with RP (270 ng/ml) than those with ACPR (705 ng/ml) (p = 0.016). The relative risk of RP was 4.8 folds higher (p = 0.034) when cut-off of <280 ng/ml was compared to ≥280 ng/ml and 7.8-folds higher (p = 0.022) when cut-off of <600 ng/ml was compared to ≥600 ng/ml. The cut-off value of 175 ng/ml was not associated with the risk of RP (p = 0.399). CONCLUSIONS: Pregnant women with day 7 LF concentration <600 ng/ml are at high risk of RP than those with ≥600 ng/ml. To achieve effective therapeutic outcome, higher day 7 venous plasma LF concentration ≥600 ng/ml is required for pregnant patients than the previously suggested cut-off value of 175 or 280 ng/ml for non-pregnant adult patients.

The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment.

BACKGROUND: HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation. METHODS: This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling. RESULTS: Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice daily for five days using the current dose could improve lumefantrine exposure and consequently malaria treatment outcomes. CONCLUSIONS: Co-treatment of AL with EFV-based ART but not NVP-based ART significantly reduces lumefantrine bioavailability and consequently total exposure. To ensure adequate lumefantrine exposure and malaria treatment success in HIV-malaria co-infected patients on EFV-based ART, an extension of the duration of AL treatment to five days using the current dose is proposed.

Outcome of artemether-lumefantrine treatment for uncomplicated malaria in HIV-infected adult patients on anti-retroviral therapy.

BACKGROUND: Malaria and HIV infections are both highly prevalent in sub-Saharan Africa, with HIV-infected patients being at higher risks of acquiring malaria. The majority of antiretroviral (ART) and anti-malarial drugs are metabolized by the CYP450 system, creating a chance of drug-drug interaction upon co-administration. Limited data are available on the effectiveness of the artemether-lumefantrine combination (AL) when co-administered with non-nucleoside reverse transcriptase inhibitors (NNRTIs). The aim of this study was to compare anti-malarial treatment responses between HIV-1 infected patients on either nevirapine- or efavirenz-based treatment and those not yet on ART (control-arm) with uncomplicated falciparum malaria, treated with AL. METHOD: This was a prospective, non-randomized, open-label study conducted in Bagamoyo district, with three arms of HIV-infected adults: efavirenz-based treatment arm (EFV-arm) n = 66, nevirapine-based treatment arm (NVP-arm) n = 128, and control-arm n = 75, with uncomplicated malaria. All patients were treated with AL and followed up for 28 days. The primary outcome measure was an adequate clinical and parasitological response (ACPR) after treatment with AL by day 28. RESULTS: Day 28 ACPR was 97.6%, 82.5% and 94.5% for the NVP-arm, EFV-arm and control-arm, respectively. No early treatment or late parasitological failure was reported. The cumulative risk of recurrent parasitaemia was >19-fold higher in the EFV-arm than in the control-arm (Hazard ratio [HR], 19.11 [95% confidence interval {CI}, 10.5-34.5]; P < 0.01). The cumulative risk of recurrent parasitaemia in the NVP-arm was not significantly higher than in the control-arm ([HR], 2.44 [95% {CI}, 0.79-7.6]; P = 0.53). The median (IQR) day 7 plasma concentrations of lumefantrine for the three arms were: 1,125 ng/m (638.8-1913), 300.4 ng/ml (220.8-343.1) and 970 ng/ml (562.1-1729) for the NVP-arm, the EFV-arm and the control-arm, respectively (P < 0.001). In all three arms, the reported adverse events were mostly mild. CONCLUSION: After 28 days of follow-up, AL was statistically safe and effective in the treatment of uncomplicated malaria in the NVP-arm. The results of this study also provide an indication of the possible impact of EFV on the performance of AL and the likelihood of it affecting uncomplicated falciparum malaria treatment outcome.