Efficacy and safety of artemether-lumefantrine against uncomplicated falciparum malaria infection in Tanzania, 2022, a single arm clinical trial.

BACKGROUND: Artemether-lumefantrine (AL) is the first line anti-malarial drug for the treatment of uncomplicated malaria in Tanzania. The World Health Organization (WHO) recommends regular efficacy monitoring of anti-malarial drugs to inform case management policy decisions. This study assessed the safety and efficacy of AL for treating uncomplicated P. falciparum malaria in Tanzania in 2022. METHODS: Children 6 months to 10 years with uncomplicated P. falciparum malaria were recruited from four sentinel sites and treated with the standard 6 dose, 3-day regimen for AL. Clinical and parasitological responses were monitored for 28 days using the WHO standard protocol. Genotyping based on msp1, msp2 and glurp was used to distinguish recrudescence from reinfection. SANGER sequencing was used to detect K13 mutations. RESULTS: 352 participants, 88 per site, were enrolled. Four withdrew and 55 experienced parasite recurrence. The PCR corrected Kaplan-Meier efficacies were, 89.9% in Pwani, 95.0% in Kigoma, 94.4% in Tanga, and 98.9% in Morogoro. No K13 mutations were found. CONCLUSIONS: Artemether-lumefantrine remains highly efficacious in three regions of Tanzania but the PCR-corrected efficacy in Pwani fell below the WHO-defined 90% threshold at which policy change is recommended. Implementing strategies to diversify ACTs to ensure effective case management in Tanzania is critical.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania. METHODS: This was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy. RESULTS: A total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018.

BACKGROUND: The use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania. METHODS: A single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety. RESULTS: A total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan-Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

Trends of Plasmodium falciparum molecular markers associated with resistance to artemisinins and reduced susceptibility to lumefantrine in Mainland Tanzania from 2016 to 2021.

BACKGROUND: Therapeutic efficacy studies (TESs) and detection of molecular markers of drug resistance are recommended by the World Health Organization (WHO) to monitor the efficacy of artemisinin-based combination therapy (ACT). This study assessed the trends of molecular markers of artemisinin resistance and/or reduced susceptibility to lumefantrine using samples collected in TES conducted in Mainland Tanzania from 2016 to 2021. METHODS: A total of 2,015 samples were collected during TES of artemether-lumefantrine at eight sentinel sites (in Kigoma, Mbeya, Morogoro, Mtwara, Mwanza, Pwani, Tabora, and Tanga regions) between 2016 and 2021. Photo-induced electron transfer polymerase chain reaction (PET-PCR) was used to confirm presence of malaria parasites before capillary sequencing, which targeted two genes: Plasmodium falciparum kelch 13 propeller domain (k13) and P. falciparum multidrug resistance 1 (pfmdr1). RESULTS: Sequencing success was ≥ 87.8%, and 1,724/1,769 (97.5%) k13 wild-type samples were detected. Thirty-seven (2.1%) samples had synonymous mutations and only eight (0.4%) had non-synonymous mutations in the k13 gene; seven of these were not validated by the WHO as molecular markers of resistance. One sample from Morogoro in 2020 had a k13 R622I mutation, which is a validated marker of artemisinin partial resistance. For pfmdr1, all except two samples carried N86 (wild-type), while mutations at Y184F increased from 33.9% in 2016 to about 60.5% in 2021, and only four samples (0.2%) had D1246Y mutations. pfmdr1 haplotypes were reported in 1,711 samples, with 985 (57.6%) NYD, 720 (42.1%) NFD, and six (0.4%) carrying minor haplotypes (three with NYY, 0.2%; YFD in two, 0.1%; and NFY in one sample, 0.1%). Between 2016 and 2021, NYD decreased from 66.1% to 45.2%, while NFD increased from 38.5% to 54.7%. CONCLUSION: This is the first report of the R622I (k13 validated mutation) in Tanzania. N86 and D1246 were nearly fixed, while increases in Y184F mutations and NFD haplotype were observed between 2016 and 2021. Despite the reports of artemisinin partial resistance in Rwanda and Uganda, this study did not report any other validated mutations in these study sites in Tanzania apart from R622I suggesting that intensified surveillance is urgently needed to monitor trends of drug resistance markers and their impact on the performance of ACT.

Describing the current status of Plasmodium falciparum population structure and drug resistance within mainland Tanzania using molecular inversion probes.

High-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programmes, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania countrywide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, approximately separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from nearby districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts (including two infections carrying pfk13-R561H), and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared.

Developmental and Nutritional Changes in Children with Severe Acute Malnutrition Provided with n-3 Fatty Acids Improved Ready-to-Use Therapeutic Food and Psychosocial Support: A Pilot Study in Tanzania.

Children with severe acute malnutrition (SAM) are at high risk of impaired development. Contributing causes include the inadequate intake of specific nutrients such as polyunsaturated fatty acids (PUFAs) and a lack of adequate stimulation. We conducted a pilot study assessing developmental and nutritional changes in children with SAM provided with a modified ready-to-use therapeutic food and context-specific psychosocial intervention in Mwanza, Tanzania. We recruited 82 children with SAM (6-36 months) and 88 sex- and age-matched non-malnourished children. We measured child development, using the Malawi Development Assessment Tool (MDAT), measures of family and maternal care for children, and whole-blood PUFA levels. At baseline, the mean total MDAT z-score of children with SAM was lower than non-malnourished children; -2.37 (95% confidence interval: -2.92; -1.82), as were their total n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels. After 8 weeks of intervention, MDAT z-scores improved in all domains, especially fine motor, among children with SAM. Total n-3 and EPA levels increased, total n-6 fatty acids decreased, and DHA remained unchanged. Family and maternal care also improved. The suggested benefits of the combined interventions on the developmental and nutritional status of children with SAM will be tested in a future trial.

The Role of Metformin in Ovarian Cancer: Does Metformin Increase Survival in Ovarian Neoplasm?

The role of metformin in ovarian cancer (OC) remains a topic of research and open discussion. Because OC has a high mortality rate for various reasons, finding a solution is vital. Although metformin has demonstrated a high level of evidence in preventing and increasing survival in other cancers, its role in OC is still not proven. This review highlights the function of metformin as an antineoplastic agent in OC and its effect on overall survival, progress-free survival, and recurrence-free survival. We conducted a literature search in the PubMed database using the medical subject heading keywords, ovarian neoplasm and metformin. The search yielded 94 articles, of which 86 remained after including only English language articles. Finally, 50 articles published between 1997 and 2020 were reviewed. We recommend more randomized controlled trials in the future to determine the safety and efficacy of metformin in OC.

Recurrent obstructive uropathy secondary to pyometrocolpos in an 8-month-old infant: a case report.

BACKGROUND: Pyometrocolpos is accumulation of infected fluid in the uterus and vagina. It is rare in children, mostly seen after menarche as a result of obstructive congenital genital malformation that impairs free drainage of the uterine secretions. In a child, it may present as an acute illness that necessitates urgent and appropriate management and treatment of the underlying cause, which can be a challenge in a resource-limited setting. CASE PRESENTATION: We report a case of pyometrocolpos in an 8-month-old African infant who presented with fever, vomiting, decreased urine output, and abdominal distension of 12 days' duration. An abdominal examination revealed a subumbilical midline incision scar and a midline lower abdominal mass. She appeared to have presented at the emergency department with similar complaints 2 months earlier and had been diagnosed with pyometra, which was managed by emergency laparotomy for pus drainage, and she was kept on antibiotics. Recovery was established after 10 days of admission, and the patient was discharged to home. Her symptoms reappeared 2 months after the first presentation. Her blood work showed significant leukocytosis with neutrophilia, and abdominal ultrasound depicted bilateral hydronephrosis with hydroureters and a fluid-filled uterus. Examination under anesthesia in the operating theater revealed normal-looking female genitalia with a cribriform hymen, beneath which lied a transverse vaginal septum. Foul-smelling pus was aspirated through the septum, and septectomy was performed to allow 350 ml of pus to drain. A pus sample was sent for culture and sensitivity, and Escherichia coli sensitive to ceftriaxone and gentamicin was isolated. CONCLUSION: Pyometrocolpos is rare in childhood but should be suspected in a girl presenting with a midline lower abdominal mass accompanied with urinary obstructive symptoms associated with fever and gastrointestinal symptoms. Escherichia coli seems to be the most probable offending organism, but pus culture is crucial for antibiotic stewardship in proper management of the infection. Definitive treatment should focus on correcting the obstructive anatomical congenital deformity that caused the obstruction in order to avoid recurrence.

Bacteremia caused by multidrug-resistant bacteria among hospitalized malnourished children in Mwanza, Tanzania: a cross sectional study.

BACKGROUND: Severe malnutrition has been known to increase susceptibility and severity of infections. Bacteremia in malnourished children has been found to increase morbidity and mortality especially if is due to multidrug resistant bacteria. Here, we report the prevalence of bacteremia among children under 5 years of age and the antibiotic susceptibility pattern of the isolates; the information that can be used by clinicians to guide on the empirical antibiotic treatment. FINDINGS: A total of 402 malnourished children were investigated for bacteremia. The median age of enrolled children were 17 (IQR 12-31) months. Severe malnutrition was observed in 19.1% of malnourished underfives. The point prevalence of bacteremia among malnourished children was 56/402 (13.9%; 95% CI 10.3-17.3). The prevalence of bacteremia was significantly higher among severely malnourished children than in children with moderate/mild malnutrition (18.0 vs. 10.7%, P = 0.03). Mortality was significantly associated with bacteremia among severely malnourished children (OR 2.77, 95% CI 1.02-6.98, P = 0.02). Pseudomonas spp. 20/56 (35.7%) were the most frequent isolates while Staphylococcus aureus and Streptococcus pneumoniae were isolated in 8/56 (14.2%) and 5/56 (8.9%) respectively. Rates of resistance for gram negative bacteria were; ampicillin (100%), amoxicillin/clavulanic acid (85.7%), gentamicin (23.8%), ceftriaxone (23.8%), ceftazidime (23.8%) meropenem (4.7%) and ciprofloxacin (2.4%). methicillin resistant S. aureus strains were confirmed in 4/8 (50%) of S. aureus isolates and 60% of S. pneumoniae isolates were resistant to 1 µg oxacillin. CONCLUSION: Bacteremia due to multi drug resistant isolates is common among severely malnourished children under 5 years of age. There is a need to review empirical antibiotic treatment coupled with antibiotic stewardship to prevent mortality and morbidity of severely malnourished children under 5 years of age.

Multi-resistant gram negative enteric bacteria causing urinary tract infection among malnourished underfives admitted at a tertiary hospital, northwestern, Tanzania.

BACKGROUND: Infections are common complications occurring in malnourished childrenas a result of impaired immunity. Urinary tract infections (UTI) have been found to be the commonest cause of fever in normal children in developing countries. However, data regarding UTI among malnourished children is limited because in most of time severe and moderately malnourished children are afebrile despite significant bacteriuria. METHODS: A total of 402 malnourished underfives were enrolled. Demographic and other clinical characteristics were collected using standardized data collection tool. Urine specimens were cultured and interpreted according to standard operating procedures. Data were analyzed using STATA version 11. RESULTS: Out of 402 malnourished underfives, 229 (56.9 %) were male. The median age in months was 17 (IQR; 12-31). Of 402 malnourished underfives, 83 (20.3 %) had significant bacteriuria of gram negative enteric bacteria. Escherichia coli 35/84 and Klebsiella pneumonia 20/84 were predominant bacteria isolated. More than 37 % of isolates were resistant to third generation cephalosporins with all of them exhibiting extended spectrum beta lactamase (ESBL) phenotype. Rates of resistance to ampicillin, amoxillin/clavulanic acid, gentamicin and ciprofloxacin were 82/84 (98.7 %), 47/55 (85.4 %), 45/84 (57.8 %) and 9/84 (10.8 %) respectively. Decrease in age and increase in lymphocytes count were independent factors on multivariate logistic regression analysis found to predict UTI (p<0.05). CONCLUSIONS: Multi-resistant gram negative enteric bacteria are common cause of UTI among underfives. A significant number of severe and moderate malnourished children with bacteriuria had no fever. Therefore, routine testing for UTI is emphasized in all malnourished underfives so that appropriate treatment can be initiated.

Blood transfusion for severe anaemia in children in a Kenyan hospital.

Severe anaemia often secondary to malaria is a major contributor to child mortality in sub-Saharan Africa. We have confirmed that use of simple clinical and laboratory criteria can identify those children likely to benefit most from treatment. We have also shown that the speed of response may be critical. The quality and capacity of blood transfusion services could therefore have a major, direct effect on inpatient child mortality.

Hypothetical performance of syndrome-based management of acute paediatric admissions of children aged more than 60 days in a Kenyan district hospital.

OBJECTIVE: To investigate whether the outpatient, syndrome-based approach of the Integrated Management of Childhood Illness (IMCI) protocol could be extended to the inpatient arena to give clear and simple minimum standards of care for poorly resourced facilities. METHODS: A prospective, one-year admission cohort retrospectively compared hypothetical performance of syndrome-based management with paediatrician-defined final diagnosis. Admission syndrome definitions were based on local adaptations to the IMCI protocol that encompassed 20 clinical features, measurement of oxygen saturation, and malaria microscopy. FINDINGS: After 315 children with clinically obvious diagnoses (e.g. sickle cell disease and burns) were excluded, 3705 admission episodes were studied. Of these, 2334 (63%) met criteria for at least one severe syndrome (mortality 8% vs <1% for "non-severe" cases), and half of these had features of two or more severe syndromes. No cases of measles were seen. Syndrome-based treatment would have been appropriate (sensitivity >95%) for severe pneumonia, severe malaria, and diarrhoea with severe dehydration, and probably for severe malnutrition (sensitivity 71%). Syndrome-directed treatment suggested the use of broad-spectrum antibiotics in 75/133 (56% sensitivity) children with bacteraemic and 63/71 (89% sensitivity) children with meningitis. CONCLUSIONS: Twenty clinical features, oxygen saturation measurements, and results of malaria blood slides could be used for inpatient, syndrome-based management of acute paediatric admissions. The addition of microscopy of the cerebrospinal fluid and haemoglobin measurements would improve syndrome-directed treatment considerably. This approach might rationalize admission policy and standardize inpatient paediatric care in resource-poor countries, although the clinical detection of bacteraemia remains a problem.