Antibiotic use from formal and informal healthcare providers in the Democratic Republic of Congo: a population-based study in two health zones.

OBJECTIVE: In the Democratic Republic of Congo and other low-resource countries, community-acquired pathogens are increasingly resistant to most locally available antibiotics. To guide efforts to optimize antibiotic use to limit antibiotic resistance, we quantified healthcare provider-specific and community-wide antibiotic use. METHODS: From household surveys, we estimated monthly healthcare visit rates by provider. From healthcare visit exit surveys, we estimated prevalence, defined daily doses, and access/watch/reserve distribution of antibiotic use by provider. Combining both, we estimated community-wide antibiotic use rates. RESULTS: Of 88.7 (95% CI 81.9-95.4) healthcare visits per 1000 person-months (n = 31221), visits to private clinics (31.0, 95% CI 30.0-32.0) and primary health centres (25.5, 95% CI 24.6-26.4) were most frequent. Antibiotics were used during 64.3% (95% CI 55.2-73.5%, 162/224) of visits to private clinics, 51.1% (95% CI 45.1-57.2%, 245/469) to health centres, and 48.8% (95% CI 44.4-53.2%, 344/454) to medicine stores. Antibiotic defined daily doses per 1000 inhabitants per day varied between 1.75 (95% CI 1.02-2.39) in rural Kimpese and 10.2 (95% CI 6.00-15.4) in (peri) urban Kisantu, mostly explained by differences in healthcare utilisation (respectively 27.8 versus 105 visits per 1000 person-months), in particular of private clinics (1.23 versus 38.6 visits) where antibiotic use is more frequent. The fraction of Watch antibiotics was 30.3% (95% CI 24.6-35.9%) in private clinics, 25.6% (95% CI 20.2-31.1%) in medicine stores, and 25.1% (95% CI 19.0-31.2%) in health centres. Treatment durations <3 days were more frequent at private clinics (5.3%, 9/169) and medicine stores (4.1%, 14/338) than at primary health centres (1.8%, 5/277). DISCUSSION: Private healthcare providers, ubiquitous in peri-urban settings, contributed most to community-wide antibiotic use and more frequently dispensed Watch antibiotics and shortened antibiotic courses. Efforts to optimize antibiotic use should include private providers at community level.

Efficacy and safety of intermittent preventive treatment in schoolchildren with sulfadoxine/pyrimethamine (SP) and SP plus piperaquine in Democratic Republic of the Congo: a randomised controlled trial.

In endemic areas, malaria and its adverse effects in schoolchildren may be prevented by intermittent preventive treatment (IPTsc). However, the most appropriate drug regimen for IPTsc remains to be identified. A randomised controlled trial was conducted in Kinshasa, DRC. Enrolled schoolchildren were assigned to a passive control arm (n = 212), sulfadoxine/pyrimethamine (SP) (n = 202) or SP plus piperaquine (SP/PQ) (n = 202). The primary endpoint was haemoglobin (Hb) change. Secondary endpoints were anaemia, parasitaemia prevalence and clinical malaria incidence. Data were analysed by modified intention-to-treat (mITT) and per-protocol. A linear mixed mode was used due to repeated measurements. Of 616 enrolled children, 410 (66.6%) were eligible for mITT analysis. The control arm was used as reference. After 12 months, the Hb level increased by 0.20 g/dL (95% CI -0.61 to 0.47; P = 0.168) and 0.39 g/dL (0.12-0.66; P <0.01) in the SP and SP/PQ arms, respectively. SP treatment reduced anaemia, malaria parasitaemia and clinical malaria by 10% (0-20%; P = 0.06), 19% (2-33%; P = 0.042) and 25% (-32 to 57%; P = 0.37), respectively. The corresponding values for SP/PQ were 28% (19-37%; P <0.001), 40% (26-52%; P <0.001) and 58% (17-79%; P <0.01). No deaths or severe adverse events (SAEs) were observed. SP/PQ offered substantial protection against anaemia, malaria parasitaemia and clinical malaria and showed no SAEs. SP/PQ, a combination of two long-acting non-artemisinin-based antimalarials, may be a valuable option for IPTsc in Africa.

The perception of parents and teachers about intermittent preventive treatment for malaria in school children in a semi-rural area of Kinshasa, in the Democratic Republic of Congo.

BACKGROUND: Intermittent preventive treatment (IPT) is likely to be the most promising therapeutic strategy to prevent malaria and its related adverse outcomes in schoolchildren. However, its successful implementation will depend on acceptability to key stakeholders such as parents and teachers. METHODS: A qualitative research was conducted, following a clinical trial assessing the effectiveness of IPT in schoolchildren (IPTsc), to understand the perceptions and experiences of parents and teachers with IPTsc, in two schools of Mokali, in Kinshasa, Democratic Republic of the Congo. Eighty parents participated in 8 focus group discussions and 6 school staff were involved in 6 semi-structured interviews. RESULTS: Parents experiences with IPTsc divided them into two groups (owning positive experiences and owning negative experiences with IPTsc). Three major themes emerged as key factors associated with reluctance of parents to IPT use in schoolchildren. These included wrong malaria-related knowledge, bad experience with IPTsc administered during the trial and misunderstanding of IPTsc. The school staff were generally willing to be trained to give medicine to schoolchildren within the scope of IPT. However, most parents were more comfortable with the use of health workers than teachers for drug administration. More importantly, all parents accepting IPT suggested to diagnose malaria infection before any administration of IPT, which is not in line with IPT principal. CONCLUSION: These results suggest that more efforts are needed to improve overall malaria-related knowledge in the community, specifically chemo-prevention strategies and the safety of the drugs used, to ensure the success of health interventions.

Efficacy and safety of re-treatment with the same artemisinin-based combination treatment (ACT) compared with an alternative ACT and quinine plus clindamycin after failure of first-line recommended ACT (QUINACT): a bicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: Quinine or alternative artemisinin-based combination treatment (ACT) is the recommended rescue treatment for uncomplicated malaria. However, patients are often re-treated with the same ACT though it is unclear whether this is the most suitable approach. We assessed the efficacy and safety of re-treating malaria patients with uncomplicated failures with the same ACT used for the primary episode, compared with other rescue treatments. METHODS: This was a bicentre, open-label, randomised, three-arm phase 3 trial done in Lisungi health centre in DR Congo, and Kazo health centre in Uganda in 2012-14. Children aged 12-60 months with recurrent malaria infection after treatment with the first-line ACT were randomly assigned to either re-treatment with the same first-line ACT, an alternative ACT, which were given for 3 days, or quinine-clindamycin (QnC), which was given for 5-7 days, following a 2:2:1 ratio. Randomisation was done by computer-generated randomisation list in a block design by country. The three treatment groups were assumed to have equivalent efficacy above 90%. Both the research team and parents or guardians were aware of treatment allocation. The primary outcome was the proportion of patients with an adequate clinical and parasitological response (ACPR) at day 28, in the per-protocol population. This trial was registered under the numbers NCT01374581 in ClinicalTrials.gov and PACTR201203000351114 in the Pan African Clinical Trials Registry. FINDINGS: From May 22, 2012, to Jan 31, 2014, 571 children were included in the trial. 240 children were randomly assigned to the re-treatment ACT group, 233 to the alternative ACT group, and 98 to the QnC group. 500 children were assessed for the primary outcome. 71 others were not included because they did not complete the follow-up or PCR genotyping result was not conclusive. The ACPR response was similar in the three groups: 91·4% (95% CI 87·5-95·2) for the re-treatment ACT, 91·3% (95% CI 87·4-95·1) for the alternative ACT, and 89·5% (95% CI 83·0-96·0) for QnC. The estimates for rates of malaria recrudescence in the three treatment groups were similar (log-rank test: χ2=0·22, p=0·894). Artemether-lumefantrine was better tolerated than QnC (p=0·0005) and artesunate-amodiaquine (p<0·0001) in the modified intention-to-treat analysis. No serious adverse events were observed. The most common adverse events reported in the re-treatment ACT group were anorexia (31 [13%] of 240 patients), asthenia (20 [8%]), coughing (16 [7%]), abnormal behaviour (13 [5%]), and diarrhoea (12 [5%]). Anorexia (13 [6%] of 233 patients) was the most frequently reported adverse event in the alternative ACT group. The most commonly reported adverse events in the QnC group were anorexia (12 [12%] of 98 patients), abnormal behaviour (6 [6%]), asthenia (6 [6%]), and pruritus (5 [5%]). INTERPRETATION: Re-treatment with the same ACT shows similar efficacy as recommended rescue treatments and could be considered for rescue treatment for Plasmodium falciparum malaria. However, the effect of this approach on the selection of resistant strains should be monitored to ensure that re-treatment with the same ACT does not contribute to P falciparum resistance. FUNDING: Fonds Wetenschappelijk Onderzoek, Vlaamse Interuniversitaire Raad-Universitaire Ontwikkelings Samenwerking, European and Developing Countries Clinical Trials Partnership, and the Belgian Technical Cooperation-Programme d'Etudes et d'Expertises-in the Democratic Republic of Congo.

The relationship between Plasmodium infection, anaemia and nutritional status in asymptomatic children aged under five years living in stable transmission zones in Kinshasa, Democratic Republic of Congo.

BACKGROUND: Malaria is preventable and treatable when recommended interventions are properly implemented. Thus, diagnosis and treatment focus on symptomatic individuals while asymptomatic Plasmodium infection (PI) plays a role in the sustainability of the transmission and may also have an impact on the morbidity of the disease in terms of anaemia, nutritional status and even cognitive development of children. The objective of this study was to assess PI prevalence and its relationship with known morbidity factors in a vulnerable but asymptomatic stratum of the population. METHODS: A simple random sample, household survey in asymptomatic children under the age of five was conducted from April to September 2012 in two health areas of the health zone of Mont Ngafula 1, Kinshasa, Democratic Republic of Congo. RESULTS: The PI prevalence were 30.9% (95% CI: 26.5-35.9) and 14.3% (95% CI: 10.5-18.1) in Cité Pumbu and Kindele health areas, respectively, (OR: 2.7; p <0.001). All were Plasmodium falciparum infected and 4% were co-infected with Plasmodium malariae. In Cité Pumbu and Kindele, the prevalence of anaemia (haemoglobin <11 g/dL) was 61.6% (95% CI: 56.6-66.5) and 39.3% (95% CI: 34.0-44.6), respectively, (OR: 2.5; p <0.001). The health area of Cité Pumbu had 32% (95% CI: 27.5-37.0) of chronic malnutrition (HAZ score ≤ -2SD) compared to 5.1% (95% CI: 2.8-7.6) in Kindele. PI was predictor factor for anaemia (aOR: 3.5, p =0.01) and within infected children, there was an inverse relationship between parasite density and haemoglobin level (ß = -5*10(-5), p <0.001). Age older than 12 months (aOR: 3.8, p = 0.01), presence of anaemia (aOR: 3.4, p =0.001), chronic malnutrition (aOR: 1.8, p = 0.01), having a single parent/guardian (aOR: 1.6, p =0.04), and the non-use of insecticide-treated nets (aOR: 1.7, p = 0.04) were all predictors for PI in the overall population. CONCLUSION: PI in asymptomatic children was correlated with anaemia and chronic malnutrition and was thus a harmful condition in the study population. Malaria control initiatives should not only focus on treatment of symptomatic infections but also take into consideration asymptomatic but infected children.

From health advice to taboo: community perspectives on the treatment of sleeping sickness in the Democratic Republic of Congo, a qualitative study.

BACKGROUND: Socio-cultural and economic factors constitute real barriers for uptake of screening and treatment of Human African Trypanosomiasis (HAT) in the Democratic Republic of Congo (DRC). Better understanding and addressing these barriers may enhance the effectiveness of HAT control. METHODS: We performed a qualitative study consisting of semi-structured interviews and focus group discussions in the Bandundu and Kasaï Oriental provinces, two provinces lagging behind in the HAT elimination effort. Our study population included current and former HAT patients, as well as healthcare providers and program managers of the national HAT control program. All interviews and discussions were voice recorded on a digital device and data were analysed with the ATLAS.ti software. FINDINGS: Health workers and community members quoted a number of prohibitions that have to be respected for six months after HAT treatment: no work, no sexual intercourse, no hot food, not walking in the sun. Violating these restrictions is believed to cause serious, and sometimes deadly, complications. These strong prohibitions are well-known by the community and lead some people to avoid HAT screening campaigns, for fear of having to observe such taboos in case of diagnosis. DISCUSSION: The restrictions originally aimed to mitigate the severe adverse effects of the melarsoprol regimen, but are not evidence-based and became obsolete with the new safer drugs. Correct health information regarding HAT treatment is essential. Health providers should address the perspective of the community in a constant dialogue to keep abreast of unintended transformations of meaning.

Performance of HRP2-based rapid test in children attending the health centre compared to asymptomatic children in the community.

BACKGROUND: The Democratic Republic of the Congo (DRC) is one of the five countries carrying half of global malaria burden with children 0-5 years old being most at risk. Rapid diagnostic tests (RDTs) are currently routinely used for the detection of Plasmodium infection in health centres and may be a useful tool for population-based survey. METHODS: This study assessed, in a stable transmission zone of Kinshasa, whether a HRP2-based RDT matches the selection criteria of the National Malaria Control Programme (NMCP), DRC and assessed the most relevant fever threshold in this context. RESULTS: RDTs and microscopy were concordant in 84.3% and 83.4% children in the health centre and at the community level, respectively. The sensitivity was high (>95%), but the specificity was too low and lower in the community (66.9%; 95%CI: 58.5-75.2) compared to the HC (79.4%; 95%CI: 75.7-83.2). The estimated parasitic threshold of 5,414 parasites/µl was with a sensitivity of 63.3% and a specificity of 71.8% not very discriminative, and thus not a threshold. CONCLUSION: HRP-based RDT gives a satisfactory proxy to estimate and monitor malaria endemicity, but the low specificity, far below the selection criteria of the NMCP, DRC is problematic for use in a clinical setting.

In vitro sensitivity testing of Leishmania clinical field isolates: preconditioning of promastigotes enhances infectivity for macrophage host cells.

Diagnostic material from patients with leishmaniasis is generally available as promastigotes, and proper testing for susceptibility to first-line drugs by the intracellular amastigote assay is frequently hampered by the poor infectivity of the promastigotes for the macrophage host cell. Several conditions for optimization of the in vitro metacyclogenesis and cell infectivity of Leishmania donovani, L. guyanensis, and L. braziliensis field strains obtained from patients receiving standard antimony medication were investigated. Triggering log-phase promastigotes to become amastigote-like by increasing the temperature or acidifying the culture medium was not successful. Adequate metacyclogenesis and the highest levels of macrophage infection were obtained after 5-day-old late-log-phase promastigote cultures were preconditioned at 25 degrees C to pH 5.4 for 24 h in Schneider's medium prior to infection. The susceptibility assay with primary peritoneal mouse macrophages included pentavalent antimony (Sb(V); sodium stibogluconate), trivalent antimony (Sb(III); potassium antimonyl tartrate), miltefosine, and the experimental drug PX-6518. All strains were sensitive to miltefosine (50% inhibitory concentration [IC(50)] < 10 microM) and PX-6518 (IC(50) < 2 microg/ml) but showed distinct susceptibility to Sb(V) and/or Sb(III), depending on whether they were derived from cured, relapse, or nonresponder patients. Within the available set of Leishmania species and strains, simultaneous Sb(V)-Sb(III) resistance was clearly associated with treatment failure; however, a larger set of isolates is still needed to judge the predictive value of Sb(V)-Sb(III) susceptibility profiling on treatment outcome. In conclusion, the proposed conditioning protocol further contributes toward a more standardized laboratory model for evaluation of the drug sensitivities of field isolates.

In vitro susceptibilities of Leishmania donovani promastigote and amastigote stages to antileishmanial reference drugs: practical relevance of stage-specific differences.

The in vitro susceptibilities of the reference strain Leishmania donovani MHOM/ET/67/L82 to sodium stibogluconate, amphotericin B, miltefosine, and the experimental compound PX-6518 were determined for extracellular log-phase promastigotes, established axenic amastigotes, fresh spleen-derived amastigotes, and intracellular amastigotes in primary mouse peritoneal macrophages. Susceptibility to amphotericin B did not differ across the various axenic models (50% inhibitory concentrations [IC50], 0.6 to 0.7 microM), and amphotericin B showed slightly higher potency against intracellular amastigotes (IC50, 0.1 to 0.4 microM). A similar trend was observed for miltefosine, with comparable efficacies against the extracellular (IC50, 0.4 to 3.8 microM) and intracellular (IC50, 0.9 to 4.3 microM) stages. Sodium stibogluconate, used either as Pentostam or as a crystalline substance, was inactive against all axenic stages (IC50, >64 microg SbV/ml) but showed good efficacy against intracellular amastigotes (IC50, 22 to 28 microg SbV/ml); the crystalline substance was about two to three times more potent (IC50, 9 to 11 microg SbV/ml). The activity profile of PX-6518 was comparable to that of sodium stibogluconate, but at a much higher potency (IC50, 0.1 microg/ml). In conclusion, the differential susceptibility determines which in vitro models are appropriate for either drug screening or resistance monitoring of clinical field isolates. Despite the more complex and labor-intensive protocol, the current results support the intracellular amastigote model as the gold standard for in vitro Leishmania drug discovery research and for evaluation of the resistance of field strains, since it also includes host cell-mediated effects. Axenic systems can be recommended only for compounds for which no cellular mechanisms are involved, for example, amphotericin B and miltefosine.

Selective antileishmania activity of 13,28-epoxy-oleanane and related triterpene saponins from the plant families Myrsinaceae, Primulaceae, Aceraceae and Icacinaceae.

Maesa saponins with the 13,28-epoxy-oleanane triterpene core skeleton were described recently to possess strong and selective in vitro and in vivo antileishmania activity. In the absence of direct chemical derivatization possibilities, a structure-based literature search was carried out to explore a structure-activity relationship. Crude alcohol extracts from several plant species of Myrsinaceae, Primulaceae, Aceraceae and Icacinaceae were evaluated for in vitro activity against Leishmania infantum intracellular amastigotes and cytotoxicity on MRC-5(SV2) cells, while the saponin content was evaluated qualitatively by TLC. A clear correlation was found between the presence of close analogue 13,28-epoxy-oleanane triterpene saponins and potent and selective antileishmania activity. This was most striking in Maesa species, except for M. macrosepala. Interesting activities were also found in extracts that did not exactly match the TLC characteristics of the Maesa saponin references, as was the case for Ardisia angusta, A. amherstiana, A. caudata, A. gigantifolia, A. roseiflora, Myrsine affinis, Acer brevipes and A. laurinum var. petelotii. This study indicates that the 13,28-epoxy-oleanane triterpene moiety is essential for selective antileishmania potential and that several other plant species could still be explored for antileishmania drug discovery.