A decade since sulfonamide-based anti-malarial medicines were limited for intermittent preventive treatment of malaria among pregnant women in Tanzania.

BACKGROUND: Despite the development of resistance to Plasmodium falciparum malaria, sulfadoxine-pyrimethamine is still effective for intermittent preventive treatment of malaria in pregnancy (IPTp). In Tanzania, more than 10 years have passed since sulfadoxine-pyrimethamine and sulfamethopyrazine-pyrimethamine (SPs) were reserved for IPTp only. However, the retail pharmaceutical outlet dispensers' knowledge and their compliance with the policies have not been recently explored. Therefore, this study was designed to investigate dispensers' knowledge about these medications together with their actual dispensing practices, a decade since they were limited for IPTp use only. METHODS: This descriptive cross-sectional study was conducted between February and July 2017 in all municipalities of Dar-es-Salaam city. Data were collected by direct interviews using a structured questionnaire to assess knowledge and a simulated client approach was used to assess the actual practice of medicine dispensers. Data analysis was done by using SPSS version 20 and Chi square test was used to test significant differences in proportions between different categorical variables. A p-value of less than 0.05 was considered to be statistically significant. RESULTS: A random sample of 422 medicine dispensers participated in this study whereby 185 (43.8%) were from community pharmacies and 237 (56.2%) from accredited drug dispensing outlets. The study revealed that SPs were available in 76% of the community pharmaceutical outlets in Dar es Salaam. In general majority of the dispensers (64%) had moderate to high knowledge about SPs and their indication. About 80% of the dispensers were aware that SP is reserved for IPTp. However, irrespective of the level of knowledge, almost all dispensers (92%) were willing to dispense the medicines for the purpose of treating malaria, contrary to the current Tanzania malaria treatment guideline. CONCLUSION: Majority of the medicine dispensers in the community pharmaceutical outlets were knowledgeable about SPs and their indications. Disappointingly, almost all dispensers irrespective of their levels of knowledge were willing to dispense SPs for treatment of malaria contrary to the available treatment guidelines.

Efficacy of a Single Oral Dose of Artesunate plus Sulfalene-Pyrimethamineversus Praziquantel in the Treatment of Schistosoma mansoni in Kenyan Children: An Open-Label, Randomized, Exploratory Trial.

Unlike praziquantel, artemisinin derivatives are effective against juvenile schistosome worms. We assessed the efficacy and safety of a single oral dose of artesunate plus sulfalene-pyrimethamine versus praziquantel in the treatment of Schistosoma mansoni. Seventy-three schoolchildren (aged 9-15 years) with confirmed S. mansoni infection in Rarieda, western Kenya, were randomly assigned to receive either a single oral dose of artesunate plus sulfalene-pyrimethamine (n = 39) or a single dose of praziquantel (n = 34). The cure and egg reduction rates at 4 weeks posttreatment were 69.4% (25/36) versus 80.6% (25/31) (P = 0.297) and 99.1% versus 97.5% (P = 0.607) in the artesunate plus sulfalene-pyrimethamine group versus praziquantel group, respectively. Fourteen children developed adverse events, and there were no serious adverse events. A single oral dose of artesunate plus sulfalene-pyrimethamine has efficacy comparable to that of praziquantel in the treatment of S. mansoni, but these results should be confirmed in larger randomized controlled trials.

Intermittent preventive therapy for malaria: arguments in favour of artesunate and sulphamethoxypyrazine - pyrimethamine combination.

Recent publications put a serious warning regarding the inefficacy of sulphadoxine-pyrimethamine (SP) for the intermittent preventive treatment of malaria in young children (IPTi). Recommendations for other therapies are being made. By using a different and better sulphonamide (sulphamethoxypyrazine), it is possible to manufacture fixed dose combination pills with artesunate and pyrimethamine. This combination permits a full therapy over 24 hours (dosing interval being 12 hours). It is recommended that this combination should be tested in future field studies of IPTi.

Therapeutic efficacy and effect on gametocyte carriage of an artemisinin and a non-based combination treatment in children with uncomplicated P. falciparum malaria, living in an area with high-level chloroquine resistance.

Combination therapy with artemesinin or non-artemesinin-based antimalarials (ACTs or NACTs) are known to retard the development and progression of drug resistance in Plasmodium falciparum (P. falciparum). The optimal antimalarial combinations in Africa are yet unknown. We evaluate the therapeutic efficacy and effects on gametocyte carriage of Artemether-Lumefantrine (AL) and Amodiaquine-Sulfalene/Pyrimethamine (ASP) in children with P. falciparum malaria in an endemic area. One-hundred and thirty-nine children aged ≤ 10 years with uncomplicated P. falciparum malaria were enrolled. The primary end points were adequate clinical and parasitological response (ACPR), late parasitological failure(LPF), late clinical failure (LCF) and early treatment failure (ETF). Polymerase chain reaction (PCR)-corrected cure rates on days 14-42 and gametocyte carriage rates were determined. Fever clearance time was significantly shorter (P = 0.009) with ASP, but parasite clearance time was similar with both regimens. Day 28 cure rates were 91.4 and 89.9% (PCR-corrected) for AL and ASP respectively. Both regimens were well tolerated. Overall, gametocyte carriage before and following treatment were similar. Both combinations were found effective and comparable for treatment of acute, uncomplicated, P. falciparum malaria.

Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial.

BACKGROUND: The efficacy of artemisinin-based combination therapy has already been demonstrated in a number of studies all over the world, and some of them can be regarded as comparably effective. Ease of administration of anti-malarial treatments with shorter courses and fewer tablets may be key determinant of compliance. METHODS: Patients with uncomplicated falciparum malaria and over six months of age were recruited in Cameroon, Mali, Rwanda and Sudan. 1,384 patients were randomly assigned to receive artesunate-sulphamethoxypyrazine-pyrimethamine (AS-SMP) three-day (once daily for 3 days) regimen (N = 476) or AS-SMP 24-hour (0 h, 12 h, 24 h) regimen (N = 458) or artemether-lumefantrine (AL), the regular 6 doses regimen (N = 450). The primary objective was to demonstrate non-inferiority (using a margin of -6%) of AS-SMP 24 hours or AS-SMP three days versus AL on the PCR-corrected 28-day cure rate. RESULTS: The PCR corrected 28-day cure rate on the intention to treat (ITT) analysis population were: 96.0%(457/476) in the AS-SMP three-day group, 93.7%(429/458) in the AS-SMP 24-hour group and 92.0%(414/450) in the AL group. Likewise, the cure rates on the PP analysis population were high: 99.3%(432/437) in the AS-SMP three-day group, 99.5%(416/419) in the AS-SMP 24-hour group and 99.7(391/394)% in the AL group. Most common drug-related adverse events were gastrointestinal symptoms (such as vomiting and diarrhea) which were slightly higher in the AS-SMP 24-hour group. CONCLUSION: AS-SMP three days or AS-SMP 24 hours are safe, are as efficacious as AL, and are well tolerated. TRIAL REGISTRATION: NCT00484900 http://www.clinicaltrials.gov.

Activities of artemether-lumefantrine and amodiaquine-sulfalene-pyrimethamine against sexual-stage parasites in falciparum malaria in children.

The activities of artemether-lumefantrine and amodiaquine-sulfalene-pyrimethamine against sexual-stage parasites were evaluated in 42 of 181 Nigerian children with uncomplicated Plasmodium falciparum malaria who had gametocytaemia before, during or after treatment with the two combination therapies. The children were randomized to the standard dose regimens. Clinical recovery from illness occurred in all children who carried gametocytes. Gametocytaemia was detected in 20 patients (11%) before treatment and in another 22 patients (12.2%) after treatment. Gametocyte carriage rates were similar in both combination treatment groups, but the area under the curve of gametocytaemia plotted against time was 8-fold higher in the amodiaquine-sulfalene-pyrimethamine-treated than in the artemether-lumefantrine-treated children. The pretreatment gametocyte sex ratio was female biased in both treatment groups. During follow-up, there was a short-lived but significant increase in the gametocyte sex ratio in children treated with amodiaquine-sulfalene-pyrimethamine but not in those treated with artemether-lumefantrine. These results indicate that both combination therapies had moderate effects on gametocyte carriage, but artemether-lumefantrine may be more potent at reducing transmissibility in P. falciparum malaria by exerting greater effects on post-treatment gametocyte density and gametocyte sex ratio.

Comparison of different artemisinin-based combinations for the treatment of Plasmodium falciparum malaria in children in Kigali, Rwanda, an area of resistance to sulfadoxine-pyrimethamine: artesunate plus sulfadoxine/pyrimethamine versus artesunate plus sulfamethoxypyrazine/pyrimethamine.

In view of the changing policy towards artemisinin-based combination therapies (ACTs), the efficacy, tolerance, and degree of re-infection of two ACTs were investigated: artesunate plus sulfadoxine/pyrimethamine (As + SP) and AS plus sulfamethoxypyrazine/pyrimethamine (As + SMP). One hundred three children were assigned to receive As + SP and 109 to receive As + SMP. In spite of the high incidence of resistance to SP, As + SP showed satisfactory results consistent with recent recommendations for ACTs (adequate clinical and parasitologic response on day 28 [ACPR] > or = 90%), but results with As + SMP fulfilled the most stringent criteria (ACPR > or = 95%). The absence of side effects and the low price of these drugs make them it worth to reconsider national therapies in favor of either of these two drug combinations.

Therapeutic efficacy and effects of artemether-lumefantrine and amodiaquine-sulfalene-pyrimethamine on gametocyte carriage in children with uncomplicated Plasmodium falciparum malaria in southwestern Nigeria.

The treatment efficacy and effects of artemether-lumefantrine (AL) and amodiaquine-sulfalene-pyrimethamine (ASP) on gametocyte carriage were evaluated in 181 children < or = 10 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive either drug combination. All children recovered clinically. Fever clearance times were similar. The rate of P. falciparum reappearance (recrudescence or re-infection) between two and six weeks after the start of therapy was significantly higher in AL-treated children (P = 0.01). Parasite clearance was significantly faster in children treated with AL (mean +/- SD = 1.7 +/- 0.6 days, 95% confidence interval = 1.58 - 1.83, P = 0.0001) but the polymerase chain reaction-corrected cure rate (90 of 91 versus 84 of 90) and the rate of resolution of malaria-related anemia two weeks after treatment began (45 of 50 versus 33 of 46) were higher in children treated with ASP. Gametocyte carriage rates were similar. Both regimens were well tolerated. Artemether-lumefantrine clears parasitemia more rapidly than ASP but both combinations are effective in treatment of uncomplicated P. falciparum malaria in Nigerian children.

Surveillance of Toxoplasma gondii infection in recipients of thoracic solid organ transplants.

We evaluated the frequency of seroconversion for toxoplasmosis in seronegative recipients of thoracic solid organ transplants with seronegative or seropositive donors and the efficacy of chemoprophylaxis with pyrimethamine+sulfametopirazine. One hundred and sixty one patients seronegative for toxoplasmosis were followed-up at different intervals. Six patients out of 79 R-/D- and twelve out of 82 R-/D+ seroconverted after chemoprophylaxis interruption. There was no difference between matched and mismatched recipients as to the frequency of seroconversion which therefore could not be related to donor seropositivity. Seroconversions were almost asymptomatic. All positive recipients should be tested if symptoms of infection are present.

A randomized trial of artesunate-sulfamethoxypyrazine-pyrimethamine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali.

The choice of artemisinin-based combination that is being adopted for malaria treatment in sub-Saharan Africa may depend on several factors, including cost, efficacy, side effects, and simplicity of administration. We tested the hypothesis that artesunate-sulfamethoxypyrazine-pyrimethamine is as efficacious as the four-dose regimen of artemether-lumefantrine for treatment of Plasmodium falciparum malaria. The study was carried out during two transmission seasons (2003 and 2004) in Sotuba, Mali. Participants at least 6 months of age with uncomplicated P. falciparum malaria were randomly assigned to receive artesunate-sulfamethoxypyrazine-pyrimethamine or artemether-lumefantrine. Treatment efficacy was assessed using the World Health Organization 28-day protocol. A total of 606 (303 in each arm) patients were enrolled. The cure rate was higher for artesunate-sulfamethoxypyrazine-pyrimethamine than for artemether-lumefantrine (98.7% versus 89.6%; P < 0.0001). After correction for cases of re-infection, the cure rates were 100% and 99.0%, respectively (P = 0.08). No serious adverse events occurred. Artesunate-sulfamethoxypyrazine-pyrimethamine is well-tolerated and effective against P. falciparum malaria. It showed an additional benefit of preventing new infections.

A fixed-dose 24-hour regimen of artesunate plus sulfamethoxypyrazine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan.

BACKGROUND: Artemisinin-based combination therapy is increasingly being adopted as first-line antimalarial therapy. The choice of appropriate therapy depends on efficacy, cost, side effects, and simplicity of administration. METHODS: the efficacy of fixed co-formulated (f) artesunate-sulfamethoxypyrazine-pyrimethamine (AS+SMP f) administered at time intervals of 12 hours for a 24-hour therapy was compared with the efficacy of the same drug given as a loose combination (AS+SMP l) with a dose interval of 24 hours for 3 days for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. RESULTS: seventy-three patients (39 and 34 in the fixed and the loose regimen of AS+SMP respectively) completed the 28-days of follow-up. On day 3; all patients in both groups were a parasitaemic but one patient in the fixed group of AS+SMP f was still febrile. Polymerase chain reaction genotyping adjusted cure rates on day 28 were 92.3% and 97.1% (P > 0.05) for the fixed and loose combination of AS+SMP respectively. Three (4.1%) patients (one in the fixed and two patients in the loose group of AS+SMP) in the study suffered drug-related adverse effects. Gametocytaemia was not detected during follow-up in any of the patients. CONCLUSION: both regimens of AS+SMP were effective and safe for the treatment of uncomplicated P. falciparum malaria in eastern Sudan. Due to its simplicity, the fixed dose one-day treatment regimen may improve compliance and therefore may be the preferred choice.

The drug sensitivities of Plasmodium falciparum in the Sonitpur district, Assam, India.

Falciparum malaria is an ongoing problem in the foothills of Northeast India. Evaluation of the drug sensitivities of P. falciparum was carried out in four endemic villages of the Sonitpur District of Assam, involving 218 cases who were tested in vivo over 35 days. Chloroquine resistance was detected at the RI level in 29 cases (13%) and RII level in 8 cases (4%). No RIII chloroquine resistant cases were detected in the study. RI resistance was observed in the age groups 6-10 years, 11-14 years, and 15 years and above in 16%, 17%, and 13%, respectively. RII level resistance was observed in 4% of all those groups combined. All the RI and RII resistant cases responded well to a single dosage of Metakelfin (sulfamethoxypyrazine I.P 1,500 mg and pyrimethamine I.P 75 mg).

Evaluating new antimalarial drugs against trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys.

An antimalarial drug testing system is described which utilizes trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys. The schizonticidal activity of standard antimalarial drugs in this system is reported. The system accurately predicted antimalarial activity in man of 8 of 9 compounds selected for clinical trials.

The influence of acetylator phenotype on the response to sulfalene in individuals with chloroquine-resistant falciparum malaria.

The disposition of sulfalene was studied in eight individuals before and during an infection with a chloroquine-resistant strain of Plasmodium falciparum. Isoniazid acetylator phenotype was determined in each individual prior to the administration of sulfalene. Following the administration of sulfalene before infection with malaria, a significant difference in half-life of non-acetylated sulfalene and percent acetylation of sulfalene in plasma was observed between rapid and slow acetylators. When sulfalene was administered during malaria, this difference was no longer apparent. Individuals who did not respond to the therapeutic administration of sulfalene alone were treated with a combination of sulfalene and pyrimethamine. Three individuals were cured by sulfalene without pyrimethamine and one was cured by the drug combination. Three of the four individuals who were not cured by any dose of sulfalene or the drug combination were slow acetylators. There was no distinct correlation between clinical response and maximum levels or half-life of nonacetylated sulfalene. These findings suggest that acetylator phenotype does not influence the therapeutic response of individuals infected with falciparum malaria to sulfalene or to the combination of sulfalene and pyrimethamine. Further information is presented, however, to confirm the importance of an as yet unidentified host factor(s) in determining therapeutic response to these agents.

Acetylator phenotype and response of individuals infected with a chloroquine-resistant strain of Plasmodium falciparum to sulfalene and pyrimethamine.

Acetylator phenotype was determined in 33 volunteers who were infected with a chloroquine-resistant strain of Plasmodium falciparum and who received, for cure, 2 g of sulfalene and 50 mg of pyrimethamine. This drug combination did not cure 5 of 14 rapid acetylators and 3 of 19 slow acetylators. This difference is not significant. Plasma levels of non-acetylated sulfalene, acetylated sulfalene, acetylation, and biologic half-life of non-acetylated sulfalene after administration of the combination did not differ importantly between the two groups. Acetylator phenotype does not appear to influence the response to sulfalene and pyrimethamine of individuals infected with chloroquine-resistant falciparum malaria.

Kelfiprim versus co-trimoxazole in recurrent and persistent urinary tract infections: multicenter double-blind trial.

Kelfiprim (KP) is a new bactericidal agent containing trimethoprim (T) and sulfametopyrazine (S), a long-acting sulfonamide (ratio 5:4). The posology is one capsule (T 250 mg + S 200 mg) daily, after a loading dose of two capsules on the first day. To evaluate the clinical value of Kelfiprim (KP) vs co-trimoxazole (CO) in urinary tract infection (UTI) a controlled multicenter double-blind trial (MDBT) was carried out in 76 patients suffering from persistent and recurrent UTIs. About 90 per cent response rate (sterile urine at the end of treatment) was obtained for KP and about 85 per cent for CO in recurrent UTI. In persistent UTI the rate of recovery was 66.8 per cent and 53 per cent for KP and CO, respectively. Safety of treatments was excellent in 97 per cent of patients treated with Kelfiprim and 87 per cent treated with co-trimoxazole. Two patients, one in each group, were dropped from the study because of adverse reactions.

Double-blind, multi-centre trial to compare a once-daily combination of trimethoprim and sulfamethopyrazine with ampicillin 4-times daily in patients with urinary infections.

Sixty-eight patients with urinary infection were allocated at random to receive treatment with either 500 mg ampicillin 4-times daily or a trimethoprim (250 mg)/sulfamethopyrazine (200 mg) combination given once daily after a double, loading dose on the first day. All patients complained of urinary symptoms and showed significant bacteriuria, E. coli being the pathogen most frequently recovered. Clinical and microbiological assessments were carried out on entry and, as a rule, after 3 to 4 days and 1 to 2 weeks of treatment. In the 35 patients receiving trimethoprim/sulfamethopyrazine, 40 (95%) of the 42 original infecting organisms were eradicated. In the 33 patients on ampicillin, the eradication rate was 32 (89%) out of 36 organisms. The course of urinary symptoms was similarly favourable in the two groups. Overall response was considered as 'excellent' or 'good' in 89% of the patients receiving the combination preparation and in 82% of those given ampicillin. Clinical and biological tolerance was satisfactory under both regimens. A longer follow-up control should confirm the value of the new combination in the treatment of urinary infections.

Efficacy and clinical tolerance of a new combination of trimethoprim with sulphonamide. A post-marketing and a literature survey.

To obtain a direct clinical evaluation of a new sulpha-trimethoprim combination product (Kelfiprim) from general practitioners or specialist practitioners, an extensive post-marketing survey has been organized in Brazil involving 1,177 doctors and 5,885 patients. These experienced different infections susceptible to oral antimicrobial chemotherapy with a sulpha-trimethoprim combination. The results indicated that the product was very effective (91.2% cure rate) and well tolerated (4% incidence of side-effects). Side-effects were usually mild and transient. No life-threatening adverse reactions were observed. The results obtained support those already published in clinical trials involving 1,119 patients.

Clinical assessment of a trimethoprim-sulfamethopyrazine combination (Kelfiprim) in lower respiratory tract infections.

The new combination of trimethoprim 250 mg and sulfamethopyrazine 200 mg was used in fourteen out-patients and eighteen in-patients with acute exacerbation of chronic bronchitis, pneumonia or bronchopneumonia due to sensitive bacteria. The drug was given for 1 to 2 weeks as one capsule daily (following a double loading dose on the first day), and ampicillin, 500 mg capsules q.i.d., was administered to another group of eleven in-patients for comparison. Overall results, based on clinical, radiological and laboratory findings, were excellent or good in 85% and 67%, respectively, of out- and in-patients receiving the combination drug; definite failures were one out of fourteen and two out of eighteen cases, and the remainder were assessed as fair. In three out of thirty-two patients mild to moderate gastro-intestinal side-effects were observed during treatment. The drug compared favourably to ampicillin for both effectiveness and safety.

[Recovery from from Listeria monocytogenes meningitis in an adult]. / Meningite da Listeria monocytogenes ad esito in guarigione in adulto.

The authors describe a case of meningitis by Listeria monocytogenes from which the patient, an adult suffering from a chronic lymphatic leukosis, recovered completely. Both the immune-suppressor treatment and the basic lymphoproliferative disease may have given rise to this infective disease. The diagnosis has been obtained by isolating the germ in liquor-cultures. We want to point out the importance of a specific and early antibiotic treatment.