trimethoprim--sulfamethoxazole-drug-combination and Malaria--Falciparum

Cotrimoxazole (CTX) has been used for half a century. It is inexpensive hence the reason for its almost universal availability and wide clinical spectrum of use. In the last decade, CTX was used for prophylaxis of opportunistic infections in HIV infected people. It also had an impact on the malaria risk in this specific group.. We performed a systematic review to explore the efficacy and safety of CTX used for P.falciparum malaria treatment and prophylaxis.. CTX is safe and efficacious against malaria. Up to 75% of the safety concerns relate to skin reactions and this increases in HIV/AIDs patients. In different study areas, in HIV negative individuals, CTX used as malaria treatment cleared 56%-97% of the malaria infections, reduced fever and improved anaemia. CTX prophylaxis reduces the incidence of clinical malaria in HIV-1 infected individuals from 46%-97%. In HIV negative non pregnant participants, CTX prophylaxis had 39.5%-99.5% protective efficacy against clinical malaria. The lowest figures were observed in zones of high sulfadoxine-pyrimethamine resistance. There were no data reported on CTX prophylaxis in HIV negative pregnant women.. CTX is safe and still efficacious for the treatment of P.falciparum malaria in non-pregnant adults and children irrespective of HIV status and antifolate resistance profiles. There is need to explore its effect in pregnant women, irrespective of HIV status. CTX prophylaxis in HIV infected individuals protects against malaria and CTX may have a role for malaria prophylaxis in specific HIV negative target groups.

Topics: Antimalarials; Humans; Malaria, Falciparum; Trimethoprim, Sulfamethoxazole Drug Combination

Microbial infections still account for considerable morbidity and mortality in sub-Saharan Africa. The importance of chemotherapeutic agents cannot be over-emphasized. Some antimicrobial agents provide broad spectrum of activity spanning different classes of bacterial and protozoan diseases. Cotrimoxazole, an antifolate antimicrobial was originally meant for treatment of bacterial diseases but has been shown to be an effective drug in the treatment of malaria amongst other conditions. This review attempted to explore the pharmacology of cotrimoxazole, its many clinical uses and adverse effects. Specific experiences of the author in the application of cotrimoxazole in the treatment of acute uncomplicated falciparum malaria were highlighted and suggestions on how to optimize the use of this drug were made.

Topics: Antimalarials; Female; Humans; Malaria, Falciparum; Male; Nigeria; Plasmodium falciparum; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Chloroquine-resistant Plasmodium falciparum is now widespread in Africa, requiring new drugs for the control of both non-severe and severe forms of the disease. For non-severe malaria, pyrimethamine-sulphadoxine, an antifolate combination antimalarial, is at present efficacious, single-dose and cheap; important characteristics for treatments in Africa. However, alternative combinations are being investigated which are intrinsically more active, less toxic and with shorter elimination half-lives. In theory, short half-life compounds reduce the selective pressure for resistance, which may be a major determinant of the useful therapeutic life of an antimalarial drug. The potential advantages/disadvantages of alternative antifolates is discussed. While the use of mefloquine and halofantrine in Africa is at present limited by cost, these drugs are likely replacements for the antifolates when parasite resistance arises. For severe, life-threatening falciparum malaria, quinine remains the treatment of choice. In contrast to quinine, artemether rapidly reduces the viability of circulating, ring-stage parasites, produces more rapid parasite clearance and may reduce the length of coma, but does not significantly reduce the mortality of severe malaria which remains at about 15% even with optimal management. It seems unlikely that chemotherapy, even with "new" antimalarials, will reduce this high figure. Other strategies are required.

Topics: Africa; Antimalarials; Artemether; Artemisinins; Drug Costs; Drug Resistance; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Sesquiterpenes; Trimethoprim, Sulfamethoxazole Drug Combination

Cotrimoxazole prevents opportunistic infections including falciparum malaria in HIV-infected individuals but there are concerns of cross-resistance to other antifolate drugs such as sulphadoxine-pyrimethamine (SP). In this study, we investigated the prevalence of antifolate-resistance mutations in Plasmodium falciparum that are associated with SP resistance in HIV-infected individuals on antiretroviral treatment randomized to discontinue (STOP-CTX), or continue (CTX) cotrimoxazole in Western Kenya.. Samples were obtained from an unblinded, non-inferiority randomized controlled trial where participants were recruited on a rolling basis for the first six months of the study, then followed-up for 12 months with samples collected at enrollment, quarterly, and during sick visits.. Plasmodium DNA was extracted from blood specimens. Initial screening to determine the presence of Plasmodium spp. was performed by quantitative reverse transcriptase real-time PCR, followed by genotyping for the presence of SP-resistance associated mutations by Sanger sequencing.. The prevalence of mutant haplotypes associated with SP-resistant parasites in pfdhfr (51I/59R/108N) and pfdhps (437G/540E) genes were significantly higher (P = 0.0006 and P = 0.027, respectively) in STOP-CTX compared to CTX arm. The prevalence of quintuple haplotype (51I/59R/108N/437G/540E) was 51.8% in STOP-CTX vs. 6.3% (P = 0.0007) in CTX arm. There was a steady increase in mutant haplotypes in both genes in STOP-CTX arm overtime through the study period, reaching statistical significance (P < 0.0001).. The frequencies of mutations in pfdhfr and pfdhps genes were higher in STOP-CTX arm compared to CTX arm, suggesting cotrimoxazole effectively controls and selects against SP-resistant parasites.. ClinicalTrials.gov NCT01425073.

Topics: Adolescent; Adult; Antimalarials; Dihydropteroate Synthase; Drug Combinations; Drug Resistance; Folic Acid Antagonists; Haplotypes; HIV Infections; Humans; Kenya; Malaria, Falciparum; Mutation; Plasmodium falciparum; Pre-Exposure Prophylaxis; Prevalence; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

The World Health Organisation (WHO) recommends parasitological diagnosis of malaria before treatment, but use of malaria rapid diagnostic tests (mRDTs) by community health workers (CHWs) has not been fully tested within health services in south and central Asia. mRDTs could allow CHWs to diagnose malaria accurately, improving treatment of febrile illness.. A cluster randomised trial in community health services was undertaken in Afghanistan. The primary outcome was the proportion of suspected malaria cases correctly treated for polymerase chain reaction (PCR)-confirmed malaria and PCR negative cases receiving no antimalarial drugs measured at the level of the patient. CHWs from 22 clusters (clinics) received standard training on clinical diagnosis and treatment of malaria; 11 clusters randomised to the intervention arm received additional training and were provided with mRDTs. CHWs enrolled cases of suspected malaria, and the mRDT results and treatments were compared to blind-read PCR diagnosis.. In total, 256 CHWs enrolled 2400 patients with 2154 (89.8%) evaluated. In the intervention arm, 75.3% (828/1099) were treated appropriately vs. 17.5% (185/1055) in the control arm (cluster adjusted risk ratio: 3.72, 95% confidence interval 2.40-5.77; p < 0.001). In the control arm, 85.9% (164/191) with confirmed Plasmodium vivax received chloroquine compared to 45.1% (70/155) in the intervention arm (p < 0.001). Overuse of chloroquine in the control arm resulted in 87.6% (813/928) of those with no malaria (PCR negative) being treated vs. 10.0% (95/947) in the intervention arm, p < 0.001. In the intervention arm, 71.4% (30/42) of patients with P. falciparum did not receive artemisinin-based combination therapy, partly because operational sensitivity of the RDTs was low (53.2%, 38.1-67.9). There was high concordance between recorded RDT result and CHW prescription decisions: 826/950 (87.0%) with a negative test were not prescribed an antimalarial. Co-trimoxazole was prescribed to 62.7% of malaria negative patients in the intervention arm and 15.0% in the control arm.. While introducing mRDT reduced overuse of antimalarials, this action came with risks that need to be considered before use at scale: an appreciable proportion of malaria cases will be missed by those using current mRDTs. Higher sensitivity tests could be used to detect all cases. Overtreatment with antimalarial drugs in the control arm was replaced with increased antibiotic prescription in the intervention arm, resulting in a probable overuse of antibiotics.. ClinicalTrials.gov, NCT01403350 . Prospectively registered.

Topics: Adolescent; Afghanistan; Antimalarials; Artemisinins; Child; Child, Preschool; Chloroquine; Community Health Workers; Diagnostic Tests, Routine; Female; Humans; Infant; Infant, Newborn; Malaria; Malaria, Falciparum; Male; Plasmodium vivax; Trimethoprim, Sulfamethoxazole Drug Combination

Asymptomatic falciparum malaria is associated with poorer cognitive performance in African schoolchildren and intermittent preventive treatment of malaria improves cognitive outcomes. However, the developmental benefits of chemoprevention in early childhood are unknown. Early child development was evaluated as a major outcome in an open-label, randomized, clinical trial of anti-malarial chemoprevention in an area of intense, year-round transmission in Uganda.. Infants were randomized to one of four treatment arms: no chemoprevention, daily trimethoprim-sulfamethoxazole, monthly sulfadoxine-pyrimethamine, or monthly dihydroartemisinin-piperaquine (DP), to be given between enrollment (4-6 mos) and 24 months of age. Number of malaria episodes, anaemia (Hb < 10) and neurodevelopment [Mullen Scales of Early Learning (MSEL)] were assessed at 2 years (N = 469) and at 3 years of age (N = 453); at enrollment 70 % were HIV-unexposed uninfected (HUU) and 30 % were HIV-exposed uninfected (HEU).. DP was highly protective against malaria and anaemia, although trial arm was not associated with MSEL outcomes. Across all treatment arms, episodes of malarial illness were negatively predictive of MSEL cognitive performance both at 2 and 3 years of age (P = 0.02). This relationship was mediated by episodes of anaemia. This regression model was stronger for the HEU than for the HUU cohort. Compared to HUU, HEU was significantly poorer on MSEL receptive language development irrespective of malaria and anaemia (P = 0.01).. Malaria with anaemia and HIV exposure are significant risk factors for poor early childhood neurodevelopment in malaria-endemic areas in rural Africa. Because of this, comprehensive and cost/effective intervention is needed for malaria prevention in very young children in these settings.

Topics: Age Factors; Anemia; Antimalarials; Artemisinins; Child, Preschool; Cognition; Cognition Disorders; Coinfection; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Male; Pyrimethamine; Quinolines; Risk Factors; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children.. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine.. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations.. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.

Topics: Antimalarials; Artemether; Artemisinins; Black People; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Recurrence; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

We investigated the circulating plasma levels of Th1- (Interleukin-2 [IL-2], tumor necrosis factor-α [TNF-α], interferon-gamma [IFN-γ]) and Th2-type (IL-4, IL-5, IL-10) cytokines in human immunodeficiency virus (HIV)-infected pregnant women living in a malaria-endemic area. We analyzed samples from 200 pregnant women included in the prevention of pregnancy-associated malaria in HIV-infected women: cotrimoxazole prophylaxis versus mefloquine (PACOME) clinical trial who were followed until delivery. Cytokine concentrations were measured by flow cytometry-based multiplex bead array. Significantly elevated levels of IL-10 and lower levels of TNF-α were observed at delivery compared with inclusion (P = 0.005). At inclusion, the presence of circulating IFN-γ, a higher CD4(+) T cell count and having initiated intermittent preventive treatment of malaria with sulfadoxine pyrimethamine (SP-IPTp) were all associated with a lower likelihood of Plasmodium falciparum infection. At delivery, the inverse relationship between the presence of infection and circulating IFN-γ persisted, although there was a positive association between the likelihood of infection and the presence of circulating TNF-α. Initiation of antiretroviral therapy was associated with elevated IL-5 production. Consistent with our own and others' observations in HIV seronegative subjects, this study shows circulating IL-10 to be a marker of infection with P. falciparum during pregnancy even in HIV-infected women, although plasma IFN-γ may be a marker of anti-malarial protection in such women.

Topics: Adult; Antimalarials; Benin; Drug Combinations; Female; HIV Infections; Humans; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-5; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Complications, Parasitic; Prospective Studies; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Tumor Necrosis Factor-alpha; Young Adult

Human immunodeficiency virus (HIV) and malaria during pregnancy cause substantial perinatal mortality. As co-trimoxazole (CMX) protects children and HIV-positive adults against malaria, we compared the effectiveness of daily CMX with sulfadoxine-pyrimethamine intermittent preventive treatment (IPT-SP) on malaria risk in HIV-positive pregnant women in a Plasmodium falciparum-endemic African area..  From January 2009 to April 2011, we included in a randomized noninferiority trial all HIV type 1-infected pregnant women (≤28 weeks' gestation, CD4 count ≥200 cells/µL, hemoglobin level ≥7 g/L) in 19 health centers in Togo. Women were randomly assigned to daily 800 mg/160 mg CMX, or IPT-SP. The primary outcome was the proportion of malaria-free pregnancies. Other outcomes included malaria incidence, parasitemia, placental malaria, anemia, and infants' birth weight.. Of 264 women randomly assigned to the CMX or IPT-SP group, 126 of 132 and 124 of 132, respectively, were included in the analysis. There were 33 confirmed cases of clinical malaria among 31 women in the CMX group, and 19 among 19 women in the IPT-SP group. Ninety-five of 126 (75.4%) women in the CMX group and 105 of 124 (84.7%) in the IPT-SP group remained malaria-free during their pregnancy (difference, 9.3%; 95% confidence interval [CI], -.53 to 19.1, not meeting the predefined noninferiority criterion). The incidence rate in intention-to-treat analysis was 108.8 malaria episodes per 100 person-years in CMX (95% CI, 105.4-112.2) and 90.1 in IPT-SP (95% CI, 86.8-93.4) (not significant). Prevalence of parasitemia was 16.7% in the CMX group vs 28% in the IPT-SP group (P = .02). Histology revealed 20.3% placental malaria in the CMX group vs. 24.6% in the IPT-SP group (not significant). Grade 3-4 anemia was more frequent in the CMX group (10% vs 4%; P = .008). No pregnant women died. Median birth weight was similar..  Daily CMX was not noninferior to IPT-SP for preventing maternal malaria but safe and at least similar regarding parasitemia or placental malaria and birth outcomes. Clinical Trials Registration  ISRCTN98835811.

Topics: Adolescent; Adult; Antimalarials; Drug Combinations; Female; HIV Infections; Humans; Incidence; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine; Togo; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

Co-infection with malaria parasite and HIV is an emerging public health problem in tropical areas, particularly in pregnant women, and management of the concurrent effects of these two infections is challenging. Co-trimoxazole is a sulfamide preparation used to prevent opportunistic infections in HIV-infected patients, and many studies have reported that it has significant activity against malaria. As the efficacy of intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) against malaria is decreasing, co-trimoxazole might be an alternative for preventing malaria among HIV-infected populations. The aim of this study is to compare the effectiveness of SP-IPT, which is recommended for the prevention of malaria during pregnancy in the Central African Republic, with that of a daily dose of co-trimoxazole against P. falciparum infections among HIV-infected pregnant women in Bangui, the capital of the Central African Republic.. The MACOMBA study (MAternity and COntrol of Malaria-HIV co-infection in BAngui) is a multicentre open-label randomized clinical trial conducted at four maternity hospitals in Bangui. All HIV-infected pregnant women presenting for an antenatal clinic visit between the weeks 16 and 28 of amenorrhoea, with a CD4 count of more than 350 cells/mm3, will be eligible. All the women will provide written consent before being enrolled in the study and will then be randomly allocated to either SP-IPT (25 mg of sulfadoxine and 1.25 mg of pyrimethamine) or daily co-trimoxazole doses (960 mg per dose). The primary end-point is the placental malaria parasitaemia rate at delivery. Other main outcome measures include the number of malaria episodes during pregnancy, safety, and treatment compliance. Furthermore, the frequency of molecular resistance markers dhfr and dhps will be measured.. In this trial, we seek to confirm whether co-trimoxazole is operationally suitable to replace SP-IPT in order to prevent malaria among pregnant women infected with HIV in the Central African Republic.. ClinicalTrials.gov Identifier: NCT01746199.

Topics: Antimalarials; Central African Republic; Clinical Protocols; Coinfection; Drug Administration Schedule; Drug Combinations; Female; Folic Acid Antagonists; HIV Infections; Hospitals, Maternity; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Prenatal Care; Pyrimethamine; Research Design; Sulfadoxine; Time Factors; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P < 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P < 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; HIV Infections; Humans; Infant; Longitudinal Studies; Malaria, Falciparum; Multivariate Analysis; Parasitemia; Plasmodium falciparum; Post-Exposure Prophylaxis; Prevalence; Proportional Hazards Models; Quinolines; Risk Factors; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Trophozoites; Uganda

The study was undertaken to evaluate the efficacy of cotrimoxazole plus artesunate and to compare the efficacy of this combination with that of artesunate plus chloroquine in the treatment of acute uncomplicated falciparum malaria in children.. Children aged between 0.5 and 12 yr with clinical and parasitological evidence of Plasmodium falciparum malaria were randomized to receive either artesunate plus cotrimoxazole or artesunate plus chloroquine. They were followed-up with clinical and parasitological assessment for a period of 14 days.. In all, 57 out of 81 (31 in the artesunate plus cotrimoxazole group and 26 in artesunate plus chloroquine group) completed the study as per protocol and were evaluated. Pre-treatment clinical and parasitological parameters were similar in the two treatment groups. The time to clear fever and other symptoms were similar in the two groups 1.0 +/- 0 vs 1.14 +/- 0.38 (p > 0.05). Parasite clearance times were also similar; 1.65 +/- 0.49 days vs 1.58 +/- 0.67 days respectively for artesunate plus cotrimoxazole and artesunate plus chloroquine (p > 0.05). The cure rates on Day 14 were 100% for both artesunate plus cotrimoxazole and artesunate plus chloroquine groups. Both drug combinations were well-tolerated in the small population of children.. These results indicate that artesunate plus cotrimoxazole has similar efficacy to artesunate plus chloroquine in the treatment of acute uncomplicated P. falciparum malaria in children resident in an endemic area of south-west Nigeria.

Topics: Antimalarials; Artemisinins; Artesunate; Child; Child, Preschool; Chloroquine; Drug Therapy, Combination; Female; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Plasmodium falciparum; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

The activities of artesunate-cotrimoxazole and artesunate-amodiaquine combinations against asexual-and sexual-stage parasites were evaluated in 182 Nigerian children with uncomplicated Plasmodium falciparum malaria. One hundred and twenty-one children received artesunate-cotrimoxazole and 61 received artesunate-amodiaquine and all were followed up for 28 days. Clinical recovery from illness occurred in all children. There was no significant difference in fever clearance time (P = 0.35). Both treatment groups achieved a parasite clearance time of less than 2 days (1.84 +/- 0.66 days and 1.31 +/- 0.48 days); gametocyte carriage rates were comparable in the two treatment groups prior to and following treatment; both treatments appeared to reduce gametocyte carriage. The pretreatment gametocyte sex ratio, which was female-biased, was maintained throughout the period of follow up in both treatment groups. Reduction of gametocyte carriage by these two treatment regimens may reduce transmissibility in P. falciparum malaria, and this reduction is presumed to be related to the accelerated clearance of the asexual forms of the parasite.

Topics: Amodiaquine; Animals; Antimalarials; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infant; Life Cycle Stages; Malaria, Falciparum; Male; Nigeria; Plasmodium falciparum; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Recently, Plasmodium falciparum bearing dihydrofolate reductase (DHFR) I164L was isolated from Africa. Quadruple mutations containing I164L confer high-level resistance to antifolate antimalarials. We prospectively measured the effect of co-trimoxazole (CTX) prophylaxis on P. falciparum antifolate resistance development among HIV-infected persons. HIV-positive patients with CD4 cell count < 350 cells/microl (n=692) received CTX; HIV-positive patients with CD4 cell count > or = 350 cells/microl (n=336) and HIV-negative patients (n=132) received multivitamins. Malaria microscopy-positive samples (n=413) and selected microscopy-negative/PCR-positive samples (n=76) were analysed for DHFR mutations at baseline and during six months follow up. We identified I164L in 14 patients. Seven were malaria microscopy-positive: two failed sulfadoxine-pyrimethamine (SP). Among seven microscopy-negative/PCR-positive patients, none developed patent infections with I164L. I164L was not associated with high-level SP resistance or poor outcome among adults living where malaria is highly endemic. Surveillance to monitor spread of I164L is critical, especially among children and pregnant women, who are potentially a source for I164L amplification.

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Animals; Antimalarials; CD4 Lymphocyte Count; Drug Combinations; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Mutation; Plasmodium falciparum; Prospective Studies; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) decreases placental malaria parasitemia and associated maternal anemia, premature delivery, and low birth weight. However, the optimal regimen in the setting of a high prevalence of human immunodeficiency virus (HIV) infection remains unclear.. In Malawi, where the efficacy of SP for the treatment of malaria in children is decreasing, we conducted a randomized, nonblinded study to compare the efficacy of monthly SP IPTp with a 2-dose regimen for the prevention of placental parasitemia in HIV-positive and -negative primigravid and secundigravid women.. Of HIV-positive women, 7.8% who received monthly SP had placental malaria, compared with 21.5% of those who received 2-dose SP (relative risk [RR], 0.36 [95% confidence interval {CI}, 0.17-0.79]). Of HIV-negative women, 2.3% who received monthly SP and 6.3% who received 2-dose SP had placental malaria (RR, 0.37 [95% CI, 0.11-1.19]). Less than 1% of women reported adverse drug reactions, with no increase in HIV-positive women or those who received monthly SP.. In HIV-positive pregnant women, monthly SP IPTp is more efficacious than a 2-dose regimen in preventing placental malaria. The study also demonstrates the continued efficacy of SP for the prevention of placental malaria, even in the face of its decreasing efficacy for the treatment of malaria in children. In areas with intense transmission of falciparum malaria and a high prevalence of HIV infection, monthly SP IPTp should be adopted.

Topics: Adolescent; Adult; Antimalarials; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; Humans; Infant, Newborn; Malaria, Falciparum; Malawi; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

We assessed the efficacy of trimethoprim/sulfamethoxazole (TRM/SMX) in vivo in relation to the frequency of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) alleles in 45 Sudanese malaria patients. Plasma levels of TRM, SMX, and acetylsulfamethoxazole (AcSMX) were measured before treatment and at days 3, 7, and 14 or upon recrudescence to ascertain drug absorption. Forty patients (89%) had an adequate clinical response, one patient (2%) had an early treatment failure response, while four patients (8%) showed late treatment failure responses. Genotyping of merozoite surface protein 1, MSP-1, MSP-2, and glutamate-rich protein before treatment and upon recrudescence showed that all recurring parasites were recrudescences. The plasma levels of TRM, AcSMX, and SMX indicated adequate drug absorption in all patients. This suggests parasite resistance as a cause of treatment failure. The presence of dhfr Ile 51 and Asn 108 alone or coupled with dhps Ala-436 among parasites that were cleared after treatment indicates that these alleles alone are insufficient to cause in vivo resistance. However, the presence of the triple mutant dhfr (Ile-51/Arg-59/Asn-108) with the dhps Gly-437 genotype in all recurring infections, suggests the importance of codon 59 and 437 alleles in susceptibility to TRM/SMX. However, the number is too little to make firm conclusions.

Topics: Animals; Antimalarials; Dihydropteroate Synthase; Genotype; Humans; Malaria, Falciparum; Plasmodium falciparum; Sudan; Tetrahydrofolate Dehydrogenase; Trimethoprim, Sulfamethoxazole Drug Combination

Trimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for persons living with human immunodeficiency virus infection and acquired immunodeficiency syndrome in Africa. TS and the antimalarial combination sulfadoxine-pyrimethamine (SP) share mechanisms of action and resistance patterns, and concerns about the impact of TS resistance on SP efficacy have contributed to reluctance to implement TS prophylaxis in Africa.. To determine whether TS prophylaxis impairs SP efficacy for treatment of uncomplicated falciparum malaria, we conducted a randomized, controlled, open-label study of TS prophylaxis. Two hundred and forty children 5-15 years old were randomized in a 2 : 1 fashion to receive either thrice-weekly TS for 12 weeks or no prophylaxis and were treated with SP for subsequent episodes of malaria. The incidence of malaria, SP efficacy, and the prevalence of parasite mutations that confer antifolate drug resistance were measured.. TS prophylaxis had a 99.5% protective efficacy against episodes of clinical malaria, with 97% efficacy against infection. Four SP treatment failures occurred in the control group, and none occurred in the TS group. No evidence was seen for selection by TS of antifolate resistance-conferring mutations in parasite dihydrofolate reductase or dihydropteroate synthase during subclinical infections.. In this setting of low antifolate resistance, TS was highly effective in preventing falciparum malaria infection and disease and did not appear to select for SP-resistant parasites.

Topics: Adolescent; Animals; Antimalarials; Chemoprevention; Child; Child, Preschool; Drug Resistance; Female; Folic Acid Antagonists; Humans; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Prevalence; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

It has been proposed that polymorphisms of the Merozoite Surface Protein 1 and 2 (MSP1 and MSP2) and the Glutamate Rich Protein (GLURP) genes can be considered as genetic markers for the genotyping of field populations of Plasmodium falciparum. During a field study on in vivo drug resistance against chloroquine, sulphadoxine/pyrimethamine (S/P) and cotrimoxazole in West Uganda, sensitive and resistant isolates were collected from patients by fingerprick for genotyping. 59 (72.8%) of the 81 P. falciparum samples isolated at day 0 showed multiclonal infection with 2-7 clones. Among the isolates we investigated, presence of the allelic family MAD20 of MSP1 at day 0 was significantly (P = 0.0041) associated with decreased resistance to antimalarials. Use of this method in a field study on in vivo drug resistance demonstrates another potential application of genotyping as a tool for epidemiological investigations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antigens, Protozoan; Antimalarials; Child; Child, Preschool; Chloroquine; Drug Combinations; Drug Resistance; Female; Genotype; Humans; Infant; Malaria, Falciparum; Male; Merozoite Surface Protein 1; Middle Aged; Parasitemia; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

Two hundred and fifteen patients with chloroquine-resistant malaria were randomised into three groups. The first group of 82 patients were given pyrimethamine and berberine (berberine group), the second group of 64 patients, pyrimethamine and tetracycline (tetracycline group) and the third group of 69 patients were given pyrimethamine and cotrimoxazole (cotrimoxazole group). In the berberine group, the clearance, rate of asexual parasitaemia was 74.4% after treatment, while in the tetracycline group it was 67.2% and in the cotrimoxazole group 47.8%. These results indicate that berberine is more effective in clearing the parasite than both tetracycline and cotrimoxazole, and that the combination of pyrimethamine and berberine gives the best results for chloroquine resistant malaria.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antimalarials; Berberine; Child; Child, Preschool; Chloroquine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Prospective Studies; Pyrimethamine; Tetracycline; Trimethoprim, Sulfamethoxazole Drug Combination

There is limited evidence on whether malaria elimination is feasible in high-transmission areas of Africa. Between 2007 and 2018, we measured the impact of malaria control interventions in young children enrolled in three clinical trials and two observational studies in Tororo, Uganda, a historically high-transmission area. Data were pooled from children aged 0.5-2 years. Interventions included individually assigned chemoprevention and repeated rounds of indoor residual spraying (IRS) of insecticide. All children received long-lasting insecticidal nets (LLINs) and treatment for symptomatic malaria with artemisinin-based combination therapy. Malaria incidence was measured using passive surveillance and parasite prevalence by microscopy and molecular methods at regular intervals. Poisson's generalized linear mixed-effects models were used to estimate the impact of various control interventions. In total, 939 children were followed over 1,221.7 person years. In the absence of chemoprevention and IRS (reference group), malaria incidence was 4.94 episodes per person year and parasite prevalence 47.3%. Compared with the reference group, implementation of IRS was associated with a 97.6% decrease (95% CI: 93.3-99.1%,

Topics: Antimalarials; Artemisinins; Child, Preschool; Cohort Studies; Communicable Disease Control; Directly Observed Therapy; Female; Housing; Humans; Infant; Insecticides; Malaria, Falciparum; Male; Mosquito Control; Organothiophosphorus Compounds; Quinolines; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

Objective : This study determined the prevalence of asymptomatic Plasmodium (P.) falciparum infection and anemia in adults living with HIV/AIDS (PLHIV) and compared malaria prevalence between 858 HIV-infected (PLHIV) and 272 uninfected individuals in Gabon where such information are lacking. Factors influencing malaria and anemia were also investigated.. Participants were screened for malaria. Available hemoglobin level, socio-demographic and use of prevention or treatment data were compared between both groups.. The prevalence of asymptomatic parasitemia was 13.5%, lower in PLHIV (7.1%) than uninfected individuals (33.8%) (p<0.01). Among the PLHIV, females (p<0.01), those aged below 25 years old (p=0.03), those with primary education (p=0.03) and those with a CD4 cell count below 200/mm3 (p=0.03) had a higher median parasitemia. Cotrimoxazole use was associated with a lower prevalence of malaria (p<0.01). Age below 25 years was independently associated with malaria in PLHIV (p<0.01). Anemia prevalence was 42.1% among the PLHIV, higher in the youngest and those with low CD4 cell count (p<0.01). P.falciparum-infected PLHIV aged below 25 years old, not under ART, with low CD4 cell count and under cotrimoxazole had the lowest median hemoglobin level.. The prevalence of asymptomatic malaria is low among the PLHIV while the burden of anemia is considerable. Age below 25 years and CD4 cell count are associated factors. The cotrimoxazole use reduces the frequency of malaria.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Antimalarials; Asymptomatic Diseases; CD4 Lymphocyte Count; Cross-Sectional Studies; Female; Gabon; HIV Infections; Humans; Malaria, Falciparum; Male; Middle Aged; Prevalence; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

Submicroscopic malaria infections contribute to malaria transmission. Describing the extent of the parasite reservoir is of importance. In people living with human immunodeficiency virus (HIV), the frequency of subpatent malaria infections is rarely reported. The aim of the present study was to determine the frequency of submicroscopic infections in people living with HIV in Gabon and its relationship with cotrimoxazole (CTX) use.. A survey was conducted in two health care centres in rural areas (Koulamoutou and Oyem) and three in urban areas (Libreville) of Gabon from March 2015 to June 2016. Blood samples were collected from consenting people living with HIV with a negative blood smear. Information on CTX and antiretroviral therapy intake was recorded from the medical file of the patient and through an interview. For molecular analysis, the Plasmodium small subunit ribosomal RNA gene was amplified by nested polymerase chain reaction.. Submicroscopic infections were detected in 10.1% (n=12/119) of the people living with HIV, more frequently in those residing in rural areas (15.1%) compared with urban areas (2.1%) (p<0.01). The proportion of anaemic patients was 1.74-fold more frequent in malaria-infected patients, although not statistically significant. Submicroscopic infections frequency did not vary according to CTX intake (p=0.6).. The present pilot study highlights a non-negligible frequency of submicroscopic malaria infections in people living with HIV from rural areas, but no relationship with CTX intake was found.

Topics: Adult; Antimalarials; Carrier State; Female; Gabon; HIV Infections; Humans; Malaria, Falciparum; Male; Middle Aged; Pilot Projects; Plasmodium falciparum; Polymerase Chain Reaction; Prevalence; Trimethoprim, Sulfamethoxazole Drug Combination

Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis in HIV-uninfected, exposed (HUE) children variably reduces clinical malaria burden despite antifolate resistance, but data regarding achieved serum levels and adherence are lacking. Serum samples from 70 HUE children aged 3-12 months from Rakai, Uganda, enrolled in an observational study were assayed for random SMX levels using a colorimetric assay. Adherence with TMP-SMX prophylaxis data (yes/no) was also collected. Of 148 visits with concurrent SMX levels available, 56% had self-reported adherence with TMP-SMX therapy. Among these 82 visits, mean (standard deviation) level was 19.78 (19.22) µg/mL, but 33% had SMX levels below half maximal inhibitory concentrations (IC50) for

Topics: Anti-Retroviral Agents; Antimalarials; Drug Resistance; Female; Folic Acid Antagonists; HIV; HIV Infections; HIV Seroprevalence; Humans; Incidence; Infant; Insecticide-Treated Bednets; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Pre-Exposure Prophylaxis; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

Human immunodeficiency virus (HIV) infection and Plasmodium falciparum malaria are 2 of the gravest health threats in sub-Saharan Africa. Multiple repeat infections with the malaria parasite as seen in endemic areas are necessary to develop specific malaria immunity. HIV is an immunosuppressive virus and in children aged <5 years, development of malaria-specific immunity may be impaired and malaria parasite clearance in theory will be delayed; hence the predisposition to increased incidence of asymptomatic malaria or severe malaria. This cross-sectional study was carried out to examine associations between immunosuppression and asymptomatic malaria parasitemia (ASMP) in HIV-infected children aged <5 years in Benin City.. One hundred seventy-nine asymptomatic HIV-1-positive and 179 age- and sex-matched HIV-1-negative children aged <5 years were recruited. The malaria parasite was determined by Giemsa-stained blood film by certified microscopy while concomitant CD4(+) count was estimated in the HIV-infected children.. The prevalence of ASMP in those who were HIV-infected of 34.1% was significantly higher than 17.3% in the HIV uninfected (P = .001). The prevalence of ASMP was highest (59.3%) among subjects who were severely immunosuppressed (CDC immunologic category 3). The prevalence of ASMP significantly increased with advanced immune disease in the subjects (P = .011). Severe (World Health Organization) clinical staging was also significantly associated with increased prevalence of ASMP (P = .031). The prevalence of ASMP is significantly higher among subjects not receiving cotrimoxazole, associated with threefold risk of having ASMP (P = .003: odds ratio = 3.5).. ASMP is more common in HIV-positive children aged <5 years and is significantly associated with declining CD4(+) T-cell count and severe clinical disease. There is a need for integration of HIV- and malaria-control programs for stronger case management. Malaria-control programs may consider malaria prevention interventions and cotrimoxazole prophylaxis for preschool children who are HIV-infected and living in malaria-endemic regions.

Topics: Antimalarials; Asymptomatic Infections; Chemoprevention; Child, Preschool; Coinfection; Cross-Sectional Studies; Female; HIV Seropositivity; HIV-1; Humans; Immune Tolerance; Immunocompromised Host; Infant; Infant, Newborn; Malaria, Falciparum; Male; Nigeria; Odds Ratio; Parasitemia; Prevalence; Trimethoprim, Sulfamethoxazole Drug Combination

Cotrimoxazole (CTX) prophylaxis, recommended in HIV-exposed uninfected (HEU) children primarily against HIV-related opportunistic infections, has been shown to have some efficacy against Plasmodium falciparum malaria. The effects of CTX prophylaxis on the acquisition of P. falciparum antigen specific CD4(+) T cells-mediated immunity in HEU children is still not fully understood.. Peripheral blood was collected from HEU and HIV-unexposed uninfected (HUU) children at 6, 12 and 18 months of age. Proportion of CD4(+) T cells subsets were determined by immunophenotyping. P. falciparum antigen-specific CD4(+) T cells responses were measured by intracellular cytokine staining assay.. There were no differences in the proportions of naïve, effector and memory CD4(+) T cell subsets between HEU and HUU children at all ages. There was a trend showing acquisition of P. falciparum-specific IFN-γ and TNF-producing CD4(+) T cells with age in both HUU and HEU children. There was, however, lower frequency of P. falciparum-specific IFN-γ-producing CD4(+) T cells in HEU compared to HUU at 6 and 12 months, which normalized 6 months after stopping CTX prophylaxis.. The results demonstrate that there is delayed acquisition of P. falciparum-specific IFN-γ-producing CD4(+) T cells in HEU children on daily cotrimoxazole prophylaxis, which is evident at 6 and 12 months of age in comparison to HUU age-matched controls. However, whether this delayed acquisition of P. falciparum-specific IFN-γ-producing CD4(+) T cells leads to higher risk to malaria disease remains unknown and warrants further investigation.

Topics: Antimalarials; CD4-Positive T-Lymphocytes; Chemoprevention; Cytokines; Female; HIV Infections; Humans; Immunophenotyping; Infant; Malaria, Falciparum; Malawi; Male; Maternal Exposure; Plasmodium falciparum; Pregnancy; Trimethoprim, Sulfamethoxazole Drug Combination

Co-trimoxazole prophylaxis, currently recommended in HIV-exposed, uninfected (HEU) children as protection against opportunistic infections, also has some anti-malarial efficacy. We determined whether daily co-trimoxazole prophylaxis affects the natural development of antibody-mediated immunity to blood-stage Plasmodium falciparum malaria infection.. Using an enzyme-linked immunosorbent assay, we measured antibodies to 8 Plasmodium falciparum antigens (AMA-1, MSP-119, MSP-3, PfSE, EBA-175RII, GLURP R0, GLURP R2 and CSP) in serum samples from 33 HEU children and 31 HIV-unexposed, uninfected (HUU) children, collected at 6, 12 and 18 months of age.. Compared to HIV-uninfected children, HEU children had significantly lower levels of specific IgG against AMA-1 at 6 months (p = 0.001), MSP-119 at 12 months (p = 0.041) and PfSE at 6 months (p = 0.038), 12 months (p = 0.0012) and 18 months (p = 0.0097). No differences in the IgG antibody responses against the rest of the antigens were observed between the two groups at all time points. The breadth of specificity of IgG response was reduced in HEU children compared to HUU children during the follow up period.. Co-trimoxazole prophylaxis seems to reduce IgG antibody responses to P. falciparum blood stage antigens, which could be as a result of a reduction in exposure of those children under this regime. Although antibody responses were regarded as markers of exposure in this study, further studies are required to establish whether these responses are correlated in any way to clinical immunity to malaria.

Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Antibody Formation; Female; HIV Infections; Humans; Immunity, Active; Immunoglobulin G; Infant; Malaria, Falciparum; Malawi; Male; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Antimalarials; Female; HIV Infections; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Antimalarials; Female; HIV Infections; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Antimalarials; Female; HIV Infections; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Trimethoprim, Sulfamethoxazole Drug Combination

 Millions of individuals being treated for human immunodeficiency virus (HIV) live in malaria-endemic areas, but the effects of these treatments on malaria transmission are unknown. While drugs like HIV protease inhibitors (PIs) and trimethoprim-sulfamethoxazole (TMP-SMX) have known activity against parasites during liver or asexual blood stages, their effects on transmission stages require further study..  The HIV PIs lopinavir and saquinavir, the nonnucleoside reverse-transcriptase inhibitor nevirapine, and the antibiotic TMP-SMX were assessed for activity against Plasmodium falciparum transmission stages. The alamarBlue assay was used to determine the effects of drugs on gametocyte viability, and exflagellation was assessed to determine the effects of drugs on gametocyte maturation. The effects of drug on transmission were assessed by calculating the mosquito oocyst count as a marker for infectivity, using standard membrane feeding assays..  Lopinavir and saquinavir have gametocytocidal and transmission blocking activities at or approaching clinically relevant treatment levels, while nevirapine does not. TMP-SMX is not gametocytocidal, but at prophylactic levels it blocks transmission..  Specific HIV treatments have gametocyte killing and transmission-blocking effects. Clinical studies are warranted to evaluate these findings and their potential impact on eradication efforts.

Topics: Animals; Anopheles; Anti-HIV Agents; Antimalarials; Dose-Response Relationship, Drug; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Nevirapine; Plasmodium falciparum; Reverse Transcriptase Inhibitors; Saquinavir; Trimethoprim, Sulfamethoxazole Drug Combination

A prospective cohort design was used to measure the association between daily cotrimoxazole-prophylaxis and infection with Plasmodium falciparum containing mutations associated with antifolate resistance among persons infected with human immunodeficiency virus (HIV) in Tororo and Busia District, in eastern Uganda. Of 149 cases of P. falciparum parasitemia diagnosed, 147 (99%) (smears from participants taking prophylaxis = 91 and smears from those not taking cotrimoxazole prophylaxis = 56) were successfully assessed for mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutations associated with antifolate resistance. Prevalences of the dhfr pure triple mutant (74% and 70%; P = 0.71), the dhps pure double mutant (95% and 88%; P = 0.21), and the dhfr/dhps pure quintuple mutant (73% and 64%; P = 0.36), were not significantly different between those taking and those not taking cotrimoxazole-prophylaxis, respectively. The overall prevalence of the pure quintuple mutant in this study was 69%, which is among the highest in Africa. Although resistance rates of P. falciparum to antifolate drugs are high, cotrimoxazole-prophylaxis in HIV-infected persons was not associated with a higher prevalence of mutations associated with antifolate resistance.

Topics: Adolescent; Adult; Animals; Antimalarials; Child; Child, Preschool; Cohort Studies; Dihydropteroate Synthase; Drug Resistance; Female; Folic Acid; Folic Acid Antagonists; HIV Infections; Humans; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Tetrahydrofolate Dehydrogenase; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda; Young Adult

Daily trimethoprim-sulfamethoxazole (TS) protects against malaria, but efficacy may be diminished as anti-folate resistance increases. This study assessed the incidence of falciparum malaria and the prevalence of resistance-conferring Plasmodium falciparum mutations in HIV-infected children receiving daily TS and HIV-uninfected children not taking TS.. Subjects were 292 HIV-infected and 517 uninfected children from two cohort studies in Kampala, Uganda observed from August 2006 to December 2008. Daily TS was given to HIV-infected, but not HIV-uninfected children and all participants were provided an insecticide-treated bed net. Standardized protocols were used to measure the incidence of malaria and identify markers of antifolate resistance.. Sixty-five episodes of falciparum malaria occurred in HIV-infected and 491 episodes in uninfected children during the observation period. TS was associated with a protective efficacy of 80% (0.10 vs. 0.45 episodes per person year, p < 0.001), and efficacy did not vary over three consecutive 9.5 month periods (81%, 74%, 80% respectively, p = 0.506). The prevalences of dhfr 51I, 108N, and 59R and dhps 437G and 540E mutations were each over 90% among parasites infecting both HIV-infected and uninfected children. Prevalence of the dhfr 164L mutation, which is associated with high-level resistance, was significantly higher in parasites from HIV-infected compared to uninfected children (8% vs. 1%, p = 0.001). Sequencing of the dhfr and dhps genes identified only one additional polymorphism, dhps 581G, in 2 of 30 samples from HIV-infected and 0 of 54 samples from uninfected children.. Despite high prevalence of known anti-folate resistance-mediating mutations, TS prophylaxis was highly effective against malaria, but was associated with presence of dhfr 164L mutation.

Topics: Antimalarials; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Dihydropteroate Synthase; Drug Combinations; Drug Resistance; Female; Folic Acid Antagonists; Follow-Up Studies; HIV Infections; Humans; Incidence; Infant; Insecticide-Treated Bednets; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Genetic; Prevalence; Risk Factors; Tetrahydrofolate Dehydrogenase; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

HIV infection increases the risk of placental malaria, which is associated with poor maternal and infant outcomes. Recommendations in Uganda are for HIV-infected pregnant women to receive daily trimethoprim-sulphamethoxazole (TS) and HIV-uninfected women to receive intermittent sulphadoxine-pyrimethamine (SP). TS decreases the risk of malaria in HIV-infected adults and children but has not been evaluated among pregnant women.. This was a cross sectional study comparing the prevalence of placental malaria between HIV-infected women prescribed TS and HIV-uninfected women prescribed intermittent preventive therapy with sulphadoxine-pyrimethamine (IPT-SP) in a high malaria transmission area in Uganda. Placental blood was evaluated for malaria using smear and PCR.. Placentas were obtained from 150 HIV-infected women on TS and 336 HIV-uninfected women on IPT-SP. The proportion of HIV-infected and HIV-uninfected women with placental malaria was 19% vs. 26% for those positive by PCR and 6% vs. 9% for those positive by smear, respectively. Among all infants, smear+ placental malaria was most predictive of low birth weight (LBW). Primigravidae were at higher risk than multigravidae of having placental malaria among HIV-uninfected, but not HIV-infected, women. Adjusting for gravidity, age, and season at the time of delivery, HIV-infected women on TS were not at increased risk for placental malaria compared to HIV-uninfected women on IPT-SP, regardless of the definition used.. Prevalence of placental malaria was similar in HIV-infected women on TS and HIV-uninfected women on IPT-SP. Nonetheless, while nearly all of the women in this study were prescribed anti-folates, the overall risk of placental malaria and LBW was unacceptably high. The population attributable risk of placental malaria on LBW was substantial, suggesting that future interventions that further diminish the risk of placental malaria may have a considerable impact on the burden of LBW in this population.

Topics: Adult; AIDS-Related Opportunistic Infections; Antimalarials; Cross-Sectional Studies; Drug Combinations; Female; Folic Acid; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Prevalence; Pyrimethamine; Risk Factors; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda; Young Adult

We assessed the effect of daily cotrimoxazole, essential for HIV care, on development of antifolate-resistant Plasmodium falciparum, naso-pharyngeal Streptococcus pneumoniae (pneumococcus), and commensal Escherichia coli. HIV-positive subjects with CD4 cell count < 350 cells/muL (lower-CD4; N = 692) received cotrimoxazole; HIV-positive with CD4 cell count > or = 350 cells/muL (higher-CD4; N = 336) and HIV-negative subjects (N = 132) received multivitamins. Specimens were collected at baseline, 2 weeks, monthly, and at sick visits during 6 months of follow-up to compare changes in resistance, with higher-CD4 as referent. P. falciparum parasitemia incidence density was 16 and 156/100 person-years in lower-CD4 and higher-CD4, respectively (adjusted rate ratio [ARR] = 0.11; 95% confidence interval [CI] = 0.06-0.15; P < 0.001) and 97/100 person-years in HIV-negative subjects (ARR = 0.62; 95% CI = 0.44-0.86; P = 005). Incidence density of triple and quintuple dihydrofolate-reductase/dihydropteroate-synthetase mutations was 90% reduced in lower-CD4 compared with referent. Overall, cotrimoxazole non-susceptibility was high among isolated pneumococcus (92%) and E. coli (76%) and increased significantly in lower-CD4 subjects by Week 2 (P < 0.005). Daily cotrimoxazole prevented malaria and reduced incidence of antifolate-resistant P. falciparum but contributed to increased pneumococcus and commensal Escherichia coli resistance.

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Cohort Studies; Drug Resistance; Escherichia coli; Female; HIV Infections; Humans; Kenya; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Prospective Studies; Streptococcus pneumoniae; Trimethoprim, Sulfamethoxazole Drug Combination

To determine the prevalence of malaria parasitemia and other common illnesses among drug store clients in one rural community, with a view to the potential role of specialist drug stores in expanding coverage of effective malaria treatment to households in highly endemic areas.. Follow-back study of 2466 client visits selected from all 10 drug stores operating in the town of Ikwiriri between May 30 and August 31 2004. Of these, 521 (21.2%) were made by or on behalf of persons ill with fever or malaria. Two hundred and ninety three were eligible as residents of the surrounding nine villages and all agreed to participate in the study. Each patient was evaluated by a clinical officer and provided a blood sample for malaria on the day of the shop visit, either at the shop or at home.. Only 50 (17.1%) visits by or on behalf of febrile patients resulted in the purchase of an antimalarial drug, while an antipyretic medication was obtained at 226 visits (77.1%). Clinicians diagnosed malaria in 63.8% of patients. Malaria parasites were identified in blood film samples from 24.2% (95% CI: 19.6, 29.5). This is double the parasite prevalence rate of 10.7% (95% CI: 8.6, 13.1) obtained from a household survey of 1004 healthy individuals selected from these villages at the same time. It is not significantly lower than the prevalence observed among 880 clients presenting with fever at health facilities in the district: 29.7% (95% CI: 23.0, 37.3). The prevalence of malaria parasitemia among children younger than 5 years whose families sought fever treatment from drug stores (42.1%; 95% CI: 31.4, 53.5) was equal to that of children presenting with fever at health facilities (42.5%; 95% CI: 25.0, 62.2).. Currently, drug store clients do not obtain malaria-specific treatment in the majority of cases where it might be warranted. Parasitological findings indicate that drug store clients, especially children, are as likely to be infected with malaria as patients seeking care for similar illnesses at health facilities. Drug stores may be attractive partners for policy makers eager to engage the private retail sector in expanding coverage of malaria treatment.

Topics: Adult; Amodiaquine; Analgesics, Non-Narcotic; Anemia; Antimalarials; Child, Preschool; Drug Combinations; Endemic Diseases; Female; Fever; Humans; Malaria, Falciparum; Male; Parasitemia; Patient Acceptance of Health Care; Pharmacies; Prevalence; Pyrimethamine; Rural Health; Sulfadoxine; Tanzania; Trimethoprim, Sulfamethoxazole Drug Combination

In many African countries, trimethoprim-sulfamethoxazole (TS) is recommended for the treatment of children with malaria and pneumonia - in accordance with the guidelines for the integrated management of childhood illness (IMCI) - and, in some settings, for the home management of febrile illnesses. There have been few studies, however, of the risk of failure of treatment with this drug combination in children with acute, Plasmodium falciparum malaria. The factors that identify children at risk of treatment failure after being given TS were therefore evaluated in 101 children with acute, symptomatic, uncomplicated, P. falciparum malaria, in a hyper-endemic area of south-western Nigeria. Overall, 11% of the children failed treatment by day 14. In a multivariate analysis, two factors were found to be independent predictors of the failure of treatment with TS: an age of <3 years (adjusted odds ratio=0.1; 95% confidence interval=0.02-0.53; P=0.007); and a body temperature of >or=38 degrees C 2 days after the commencement of treatment (adjusted odds ratio=4.9; 95% confidence interval=1.2-21.3; P=0.03). These findings may have implications for control efforts in some sub-Saharan African countries, where TS is recommended for the management of malaria in children, with or without pneumonia.

Topics: Antimalarials; Child; Child, Preschool; Endemic Diseases; Female; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Risk Factors; Treatment Failure; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Africa South of the Sahara; Antimalarials; Chemoprevention; Disease Outbreaks; Drug Combinations; Female; HIV Infections; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Prevalence; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: HIV Infections; Humans; Malaria, Falciparum; Pyrimethamine; Sulfadoxine; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination

The purpose of this prospective cohort study was to assess the effect of cotrimoxazole prophylaxis taken by human immunodeficiency virus (HIV)-infected persons on the selection of sulfadoxine-pyrimethamine (SP)-resistant malaria parasites among HIV-uninfected household members. A total of 2,567 HIV-uninfected persons from 605 households were followed and blood specimens were collected each time an episode of Plasmodium falciparum malaria was diagnosed. Study participants were living in households where HIV-infected persons were either taking (exposed) or not taking (unexposed) cotrimoxazole prophylaxis. From all malaria episodes diagnosed, 50% of the specimens were randomly selected and tested for the presence of five key mutations known to mediate resistance to SP (dihydrofolate reductase [dhfr] Asn-108, Ile-51, and Arg-59, and dihydropteroate synthase [dhps] Gly-437 and Glu-540). Plasmodium falciparum isolates were recovered from 163 specimens in the exposed households and 113 specimens in the unexposed households, with similar proportions containing the dhfr triple mutant (37% versus 45%; P = 0.18), the dhps double mutant (64% versus 62%; P = 0.81), and the dhfr/dhps quintuple mutant (30% versus 32%; P = 0.74). The HIV-uninfected persons living with HIV-infected household members taking cotrimoxazole prophylaxis had a lower incidence of malaria (incidence rate ratio [IRR] = 0.64, 95% confidence interval [CI] = 0.50-0.83, P = 0.001) and fewer malaria episodes due to parasites containing the dhfr/dhps quintuple mutant (IRR = 0.61, 95% CI = 0.41-0.91, P = 0.014). Cotrimoxazole prophylaxis taken by HIV-infected persons did not select for SP-resistant malaria parasites among HIV-uninfected household members, and was associated with a lower overall incidence of SP-resistant malaria among household members.

Topics: Animals; Antimalarials; Cohort Studies; Drug Combinations; Drug Resistance; Family; HIV Infections; Humans; Malaria, Falciparum; Mutation; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

Antimalarial drugs including the antifolate, pyrimethamine-sulfadoxine (PS), can modulate the prevalence and intensities of gametocytaemia following treatment of acute malaria infections. They may also directly influence the transmission and spread of drug insensitivity. Little is known of the effects of co-trimoxazole (Co-T), another antifolate antimalarial, on gametocytes in children with acute malaria infections. We compared the effects of Co-T and PS on the prevalence and intensities of gametocytaemia and gametocyte sex ratios in 102 children aged 0.5-12 years presenting with acute and uncomplicated falciparum malaria. Compared to pre-treatment, both drugs significantly increased gametocyte carriage post-initiation of treatment. However, gametocyte carriage was significantly lower on day 14 in those treated with Co-T than PS. Significant increase in gametocytaemia with time occurred in PS--but not Co-T-treated children. Kaplan-Meier survival curve of the cumulative probability of remaining gametocyte-free in children who were agametocytaemic at enrollment showed that by day 7 of follow up, children treated with PS had a significantly higher propensity to have developed gametocytes than in Co-T-treated children (Log-rank statistic 5.35, df = 1, P = 0.02). Gametocyte sex ratio changes were similar following treatment with both drugs. PS and Co-T treatment of acute malaria infections in children from this endemic area is associated with significant increases in prevalence and intensities of gametocytaemia but these effects are more marked in those treated with PS than Co-T.

Topics: Acute Disease; Animals; Antimalarials; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Female; Folic Acid Antagonists; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Pyrimethamine; Sex Ratio; Sulfadoxine; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

The antifolate drugs sulphadoxine and pyrimethamine are used for treatment of chloroquine-resistant Plasmodium falciparum in Africa. Resistance to pyrimethamine has been associated with point mutations in the dhfr-gene and resistance to sulphadoxine with mutations in the dhps-gene. There is concern that the use of the antifolates trimethoprim and sulphamethoxazole for treatment of other infectious diseases will result in the selection of malaria parasites with mutations in these genes. In Guinea-Bissau, where sulfonamide and trimethoprim-containing drugs have been used extensively, we decided to assess the prevalence of mutations in the dhfr-and dhps-gene in P. falciparum isolated from children suffering from acute malaria and to assess the resistance patterns to trimethoprim/sulphamethoxazole in Escherichia coli isolated from the same patients. A thick film and a blood sample for polymerase chain reaction (PCR) were obtained from 100 children attending the Bandim Health Centre in Bissau with symptoms compatible with malaria. Furthermore, a stool sample was collected from the same children and cultured for E. coli. Of the cultured E. coli, 67% were resistant both to sulfonamides and trimethoprim, 4% to sulfonamides alone, 3% to trimethoprim alone while 26% were fully sensitive to both drugs. PCR was successfully performed in 97 blood samples. Of these, 41% had triple mutations at the dhfr-gene (at codons 51, 59 and 108), and 15% had triple mutations plus mutation at codon 437 in the dhps-gene. Only 45% harboured the wild-type dhfr-gene. Thus both bacterial resistance and mutations in the parasitic genes were common, but not linked in the individual child. As sulphadoxine-pyrimethamine has only been used as a second line treatment for chloroquine resistant malaria in Guinea-Bissau for a few years, it is worrying to find a high prevalence of mutations in the parasitic genes coding for resistance to these drugs. Therefore, restricting the use of sulphadoxine-pyrimethamine for the treatment of chloroquine resistant malaria might not be sufficient to prevent the development of resistance in the parasites as long as antifolate drugs are used extensively.

Topics: Adolescent; Animals; Antimalarials; Child; Child, Preschool; Drug Combinations; Drug Resistance; Escherichia coli; Escherichia coli Infections; Female; Genetic Markers; Guinea-Bissau; Humans; Infant; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Africa South of the Sahara; AIDS-Related Opportunistic Infections; Anti-Infective Agents; Child; Drug Resistance, Microbial; Humans; Malaria, Falciparum; Trimethoprim, Sulfamethoxazole Drug Combination

The clinical characteristics and the responses to oral antimalarial therapy of 104 children presenting consecutively with or without Plasmodium falciparum hyperparasitaemia (HP) were investigated in an endemic area. At presentation, although the 52 children with HP were significantly younger and had significantly higher heart rates than the 52 without, there were no significant differences between the two groups in their symptoms or in any other clinical feature of their malaria. Responses to oral antimalarial drugs were similar in both groups. Analysis of the disposition kinetics of parasitaemia, using a non-compartmental model similar to that used in characterizing drug disposition, showed that the two groups had similar half-lives of parasitaemia (t1/2pd), volumes of blood completely cleared of parasites per unit time (CLBpd), and parasite-clearance-time:t1/2pd ratios. Three children in the HP group, all aged < 3 years, progressed to cerebral malaria within 8 h of presentation, and another HP child presented with isolated trunkal ataxia, indicative of cerebellar involvement. No child in the non-HP group had any of the features of severe malaria. Although the clinical characteristics and responses to oral therapy of children with and without HP are therefore very similar, young children with HP appear to have an increased risk of developing other features of severe malaria.

Topics: Adolescent; Age Factors; Analysis of Variance; Antimalarials; Child; Child, Preschool; Chloroquine; Drug Therapy, Combination; Endemic Diseases; Female; Heart Rate; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasitemia; Prospective Studies; Pyrimethamine; Sulfadoxine; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

In vivo testing for resistance of Plasmodium falciparum to co-trimoxazole (trimethoprim/sulfamethoxazole) was performed in Uganda in 41 children with uncomplicated malaria, and blood samples were screened before and after treatment for polymorphisms in the antifolate target genes for dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). Selection towards a specific genotype at some codons of the DHFR and DHPS genes was observed in samples collected after exposure to co-trimoxazole drug pressure. The alleles 51-isoleucine, 59-arginine, and 108-serine of DHFR were significantly associated with clinical resistance, as was allele 581-alanine of DHPS. Resistance against antifolate combinations probably requires resistance-related polymorphisms in both the DHFR and the DHPS genes. In addition, it appears that the trimethoprim-resistant DHFR genotype differs from that for pyrimethamine at residue 108.

Topics: Alleles; Animals; Antimalarials; Blood; Child, Preschool; Dihydropteroate Synthase; DNA Primers; DNA Restriction Enzymes; DNA, Protozoan; Drug Resistance; Electrophoresis, Agar Gel; Female; Genetic Variation; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Tetrahydrofolate Dehydrogenase; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

Topics: Antimalarials; Drug Costs; Drug Resistance; Humans; Madagascar; Malaria, Falciparum; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Diagnosis, Differential; Humans; Malaria, Falciparum; Male; Melioidosis; Otitis Media, Suppurative; Trimethoprim, Sulfamethoxazole Drug Combination