trimethoprim--sulfamethoxazole-drug-combination and fanasil--pyrimethamine-drug-combination

The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine.. To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:• the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and• the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine.. We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials.. Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen.. Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting.. Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I. Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women.

Topics: Abortion, Spontaneous; Africa South of the Sahara; Antimalarials; Dizziness; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant, Low Birth Weight; Insecticide-Treated Bednets; Malaria; Mefloquine; Parasitemia; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Randomized Controlled Trials as Topic; Sulfadoxine; Thailand; Trimethoprim, Sulfamethoxazole Drug Combination; Vomiting

The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine.. To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:• the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and• the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine.. We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials.. Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen.. Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting.. Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I. Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women.

Topics: Anemia; Antimalarials; Drug Combinations; Drug Therapy, Combination; Female; HIV Seronegativity; Humans; Malaria; Mefloquine; Parasitemia; Placenta Diseases; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pyrimethamine; Randomized Controlled Trials as Topic; Stillbirth; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Vomiting

Cotrimoxazole prophylactic treatment (CPT) prevents opportunistic infections in HIV-infected or HIV-exposed children, but estimates of the effectiveness in preventing malaria vary. We reviewed studies that examined the effect of CPT on incidence of malaria in children in sub-Saharan Africa.. We searched PubMed and EMBASE for randomised controlled trials (RCTs) and cohort studies on the effect of CPT on incidence of malaria and mortality in children and extracted data on the prevalence of sulphadoxine-pyrimethamine resistance-conferring point mutations. Incidence rate ratios (IRR) from individual studies were combined using random effects meta-analysis; confounder-adjusted estimates were used for cohort studies. The importance of resistance was examined in meta-regression analyses.. Three RCTs and four cohort studies with 5039 children (1692 HIV-exposed; 2800 HIV-uninfected; 1486 HIV-infected) were included. Children on CPT were less likely to develop clinical malaria episodes than those without prophylaxis (combined IRR 0.37, 95% confidence interval: 0.21-0.66), but there was substantial between-study heterogeneity (I-squared = 94%, P < 0.001). The protective efficacy of CPT was highest in an RCT from Mali, where the prevalence of antifolate resistant plasmodia was low. In meta-regression analyses, there was some evidence that the efficacy of CPT declined with increasing levels of resistance. Mortality was reduced with CPT in an RCT from Zambia, but not in a cohort study from Côte d'Ivoire.. Cotrimoxazole prophylactic treatment reduces incidence of malaria and mortality in children in sub-Saharan Africa, but study designs, settings and results were heterogeneous. CPT appears to be beneficial for HIV-infected and HIV-exposed as well as HIV-uninfected children.

Topics: Africa South of the Sahara; Antimalarials; Child; Drug Combinations; Drug Resistance; HIV Infections; Humans; Malaria; Mutation; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acquired Immunodeficiency Syndrome; Aerosols; Animals; Cryptococcosis; Cytomegalovirus Infections; Dapsone; Drug Combinations; Humans; Mycobacterium avium-intracellulare Infection; Opportunistic Infections; Pentamidine; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadoxine; Toxoplasma; Toxoplasmosis; Trimethoprim, Sulfamethoxazole Drug Combination

Although Pneumocystis carinii pneumonia (PCP) can occur in any patient with severe impairment of immunity, there has been a sharp rise in incidence with the spread of human immunodeficiency virus through the USA and Western Europe, where nearly 80% of patients with HIV infection have at least one episode of PCP during their lifetime (Murray et al, 1984).

Topics: Antimalarials; CD4-Positive T-Lymphocytes; Clinical Protocols; Dapsone; Drug Combinations; HIV Infections; HIV-1; Humans; Pentamidine; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acquired Immunodeficiency Syndrome; Cryptococcosis; Cytomegalovirus Infections; Dapsone; Drug Combinations; Humans; Opportunistic Infections; Pentamidine; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadoxine; Toxoplasmosis; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acquired Immunodeficiency Syndrome; Aerosols; Dapsone; Drug Combinations; Humans; Pentamidine; Pneumonia, Pneumocystis; Pyrimethamine; Recurrence; Sulfadoxine; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The main objective of the MACOMBA (Maternity and Control of Malaria-HIV co-infection in Bangui) trial was to show that cotrimoxazole (CTX) is more effective than sulphadoxine-pyremethamine-IPTp (IPTp-SP) to prevent placental malaria infection (primary end point) among HIV-positive pregnant women with a CD4+ count ≥350 cells/mm. MACOMBA is a multicentre, open-label randomised trial conducted in four maternity hospitals in Bangui. Between 2013 and 2017, 193 women were randomised and 112 (59 and 53 in CTX and IPTp-SP arms, respectively) were assessed for placental infection defined by microscopic parasitaemia or PCR.. Thirteen women had a placental infection: five in the CTX arm (one by microscopic placental parasitaemia and four by PCR) and eight by PCR in the SP-IPTp (8.5% vs. 15.1%, p = 0.28). The percentage of newborns with low birthweight (<2500 g) did not differ statistically between the two arms. Self-reported compliance to CTX prophylaxis was good. There was a low overall rate of adverse events in both arms.. Although our results do not allow us to conclude that CTX is more effective, drug safety and good compliance among women with this treatment favour its widespread use among HIV-infected pregnant women, as currently recommended by WHO.

Topics: Adult; Antimalarials; Central African Republic; Drug Combinations; Female; HIV Infections; Humans; Malaria; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

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

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

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

Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children.. This study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered at home without supervision. Piperaquine (PQ) levels were used as a measure of compliance in the DP arm. Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were ill. Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year. Primary outcome was the incidence of malaria during the intervention period. During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk. Protective efficacy was 58% (95% CI, 45%-67%, p<0.001) for DP, 28% (95% CI, 7%-44%, p = 0.01) for TS, and 7% for SP (95% CI, -19% to 28%, p = 0.57). PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence. There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped.. For preventing malaria in children living in an area of high transmission intensity, monthly DP was the most efficacious and safe, although adherence may pose a problem. Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates.. www.ClinicalTrials.gov NCT00948896 Please see later in the article for the Editors' Summary.

Topics: Antimalarials; Artemisinins; Cohort Studies; Drug Combinations; Female; Humans; Incidence; Infant; Malaria; Male; Pyrimethamine; Quinolines; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

Trimethoprim-sulfamethoxazole prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children.. An open-label, randomized controlled trial.. Tororo, Uganda, a rural area with intense, year-round, malaria transmission.. Two hundred infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age).. No chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole or monthly dihydroartemisinin-piperaquine given from randomization to 24 months of age.. The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrhoeal illness, or respiratory tract infection; prevalence of anaemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped.. During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% [95% confidence interval (95% CI) 53-80, P < 0.001] for dihydroartemisinin-piperaquine, 49% (95% CI 23-66, P = 0.001) for trimethoprim-sulfamethoxazole and 9% for sulfadoxine-pyrimethamine (95% CI -35 to 38, P = 0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the dihydroartemisinin-piperaquine arm.. Monthly chemoprevention with dihydroartemisinin-piperaquine was well tolerated and associated with a significant reduction in malaria in young HIV-exposed children.

Topics: Antimalarials; Artemisinins; Chemoprevention; Child, Preschool; Cohort Studies; Drug Combinations; Female; Humans; Infant; Malaria; Male; Pyrimethamine; Quinolines; Sulfadoxine; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

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

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

In Malawi, trimethoprim-sulfamethoxazole (TS) is the recommended first-line treatment for children with Integrated Management of Childhood Illness dual classifications of malaria and pneumonia, and sulfadoxine-pyrimethyamine (SP) plus five days of treatment with erythromycin (SP plus E) is the recommended second-line treatment. Using a 14-day, modified World Health Organization protocol, children with dual IMCI classifications of malaria and pneumonia with Plasmodium falciparum parasitemia were randomized to receive TS or SP plus E. Clinical and parasitologic responses and gametocytemia prevalence were obtained. A total of 87.2% of children receiving TS and 80.0% receiving SP plus E reached adequate clinical and parasitologic responses (ACPRs) (P = 0.19). Severely malnourished children were less likely to achieve ACPRs than those better nourished (relative risk = 3.34, P = 0.03). Day 7 gametocyte prevalence was 55% and 64% among children receiving TS and SP plus E, respectively (P = 0.19). Thus, TS and SP plus E remain efficacious treatment of P. falciparum malaria in this setting. However, patient adherence and effectiveness of five days of treatment with TS is unknown.

Topics: Anti-Infective Agents; Child, Preschool; Drug Combinations; Erythromycin; Humans; Infant; Malaria; Malawi; Nutritional Status; Pneumonia, Bacterial; Pyrimethamine; Risk Factors; Sulfadoxine; Treatment Failure; 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

We conducted a prospective, randomized clinical trial among liver transplant patients to assess the efficacy and safety of weekly sulfadoxine/pyrimethamine compared with daily trimethoprim-sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia. The studied drugs were given during 6 months after transplantation. One hundred twenty patients were included. None of the 60 patients receiving weekly sulfadoxine/pyrimethamine developed Pneumocystis carinii pneumonia, whereas two cases (3%) developed among the 60 patients who received trimethoprim-sulfamethoxazole. For both patients, the studied medication had been discontinued several weeks earlier because of adverse effects. No differences were observed in the incidence of adverse effects. We conclude that weekly sulfadoxine/pyrimethamine is as effective and safe as is daily trimethoprim-sulfamethoxazole in the prophylaxis of Pneumocystis carinii pneumonia after liver transplantation.

Topics: Adult; Aged; Anti-Infective Agents; Drug Combinations; Female; Humans; Liver Transplantation; Male; Middle Aged; Pneumonia, Pneumocystis; Prospective Studies; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

In this work we presented our own experience with recognized and treated toxoplasmosis among children. Treated cases were observed over several years afterwards. We analyzed the frequency and character of clinical changes, evaluated the validity of serological screening and the effectiveness of treatment. The largest age group treated were children 13 months to 5 years old. 13 children had the congenital and 12 the acquired form. The most cases occurred in the nodal, ocular and ocular-cranial forms. Thus, the most common symptoms were enlarged lymphatic nodes, strabismus, febrile seizures, intracranial calcifications. In the acquired forms of the illness a distinct correlation between treatment and the decrease antibody levels, the clinical pictures showed stagnation. The fall in antibody levels occurred earlier with intermediate immunofluorescence than with ELISA method. Among 20 children associated 30-day treatment was implemented (Daraprim, Rovamycine, Biseptol), among 4 with Fansidar and Rovamycine for 2-3 weeks. Few complications occurred at the end of or after treatment and did not require treatment/intervention. Usually it was leukopenia and thrombocytopenia. Long time observation allows to state that both therapeutic models prevent renewal of illness and can be recommended for further use.

Topics: Adolescent; Anti-Infective Agents; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Follow-Up Studies; Humans; Infant; Infant, Newborn; Mass Screening; Pyrimethamine; Serologic Tests; Spiramycin; Sulfadoxine; Toxoplasmosis; Toxoplasmosis, Congenital; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acquired Immunodeficiency Syndrome; Aerosols; Animals; Cryptococcosis; Cytomegalovirus Infections; Dapsone; Drug Combinations; Humans; Mycobacterium avium-intracellulare Infection; Opportunistic Infections; Pentamidine; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadoxine; Toxoplasma; Toxoplasmosis; Trimethoprim, Sulfamethoxazole Drug Combination

Malaria is a leading cause of morbidity and mortality among HIV-infected pregnant women in sub-Saharan Africa: at least 1 million pregnancies among HIV-infected women are complicated by co-infection with malaria annually, leading to increased risk of premature delivery, severe anaemia, delivery of low birth weight infants, and maternal death. Current guidelines recommend either daily cotrimoxazole (CTX) or intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for HIV-infected pregnant women to prevent malaria and its complications. The cost-effectiveness of CTX compared to IPTp-SP among HIV-infected pregnant women was assessed.. A microsimulation model of malaria and HIV among pregnant women in five malaria-endemic countries in sub-Saharan Africa was constructed. Four strategies were compared: (1) 2-dose IPTp-SP at current IPTp-SP coverage of the country ("2-IPT Low"); (2) 3-dose IPTp-SP at current coverage ("3-IPT Low"); (3) 3-dose IPTp-SP at the same coverage as antiretroviral therapy (ART) in the country ("3-IPT High"); and (4) daily CTX at ART coverage. Outcomes measured include maternal malaria, anaemia, low birth weight (LBW), and disability-adjusted life years (DALYs). Sensitivity analyses assessed the effect of adherence to CTX.. Compared with the 2-IPT Low Strategy, women receiving CTX had 22.5% fewer LBW infants (95% CI 22.3-22.7), 13.5% fewer anaemia cases (95% CI 13.4-13.5), and 13.6% fewer maternal malaria cases (95% CI 13.6-13.7). In all simulated countries, CTX was the preferred strategy, with incremental cost-effectiveness ratios ranging from cost-saving to $3.9 per DALY averted from a societal perspective. CTX was less effective than the 3-IPT High Strategy when more than 18% of women stopped taking CTX during the pregnancy.. In malarious regions of sub-Saharan Africa, daily CTX for HIV-infected pregnant women regardless of CD4 cell count is cost-effective compared with 3-dose IPTp-SP as long as more than 82% of women adhere to daily dosing.

Topics: Africa South of the Sahara; Antimalarials; Coinfection; Cost-Benefit Analysis; Drug Combinations; Female; HIV Infections; Humans; Malaria; Models, Theoretical; Pregnancy; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

Substandard and falsified anti-malarial medicines pose a serious threat to public health, especially in low-income countries. Appropriate technologies for drug quality analysis in resource-limited settings are important for the surveillance of the formal and informal drug market. The feasibility of thin-layer chromatography (TLC) with different solvent systems was tested using the GPHF Minilab in a study of the quality of sulfadoxine/pyrimethamine tablets in Malawi.. Twenty eight samples of sulfadoxine/pyrimethamine tablets were collected from randomly selected health facilities of four districts of southern Malawi. A mystery shopper approach was used when collecting samples from illegal street vendors, and an overt approach for the other facilities. Samples were subjected to visual inspection, disintegration testing and TLC analysis. 10 samples were further investigated according to the methods of the US Pharmacopeia using high performance liquid chromatography (HPLC).. One sample was found to be falsified, containing a mixture of paracetamol tablets and co-trimoxazole tablets. These had been repackaged into paper strip packs labelled as a brand of sulfadoxine/pyrimethamine. TLC with different solvent systems readily proved that these tablets did not comply with their declaration, and provided strong evidence for the active pharmaceutical ingredients which were actually contained. Full pharmacopeial analysis by HPLC confirmed the results suggested by TLC for this sample, and showed two further samples to be of substandard quality.. Due to the absence of the declared anti-malarial ingredients and due to the presence of other pharmaceutical ingredients, the identified falsified medicine represents a serious health risk for the population. Thin-layer chromatography (TLC) using different solvent systems proved to be a powerful method for the identification of this type of counterfeiting, presenting a simple and affordable technology for use in resource-limited settings.

Topics: Acetaminophen; Antimalarials; Chromatography, Thin Layer; Counterfeit Drugs; Drug Combinations; Feasibility Studies; Malawi; Pyrimethamine; Quality Control; Sulfadoxine; Tablets; Technology, Pharmaceutical; Trimethoprim, Sulfamethoxazole Drug Combination

As the incidence of HIV infection has increased its neurological complications are being encountered in our clinical practice. Toxoplasmosis is a common cerebral opportunistic infection seen in HIV-infected patients, even though the incidence has declined with the use of antiretroviral therapy. Establishing a definitive diagnosis of cerebral toxoplasmosis is difficult in resource limited settings.. A 20 year old gentleman was referred to our institute as a case of stroke. Magnetic resonance imaging (MRI) of his brain showed multiple ill-defined and nodular enhancing lesions in bilateral supratentorial and infratentorial neuroparenchyma. Test for HIV-1 was reactive. Toxoplasma serology revealed raised IgG antibody levels. Based on the MRI features and positive toxoplasma serology a diagnosis of cerebral toxoplasmosis was made. He was treated with trimethoprim/sulfamethoxazole and pyrimethamine/ Sulfadoxine for 3 weeks. After 2 weeks of treatment, repeat MRI of brain was done which showed significant resolution of the lesions.. We are presenting this case to highlight the fact that cerebral toxoplasmosis should be considered in the differential diagnosis of multiple neuroparenchymal lesions in young individuals who present with neurological deficits.

Topics: AIDS-Related Opportunistic Infections; Antibodies, Protozoan; Brain; Drug Combinations; Humans; Immunoglobulin G; Magnetic Resonance Imaging; Male; Pyrimethamine; Serologic Tests; Stroke; Sulfadoxine; Toxoplasma; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

The Cryptococcus neoformans species complex contains the most important agents of fungal meningoencephalitis. Therapeutic choices are limited and issues related to toxicity and resistance to antifungals have been described. The present study evaluated the inhibitory effect of the antifolate combinations sulfamethoxazole-trimethoprim (SMX/TMP) and sulfadiazine-pyrimethamine (SDZ/PYR) against planktonic cells and biofilms of C. neoformans and C. gattii. The influence of the antifolate combinations on the amphotericin minimum inhibitory concentration (MIC) of planktonic cells was also investigated. In addition, the effect of these combinations on the cellular ergosterol content of planktonic cells was studied. Strains of C. neoformans (n = 15) and C. gattii (n = 15) obtained from environmental or clinical sources were evaluated by the broth microdilution method. SMX/TMP and SDZ/PYR showed antifungal activity against free living cells and sessile cells of Cryptococcus spp. Moreover, planktonic cells showed increased susceptibility to amphotericin B after pre-incubation with sub-inhibitory concentrations of SMX/TMP or SDZ/PYR. The drug combinations SMX/TMP and SDZ/PYR were able to prevent the biofilm formation and showed inhibitory effect against mature biofilms of both species. Additionally, the study showed that antifolate drugs reduced the ergosterol content in C. neoformans and C. gattii planktonic cells. Our results highlight the antifungal potential of antifolate drugs.

Topics: Amphotericin B; Antifungal Agents; Biofilms; Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Drug Combinations; Environmental Microbiology; Folic Acid Antagonists; Humans; Microbial Sensitivity Tests; Pyrimethamine; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination

Effectiveness of cotrimoxazole (CTX) compared with sulfadoxine-pyrimethamine (SP) intermittent-preventive-therapy (IPTp) for malaria in HIV-infected pregnant women is unknown. We examined effectiveness of CTX with or without SP-IPTp versus SP-IPTp at reducing malaria parasitemia and anemia.. From 2005 to 2009, we conducted a cross-sectional study of HIV-infected pregnant women at Thyolo Hospital, Malawi. Blood was tested for malaria parasitemia and anemia (hemoglobin<11 g/dl). Data were collected on use of anti-malaria interventions and other risk factors. CTX prophylaxis policy for HIV-infected pregnant women was introduced in 2007, but implementation problems resulted in some women receiving both CTX and SP-IPTp.. We enrolled 1,142 women, of whom 1,121 had data on CTX and/or SP-IPTp intake. Of these, 49.7%, 29.8%, and 15.4% reported taking SP-IPTp only, CTX only and SP-IPTp plus CTX, respectively. Compared with women taking SP-IPTp, those taking SP-IPTp plus CTX and CTX were less likely to have malaria parasitemia (OR, [95%CI]: 0.09, [0.01-0.66] and 0.43, [0.19-0.97], respectively) or anemia (PR, [95% CI]: 0.67, [0.54-0.83] and 0.72, [0.61-0.83], respectively).. In HIV-infected pregnant women, daily CTX was associated with reduced malaria parasitemia and anemia compared with SP-IPTp. CTX plus SP-IPTp was associated with further reduction in malaria parasitemia but toxicity was not fully assessed.

Topics: Adolescent; Adult; Anemia; Antimalarials; Chemoprevention; Cross-Sectional Studies; Drug Combinations; Female; HIV Infections; Humans; Malaria; Malawi; Middle Aged; Parasitemia; Pregnancy; Pregnancy Complications, Infectious; Prevalence; Pyrimethamine; Sulfadoxine; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

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

A retrospective study of the presentation, etiology, and prognosis of non-burn epidermal loss managed at the Lagos University Teaching Hospital Nigeria over a 12-year period.. Admission records of patients managed for non-burn skin loss were retrieved from the medical records. Demographic details of the patients, the initial diagnosis, final diagnosis, treatment and outcome of treatment was noted.. A total of 23 patients were identified, 17 (74%) had idiosyncratic drug reactions. Of this 17, 6 (26%) had Steven Johnson Syndrome, 6 (26%) had Steven Johnson Syndrome/toxic epidermal necrolysis while 5 (22%) presented with toxic epidermal necrolysis. Three of the five patients with toxic epidermal necrolysis died. The age range of patients with idiosyncratic adverse drug reactions was 2-28 years, mean, 10.18+/-1.44 years and male to female ratio of 1:1.83. The body surface area involved ranged from 8 to 78%; mean 26.65+/-6.08%. The agents suspected for the reactions were Co-trimoxazole (41.2%) and combination of Co-trimoxazole, and Fansidar (17.6%). Other conditions seen were two (9%) Staphylococcal Scalded Skin Syndrome, three (13%) had Necrotizing Faciitis, one of whom was HIV positive and died. One (4%) patient presented with pemphigus vulgaris. The presentation and management of the patients was discussed.

Topics: Adolescent; Adult; Anti-Infective Agents; Bandages; Burn Units; Child; Child, Preschool; Developing Countries; Drug Combinations; Female; Humans; Male; Nigeria; Prognosis; Pyrimethamine; Retrospective Studies; Staphylococcal Scalded Skin Syndrome; Stevens-Johnson Syndrome; Sulfadoxine; 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

We estimated the frequency of clinically diagnosed Stevens-Johnson syndrome and toxic epidermal necrolysis associated with sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (CTX) in Blantyre District, Malawi. Cases were detected by passive surveillance at 22 health centers from March 2001 through September 2002. Denominators were estimated from the Malawi national census for Blantyre District and the frequency of SP and CTX use reported in five household surveys. Crude rates of adverse reactions were estimated to be 1.2 per 100,000 exposures for SP and 1.5 per 100,000 exposures for CTX. Rates were higher in adults (1.7 cases per 100,000 SP exposures and 2.6 cases per 100,000 CTX exposures) and in persons positive for human immunodeficiency virus (4.9 cases per 100,000 SP exposures and 8.4 cases per 100,000 CTX exposures). Infrequent treatment doses with SP are associated with a low risk of an adverse cutaneous reaction, and SP can be recommended for treatment of malaria in areas where P. falciparum is susceptible.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Antimalarials; Child; Child, Preschool; Drug Combinations; Drug Eruptions; Female; Humans; Infant; Infant, Newborn; Malaria; Malawi; Male; Middle Aged; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Severity of Illness Index; Sulfadoxine; 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

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

Highly active antiretroviral therapy (HAART) has resulted in a reduction of morbidity and mortality in HIV-associated cerebral opportunistic infection. Before HAART, up to 50% of all HIV-infected patients in Europe developed cerebral toxoplasmosis, an encephalitis caused by reactivation of Toxoplasma gondii infection. Although potent therapeutical options exist, the prognosis is still poor. We describe the course of 36 AIDS patients with cerebral toxoplasmosis and present a review of clinical signs, diagnosis, therapy, and survival times. The main criteria for differential diagnosis from other secondary neuromanifestations such as primary CNS lymphoma, progressive multifocal leukencephalopathy, abscesses, and ischemic infarctions are described. Indications and problems of stereotactic biopsy are discussed.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Brain; Dapsone; Diagnosis, Differential; Diagnostic Imaging; Drug Combinations; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyrimethamine; Retrospective Studies; Sulfadoxine; Survival Rate; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination

An attempt was made to estimate the risk of severe cutaneous adverse reactions (SCARs) to Fansidar (sulfadoxine plus pyrimethamine). Cases were identified through a spontaneous reporting system. Persons exposed were estimated using sales data of 27 countries reporting one SCAR case for either Fansidar or a related product, Bactrim (cotrimoxazole; sulfamethoxazole plus trimethoprim). Between 1974 and 1989, 126 cases were notified for Fansidar: 87 cases of erythema multiforme or Stevens-Johnson syndrome, and 39 cases of toxic epidermic necrolysis. 86% of cases were reported in Europe or North America. In 116 cases with use known, prophylaxis was the reason in 103, and treatment in 13. Toxic epidermolysis and erythema multiforme/Stevens-Johnson syndrome had case fatalities of 36 (95% confidence intervals 21 to 53%) and 9% (4 to 18%), respectively. Fansidar users were estimated at 117 million, and the overall SCAR risk to be 1.1 (0.9 to 1.3) per million. For developing countries with mainly single dose use, the risk was estimated to 0.1 (0.0 to 0.1) per million. For Europe and North America with mainly prophylactic use, the risk was 10 (8 to 12) and 36 (23 to 48) per million, respectively. Prophylactic use had a 40 times higher risk than single dose therapeutic use. The aggregated risk peaked in 1984-1985, with global and North American SCAR frequencies of 3.4 (2.4 to 4.3) and 72 (41 to 102) per million, respectively. After 1985, North America reported only one further case despite continued use by an estimated 0.3 million persons.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adverse Drug Reaction Reporting Systems; Antimalarials; Drug Combinations; Drug Eruptions; Drug Utilization; Erythema Multiforme; Humans; Malaria; Pyrimethamine; Risk Factors; Stevens-Johnson Syndrome; Sulfadoxine; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination

Six cases of drug-induced toxic epidermal necrolysis treated in a burns unit are presented. The mean skin loss was 67.3 per cent of the total body surface area. Two patients developed renal failure and two had ocular symptoms. The mortality rate was 50 per cent, with two patients dying from septicaemia and one from respiratory and renal failure. The diagnosis of toxic epidermal necrolysis can be confirmed by skin biopsy. We recommend that this disease is treated in a burns unit so that both adequate wound care and essential intensive supportive treatment can be given. Antibiotics are indicated only for specific infections such as septicaemia or pneumonia. Steroids have been shown to increase greatly the mortality from septic complications and are not recommended. The mortality ranges from 10 per cent to 70 per cent and bad prognostic factors include increasing age, greater than 50 per cent of body surface skin loss and neutropenia.

Topics: Adolescent; Adult; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Antimalarials; Chlorpromazine; Clavulanic Acids; Diagnosis, Differential; Drug Combinations; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Pyrimethamine; Retrospective Studies; Stevens-Johnson Syndrome; Sulfadoxine; Trimethoprim, Sulfamethoxazole Drug Combination; Zimeldine

We have reviewed admission data, some diagnostic tests, treatment and outcome of 31 male homosexual patients infected with the human immunodeficiency virus with 37 consecutive episodes of presumptive Pneumocystis carinii pneumonia treated at the infectious disease unit, Auckland Hospital, between 1985 and 30 June 1988. The median age was 39 years. Eight episodes were proven Pneumocystis carinii pneumonia, 18 satisfied Centres for Disease Control criteria for presumptive Pneumocystis carinii pneumonia and 11 lacked one Centres for Disease Control criterion. Patients began intravenous or oral cotrimoxazole in 32 episodes, initially 20 mg/k/d of trimethoprim component, but since early 1988 10 mg/k/d. In nine episodes treatment was changed to intravenous pentamidine because of side effects or failure to respond while five received pentamidine as their only drug. Cotrimoxazole caused side effects in 20 of 32 episodes (rash in 11) and pentamidine in 10 of 14 (renal impairment in nine). Two patients died (ie, a 5% mortality for all 37 episodes or 8% for 26 proven and Centres for Disease Control presumptive episodes). Median hospital stay for survivors was 11 days. Fourteen other patients have subsequently died a median eight months after the initial episode. Pneumocystis carinii pneumonia is an important infection in patients infected with the human immunodeficiency virus.

Topics: Acquired Immunodeficiency Syndrome; Adult; Bronchoscopy; Drug Combinations; Follow-Up Studies; Homosexuality; Humans; Length of Stay; Male; Middle Aged; New Zealand; Pentamidine; Pneumonia, Pneumocystis; Pyrimethamine; Recurrence; Retrospective Studies; Sulfadoxine; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Zidovudine

Two isolates of Plasmodium falciparum (F 32 and K 1) were tested against sulfadoxine (SDX), sulfamethoxazole (SMZ), pyrimethamine (PYR) and trimethoprim (TMP), using a 48 h microtest, with RPMI-1640 low in PABA and folic acid. The IC50 for F 32 was: PYR 6.1 X 10(-9) M (mol/litre), TMP 1.3 X 10(-7) M, Fansidar (SDX/PYR 80:1) less than 10(-8) to 1.3 X 10(-10) M and cotrimoxazole (SMZ/TMP 20:1) 2.6 X 10(-7) to 1.3 X 10(-8) M. The IC50 for K 1 was: PYR greater than 10(-6) M, TMP 8.2 X 10(-7) M, Fansidar 4.1 X 10(-7) to 1.1 X 10(-9) M and cotrimoxazole 1.8 X 10(-6) to 9.0 X 10(-8) M. The difference in IC50 between F 32 and K 1 against TMP and cotrimoxazole is much less than the difference between the IC50 values against PYR and Fansidar, indicating that cross-resistance between PYR and TMP exists, but is not complete. A method for calculating the IC50 by linear regression analysis is described.

Topics: Animals; Antimalarials; Drug Combinations; Drug Synergism; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Sulfamethoxazole; Sulfanilamides; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; Drug Hypersensitivity; Humans; Pyrimethamine; Sulfadoxine; Sulfamethoxazole; Sulfanilamides; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination