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1.
Stat Methods Med Res ; 17(2): 191-206, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17698933

ABSTRACT

The effect of missing data in causal inference problems is widely recognized. In malaria drug efficacy studies, it is often difficult to distinguish between new and old infections after treatment, resulting in indeterminate outcomes. Methods that adjust for possible bias from missing data include a variety of imputation procedures (extreme case analysis, hot-deck, single and multiple imputation), weighting methods, and likelihood based methods (data augmentation, EM procedures and their extensions). In this article, we focus our discussion on multiple imputation and two weighting procedures (the inverse probability weighted and the doubly robust (DR) extension), comparing the methods' applicability to the efficient estimation of malaria treatment effects. Simulation studies indicate that DR estimators are generally preferable because they offer protection to misspecification of either the outcome model or the missingness model. We apply the methods to analyze malaria efficacy studies from Uganda.


Subject(s)
Antimalarials/therapeutic use , Malaria/drug therapy , Humans , Models, Theoretical , Uganda
2.
Clin Pharmacol Ther ; 102(3): 520-528, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28187497

ABSTRACT

Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC0-21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC0-8hr and piperaquine AUC0-21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed.


Subject(s)
Antimalarials/administration & dosage , Artemisinins/administration & dosage , Benzoxazines/administration & dosage , Malaria/prevention & control , Quinolines/administration & dosage , Adolescent , Adult , Alkynes , Antimalarials/pharmacokinetics , Area Under Curve , Artemisinins/pharmacokinetics , Chemoprevention/methods , Cyclopropanes , Dose-Response Relationship, Drug , Drug Combinations , Drug Interactions , Female , HIV Infections/drug therapy , Humans , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Parasitic/prevention & control , Quinolines/pharmacokinetics , Reverse Transcriptase Inhibitors/administration & dosage , Uganda , Young Adult
3.
Arch Intern Med ; 160(16): 2505-10, 2000 Sep 11.
Article in English | MEDLINE | ID: mdl-10979063

ABSTRACT

BACKGROUND: Imported malaria is quite common in the United States. Increasing antimalarial drug resistance and changes in travel patterns may have important implications for the prevention, clinical presentation, and management of this disease. METHODS: Medical records were reviewed for 121 patients with microscopically confirmed malaria diagnosed at 2 university-affiliated hospitals in San Francisco, Calif, between 1988 and 1997. RESULTS: Among 57 travelers from the United States, only 13 (23%) had been compliant with an appropriate chemoprophylactic regimen. No patients developed falciparum malaria after consistent chemoprophylactic therapy with mefloquine hydrochloride. However, 12 (19%) of US residents with imported malaria developed Plasmodium vivax or Plasmodium ovale infections despite an appropriate chemoprophylactic regimen, generally with a late onset suggestive of relapsing disease. Clinical presentations were similar between foreign residents and American travelers and between patients with falciparum and nonfalciparum infections; 98% of patients had a history of fever. Sixteen percent of patients had received previous evaluations during which the diagnosis of malaria was not considered. In 9% of patients, there were errors in treatment. Only 1 patient developed severe malaria. CONCLUSIONS: Our results suggest that a standard chemoprophylactic regimen is highly effective in preventing falciparum malaria, but that many American travelers do not receive it. Also, relapsing P vivax or P ovale infection despite appropriate chemoprophylactic therapy was not uncommon among our cases. The presentation of imported malaria is nonspecific, highlighting the need to consider the diagnosis in any febrile patient who has been in a malaria-endemic area. Although errors in diagnosis and treatment were quite common in our study population, patient outcomes were good once the appropriate therapy was initiated.


Subject(s)
Malaria , Malaria/therapy , Adolescent , Adult , Antimalarials/therapeutic use , Child , Child, Preschool , Female , Humans , Malaria/diagnosis , Malaria/drug therapy , Malaria/prevention & control , Male , Middle Aged , Patient Compliance , Retrospective Studies , Travel , Treatment Outcome
4.
J Med Chem ; 38(14): 2621-7, 1995 Jul 07.
Article in English | MEDLINE | ID: mdl-7629802

ABSTRACT

A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.


Subject(s)
3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 5-alpha Reductase Inhibitors , Adrenal Glands/enzymology , Azasteroids/pharmacology , Steroid Isomerases/antagonists & inhibitors , Animals , Azasteroids/chemistry , Azasteroids/pharmacokinetics , Dogs , Humans , Male , Models, Molecular , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
5.
J Med Chem ; 37(15): 2352-60, 1994 Jul 22.
Article in English | MEDLINE | ID: mdl-8057283

ABSTRACT

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.


Subject(s)
3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 5-alpha Reductase Inhibitors , Adrenal Glands/enzymology , Azasteroids/pharmacology , Isoenzymes/antagonists & inhibitors , Steroid Isomerases/antagonists & inhibitors , Animals , Azasteroids/chemistry , Dogs , Humans , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
6.
J Med Chem ; 41(10): 1581-97, 1998 May 07.
Article in English | MEDLINE | ID: mdl-9572884

ABSTRACT

Toward establishing the general efficacy of using trisubstituted cyclopropanes as peptide mimics to stabilize extended peptide structures, the cyclopropanes 20a-d were incorporated as replacements into 9-13, which are analogues of the known HIV-1 protease inhibitors 14 and 15. The syntheses of 20a-d commenced with the Rh2[5(S)-MEPY]4-catalyzed cyclization of the allylic diazoesters 16a-d to give the cyclopropyl lactones 17a-d in high enantiomeric excess. Opening of the lactone moiety using the Weinreb protocol and straightforward refunctionalization of the intermediate amides 18a-d gave 20a-d. A similar sequence of reactions was used to prepare the N-methyl-2-pyridyl analogue 28. Coupling of 20a-d and 28 with the known diamino diol 22 delivered 9-13. Pseudopeptides 9-12 were found to be competitive inhibitors of wild-type HIV-1 protease in biological assays having Kis of 0.31-0.35 nM for 9, 0.16-0.21 nM for 10, 0.47 nM for 11, and 0.17 nM for 12; these inhibitors were thus approximately equipotent to the known inhibitor 14(IC50 = 0.22 nM) from which they were derived. On the other hand 13 (Ki = 80 nM) was a weaker inhibitor than its analogue 15 (Ki = 0.11 nM). The solution structures of 9 and 10 were analyzed by NMR spectroscopy and simulated annealing procedures that included restraints derived from homo- and heteronuclear coupling constants and NOEs; because of the molecular symmetry of9 and 10, a special protocol to treat the NOE data was used. The final structure was checked by restrained and free molecular dynamic calculations using an explicit DMSO solvent box. The preferred solution conformations of 9 and 10 are extended structures that closely resemble the three-dimensional structure of 10 bound to HIV-1 protease as determined by X-ray crystallographic analysis of the complex. This work convincingly demonstrates that extended structures of peptides may be stabilized by the presence of substituted cyclopropanes that serve as peptide replacements. Moreover, the linear structure enforced in solution by the two cyclopropane rings in the pseudopeptides 9-12 appears to correspond closely to the biologically active conformation of the more flexible inhibitors 14 and 15. The present work, which is a combination of medicinal, structural, and quantum chemistry, thus clearly establishes that cyclopropanes may be used as structural constraints to reduce the flexibility of linear pseudopeptides and to help enforce the biologically active conformation of such ligands in solution.


Subject(s)
Cyclopropanes , Drug Design , HIV Protease Inhibitors , HIV Protease/metabolism , Molecular Mimicry , Oligopeptides/chemistry , Binding Sites , Crystallography, X-Ray , Cyclopropanes/chemistry , Cyclopropanes/metabolism , Cyclopropanes/pharmacology , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacology , Kinetics , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Protein Structure, Secondary , Solutions
7.
J Med Chem ; 41(11): 1894-908, 1998 May 21.
Article in English | MEDLINE | ID: mdl-9599239

ABSTRACT

The design, synthesis, and evaluation of dipeptide analogues as ligands for the pp60c-src SH2 domain are described. The critical binding interactions between Ac-Tyr-Glu-N(n-C5H11)2 (2) and the protein are established and form the basis for our structure-based drug design efforts. The effects of changes in both the C-terminal (11-27) and N-terminal (51-69) portions of the dipeptide are explored. Analogues with reduced overall charge (92-95) are also investigated. We demonstrate the feasibility of pairing structurally diverse subunits in a modest dipeptide framework with the goal of increasing the druglike attributes without sacrificing binding affinity.


Subject(s)
Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins pp60(c-src)/antagonists & inhibitors , src Homology Domains , Crystallography, X-Ray , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Ligands , Models, Molecular , Molecular Conformation , Proto-Oncogene Proteins pp60(c-src)/metabolism , Structure-Activity Relationship
8.
Infect Control Hosp Epidemiol ; 21(7): 465-9, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10926397

ABSTRACT

OBJECTIVE: To investigate an outbreak of invasive disease due to Enterobacter cloacae and Serratia marcescens in a surgical intensive care unit (ICU). DESIGN: Pulsed-field gel electrophoresis (PFGE) analysis of restriction fragments was used to characterize the outbreak isolate genotypes. A retrospective cohort study of surgical ICU patients was conducted to identify risk factors associated with invasive disease. Unit staffing data were analyzed to compare staffing levels during the outbreak to those prior to and following the outbreak. SETTING: An urban hospital in San Francisco, California. PATIENTS: During the outbreak period, December 1997 through January 1998, there were 52 patients with a minimum ICU stay of > or = 72 hours. Of these, 10 patients fit our case definition of recovery of E. cloacae or S. marcescens from a sterile site. RESULTS: PFGE analysis revealed a highly heterogeneous population of isolates. Bivariate analysis of patient-related risk factors revealed duration of central lines, respiratory colonization, being a burn patient, and the use of gentamicin or nafcillin to be significantly associated with invasive disease. Both respiratory colonization and duration of central lines remained statistically significant in a multivariate analysis. Staffing data suggested a temporal correlation between understaffing and the outbreak period. CONCLUSIONS: Molecular epidemiological techniques provided a rapid means of ruling out a point source or significant cross-contamination as modes of transmission. In this setting, patient-related risk factors, such as respiratory colonization and duration of central lines, may provide a focus for heightened surveillance, infection control measures, and empirical therapy during outbreaks caused by common nosocomial pathogens. In addition, understaffing of nurses may have played a role in this outbreak, highlighting the importance of monitoring staffing levels.


Subject(s)
Cross Infection , Disease Outbreaks , Enterobacter cloacae/pathogenicity , Enterobacteriaceae Infections/epidemiology , Intensive Care Units , Serratia Infections/epidemiology , Serratia marcescens/pathogenicity , Cohort Studies , DNA, Bacterial/analysis , Electrophoresis, Gel, Pulsed-Field , Enterobacter cloacae/genetics , Enterobacter cloacae/isolation & purification , Hospitals, Urban , Humans , Infection Control , Molecular Epidemiology , Nursing Staff, Hospital/supply & distribution , Retrospective Studies , Risk Factors , Serratia marcescens/genetics , Serratia marcescens/isolation & purification
9.
Am J Trop Med Hyg ; 62(6): 686-92, 2000 Jun.
Article in English | MEDLINE | ID: mdl-11304055

ABSTRACT

Chloroquine-resistant falciparum malaria is a serious problem in much of sub-Saharan Africa. However, it is desirable to continue to use chloroquine as first-line therapy for uncomplicated malaria where it remains clinically effective. To identify predictors of chloroquine treatment failure, a 14-day clinical study of chloroquine resistance in patients with uncomplicated falciparum malaria was performed in Kampala, Uganda. Among the 258 patients (88% follow-up), 47% were clinical failures (early or late treatment failure) and 70% had parasitological resistance (RI-RIII). Using multivariate analysis, an age less than five (odds ratio [OR] = 3.4, 95% CI = 1.8-6.3) and a presenting temperature over 38.0 degreesC (OR = 2.0, 95% CI = 1.1-3.7) were independent predictors of treatment failure. In addition, patients who last took chloroquine 3 to 14 days prior to study entry were significantly more likely to be treatment failures compared to patients with very recent (less than 3 days) or no recent chloroquine use. In areas with significant chloroquine resistance, easily identifiable predictors of chloroquine treatment failure might be used to stratify patients into those for whom chloroquine use is acceptable and those for whom alternative treatment should be used.


Subject(s)
Antimalarials/therapeutic use , Chloroquine/therapeutic use , Malaria, Falciparum/drug therapy , Adolescent , Adult , Age Factors , Animals , Antimalarials/pharmacology , Body Temperature , Child , Child, Preschool , Chloroquine/pharmacology , Drug Resistance , Female , Humans , Infant , Malaria, Falciparum/parasitology , Male , Middle Aged , Multivariate Analysis , Plasmodium falciparum/drug effects , Predictive Value of Tests , Treatment Failure , Uganda , Urban Population
10.
Trans R Soc Trop Med Hyg ; 95(1): 50-5, 2001.
Article in English | MEDLINE | ID: mdl-11280066

ABSTRACT

Chloroquine (CQ) remains the first-line treatment for uncomplicated malaria in much of Africa despite the growing problem of resistance to this drug. Sulfadoxine-pyrimethamine (SP) is often used after CQ treatment failure and has replaced CQ as the first-line treatment in parts of Africa. To compare the efficacy of these 2 regimens, we evaluated, in March-August 1999, clinical and parasitological responses over 28 days in 214 children and adults from Kampala, Uganda, with uncomplicated falciparum malaria. Compared to SP, significantly more patients treated with CQ developed early or late clinical failure (54% vs 11%, P < 0.001) and parasitological failure (72% vs 30%, P < 0.001) during 14 days of follow-up. The risk of treatment failure occurring after day 14 was similar between the 2 treatment groups. Among those treated with CQ, children aged < 5 years were at higher risk of clinical failure than older individuals (76% vs 28%, P < 0.001), an association not seen with SP (11% vs 10%, P = 0.91). Although early parasite clearance was significantly better in the SP group (P = 0.001), fever clearance at day 3 was the same (CQ 85%, SP 86%). These and other recent findings suggest that consideration be given to replacing CQ as the first-line therapy for uncomplicated malaria in Uganda, particularly in young children.


Subject(s)
Antimalarials/therapeutic use , Chloroquine/therapeutic use , Malaria, Falciparum/drug therapy , Pyrimethamine/therapeutic use , Sulfadoxine/therapeutic use , Adolescent , Adult , Aged , Child , Child, Preschool , Drug Combinations , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Middle Aged , Treatment Outcome
13.
J Infect Dis ; 183(9): 1417-20, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11294677

ABSTRACT

The molecular mechanism of chloroquine resistance in Plasmodium falciparum remains uncertain. Polymorphisms in the pfcrt and pfmdr-1 genes have been associated with chloroquine resistance in vitro, although field studies are limited. In evaluations of known polymorphisms in parasites from patients with uncomplicated malaria in Kampala, Uganda, the presence of 8 pfcrt mutations and 2 pfmdr-1 mutations did not correlate with clinical response to therapy with chloroquine. Most notably, the pfcrt lysine-->threonine mutation at position 76, which recently correlated fully with chloroquine resistance in vitro, was present in 100% of 114 isolates, of which about half were from patients who recovered clinically after chloroquine therapy. These results suggest that, although key pfcrt polymorphisms may be necessary for the elaboration of resistance to chloroquine in areas with high levels of chloroquine resistance, other factors, such as host immunity, may contribute to clinical outcomes.


Subject(s)
ATP-Binding Cassette Transporters , Antimalarials/pharmacology , Chloroquine/pharmacology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Plasmodium falciparum/genetics , Polymorphism, Genetic , Protozoan Proteins/genetics , Animals , Case-Control Studies , Child, Preschool , Drug Resistance/genetics , Female , Genes, Protozoan , Humans , Infant , Male , Membrane Proteins/genetics , Membrane Transport Proteins , Point Mutation , Polymerase Chain Reaction , Treatment Outcome , Uganda
14.
Arch Toxicol ; 49(3-4): 185-90, 1982 Mar.
Article in English | MEDLINE | ID: mdl-7092557

ABSTRACT

4,4'-Methylenedianiline and its derivatives were assayed for mutagenicity in the Salmonella/microsomal mutagenicity assay develop by Ames. A specificity to revert strain TA98 suggests a mechanism of frameshift mutagenesis. Liver microsomal preparations (S-9) from rats induced with phenobarbital were most effective for metabolic activation. Alkyl substitution of 4,4'-methylenedianiline did not alter its mutagenic activity; however, substitution of both positions ortho to the amino group eliminated mutagenic activity. Substitution with alkoxy-carbonyl groups eliminated mutagenic activity, whereas halogen substitution (chlorine, fluorine) enhanced the mutagenic activity. The results presented here show the use of structure-activity studies as predictive tools for the assessment of genotoxic properties of industrial chemicals.


Subject(s)
Aniline Compounds/toxicity , Mutagens , Salmonella/drug effects , Animals , Histidine/metabolism , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Mutagenicity Tests , Rats , Rats, Inbred Strains , Salmonella/metabolism , Structure-Activity Relationship
15.
Lancet ; 358(9279): 368-74, 2001 Aug 04.
Article in English | MEDLINE | ID: mdl-11502317

ABSTRACT

BACKGROUND: Increasing Plasmodium falciparum resistance to chloroquine in sub-Saharan Africa necessitates use of alternative antimalarial agents. Affordable alternative treatments include sulfadoxine/pyrimethamine and amodiaquine. Combination of antimalarial agents can increase therapeutic efficacy and delay emergence of drug resistance. We compared the efficacy of sulfadoxine/pyrimethamine, amodiaquine, and an amodiaquine/sulfadoxine/pyrimethamine combination for treatment of uncomplicated malaria in a region of high chloroquine resistance. METHODS: Patients with symptoms of uncomplicated falciparum malaria and confirmed disease in Kampala, Uganda, were randomly assigned to receive sulfadoxine/pyrimethamine (25 mg/kg sulfadoxine, and 1.25 mg/kg pyrimethamine) plus placebo; amodiaquine (25 mg/kg) plus placebo; or amodiaquine plus sulfadoxine/pyrimethamine. Patients were followed up for 14 days, and clinical and parasitological outcomes were assessed. FINDINGS: 90% (400/445) of patients enrolled in the study successfully completed 14 days of follow-up. Treatment failure based on clinical criteria occurred in 13 of 131 (10%) patients on sulfadoxine/ pyrimethamine, nine of 131 (7%) on amodiaquine, and four of 138 (3%) on amodiaquine/sulfadoxine/pyrimethamine. Based on parasitological criteria, treatment failed in 26%, 16%, and 10% of these patients, respectively. Amodiaquine/sulfadoxine/pyrimethamine was significantly more effective than sulfadoxine/pyrimethamine alone in children aged younger than 5 years (clinical failure in 3.5% vs 13.9%, respectively, risk difference 10.4% [95% CI, 1.6-19.3] p=0.021; parasitological failure in 12.8% vs 26.4%, risk difference 13.6% [1.2-26.0] p=0.041). INTERPRETATION: Sulfadoxine/pyrimethamine, amodiaquine, and amodiaquine/sulfadoxine/pyrimethamine were all effective for treatment of uncomplicated falciparum malaria in Uganda. The amodiaquine/sulfadoxine/pyrimethamine combination was the most effective, and could be the optimum low-cost alternative to chloroquine in Africa.


Subject(s)
Antimalarials/therapeutic use , Malaria, Falciparum/drug therapy , Adolescent , Amodiaquine/administration & dosage , Amodiaquine/therapeutic use , Antimalarials/administration & dosage , Child , Child, Preschool , Drug Therapy, Combination , Female , Humans , Malaria, Falciparum/epidemiology , Male , Pyrimethamine/administration & dosage , Pyrimethamine/therapeutic use , Sulfadoxine/administration & dosage , Sulfadoxine/therapeutic use , Time Factors , Treatment Outcome , Uganda/epidemiology
16.
Malaria journal ; 6(7)2006.
Article in English | AIM | ID: biblio-1265209

ABSTRACT

Background: Presumptive treatment of malaria in febrile children is widely advocated in Africa. This may occur in the absence of diagnostic testing or even when diagnostic testing is performed but fails to detect malaria parasites. Such over-treatment of malaria has been tolerated in the era of inexpensive and safe monotherapy. However; with the introduction of new artemisinin-based combination therapy (ACT); presumptive treatment becomes economically and clinically less acceptable. Methods: The risks and benefits of only treating children with microscopy confirmed malaria using a prospective cohort design were investigated. A representative sample of 601 children between one and 10 years of age were recruited from a census population in Kampala; Uganda and were followed for all of their health care needs in a study clinic. Standard microscopy was performed each time a child presented with a new episode of fever and antimalarial therapy given only if the blood smear was positive. Results: Of 5;895 visits for new medical problems 40were for febrile illnesses. Of the 2;359 episodes of new febrile illnesses; blood smears were initially reported as negative in 1;608 (68) and no antimalarial therapy was given. Six of these initially negative smears were reported to be positive following quality control reading of all blood smears: four of these patients were subsequently diagnosed with uncomplicated malaria and two cleared their parasites without antimalarial treatment. Of the 1;602 new febrile illnesses in which the final blood smear reading was classified as negative; only 13 episodes (0.8) were diagnosed with malaria in the subsequent 7 days. All 13 of these episodes of malaria were uncomplicated and were successfully treated.Conclusions: In this urban setting; malaria was responsible for only 32of febrile episodes. Withholding antimalarial therapy in febrile children with negative blood smears was safe and saved over 1;600 antimalarial treatments in 601 children over an 18-month period. In the era of expensive ACT; directing resources towards improving diagnostic and treatment practices may provide a cost-effective measure for promoting rational use of antimalarial therapy


Subject(s)
Child , Clinical Laboratory Techniques , Malaria/therapy
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