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Malaria-endemic countries are switching antimalarial drug policy from cheap ineffective monotherapies to artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria and the global community are considering setting up a global subsidy to fund their purchase. However, in order to ensure that ACTs are correctly used and are accessible to the poor and remote communities who need them, specific interventions will be necessary and the additional costs need to be considered. This paper presents an incremental cost analysis of some of these interventions in Cambodia, the first country to change national antimalarial drug policy to an ACT of artesunate and mefloquine. These costs include the cost of rapid diagnostic tests (RDTs), the cost of blister-packaging the drugs locally and the costs of increasing access to diagnosis and treatment to remote communities through malaria outreach teams (MOTs) and Village Malaria Workers (VMW). At optimum productive capacity, the cost of blister-packaging cost under $0.20 per package but in reality was significantly more than this because of the low rate of production. The annual fixed cost (exclusive of RDTs and drugs) per capita of the MOT and VMW schemes was $0.44 and $0.69 respectively. However because the VMW scheme achieved a higher rate of coverage than the MOT scheme, the cost per patient treated was substantially lower at $5.14 compared to $12.74 per falciparum malaria patient treated. The annual cost inclusive of the RDTs and drugs was $19.31 for the MOT scheme and $11.28 for the VMW scheme given similar RDT positivity rates of around 22% and good provider compliance to test results. In addition to the cost of ACTs themselves, substantial additional investments are required in order to ensure that they reach the targeted population via appropriate delivery systems and to ensure that they are used appropriately. In addition, differences in local conditions, in particular the prevalence of malaria and the pre-existing infrastructure, need to be considered in choosing appropriate diagnostic and delivery strategies.

No abstract is provided for this article.

The relationship of the platelet-mediated autoagglutination of Plasmodium falciparum-infected red blood cells (IRBCs) to disease severity was investigated in 182 Thai patients with falciparum malaria; it was evident in 43% of uncomplicated malaria (n=63), 41% of severe malaria (n=104), and 100% of cerebral malaria (n=15; P=.001) isolates. The median (range) number of IRBCs in agglutinates per 1000 IRBCs was significantly higher in cerebral malaria (6 [3-42]) than in severe (0 [0-52]) and uncomplicated (0 [0-24]) malaria (P=.01). In multivariate analyses, high parasitemia and cerebral malaria were associated independently with parasite agglutination.

Pharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine. A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC). The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840–0.982) in the AS+AQ group and 0.892 (95% CI: 0.787 – 0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (<1,000/μL). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28. The bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.

In vertebrates, reproductive endocrine concentrations are strongly differentiated by sex, with androgen biases typifying males and estrogen biases typifying females. These sex differences can be reduced in female-dominant species; however, even the most masculinised of females have less testosterone (T) than do conspecific males. To test if aggressively dominant, female meerkats ( Suricata suricatta ) may be hormonally masculinised, we measured serum androstenedione (A 4 ), T and estradiol (E 2 ) in both sexes and social classes, during both ‘baseline’ and reproductive events. Relative to resident males, dominant females had greater A 4 , equivalent T and greater E 2 concentrations. Males, whose endocrine values did not vary by social status, experienced increased T during reproductive forays, linking T to sexual behaviour, but not social status. Moreover, substantial E 2 concentrations in male meerkats may facilitate their role as helpers. In females, dominance status and pregnancy magnified the unusual concentrations of measured sex steroids. Lastly, faecal androgen metabolites replicated the findings derived from serum, highlighting the female bias in total androgens. Female meerkats are thus strongly hormonally masculinised, possibly via A 4 ’s bioavailability for conversion to T. These raised androgen concentrations may explain female aggressiveness in this species and give dominant breeders a heritable mechanism for their daughters’ competitive edge.

The MIC is an essential quantitative measure of the asexual blood-stage effect of an antimalarial drug. In areas of high malaria transmission, and thus frequent individual infection, patients who are treated with slowly eliminated antimalarials become reinfected as drug concentrations decline. In the frequent relapse forms of Plasmodium vivax and in Plasmodium ovale malaria, recurrent infection occurs from relapses which begin to emerge from the liver approximately 2 weeks after the primary illness. An important determinant of the interval from starting treatment of a symptomatic infection to the patency of these recurrent infections is the in vivo concentration-response relationship and thus the in vivo MIC. Using mechanistic knowledge of parasite asexual replication and the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs, a generative statistical model was derived which relates the concentration-response relationship to time of reinfection patency. This model was used to estimate the in vivo MIC of chloroquine in the treatment of Plasmodium vivax malaria.

Background The current antiparasitic treatment for chronic Chagas disease of 8 weeks daily benznidazole or nifurtimox is poorly tolerated and reaches only a small minority of those with chronic infections. Defining parasitological cure is compromised by the low blood trypomastigote densities, which fluctuate close to or below the limit of qPCR detection. Methods To address this limitation and improve the assessment of parasitological cure we developed a probabilistic model of therapeutic efficacy based on serial qPCR data. We pooled clinical and laboratory data from two prospective trials in Bolivian adults with chronic indeterminate Chagas disease. In both trials randomised arms included placebo or standard of care benznida-zole (300mg/day for 8 weeks). In the first trial, the experimental arms were fosravuconazole monotherapies (400mg/week for 4 or 8 weeks, or 200mg/week for 8 weeks); in the second trial the experimental arms were shorter or lower dose benznidazole regimens (300mg/day for 2 or 4, or 150mg/day for 4 weeks), or combinations of fosravuconazole 300mg weekly for 8 weeks with either benznidazole 150mg/day for 4 weeks or benznidazole 300mg/week for 8 weeks. Serial parasite densities were estimated from triplicate qPCRs targeting T. cruzi satellite DNA taken from one to three 5 or 10ml blood samples at 8-12 visits over one year. Treatment efficacies were estimated under a hierarchical Bayesian model, taking as input serial cycle threshold (Ct) data grouped by time point, blood draw and technical replicate. The primary analysis was done in a per-protocol population defined as patients randomised to placebo or patients who took an active treatment &gt;80% of the allocated treatment duration. Results The two trials randomised 441 patients. 34,804 qPCR Ct values were recorded over 5,402 unique visits, comprising 449 participant years follow-up. In a per-protocol population ( n =424), an estimated 81% (95% Credible Interval [CrI] 70 to 89%, n =69) had parasitological cure following benznidazole 300mg/day for 8 weeks. All other benznidazole regimens had similar estimated cure proportions (95% CrIs &gt;63%) except the 2-week regimen (63% cured [95%CrI 43-81%], n =27, probability of inferiority relative 8-week: 0.95). Recurrent parasitaemias following benznidazole were at substantially lower densities than at baseline. In comparison, only 3.9% of patients allocated to placebo were cured (95%CrI 1 to 9%, n =77). Fosravuconazole was relatively ineffective: 23% cured following 400mg for 8 weeks (95%CrI, 10 to 40%, n =45); 9% following 400mg for 4 weeks (95%CrI 3 to 21%, n =46); and 2% following 200mg for 8 weeks (95%CrI 0 to 11%, n =48). Recurrent parasitaemias one year after fosravuconazole treatment were only slightly lower than at baseline. Fosravuconazole caused dose-dependent increases in liver transaminases. Conclusions Therapeutic assessments in Chagas disease must account probabilistically for qPCR test performance and low density post treatment parasitaemias. In Bolivian chronic Chagas disease, weekly dosing for eight weeks or daily dosing over four weeks both appear as effective as the current eight weeks daily regimen. The total dose of benznidazole in the current standard of care regimen is excessive.

Two antibiotic regimens are used commonly in Thailand for the initial treatment of severe melioidosis: ceftazidime in combination with trimethoprim-sulfamethoxazole (TMP-SMX) and ceftazidime monotherapy. It is not known whether TMP-SMX provides an additional benefit.Two prospective, randomized trials that compared these regimens for patients presenting with acute severe melioidosis were started independently at tertiary care hospitals in Ubon Ratchathani and Khon Kaen (in northeastern Thailand), and the results were analyzed together as a prospective, individual-patient data meta-analysis. The primary end point was in-hospital mortality rate.The in-hospital mortality rate among all enrolled patients (n=449) was not significantly different between those randomized to ceftazidime alone (25.1%; 56 of 223 subjects) and those randomized to ceftazidime with TMP-SMX (26.6%; 60 of 226 subjects; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.7-1.7; stratified P=.73). Of the 241 patients with culture-confirmed melioidosis, 51 (21.2%) died. Of these 241 patients, 31 (12.9%) died > or =48 h after the time of study entry. Among patients with melioidosis, there was no difference in death rate between the 2 treatment groups for either all deaths (OR, 0.88; 95% CI, 0.48-1.6; stratified P=.70) or for deaths that occurred > or =48 h after hospital admission (OR, 0.88; 95% CI, 0.41-1.9; stratified P=.73). Conditional logistic regression analysis revealed that bacteremia, respiratory failure, and renal failure were independently associated with death and treatment failure. Drug regimens were not associated with death or treatment failure in this model.We conclude that the addition of TMP-SMX to ceftazidime therapy during initial treatment of severe melioidosis does not reduce the acute mortality rate.

To evaluate immune cell activation in patients with melioidosis, serum samples were assayed for interferon-γ (IFN-γ), soluble interleukin-2 receptors (sIL-2R), and soluble CDS protein (sCDS). Forty patients with sepsis (23 fatal cases, 17 survivors) and 13 with localized disease were studied during acute illness; 12 additional patients were studied after discharge while on maintenance antimicrobial therapy. Serum concentrations of IFN-γ and sIL-2R were greatly elevated, but sCDS concentrations were not. These levels increased with disease severity and were associated with fatal outcomes. Macrophage activation by high concentrations of the cytokine IFN-γ may contribute to pathophysiology and death in septicemic patients. Both IFN-γ and sIL-2R seem to be predictive of outcome in patients with severe melioidosis and may prove useful in detection of relapse.

Melioidosis is a potentially lethal infection of humans and animals in Southeast Asia and northern Australia. Current methods for detection of the causative organism, Burkholderia pseudomallei, lack both speed and sensitivity. We report the development of a highly sensitive polymerase chain reaction-based method that can detect as few as 35 colony-forming units of B. pseudomallei/mL in saline suspensions. This polymerase chain reaction test also detected the presence of B. pseudomallei DNA in culture-negative splenic tissue obtained from mice infected with the organism, but without clinical evidence of disease. Specificity has been confirmed using a variety of pathogenic and nonpathogenic organisms, including B. mallei, B. cepacia, and Pseudomonas species. The clinical usefulness of this test should be assessed prospectively and compared with conventional diagnostic techniques.