David Hutchinson

Fosmidomycin, a Novel Chemotherapeutic Agent for Malaria

ABSTRACT In previous studies, fosmidomycin has been shown to possess activity against Plasmodium falciparum in vitro and in the mouse model. It has a novel mode of action through inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this open-label, uncontrolled trial, the efficacy and safety of fosmidomycin, in an oral dose of 1,200 mg every 8 h for 7 days, were evaluated in the treatment of acute uncomplicated Plasmodium falciparum malaria in 20 adult subjects in Gabon and Thailand. Clinical assessments were performed and thick blood smears were evaluated every 8 h until parasite clearance and resolution of symptoms were achieved; assessments continued at weekly intervals thereafter for the duration of the 28-day followup period. All subjects were clinically and parasitologically cured on day 7 (primary end point). Parasite and fever clearance were rapid, with means of 44 and 41 h, respectively. On day 28, seven out of nine subjects (78%) were cured in Gabon and two out of nine subjects (22%) were cured in Thailand. The drug was well tolerated, although mild gastrointestinal side effects were recorded for five subjects. Analysis of hematological and biochemical parameters showed no clinically significant changes throughout the study. Fosmidomycin is an effective and safe antimalarial drug, although its use as a single agent is restricted by the occurrence of recrudescent infections. However, its role in combination therapy should be explored.

In Vitro and In Vivo Synergy of Fosmidomycin, a Novel Antimalarial Drug, with Clindamycin

ABSTRACT Fosmidomycin acts through inhibition of 1-deoxy-d-xylulose 5-phosphate (DOXP) reductoisomerase, a key enzyme of the nonmevalonate pathway of isoprenoid biosynthesis. It possesses potent antimalarial activity in vitro and in murine malaria. In a recent clinical study, fosmidomycin was effective and well tolerated in the treatment of patients with acute uncomplicated Plasmodium falciparum malaria but resulted in an unacceptably high rate of recrudescence. In order to identify a potential combination partner, the interaction of fosmidomycin with a number of antimalarial drugs in current use was investigated in a series of in vitro experiments. Synergy was observed between fosmidomycin and the lincosamides, lincomycin and clindamycin. The efficacy of a combination of fosmidomycin and clindamycin was subsequently demonstrated in the Plasmodium vinckei mouse model.

Fosmidomycin plus Clindamycin for Treatment of Pediatric Patients Aged 1 to 14 Years with Plasmodium falciparum Malaria

ABSTRACT Fosmidomycin plus clindamycin was shown to be efficacious in the treatment of uncomplicated Plasmodium falciparum malaria in a small cohort of pediatric patients aged 7 to 14 years, but more data, including data on younger children with less antiparasitic immunity, are needed to determine the potential value of this new antimalarial combination. We conducted a single-arm study to improve the precision of efficacy estimates for an oral 3-day fixed-ratio combination of fosmidomycin and clindamycin at 30 and 10 mg/kg of body weight, respectively, every 12 hours for the treatment of uncomplicated P. falciparum malaria in 51 pediatric outpatients aged 1 to 14 years. Fosmidomycin plus clindamycin was generally well tolerated, but relatively high rates of treatment-associated neutropenia (8/51 [16%]) and falls of hemoglobin concentrations of ≥2 g/dl (7/51 [14%]) are of concern. Asexual parasites and fever were cleared within median periods of 42 h and 38 h, respectively. All patients who could be evaluated were parasitologically and clinically cured by day 14 (49/49; 95% confidence interval [CI], 93 to 100%). The per-protocol, PCR-adjusted day 28 cure rate was 89% (42/47; 95% CI, 77 to 96%). Efficacy appeared to be significantly reduced in children aged 1 to 2 years, with a day 28 cure rate of only 62% for this small subgroup (5/8). The inadequate efficacy in children of <3 years highlights the need for continued systematic studies of the current dosing regimen, which should include randomized trial designs.

Atovaquone-Proguanil Compared with Chloroquine and Chloroquine-Sulfadoxine-Pyrimethamine for Treatment of Acute Plasmodium falciparum Malaria in the Philippines

This randomized, open-label clinical trial compared a fixed-dose combination of atovaquone and proguanil (n=55) with chloroquine (n=23) or a combination of chloroquine, sulfadoxine, and pyrimethamine (n=32) for treatment of acute falciparum malaria in the Philippines. Patients were hospitalized for 28 days to ensure medication compliance and prevent reinfection. Atovaquone-proguanil produced a significantly higher cure rate (100%) compared with that for chloroquine (30.4%; P<.0001) or chloroquine-sulfadoxine-pyrimethamine (87.5%; P<.05). Treatments did not differ significantly with respect to parasite clearance time (mean: 46.7 h for atovaquone-proguanil, 60.0 h for chloroquine, and 42.8 h for chloroquine-sulfadoxine-pyrimethamine) or fever clearance time (mean, 38.8, 46.8, and 34.5 h, respectively). Adverse events were typical of malaria symptoms; the most frequently reported events were vomiting (18% for atovaquone-proguanil, 17% for chloroquine, and 9% for chloroquine-sulfadoxine-pyrimethamine), abdominal pain (15%, 17%, and 3%, respectively), anorexia (11%, 13%, and 0%, respectively), and headache (6%, 17%, and 3%, respectively). Atovaquone-proguanil was well tolerated and more effective than chloroquine or chloroquine-sulfadoxine-pyrimethamine for treatment of multidrug-resistant falciparum malaria in the Philippines.

Short-Course Regimens of Artesunate-Fosmidomycin in Treatment of Uncomplicated Plasmodium falciparum Malaria

ABSTRACT Fosmidomycin is effective against malaria, but it needs to be given for ≥4 days when used alone. We conducted a study of 50 children with Plasmodium falciparum malaria to evaluate the safety and efficacy of consecutively shortened regimens of artesunate-fosmidomycin (1 to 2 mg/kg of body weight and 30 mg/kg of body weight, respectively; doses given every 12 hours). All dosing regimens were well tolerated. Artesunate-fosmidomycin acted rapidly, resulting in consolidated geometric mean parasite and fever clearance times of 24 h and 15 h, respectively. Treatment regimens of ≥2 days led to cure ratios of 100% by day 14 (39/39; 95% confidence interval [95% CI], 91% to 100%). Most importantly, the 3-day regimen achieved 100% cure on day 28 (10/10; 95% CI, 69% to 100%). Treatment with artesunate-fosmidomycin was associated with transient grade I or II neutropenia (absolute neutrophil counts of 750 to 1,200/μl and 400 to 749/μl, respectively) in six or two patients, respectively. Artesunate-fosmidomycin demonstrates the feasibility and potential value of short-course artemisinin-based combination chemotherapy with rapidly eliminated combination partners.

Inadequate Efficacy of a New Formulation of Fosmidomycin-Clindamycin Combination in Mozambican Children Less than Three Years Old with Uncomplicated Plasmodium falciparum Malaria

ABSTRACT The combination of fosmidomycin and clindamycin (F/C) is effective in adults and older children for the treatment of malaria and could be an important alternative to existing artemisinin-based combinations (ACTs) if proven to work in younger children. We conducted an open-label clinical trial to assess the efficacy, safety, and tolerability of F/C for the treatment of uncomplicated P. falciparum malaria in Mozambican children <3 years of age. Aqueous solutions of the drugs were given for 3 days, and the children were followed up for 28 days. The primary outcome was the PCR-corrected adequate clinical and parasitological response at day 28. Secondary outcomes included day 7 and 28 uncorrected cure rates and fever (FCT) and parasite (PCT) clearance times. Fifty-two children were recruited, but only 37 patients were evaluable for the primary outcome. Day 7 cure rates were high (94.6%; 35/37), but the day 28 PCR-corrected cure rate was 45.9% (17/37). The FCT was short (median, 12 h), but the PCT was longer (median, 72 h) than in previous studies. Tolerability was good, and most common adverse events were related to the recurrence of malaria. The poor efficacy observed for the F/C combination may be a consequence of the new formulations used, differential bioavailability in younger children, naturally occurring variations in parasite sensitivity to the drugs, or an insufficient enhancement of their effects by naturally acquired immunity in young children. Additional studies should be conducted to respond to the many uncertainties arising from this trial, which should not discourage further evaluation of this promising combination.

Whole genome sequencing to evaluate the resistance landscape following antimalarial treatment failure with fosmidomycin-clindamycin

Novel antimalarial therapies are needed in the face of emerging resistance to artemisinin combination therapies. A previous study found a high cure rate in Mozambican children with uncomplicated Plasmodium falciparum malaria 7 days after combination treatment with fosmidomycin-clindamycin. However, 28-day cure rates were low (45.9%), owing to parasite recrudescence. We sought to identify any genetic changes underlying parasite recrudescence. To this end, we used a selective whole-genome amplification method to amplify parasite genomes from blood spot DNA samples. Parasite genomes from pretreatment and postrecrudescence samples were subjected to whole-genome sequencing to identify nucleotide variants. Our data did not support the existence of a genetic change responsible for recrudescence following fosmidomycin-clindamycin treatment. Additionally, we found that previously described resistance alleles for these drugs do not represent biomarkers of recrudescence. Future studies should continue to optimize fosmidomycin combinations for use as antimalarial therapies.

FOSMIDOMYCIN-PIPERAQUINE AS NON-ARTEMISININ-BASED COMBINATION FOR ACUTE UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA

Background As investment in research related to artemisinin resistance is a key objective of the Global Plan for Artemisinin Resistance Containment (GPARC), fosmidomycin and piperaquine are being developed to address the delay in parasite clearance following treatment with Artemisinin-based Combination Therapy (ACT). Though artemisinin resistance occurs principally in the Greater Mekong Region, there are concerns that it will emerge in sub-Saharan Africa. Methods A proof-of-concept study has been conducted in Gabon to determine the efficacy, tolerance and safety of fosmidomycin and piperaquine when administered orally for three days. A total of 100 subjects, including 10 adults, 40 children aged 5–14 years and 50 children aged 1–5 years fulfilling the inclusion criteria of mono-infection with Plasmodium falciparum and initial parasite counts between 1,000 and 150,000/µL were enrolled and followed up for 63 days. The primary efficacy endpoint was per protocol, the PCR-corrected cure rate on Day 28. Safety endpoints included the incidence, severity, drug-relatedness and seriousness of adverse events and laboratory abnormalities. ClinicalTrials.gov Identifier: NCT02198807 Results The PCR-corrected 28-day cure rate in the older children was 100% (n=31). It was also 100% (n=38) in the younger children, a group deemed to be more therapeutically challenging on account of their lower immune status. Tolerance was excellent and there were no drug-related safety issues. Full results will be presented. Conclusions Fulfilling the WHO criteria for combination therapy, fosmidomycin as a rapidly acting blood schizonticide and piperaquine with its prolonged post-treatment prophylactic effect have been shown to be highly efficacious for the treatment of acute uncomplicated falciparum malaria in an area of intense malaria transmission. Dose optimisation studies with the dual aim of achieving a reduction in the dose of fosmidomycin within a therapeutic regimen of once daily dosing are planned.

Efficacy and Safety of Fosmidomycin–Piperaquine as Nonartemisinin-Based Combination Therapy for Uncomplicated Falciparum Malaria: A Single-Arm, Age De-escalation Proof-of-Concept Study in Gabon

Fosmidomycin–piperaquine is being developed as nonartemisinin-based combination therapy to meet the challenge of emerging artemisinin resistance. The combination appeared to have high efficacy and be safe and well tolerated despite observed transient changes in electrocardiogram with prolongation of the QT interval.

Fosmidomycin as an Antimalarial Agent

The isoprenoid biosynthesis of Plasmodium falciparum, the causative agent of malignant tertiana malaria, solely depends on the mevalonate-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway [also known as the 1-deoxy-d-xylulose 5-phosphate (DXP) pathway]. The enzymes of the MEP pathway of P. falciparum are located in a plastid-like organelle called the apicoplast. The growth of P. falciparum parasites is rapidly inhibited by fosmidomycin, an inhibitor of DXP reductoisomerase. The antimalarial activity of fosmidomycin has been substantiated in several clinical phase II studies. Most thoroughly, the treatment of malaria patients with a drug combination consisting of fosmidomycin and clindamycin has been investigated. With this combination, cure rates of approximately 90% were achieved after 3 days of treatment. In vitro studies revealed improved antimalarial activity of several fosmidomycin derivatives. At present, the compound FR-900098 represents the most promising derivative with respect to its low toxicity and proven activity in the P. vinckei mouse model.