fosfomycin and Malaria--Falciparum

fosfomycin has been researched along with Malaria--Falciparum* in 24 studies

Reviews

3 review(s) available for fosfomycin and Malaria--Falciparum

ArticleYear
Fosmidomycin as an antimalarial drug: a meta-analysis of clinical trials.
    Future microbiology, 2015, Volume: 10, Issue:8

    With first indications of resistance against artemisinin compounds, the development of novel alternative antimalarials remains an urgent need. One candidate is fosmidomycin (Fos), a phosphonic acid derivative. This PRISMA guideline-adhering and PROSPERO-registered systematic review and meta-analysis provides an overview of the state-of-the-art of the clinical development of Fos as an antimalarial. Pooling six clinical trials of Fos against uncomplicated malaria in African children yielded an overall day 28 cure rate of 85% (95% CI: 71-98%); a parasite clearance time of 39 h; and a fever clearance time of 30 h. In four adult cohorts, the corresponding values were 70% (95% CI: 40-100%), 49 and 42 h, respectively. Data suggest that besides the partner drug, formulation determines efficacy. We advocate further clinical development of Fos-combinations. PROSPERO registration number: CRD42014013688.

    Topics: Adult; Antimalarials; Child; Child, Preschool; Clinical Trials as Topic; Drug Therapy, Combination; Fosfomycin; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum

2015
Isoprenoid biosynthesis in Plasmodium falciparum.
    Eukaryotic cell, 2014, Volume: 13, Issue:11

    Malaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.

    Topics: Antimalarials; Fosfomycin; Malaria, Falciparum; Plasmodium falciparum; Terpenes

2014
Fosmidomycin for the treatment of malaria.
    Parasitology research, 2003, Volume: 90 Suppl 2

    In malaria parasites, isoprenoids are synthesised by the mevalonate independent 1-deoxy- D-xylulose 5-phosphate (DOXP) pathway. Fosmidomycin, a natural antibiotic originally developed for the treatment of bacterial infections, represents an inhibitor of DOXP reductoisomerase, an essential enzyme of this pathway. In recent clinical studies it was shown that fosmidomycin is effective in curing uncomplicated Plasmodium falciparum malaria in humans. The treatment was well tolerated and resulted in a fast parasite and fever clearance. However, the high rate of recrudescence precludes the use of fosmidomycin as a monotherapy. In drug combination studies, synergy of fosmidomycin with clindamycin was observed. Clinical studies with a fosmidomycin-clindamycin combination are currently ongoing.

    Topics: Animals; Antimalarials; Chemistry, Pharmaceutical; Clindamycin; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Humans; Malaria, Falciparum; Pentosephosphates; Plasmodium; Plasmodium falciparum; Terpenes

2003

Trials

10 trial(s) available for fosfomycin and Malaria--Falciparum

ArticleYear
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.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018, 06-01, Volume: 66, Issue:12

    Fosmidomycin-piperaquine is being developed as nonartemisinin-based combination therapy to meet the challenge of emerging artemisinin resistance.. The study was a phase 2, single-arm, proof-of-concept study of the efficacy, tolerability, and safety of fosmidomycin-piperaquine for the treatment of uncomplicated Plasmodium falciparum monoinfection in Gabon. Adults and children of both sexes with initial parasite counts between 1000 and 150000/µL received oral treatment with fosmidomycin (twice daily doses of 30 mg/kg) and piperaquine (once daily dose of 16 mg/kg) for 3 days and followed-up for 63 days. The primary efficacy endpoint was the per-protocol polymerase chain reaction (PCR)-corrected day 28 adequate clinical and parasitological response (ACPR).. One hundred patients were enrolled. The PCR-corrected day 28 ACPR rate was 83/83, or 100% (95% confidence interval, 96-100). Fourteen patients had asexual parasitaemia between day 28 and day 63; all were typed by PCR as new infections. Fosmidomycin-piperaquine therapy led to rapid parasite clearance (median, 36 hours; interquartile range [IQR], 6-60) and fever clearance time (median, 12 hours; IQR, 6-48). The electrocardiogram assessments showed 2 patients with prolonged QT interval >500 msec following study drug administration. The majority of adverse events affected the gastrointestinal and respiratory tracts and were transient and mild to moderate in severity.. This is the first report of the use of the combination fosmidomycin-piperaquine. 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. Clinical Trials Registration. NCT02198807.

    Topics: Adolescent; Adult; Age Factors; Antimalarials; Artemisinins; Child; Child, Preschool; Combined Modality Therapy; Drug Therapy, Combination; Female; Fosfomycin; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Proof of Concept Study; Quinolines; Treatment Outcome; Young Adult

2018
Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria.
    Antimicrobial agents and chemotherapy, 2012, Volume: 56, Issue:6

    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.

    Topics: Antimalarials; Child, Preschool; Clindamycin; Drug Therapy, Combination; Fosfomycin; Humans; Infant; Infant, Newborn; Malaria, Falciparum

2012
Randomized controlled trial of fosmidomycin-clindamycin versus sulfadoxine-pyrimethamine in the treatment of Plasmodium falciparum malaria.
    Antimicrobial agents and chemotherapy, 2007, Volume: 51, Issue:5

    Fosmidomycin-clindamycin therapy given every 12 h for 3 days was compared with a standard single oral dose of sulfadoxine-pyrimethamine. The two treatments showed comparably good tolerabilities and had an identical high degree of efficacy of 94% in a randomized trial carried out with 105 Gabonese children aged 3 to 14 years with uncomplicated malaria. These antimalarials merit further clinical exploration.

    Topics: Adolescent; Antimalarials; Child; Child, Preschool; Clindamycin; Drug Combinations; Female; Fosfomycin; Humans; Malaria, Falciparum; Male; Pyrimethamine; Sulfadoxine

2007
Pharmacokinetics and pharmacodynamics of fosmidomycin monotherapy and combination therapy with clindamycin in the treatment of multidrug resistant falciparum malaria.
    Malaria journal, 2007, May-25, Volume: 6

    The study investigated the pharmacokinetics of fosmidomycin when given alone and in combination with clindamycin in patients with acute uncomplicated falciparum malaria.. A total of 15 and 18 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from out-patient department of Mae Sot Hospital, Tak Province, Thailand. Patients were treated with monotherapy with fosmidomycin at the dose of 1,200 mg every 8 hours for 7 days (n = 15) or combination therapy with fosmidomycin (900 mg every 12 hours for 7 days) and clindamycin (600 mg every 12 hours for 7 days) (n = 18). Blood samples were taken for pharmacokinetic investigations of clindamycin and/or fosmidomycin and 24-hour urine samples were collected during dosing period. Efficacy assessments included clinical and parasitological evaluation. Safety and tolerability were assessed based on clinical and laboratory investigations.. Both mono- and combination therapy regimens of fosmidomycin were well tolerated with no serious adverse events. Combination therapy with fosmidomycin and clindamycin was proven highly effective with 100% cure rate, whereas cure rate of monotherapy was 22% (28-day follow up). Pharmacokientics of fosmidomycin following mono- and combination therapy were similar except Vz/F and CL/F, which were significantly smaller in the combination regimen. Plasma concentration-time profiles of both fosmidomycin and clindamycin were best fit with a one-compartment open model with first-order absorption and elimination and with absorption lag time. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about the second or third dose. There was no evidence of dose accumulation during multiple dosing. Urinary recovery of fosmidomycin was 18.7 and 20% following mono- and combination therapy, respectively.. Pharmacokinetic dose optimization of fosmidomycin-clindamycin combination therapy with the course of treatment of not longer than three days is required to obtain a regimen which is safe and produced 100% cure for multidrug-resistant P. falciparum.

    Topics: Adolescent; Adult; Antimalarials; Clindamycin; Drug Resistance, Multiple; Drug Therapy, Combination; Female; Fosfomycin; Humans; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Thailand; Treatment Outcome

2007
Fosmidomycin plus clindamycin for treatment of pediatric patients aged 1 to 14 years with Plasmodium falciparum malaria.
    Antimicrobial agents and chemotherapy, 2006, Volume: 50, Issue:8

    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 > or =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.

    Topics: Administration, Oral; Adolescent; Animals; Antimalarials; Blood; Child; Clindamycin; Drug Therapy, Combination; Follow-Up Studies; Fosfomycin; Hemoglobins; Humans; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum

2006
Short-course regimens of artesunate-fosmidomycin in treatment of uncomplicated Plasmodium falciparum malaria.
    Antimicrobial agents and chemotherapy, 2005, Volume: 49, Issue:9

    Fosmidomycin is effective against malaria, but it needs to be given for > or =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 > or =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/microl and 400 to 749/microl, 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.

    Topics: Antimalarials; Artemisinins; Artesunate; Chemistry, Pharmaceutical; Child; Cohort Studies; Dose-Response Relationship, Drug; Drug Combinations; Endpoint Determination; Female; Fosfomycin; Humans; Malaria, Falciparum; Male; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes

2005
Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children.
    The Journal of infectious diseases, 2004, Mar-01, Volume: 189, Issue:5

    Fosmidomycin is a new antimalarial drug with a novel mechanism of action. Studies in Africa that have evaluated fosmidomycin as monotherapeutic agent demonstrated its excellent tolerance, but 3-times-daily treatment regimens of >or=4 days were required to achieve radical cure, prompting further research to identify and validate a suitable combination partner to enhance its efficacy.. We conducted a randomized, controlled, open-label study to evaluate the efficacy and safety of fosmidomycin combined with clindamycin (n=12; 30 and 5 mg/kg body weight every 12 h for 5 days, respectively), compared with fosmidomycin alone (n=12; 30 mg/kg body weight every 12 h for 5 days) and clindamycin alone (n=12; 5 mg/kg body weight every 12 h for 5 days) for the clearance of asymptomatic Plasmodium falciparum infections in schoolchildren in Gabon aged 7-14 years.. Asexual parasites were rapidly cleared in children treated with fosmidomycin-clindamycin (median time, 18 h) and fosmidomycin alone (25 h) but slowly in children treated with clindamycin alone (71 h; P=.004). However, only treatment with fosmidomycin-clindamycin or clindamycin alone led to the radical elimination of asexual parasites as measured by day 14 and 28 cure rates of 100%. Asexual parasites reappeared by day 28 in 7 children who received fosmidomycin (day 14 cure rate, 92% [11/12; day 28 cure rate, 42% [5/12]). All regimens were well tolerated, and no serious adverse events occurred.. The combination of fosmidomycin and clindamycin is well tolerated and superior to either agent on its own with respect to the rapid and radical clearance of P. falciparum infections in African children.

    Topics: Antimalarials; Child; Clindamycin; Cohort Studies; Drug Therapy, Combination; Fosfomycin; Gabon; Hemoglobins; Humans; Malaria, Falciparum; Research Design

2004
Fosmidomycin-clindamycin for the treatment of Plasmodium falciparum malaria.
    The Journal of infectious diseases, 2004, Nov-01, Volume: 190, Issue:9

    It has been demonstrated that fosmidomycin has good tolerability and rapid onset of action, but late recrudescences preclude its use alone; in vitro, clindamycin has been shown to act synergistically with fosmidomycin against Plasmodium falciparum. We conducted a study in pediatric outpatients with P. falciparum malaria in Gabon to evaluate the efficacy and safety of an oral combination of fosmidomycin-clindamycin of 30 mg/kg and 10 mg/kg of body weight, respectively, every 12 h. Patients 7-14 years old were recruited in cohorts of 10. The first 10 patients were treated for 5 days. The duration of treatment was then incrementally shortened in intervals of 1 day if >85% of the patients in a cohort were cured by day 14. All dosing regimens were well tolerated, and no serious adverse events occurred. Asexual parasites and fever rapidly cleared in all patients. Cure ratios of 100% on day 14 were achieved with treatment durations of 5 (10/10 patients), 4 (10/10 patients), 3 (10/10 patients), and 2 days (10/10 patients); 1 day of treatment led to a cure ratio of 50% (5/10 patients). Fosmidomycin-clindamycin is safe and well tolerated, and short-course regimens achieved high efficacy in children with P. falciparum malaria. Fosmidomycin-clindamycin is a promising novel treatment option for malaria.

    Topics: Administration, Oral; Adolescent; Animals; Antimalarials; Blood; Child; Clindamycin; Drug Therapy, Combination; Female; Fever; Fosfomycin; Gabon; Humans; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum

2004
Fosmidomycin, a novel chemotherapeutic agent for malaria.
    Antimicrobial agents and chemotherapy, 2003, Volume: 47, Issue:2

    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.

    Topics: Adult; Animals; Antimalarials; Endpoint Determination; Female; Fosfomycin; Gabon; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Thailand

2003
Fosmidomycin for malaria.
    Lancet (London, England), 2002, Dec-14, Volume: 360, Issue:9349

    Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1.2 g every 8 h), in nine, eight, and ten evaluable patients, respectively. All treatment regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88% (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3 days, respectively. These data suggest that fosmidomycin is a safe and effective treatment for uncomplicated malaria if given for 4 days or more.

    Topics: Adult; Animals; Drug Administration Schedule; Female; Fosfomycin; Gabon; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Treatment Outcome

2002

Other Studies

11 other study(ies) available for fosfomycin and Malaria--Falciparum

ArticleYear
GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites.
    PLoS pathogens, 2022, Volume: 18, Issue:9

    Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the Plasmodium falciparum malaria parasites that allow evasion of our most promising therapeutics and may reveal new drug targets. We utilized fosmidomycin (FSM) as a chemical inhibitor of plastidial isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway. We have thus identified an unusual metabolic regulation scheme in the malaria parasite through the essential glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Two parallel genetic screens converged on independent but functionally analogous resistance alleles in GAPDH. Metabolic profiling of FSM-resistant gapdh mutant parasites indicates that neither of these mutations disrupt overall glycolytic output. While FSM-resistant GAPDH variant proteins are catalytically active, they have reduced assembly into the homotetrameric state favored by wild-type GAPDH. Disrupted oligomerization of FSM-resistant GAPDH variant proteins is accompanied by altered enzymatic cooperativity and reduced susceptibility to inhibition by free heme. Together, our data identifies a new genetic biomarker of FSM-resistance and reveals the central role of GAPDH in MEP pathway control and antimalarial sensitivity.

    Topics: Animals; Antimalarials; Biomarkers; Drug Resistance; Fosfomycin; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Heme; Humans; Malaria, Falciparum; Parasites; Phosphates; Plasmodium falciparum; Terpenes

2022
Metabolic Survival Adaptations of Plasmodium falciparum Exposed to Sublethal Doses of Fosmidomycin.
    Antimicrobial agents and chemotherapy, 2021, 03-18, Volume: 65, Issue:4

    The malaria parasite

    Topics: Antimalarials; Apicoplasts; Fosfomycin; Humans; Malaria, Falciparum; Plasmodium falciparum

2021
The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in Plasmodium falciparum.
    mBio, 2019, 12-10, Volume: 10, Issue:6

    Members of the haloacid dehalogenase (HAD) family of metabolite phosphatases play an important role in regulating multiple pathways in

    Topics: Antimalarials; Carbon; Drug Resistance; Fosfomycin; Glycolysis; Humans; Lactates; Malaria, Falciparum; Phosphoric Monoester Hydrolases; Plasmodium falciparum; Sugar Acids

2019
MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria.
    Journal of medicinal chemistry, 2018, 10-11, Volume: 61, Issue:19

    Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans. In this study, we designed and synthesized a series of α,β-unsaturated analogues of fosmidomycin, a natural product that inhibits DXR in P. falciparum. All compounds were evaluated as inhibitors of P. falciparum. The most promising compound, 18a, displays on-target, potent inhibition against the growth of P. falciparum (IC

    Topics: Aldose-Ketose Isomerases; Animals; Antimalarials; Female; Fosfomycin; Malaria, Falciparum; Mice; Plasmodium falciparum; Prodrugs; Structure-Activity Relationship

2018
Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin.
    The Journal of infectious diseases, 2016, 10-01, Volume: 214, Issue:7

    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.

    Topics: Antimalarials; Child, Preschool; Clindamycin; Clinical Trials as Topic; Drug Resistance; Fosfomycin; Genome, Protozoan; Genomics; Genotype; Humans; Infant; Malaria, Falciparum; Mozambique; Plasmodium falciparum; Sequence Analysis, DNA; Treatment Failure

2016
Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria.
    Malaria journal, 2008, Oct-31, Volume: 7

    This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria.. A total of 70 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrolment criteria were recruited in the pharmacokinetic study. Patients were treated with two different dosage regimens of fosmidomycin in combination with clindamycin as follows:Group I: fosmidomycin (900 mg) and clindamycin (300 mg) every 6 hours for 3 days (n = 25); and Group II: fosmidomycin (1,800 mg) and clindamycin (600 mg) every 12 hours for 3 days (n = 54).. Both regimens were well tolerated with no serious adverse events. The 28-day cure rates for Group I and Group II were 91.3 and 89.7%, respectively. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about 24 hr after the first dose. The pharmacokinetics of both fosmidomycin and clindamycin analysed by model-independent and model-dependent approaches were generally in broad agreement. There were marked differences in the pharmacokinetic profiles of fosmidomycin and clindamycin when given as two different combination regimens. In general, most of the dose-dependent pharmacokinetic parameters (model-independent C(max): 3.74 vs 2.41 microg/ml; C(max-ss): 2.80 vs 2.08 microg/ml; C(max-min-ss): 2.03 vs 0.71 microg/ml; AUC: 23.31 vs 10.63 microg.hr/ml (median values) were significantly higher in patients who received the high dose regimen (Group II). However, C(min-ss) was lower in this group (0.80 vs 1.37 microg/ml), resulting in significantly higher fluctuations in the plasma concentrations of both fosmidomycin and clindamycin following multiple dosing (110.0 vs 41.9%). Other pharmacokinetic parameters, notably total clearance (CL/F), apparent volume of distribution (V/F, V(z)/F) and elimination half-life (t(1/2z), t(1/2e)) were also significantly different between the two dosage regimens. In addition, the dose-dependent pharmacokinetics of both fosmidomycin and clindamycin tended to be lower in patients with recrudescence responses in both groups.. The findings may suggest that dosing frequency and duration have a significant impact on outcome. The combination of fosmidomycin (900 mg) and clindamycin (300-600 mg) administered every six hours for a minimum of five days would constitute the lowest dose regimen with the shortest duration of treatment and which could result in a cure rate greater than 95%.

    Topics: Adolescent; Adult; Animals; Antimalarials; Area Under Curve; Clindamycin; Drug Therapy, Combination; Female; Fosfomycin; Half-Life; Humans; Malaria, Falciparum; Male; Metabolic Clearance Rate; Middle Aged; Plasma; Plasmodium falciparum; Time Factors; Treatment Outcome

2008
Molecular epidemiology of malaria in Cameroon. XXV. In vitro activity of fosmidomycin and its derivatives against fresh clinical isolates of Plasmodium falciparum and sequence analysis of 1-deoxy-D-xylulose 5-phosphate reductoisomerase.
    The American journal of tropical medicine and hygiene, 2007, Volume: 77, Issue:2

    The in vitro activities of fosmidomycin derivatives, chloroquine, and pyrimethamine were assessed by the radioisotopic assay in clinical isolates of Plasmodium falciparum. In a series of experiments with RPMI 1640 medium-10% fetal bovine serum, the geometric mean 50% inhibitory concentrations (IC(50)s) (n = 34) for fosmidomycin and FR900098 were 301 nM and 118 nM, respectively. In another series of experiments, the geometric mean IC(50)s (n = 33) for fosmidomycin and TH II46 were 413 nM and 249 nM, respectively. The IC(50)s were 2-3 times lower with RPMI-10% fetal bovine serum than the IC(50)s obtained with RPMI-10% human serum. FR900098 and TH II46 were 2.6 and 1.7 times more potent, respectively, than fosmidomycin. There was no correlation between chloroquine or pyrimethamine and fosmidomycin, which suggested the absence of in vitro cross-resistance. Sequence analysis showed five amino acid substitutions, but their possible relationship with the response to fosmidomycin is not clear. Fosmidomycin derivatives are promising candidates for further development.

    Topics: Adolescent; Aldose-Ketose Isomerases; Amino Acid Sequence; Animals; Cameroon; DNA, Protozoan; Enzyme Inhibitors; Fosfomycin; Humans; Malaria, Falciparum; Molecular Epidemiology; Multienzyme Complexes; Oxidoreductases; Parasitic Sensitivity Tests; Plasmodium falciparum; Sequence Alignment; Sequence Analysis, DNA

2007
Assessment of in vitro antimalarial interactions between dihydroartemisinin and fosmidomycin.
    The Southeast Asian journal of tropical medicine and public health, 2007, Volume: 38, Issue:5

    Malaria remains one of the leading causes of morbidity and mortality in the tropics with an annual estimate of 500 million clinical cases and 2 million deaths. The treatment and control of malaria is becoming increasingly difficult due to Plasmodium falciparum resistance to commonly used antimalarials. Combination therapy is currently the strategy for combating multi-drug resistant falciparum malaria, through exploiting pharmacodynamic synergistic effects and delaying the emergence of drug resistance. The combination of artemisinin derivatives with fosmidomycin, which have different modes of action, appears to be one of the most promising combinations. The objective of the present study was to investigate the antimalarial interactions between dihydroartemisinin and fosmidomycin in vitro, against chloroquine-resistant (K1) and chloroquine-sensitive (G112) P. falciparum strains. Concentration-response analysis was performed based on an in vitro schizont maturation inhibition test. The fixed concentration ratios of dihydroartemisinin: fosmidomycin used were 0:5,000, 2:4,500, 6:3,500, 10:2,500, 14:1,500, 18:500 and 20:0 nM. The highest final concentrations of dihydroartemisinin and fosmidomycin were 20 and 5,000 nM, respectively. Results showed IC50 (drug concentration which produced 50% schizont maturation inhibition) medians (range) for dihydroartemisinin against K1 and G112 strains to be 1.6 (1.2-2.0) and 2.5 (2.4-2.6) nM, respectively. The IC50 medians (range) for fosmidomycin against K1 and G112 strains were 1,347 (1,068-1,625) and 786 (737-834) nM, respectively. An isobologram revealed an increasing trend for the fraction IC50 (FIC), which indicates marked antagonism of this drug combination against both chloroquine resistant and chloroquine sensitive strains.

    Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Fosfomycin; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Plasmodium falciparum; Schizonts; Sesquiterpenes

2007
The methylerythritol phosphate pathway is functionally active in all intraerythrocytic stages of Plasmodium falciparum.
    The Journal of biological chemistry, 2004, Dec-10, Volume: 279, Issue:50

    Two genes encoding the enzymes 1-deoxy-D-xylulose-5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase have been recently identified, suggesting that isoprenoid biosynthesis in Plasmodium falciparum depends on the methylerythritol phosphate (MEP) pathway, and that fosmidomycin could inhibit the activity of 1-deoxy-D-xylulose-5-phosphate reductoisomerase. The metabolite 1-deoxy-D-xylulose-5-phosphate is not only an intermediate of the MEP pathway for the biosynthesis of isopentenyl diphosphate but is also involved in the biosynthesis of thiamin (vitamin B1) and pyridoxal (vitamin B6) in plants and many microorganisms. Herein we report the first isolation and characterization of most downstream intermediates of the MEP pathway in the three intraerythrocytic stages of P. falciparum. These include, 1-deoxy-D-xylulose-5-phosphate, 2-C-methyl-D-erythritol-4-phosphate, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol-2-phosphate, and 2-C-methyl-D-erythritol-2,4-cyclodiphosphate. These intermediates were purified by HPLC and structurally characterized via biochemical and electrospray mass spectrometric analyses. We have also investigated the effect of fosmidomycin on the biosynthesis of each intermediate of this pathway and isoprenoid biosynthesis (dolichols and ubiquinones). For the first time, therefore, it is demonstrated that the MEP pathway is functionally active in all intraerythrocytic forms of P. falciparum, and de novo biosynthesis of pyridoxal in a protozoan is reported. Its absence in the human host makes both pathways very attractive as potential new targets for antimalarial drug development.

    Topics: Animals; Antimalarials; Dolichols; Erythritol; Erythrocytes; Fosfomycin; Genes, Protozoan; Humans; Malaria, Falciparum; Molecular Structure; Pentosephosphates; Plasmodium falciparum; Pyridoxal Phosphate; Spectrometry, Mass, Electrospray Ionization; Sugar Phosphates; Ubiquinone

2004
Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs.
    Science (New York, N.Y.), 1999, Sep-03, Volume: 285, Issue:5433

    A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably located in the apicoplast. The recombinant P. falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its derivative, FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.

    Topics: Aldose-Ketose Isomerases; Amino Acid Sequence; Animals; Antimalarials; Cloning, Molecular; Enzyme Inhibitors; Fosfomycin; Genes, Protozoan; Hemiterpenes; Malaria; Malaria, Falciparum; Mevalonic Acid; Mice; Molecular Sequence Data; Multienzyme Complexes; Organelles; Organophosphorus Compounds; Oxidoreductases; Pentosephosphates; Plasmodium falciparum; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Terpenes

1999
Planting the seeds of new antimalarial drugs.
    Science (New York, N.Y.), 1999, Sep-03, Volume: 285, Issue:5433

    Topics: Aldose-Ketose Isomerases; Animals; Antimalarials; Drug Design; Enzyme Inhibitors; Fosfomycin; Hemiterpenes; Humans; Malaria; Malaria, Falciparum; Mice; Multienzyme Complexes; Organelles; Organophosphorus Compounds; Oxidoreductases; Plasmodium falciparum; Steroids; Transferases

1999