BioWorld International Correspondent
LONDON - An antibiotic that was partially developed and then left on the shelf two decades ago has been hailed as "quite a breakthrough" in the treatment of malaria. The compound, fosmidomycin, can treat malaria with 100 percent success within four days. It can be taken by mouth and has few side effects.
Peter Kremsner, professor at the Institute of Tropical Medicine of the University of Tubingen in Germany, told BioWorld International that he and his colleagues have already begun trials to evaluate the use of fosmidomycin in combination with other antimalarials, in the hope of being able to bring about a cure in three days or less. He said, "We are very pleased with the results with fosmidomycin, but on its own it will not be enough because people will not usually take antimalarial drugs for longer than three days."
The study is reported in a paper in the Dec. 14, 2002, issue of The Lancet titled "Fosmidomycin for malaria."
Fosmidomycin was originally discovered during the 1980s. More recently, Hassan Jomaa, of Jomaa Pharmaka GmbH in Giessen, Germany, reinvestigated it after scanning the genome of the malarial parasite, Plasmodium falciparum. He realized that the parasite had some of the same metabolic pathways as some bacteria, and that it might succumb to some drugs previously thought to act only against certain bacteria.
P. falciparum, like other malarial parasites, and some other unicellular parasites (such as Toxoplasma), has a cellular organelle called an apicoplast. The metabolic pathways inside the apicoplast are geared toward making isoprenoids, which are used in making several essential molecules for the parasite. Fosmidomycin, which is a derivative of phosphonic acid, blocks one of the key enzymes of the apicoplast, known as 1-deoxy-D-xylulose 5-phosphate, or DOXP.
The drug can inhibit the growth of multidrug-resistant strains of malaria in vitro. In clinical trials, it has been shown to be safe and well tolerated.
The paper in The Lancet reports the results of a trial of fosmidomycin in patients with malaria, which was funded mainly by the European Commission. Kremsner, Jomaa and their colleagues worked with colleagues at the Albert Schweitzer Hospital in Lambarene, Gabon. In that part of the world, 100 percent of P. falciparum isolated is resistant to chloroquine in laboratory tests, and 30 percent is resistant to the combination of sulfadoxine and pyrimeth-amine.
Adult patients with parasitemia of 1,000 to 100,000 parasites per microliter of blood received the drug, in a dose of 1.2 grams every 8 hours. The group initially treated 10 patients for seven days, and achieved a 100 percent cure rate, with no relapse within 14 days. They found they could achieve a cure rate of 89 percent with just five days of treatment. With four days of treatment, the cure rate was 88 percent. With shorter periods of treatment, the cure rate dropped below the researchers' definition of an effective cure, which they set at 80 percent.
Among the 32 patients treated, 19 reported side effects possibly related to the drug. The most frequent were headache, weakness, muscle pains, abdominal pain and loose stools.
Kremsner and his colleagues are already preparing a paper on their subsequent study, which involved treating patients with several other antimalarials, including clindamycin, but could not comment on these results.
He predicted that if fosmidomycin becomes widely used, the parasites will become resistant to it. "We will face that at some point," he said, "but the good news is that fosmidomycin is not related to any other compound used to treat malaria, so there is no pressure on the parasite so far. This drug has an entirely new mode of action."