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Antibacterials for filarial infections
Newsdesk Antibacterials for filarial infections “I work on worms, or at least I thought I did”, said Mark Taylor (Liverpool School of Tropical Medicine, UK) as he described the role of symbiotic Wolbachia spp bacteria in the pathogenesis of filarial nematode diseases, at the International Congress on Infectious Diseases (Cancun, Mexico, March 3–7, 2004). Filarial diseases, which affect more than 150 million people, include lymphatic filariasis (see page 223) caused by Wuchereria bancrofti and Brugia malayi, and river blindness caused by Onchocerca volvulus. Wolbachia spp, which are a type of rickettsia related to Ehrlichia spp, are, said Taylor, largely responsible for the pathogenesis of filarial disease: they are the major stimulus of innate inflammation, their release coincides with severe inflammatory adverse reaction, they recruit neutrophils to onchocerca nodules and causes neutrophil-mediated keratitis in a mouse model, and the antibody
responses to wolbachia surface protein is associated with presentation of chronic pathology. In lymphatic filariasis, the bacteria can be detected in hydrocoele fluid and are found in W bancrofti samples worldwide. The discovery that antirickettsial drugs such as doxycycline can eliminate wolbachia has led to trials of antibiotics in the treatment of filarial diseases. Antibacterial treatment produces a therapeutic double-whammy, and demonstrates just how dependent the nematodes are on their intracellular symbiotic companions. Not only are wolbachia eliminated, but killing the bacteria is lethal to larval and embryonic development stages of the worms, permanently blocks embryogenesis leading to sustained reductions in microfilaria, and has long-term effects on adult worm fertility and viability. Taylor presented the results of a double-blind, placebo-controlled trial of doxycycline to treat lymphatic
filariasis, which was completed recently in Tanzania. Men with greater than 100 microfilaria/mL of blood were randomised to receive for 8 weeks either 200 mg per day of doxycycline (34 patients) or placebo (38 patients). Reported side-effects were mild and none were reported after 10 days. By 8 months of follow-up, complete elimination of microfilaraemia was observed in the treatment group, with no change in the placebo group. At 14 months of follow-up, ultrasound detection of worm “dance sign” showed that adults worms has disappeared from 78% of patients in the doxycycline group. Among the questions that remain to be answered in this highly promising line of research are the optimum timing of co-treatment with antifilarial drugs, and whether antibiotics can alleviate adverse reactions to antifilarial drugs and prevent the onset of pathology. John McConnell
Diarrhoeal gases emit chemical fingerprints Using equipment more familiar to the organic chemist than to the microbiologist, researchers capture the volatile chemicals emitted from stool samples to identify diarrhoeal pathogens (Gut 2004; 53: 58–61). “Specific volatile chemicals are associated with particular infections, thus these volatiles could be used to identify the type of organism causing the diarrhoea”, Christopher Probert (Bristol Royal Infirmary, Bristol, UK) told TLID. For example, furan species without indoles indicated Clostridium difficile, ethyl dodecanoate indicated rotavirus, and ammonia without ethyl dodecanoate suggested Norwalk virus. However, campylobacter infection was identified by the absence of hydrocarbons and terpenes, according to the authors. Herbert Dupont (Department of Medicine, Baylor College of Medicine, Houston, TX, USA) praised the concept but warned that, “Its
194
applicability needs to be explored and worked out”. Sealed headspace vials containing stool samples (about 0·75g) were
A mass spectrometer at work
equilibrated at 37⬚C; volatile compounds were adsorbed from the headspace onto solid-phase microextraction fibre and analysed using gas chromatography and mass
spectroscopy. Probert’s co-authors had previously used the technique to identify diseased vegetables. Analysis included fresh stool and frozen archived samples from 38 patients with diarrhoea (C difficile, Campylobacter spp, rotavirus, Norwalk virus, adenovirus, astrovirus, and giardiasis were identified) and six healthy controls. Dupont says that many more samples need to be analysed before the applicability of the new method can be determined. According to Probert, the new method could be made much faster than standard microbiological workups. Says Probert: “we hope that aid agencies and NGOs assisting during natural disasters and other publichealth emergencies will use it”. Probert expects that “the analysis could be made very low tech”, which would make mass spectroscopy accessible in developing countries. Mary Quirk
THE LANCET Infectious Diseases Vol 4 April 2004
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
responses to wolbachia surface protein is associated with presentation of chronic pathology. In lymphatic filariasis, the bacteria can be detected in hydrocoele fluid and are found in W bancrofti samples worldwide. The discovery that antirickettsial drugs such as doxycycline can eliminate wolbachia has led to trials of antibiotics in the treatment of filarial diseases. Antibacterial treatment produces a therapeutic double-whammy, and demonstrates just how dependent the nematodes are on their intracellular symbiotic companions. Not only are wolbachia eliminated, but killing the bacteria is lethal to larval and embryonic development stages of the worms, permanently blocks embryogenesis leading to sustained reductions in microfilaria, and has long-term effects on adult worm fertility and viability. Taylor presented the results of a double-blind, placebo-controlled trial of doxycycline to treat lymphatic
filariasis, which was completed recently in Tanzania. Men with greater than 100 microfilaria/mL of blood were randomised to receive for 8 weeks either 200 mg per day of doxycycline (34 patients) or placebo (38 patients). Reported side-effects were mild and none were reported after 10 days. By 8 months of follow-up, complete elimination of microfilaraemia was observed in the treatment group, with no change in the placebo group. At 14 months of follow-up, ultrasound detection of worm “dance sign” showed that adults worms has disappeared from 78% of patients in the doxycycline group. Among the questions that remain to be answered in this highly promising line of research are the optimum timing of co-treatment with antifilarial drugs, and whether antibiotics can alleviate adverse reactions to antifilarial drugs and prevent the onset of pathology. John McConnell
Diarrhoeal gases emit chemical fingerprints Using equipment more familiar to the organic chemist than to the microbiologist, researchers capture the volatile chemicals emitted from stool samples to identify diarrhoeal pathogens (Gut 2004; 53: 58–61). “Specific volatile chemicals are associated with particular infections, thus these volatiles could be used to identify the type of organism causing the diarrhoea”, Christopher Probert (Bristol Royal Infirmary, Bristol, UK) told TLID. For example, furan species without indoles indicated Clostridium difficile, ethyl dodecanoate indicated rotavirus, and ammonia without ethyl dodecanoate suggested Norwalk virus. However, campylobacter infection was identified by the absence of hydrocarbons and terpenes, according to the authors. Herbert Dupont (Department of Medicine, Baylor College of Medicine, Houston, TX, USA) praised the concept but warned that, “Its
194
applicability needs to be explored and worked out”. Sealed headspace vials containing stool samples (about 0·75g) were
A mass spectrometer at work
equilibrated at 37⬚C; volatile compounds were adsorbed from the headspace onto solid-phase microextraction fibre and analysed using gas chromatography and mass
spectroscopy. Probert’s co-authors had previously used the technique to identify diseased vegetables. Analysis included fresh stool and frozen archived samples from 38 patients with diarrhoea (C difficile, Campylobacter spp, rotavirus, Norwalk virus, adenovirus, astrovirus, and giardiasis were identified) and six healthy controls. Dupont says that many more samples need to be analysed before the applicability of the new method can be determined. According to Probert, the new method could be made much faster than standard microbiological workups. Says Probert: “we hope that aid agencies and NGOs assisting during natural disasters and other publichealth emergencies will use it”. Probert expects that “the analysis could be made very low tech”, which would make mass spectroscopy accessible in developing countries. Mary Quirk
THE LANCET Infectious Diseases Vol 4 April 2004
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet.