Fighting hospital superbugs

In recent years the “hospital superbug” Clostridium difficile has gained notoriety as a major cause of illness and death among patients, and poses a particular danger to the elderly.   C.diff is found naturally in the intestines of a minority of the human population and usually poses no threat, but when the bacterial population of the gut is disturbed, for example by treatment with antibiotics that kill a broad range of bacteria, it can quickly multiply, producing toxins that cause diarrhea and colitis.  Rigorous cleaning can help prevent the spread of C.diff but it cannot prevent it entirely because many patients will be carrying the bacteria upon admission to hospital.  As you’d expect treatment with antibiotics is the usual practice when C.diff infection is diagnosed, but here there is another problem; C.diff is resistant to most available antibiotics. Only two antibiotics, metronidazole and vancomycin are commonly used to treat it.   This lack of antibiotic options is of grave concern since neither antibiotic is successful in clearing the infection in all patients, but the greatest worry for the medical community is that C.diff will evolve resistance to one or both of these antibiotics, a development that would drastically reduce treatment options.

The development of new drugs that can kill C.diff is a priority, so it was good to hear that a new antibiotic named OPT-80, developed by the San Diego based Optimer Pharmaceuticals, has performed well in a large clinical trial. In the Phase III trial OPT-80 was found to be as good at clearing C.diff infection as vancomycin and better at preventing a reoccurrence of the disease.  It was also found in an earlier Phase II trial to be free from adverse reactions (1), due in part to the fact that it is very selective for C.diff, leaving other gut bacteria intact, and to the fact that it stays in the intestine, with almost none crossing into the bloodstream.

These properties were selected during early research when OPT-80, then named tiacumicin B, was identified by Abbott Laboratories during screening of antibiotics produced by the bacterium Dactylosporangium aurantiacum for any that could be medically useful (2). Tiacumicin B was found to have a strong and selective anti-bacterial activity against C.diff in vitro.  Good activity in vitro does not necessarily predict whether an antibiotic will clear an infection in a living patient, toxicity, accumulation in the wrong organs, or a poor metabolic profile can all scupper a promising drug, so the scientists at Abbott turned to the hamster, an animal in which the full spectrum of symptoms including diarrhoea and colitis following C. difficile infection are seen.  In hamsters tiacumicin B was found to be as effective as vancomycin in treating C.diff and to stay within the intestine when given orally, just as was later observed in human patients.  These results, and later pre-clinical safety studies which showed it to be safe even at high doses when given orally to rats and monkeys, lead to tiacumicin B, by now renamed OPT-80, entering clinical trials in human patients where it appears to be performing well.

Turning to another, and it must be admitted sexier, field of research Mo over at the Neurophilosophy blog has written a nice account of research by Japanese scientists who are producing brain tissue from embryonic stem cells.  This research may in time aid the development of stem cell treatments for diseases such as Alzheimers and ALS but in the short term it should help scientists to develop better in vitro models of brain development and function, to be used in basic research and the evaluation of new drugs. Good work, and a blog worth keeping an eye on!

Regards
Paul Browne
1) Louie T. et al. “Clinical outcomes, safety and pharmacokinetics of OPT-80 in a phase 2 trial of patients with Clostridium difficile infection.” Antimicrobial Agents and Chemotherapy, Published Online Oct 2008, DOI:10.1128/AAC.01442-07.2) Swanson R.N. et al. “In vitro and in vivo evaluation of tiacumicins B and C against Clostridium difficile.” Antimicrobial Agents and Chemotherapy, Vol. 35(6), pages 1108-1111 (1991). PubMed Central: PMC284295.

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