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691the urine (preferably 100% of unchanged material) will give valuable information about possible metabolism or excretion by other routes or inactivation by binding. Very occasionally an antibiotic is found which appears to have little or no means of elimination. A new polypeptide antibiotic, highly active against staphylococci resistant to many other antibiotics, was found recently which, upon injection, circulated for days on end (P W Muggleton & W F J Cuthbertson, personal communication). Protection could be obtained in mice when a challenge dose of staphylococci was preceded by a single dose of the antibiotic given more than 24 hours previously. The accumulation and toxic effects which might occur if repeated doses of such an antibiotic were given led to its rejection. Toxicity testingRegardless of how effective an antibiotic might be in protecting animals against an experimental infection, it cannot be used if it is likely to be toxic. Such is the armamentarium of antibiotics now available to the physician that very high standards of acceptability must be met. In progressing a compound which looks promisingly effective in vitro and in vivo, it is usual to do preliminary tests in two species to eliminate quickly any highly toxic substance and to look for any specific target organs as the sites of toxicity. Obviously, whether it will be safe to proceed further with the compound will depend partly on the size of the ratio between the maximum dose producing no toxic effect and the dose producing a therapeutic effect, as revealed by the previous protection tests in animals. If this therapeutic ratio appears favourable, then further tests for possible toxicity must be done to progress the compound for administration to man. Often this progression occurs in three stages, the first of which is to clear the compound for the administration of single or a few repeat doses to human volunteers for pharmacokinetic studies. If the results of these studies are no good, the compound is rejected and the use of further laboratory animals is avoided. If the results are satisfactory, the second stage of much more extensive toxicity testing is undertaken, sufficient to clear the compound for limited clinical trial in patients. At this stage if full teratology studies have not been done, women of childbearing potential would be excluded from the trials. If these pilot, limited trials are satisfactory, full teratological and embryopathological studies will be done, together with any special toxicological investigations that may be necessary, such as determination of sensitizing potential and mutagenicity.Assuming all goes well and extended clinical trials indicate that we have an antibiotic worthy of introduction into medical use, i.e. the results indicate that it may do something new, better or more safely, still further animal testing may be required to satisfy the registration authorities -the requirements often differing from country to country -before a licence to sell the substance is given.It would be impossible at present...

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