Comment: anticholinesterase insecticide reactions.

Abstract

was the major disqualifying factor. Perhaps this was a function of the patients' ages, as there were many elderly patients in both groups. Because at both institutions patients must be able to give informed consent, those patients not of sound mind were excluded from study participation. Numerous patients had received prior antibiotics either at home or at outlying hospitals before admission to Duke. Many patients at both institutions had multiple exclusion factors, but the percentage of these patients was higher at the tertiary care center. According to a survey of members of the Infectious Diseases Society of America, approximately 70 percent of respondents (primarily in academic centers) are involved in conducting trials with investigational antibiotics." Therefore, it appears that most Phase II and III antibiotic protocols are conducted in academic centers which traditionally house more seriously ill patients and, therefore, where fewer numbers of patients are eligible for inclusion. Nonetheless, in our study, a much lower number of community hospital patients were deemed eligible for protocol enrollment than would be expected. These data are disturbing. A consequence of the low numbers of patients in both community and teaching hospitals eligible for investigational antibiotic protocols is that most seriously ill, debilitated patient groups who will be receiving the marketed drug never will have been exposed to it during the drug approval process. Food and Drug Administration guidelines suggest that patients for whom new drugs are intended (especially the elderly) should be included in clinical trials. 5 Without the inclusion of these patients in Phases II and III studies, we will have little premarketing data on antibiotic efficacy and safety in these groups. We have other clues with which we can make intelligent judgments on patient response or failure to respond to antibiotics, such as in vitro activity, pharmacokinetics, and host defense status, but little data on toxicity and adverse effect profiles in these patient populations will be available. Because these patients are more complicated, they are likely to be at higher risk for developing adverse effects. We have seen how these toxicities tend to surface once the drugs are used in the intended populations: for example, the bleeding problems seen when antibiotics containing the N-methylthiotetrazole side chain are administered to malnourished, debilitated patients" and the incidence of seizures reported with imipenemcilastatin." We see no easy solution to this problem, and agree with other authors that better designed trials that include more complex patients stratified by severity of infection and underlying diseases are needed. These investigations will be more complicated and will take longer to complete, and the industry is not likely to welcome this situation. We can only hope that the present system of drug approval is not ultimately compromising drug efficacy and safety in the intended patient populations.