Antibiotic Approvals by ID Fellows Compared With Antibiotic Management Team
In a study conducted at the Hospital of the University of Pennsylvania in November 1993 (Gross et al, Clin Infec Dis 2001;33:289–95), a comparison was made of the appropriateness of antibiotic approvals for restricted drugs between first-and second-year ID fellows and an Antibiotic Management Team (AMT). The AMT consisted of a full-time clinical pharmacist with an ID director. The ID fellows had access to a handbook containing guidelines for appropriate antibiotic treatment. Requests for restricted drugs were transmitted via a dedicated beeper that was carried by the AMT pharmacist during weekdays and by ID fellows during evenings and weekends. The respondent entered demographic details, culture results, the name of the requested drug, and the name of the drug recommended by the staff (AMT or fellow) onto a card. As assessed in a blinded fashion by the director of the AMT, there was a significantly higher rate of “appropriate” recommendations and a higher rate of “cure” and a lower rate of “failure” of treatment when recommendations were made by the AMT rather than by fellows. The study was not randomized, but the two groups of patients were similar. The main reasons for inappropriateness of the antibiotic choice were excessive cost (compared with an equivalent regimen) and unnecessarily broad spectrum. It is difficult to understand why either of these deficiencies of an antibiotic choice would affect the clinical outcomes. The authors suggest that one explanation for the higher rate of appropriate recommendations by the AMT may be that the incentive to be firm and adherent to guidelines may have been greater for the clinical pharmacist, “whose job evaluation depended on the quality of her recommendations,” than it was for ID fellows, for whom the approval process may have been perceived as a burdensome distraction. I would also question whether requests made during evenings and weekends (those the fellows dealt with) might not be dealt with more summarily than those transmitted during weekdays. It is not clear what other medical information may have been solicited and provided at the time of the request. Overall, I find the study interesting and the results plausible but, because of the study design, not absolutely convincing.
Biofilms and Bacterial Persistence
It is well known to ID physicians that bacteria growing on implanted medical devices grow in the form of biofilms (matrices of polysaccharide and protein) and that infections of these devices are difficult to eradicate without removing the devices. The minimal inhibitory concentrations (MICs) required to inhibit or kill bacteria growing in biofilms usually are many-fold higher than those for bacteria growing in suspensions or tissue fluids. The precise reasons for this phenomenon are not fully understood. An excellent review by Stewart and Costerton (Lancet 2001;358:135–8) summarizes recent information in this area. It is well established that ordinary antibiotic-resistance mechanisms such as target mutations, antibiotic-modifying enzymes, and efflux pumps usually play little or no role. Instead, three possible mechanisms have been advanced. One relates to poor antibiotic penetration through the biofilm matrix. However, the matrices consist primarily of water and should not pose a barrier to most antibiotics. Certain antibiotics such as aminoglycosides (positively charged) could be adsorbed to the negatively charged matrix proteins, but such binding would not apply to most antibiotics. A second hypothesis relates to altered chemical microenvironments within the biofilm. There appear to be niches in which the microenvironment is relatively anaerobic or acidic, which could affect the activity of some drugs. Depletion of substrate or accumulation of certain waste products could cause bacteria to enter into a non-growing or metabolically inactive state, which could mitigate the activity of some drugs. (I, personally, favor this hypothesis and think it may apply to most categories of antibiotics, not just those that act on the cell wall.) A third potential mechanism is that a subpopulation of bacteria within the biofilm might enter into a unique phenotypic state akin to spore formation. (One wonders if this state might be one of extreme metabolic inactivity, as noted above.) Whatever the mechanism, it is a temporary one because bacteria taken from biofilms and studied in suspensions show normal MICs. Interestingly, the review does not mention the resistance to ingestion by phagocytes conferred by growth in the biofilm mode. The review is an excellent summary of an increasingly important area in infectious disease.
Polio Eradication: Are We Near?
In a recent issue of ASM News (2001;67:397–402), Walter Dowdle, former Deputy Director of the CDC and an advisor to the World Health Organization (WHO) Polio Eradication Initiative, summarizes the status of the polio eradication campaign. The WHO assembly resolved in 1988 to eradicate polio worldwide by 2000. That goal has not been reached, but it is close and there is reason to hope for eradication by 2005. The last indigenous case occurred in 1991 in the Americas, in 1997 in the Western Pacific Region, and in 1998 in Europe. Key to eradication has been mass immunization strategies with oral polio vaccine (OPV) for children under 5 years of age, together with aggressive surveillance. All cases of acute flaccid paralysis are investigated and stool specimens are studied to determine if isolates are wild virus, “drifted” OPV-derived viruses, or laboratory contaminants. Three criteria have been suggested by a WHO Committee that should be met before immunization is discontinued: 1) no isolations of wild polioviruses for at least 3 years from all six global regions; 2) assurance that vaccinederived polioviruses (VDPV) will not continue to circulate; and 3) containment of remaining stocks of infected materials. The second item can be problematic in that OPV strains occasionally revert to virulence (feral VDPV). Indeed, recently there was an outbreak of feral VDPV on the island of Hispaniola; it was contained by appropriate immunization. Although vaccine strains generally disappear from well-immunized populations within approximately 3 months of the last administration, immunocompromised people rarely continue to excrete the vaccine strain for prolonged periods; generally, this problem can be addressed by hygienic measures. The containment of remaining stocks of the virus or infected material is a much larger problem than it was for smallpox in that materials containing the virus are present in many laboratories—for example, in throat or fecal samples that are being retained for a variety of investigations, possibly not relating to viral infection. Even if the three WHO criteria can be met, some argue that OPV should continue to be given because of uncertainty that the virus has been eradicated. This article is a superb overview of the complexities involved in attempts to eradicate a disease.