ABSTRACT
When measuring the effects of chemotherapeutic agents (antibacterial, antiviral, antifungal, antiprotozoal, and anticancer drugs) the primary end point is killing cells of the pathogen. Many important aspects of drug action can be understood at the whole-cell level — dose-response relationships, selectivity, resistance, and cell cycle specificity. Cell proliferation, cell killing, and cytostasis can all be measured in vitro, and these in vitro parameter values may then be used to predict the course of the disease and its treatment in vivo. The science of cytokinetics provides quantitative tools for the study of these questions. The simplest kinds of cytokinetic model assume a homogeneous pathogen population, with a uniform cell doubling time (and thus exponential growth). Even an unrealistically simple model, neglecting effects of the immune system, acquired drug resistance, heterogeneity of doubling times, and noncycling cell populations, can be useful for asking some kinds of questions. For example, if we have an antimicrobial drug that can eliminate 3 logs of pathogen at its maximum tolerated daily dose, and survivors grow back with a 2.5-h doubling time, and if 11 logs of pathogen cells constitute a lethal dose, what is the largest initial inoculum that can be completely eliminated by daily treatments, and how many treatments will be required? These questions may be studied using the ANTIBACT program (see Appendix). This is a program that simulates effects of antibacterial drugs, administered singly or in combination, at doses and times chosen by the user, on exponentially growing populations of bacteria. Sample output from ANTIBACT is shown in Figure 6.1. Starting with an inoculum of 100 cells, a regimen that gave three log kill every 24 h (beginning at 24 h) eliminated the infection in 19 d. If the inoculum was increased to 2000 cells, the infection could be eliminated in 30 treatments. Larger inocula could not be controlled by 30 daily treatments. If the doubling time was increased to 3 h, even very large inocula (anything that did not cause death before the first treatment at 24 h) could be controlled by not more than 15 daily treatments. Conversely, if the doubling time was decreased to 2 h,
Days
treatment with a regimen that gave three log kill every 24 h could not control bacterial proliferation, and even an inoculum of one cell was lethal.
