Merrill J. Snyder

An evaluation of optimal sampling strategy and adaptive study design

We have evaluated the utility of optimal sampling strategy coupled with adaptive study design in the determination of individual patient and population pharmacokinetic parameter values. In 9 patients with cystic fibrosis receiving a short (1 minute) infusion of ceftazidime pharmacokinetic parameter values were determined with a nonlinear least‐squares estimator analyzing a traditional, geometrically spaced set of 12 postinfusion serum samples drawn over 8 hours. These values were compared with values generated from four sample subsets of the 12 obtained at optimal times and analyzed by nonlinear least‐squares estimator, as well as a maximum a posteriori probability Bayesian estimator with prior distributions placed on β and clearance. The four sampling times were determined according to an adaptive design optimization technique that employs sequential updating of population prior distributions on parameter values. Compared with the 12‐point determination, the four optimal points analyzed with the maximum a posteriori probability Bayesian estimator faithfully reproduced both microscopic and hybrid pharmacokinetic parameter values for individual patients and, consequently, also produced accurate measures of population central tendency and dispersion. This has important implications in being able to more efficiently derive target patient population pharmacokinetic information for new drugs. This should also allow generation of better concentration‐effect relationships in populations of interest.

EXPERIMENTAL MODELS IN THE INVESTIGATION OF THE VIRULENCE OF DYSENTERY BACILLI AND ESCHERICHIA COLI

The knowledge gained from experiments in laboratory models has been very useful in helping us to reach our present understanding of the pathogenesis of some diarrheal diseases of human beings. This is especially true of bacillary dysentery. Dysentery may be defined as a syndrome in which blood, inflammatory cells, and mucus are present in the watery stool. A cardinal feature of classical shigellosis is an ulcerative lesion of the colonic mucosa, for it is through this defect in the epithelial barrier that the red blood cells reach the intestinal lumen. Thus, in order to gain some insight into at least one aspect of the pathogenesis of classical bacillary dysentery, one must understand how the ulcerative lesion evolves. The previous concept of the evolution of the colonic ulcer envisioned consecutive waves of absorption and excretion of heat-stable toxin across the intestinal wall, resulting in hypoxia and death of the epithe1ium.l For a variety of reasons2 we rejected this hypothesis and sought an alternate explanation. We started by using a virulent Shigella flexneri 2a strain and an avirulent mutant derived from it. As far as could be ascertained, the two strains were identical, with the exception that the parent strain caused disease when fed to starved, opiated guinea pigs or to rhesus monkeys, while the mutant failed to do so. When animals infected with either of the strains were studied using the fluorescent antibody technique, a distinctly different pattern of distribution of the organisms in the intestine was observed. The avirulent mutant was seen only in the lumen of the bowel. On the other hand the virulent bacteria were present in the epithelial cells of the intestine, and also both free and within phagocytic cells in the lamina propria. Rarely were the organisms viewed in the submucosa or in the mesenteric lymph nodes.2 From the results of these experiments we concluded that an essential step in the pathogenesis of bacillary dysentery is the penetration of the intestinal epithelial cell by the pathogen. If the organism is unable to enter the epithelium for one reason or another, few, if any, signs of disease are observed. Similar observations have been made independently by Voino-Yasenetsky and Khavkin and confirmed in extensive studies by Ogawa and colleague^.^ Other procedures are available to test for the ability of dysentery bacilli to

Evaluation of chloramphenicol acid succinate therapy of induced typhoid fever and rocky mountain spotted fever.

Abstract In volunteers with induced typhoid fever, plasma levels of free biologically active chloramphenicol were approximately twice as high in those treated with oral chloramphenicol (four subjects) as in those treated with the same dose of intramuscular chloramphenicol succinate (four subjects), apparently owing to the failure of the intramuscularly administered succinate ester to be completely hydrolyzed to the active drug. Plasma chloramphenicol levels in nine volunteers infected with Rocky Mountain spotted fever and treated with chloramphenicol succinate intramuscularly revealed that approximately a third of the administered drug was present in the biologically inactive unhydrolyzed form. Although chloramphenicol succinate was effective in controlling the early toxicity of induced typhoid fever and Rocky Mountain spotted fever, the delayed response and high relapse rate made this preparation inadequate as the sole form of therapy given intramuscularly in conventional doses.

COMPARATIVE EFFICACY OF CHLORAMPHENICOL, AMPICILLIN, AND CO-TRIMOXAZOLE IN THE TREATMENT OF

Two clinical trials were conducted to compare the efficacy of 3 antimicrobial agents often recommended for the treatment of typhoid fever. Chloramphenicol was more effective than parenteral ampicillin or oral co-trimoxazole (trimethaprim/sulphamethoxazole) in reducing the duration of fever. Oral chloramphenicol was more effective than parenteral chloramphenicol probably because oral doses resulted in higher blood concentrations of the drug. However, parenteral chloramphenicol was given during the initial period of acute illness, without loss of efficacy.

Gross-Reacting Typhus Antibodies in Rocky Mountain Spotted Fever

Conclusion Serological studies on convalescent specimens from cases of Rocky Mountain spotted fever show the presence of epidemic and murine agglutinins and epidemic neutralizing antibodies although there is no evidence of cross complement fixation. This evidence fits in with the observations of Castaneda and Silva and those of Parker, and indicates that there is a serologic relationship between epidemic typhus fever and Rocky Mountain spotted fever. The data presented in this paper must be considered in evaluating the results obtained with rickettsial agglutination or the neutralizing antibody when these tests are used as diagnostic procedures.

Pirbenicillin: Comparison with Carbenicillin and BL-P1654, Alone and with Gentamicin, Against Pseudomonas aeruginosa

Minimum inhibitory concentrations (MIC) of pirbenicillin against 135 clinical isolates of Pseudomonas aeruginosa were one-fourth of those required for carbenicillin but two times higher than those for BL-P1654. Increasing the inoculum size produced an adverse effect on the bactericidal activity for all three antibiotics. This was more apparent for pirbenicillin than for carbenicillin, but less than the effect on BL-P1654. When concentrations of antibiotics likely to be achieved clinically were used, gentamicin increased the inhibitory and bactericidal effects of all three semisynthetic penicillins for the majority of isolates. Strains highly resistant to the aminoglycoside antibiotic, however, were inhibited no more by the penicillin-gentamicin combinations than by the most effective of the antibiotics alone.