Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint.

One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial agents is dose selection. The choice is often based on preclinical data from pharmacokinetic (PK) studies with animals and healthy volunteers but is rarely linked directly to the target organisms except by the MIC, an in vitro measure of antimicrobial activity with many limitations. It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model which uses four data sets: (i) the distribution of MICs for clinical isolates, (ii) the distribution of the values of the PK parameters for the test drug in the population, (iii) the PD target(s) developed from animal models of infection, and (iv) the protein binding characteristics of the test drug. In performing this study with the new anti-infective agent evernimicin, we collected a large number (n = 4,543) of recent clinical isolates of gram-positive pathogens (Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium, and Staphylococcus aureus) and determined the MICs using E-test methods (AB Biodisk, Stockholm, Sweden) for susceptibility to evernimicin. Population PK data were collected from healthy volunteers (n = 40) and patients with hypoalbuminemia (n = 12), and the data were analyzed by using NPEM III. PD targets were developed with a neutropenic murine thigh infection model with three target pathogens: S. pneumoniae (n = 5), E. faecalis (n = 2), and S. aureus (n = 4). Drug exposure or the ratio of the area under the concentration-time curve/MIC (AUC/MIC) was found to be the best predictor of microbiological efficacy. There were three possible microbiological results: stasis of the initial inoculum at 24 h (10(7) CFU), log killing (pathogen dependent, ranging from 1 to 3 log(10)), or 90% maximal killing effect (90% E(max)). The levels of protein binding in humans and mice were similar. The PK and PD of 6 and 9 mg of evernimicin per kg of body weight were compared; the population values for the model parameters and population covariance matrix were used to generate five Monte Carlo simulations with 200 subjects each. The fractional probability of attaining the three PD targets was calculated for each dose and for each of the three pathogens. All differences in the fractional probability of attaining the target AUC/MIC in this PD model were significant. For S. pneumoniae, the probability of attaining all three PD targets was high for both doses. For S. aureus and enterococci, there were increasing differences between the 6- and 9-mg/kg evernimicin doses for reaching the 2 log killing (S. aureus), 1 log killing (enterococci), or 90% E(max) AUC/MIC targets. This same approach may also be used to set preliminary in vitro MIC breakpoints.

Pseudomonas aeruginosa: assessment of risk from drinking water.

Pseudomonas aeruginosa is an ubiquitous environmental bacterium. It can be recovered, often in high numbers, in common food, especially vegetables. Moreover, it can be recovered in low numbers in drinking water. A small percentage of clones of P. aeruginosa possesses the required number of virulence factors to cause infection. However, P. aeruginosa will not proliferate on normal tissue but requires previously organs. Further narrowing the risk to human health is that only certain specific hosts are at risk, including patients with profound neutropenia, cystic fibrosis, severe burns, and those subject to foreign device installation. Other than these very well-defined groups, the general population is refractory to infection with P. aeruginosa. Because of its ubiquitous nature, it is not only not practical to eliminate P. aeruginosa from our food and drinking water, but attempts to do so would produce disinfection byproducts more hazardous than the species itself. Moreover, because there is no readily available sensitive and specific means to detect and identify P. aeruginosa available in the field, any potential regulation governing its control would not have a defined laboratory test measure of outcome. Accordingly, attempts to regulate P. aeruginosa in drinking water would not yield public health protection benefits and could, in fact, be counterproductive in this regard.

Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection.

We reviewed 153 episodes of invasive pneumococcal disease involving 147 hospitalized patients with and without human immunodeficiency virus (HIV) disease to examine and compare epidemiologic and clinical features, capsular serotypes, and antibiotic susceptibility patterns. HIV infection was the most common risk factor for invasive pneumococcal disease. Pneumococcal disease in HIV-infected individuals was characterized by the greater frequency with which pneumonia was the source of bacteremia (90% vs. 63%) (P < .01) and an increased recurrence rate (15% vs. < 1%) (P < .01). The overall mortality rate was 12% and did not vary by HIV serostatus. Capsular-type data were available for 149 episodes; 90% of the types were among those found in the polyvalent pneumococcal vaccine. The four most common capsular types causing invasive disease were 14, 6b, 9v, and 22f; capsular type 9v was significantly more common among HIV-infected patients (P < .01). Penicillin-resistant isolates were identified in 7.2% of all cases, and their presence did not vary by HIV status; 20% of isolates from cerebrospinal fluid were resistant. The majority of the resistant isolates were of capsular type 9v. Given the worldwide increase in both HIV and penicillin-resistant pneumococcal infections, better preventative and therapeutic strategies are greatly needed.

Human granulocytic ehrlichiosis in Connecticut: report of a fatal case.

We report a case of granulocytic ehrlichiosis in a 71-year-old man who presented with an acute febrile illness and subsequently developed multisystem organ dysfunction and sudden severe anemia with thrombocytopenia requiring intensive care, mechanical ventilation, hemodialysis, and transfusions. The diagnosis was suspected on the fifth hospital day after a peripheral blood smear was examined; intracytoplasmic inclusion bodies were present in granulocytes only. Results of serological tests of acute and convalescent sera confirmed the diagnosis of granulocytic ehrlichiosis. We discuss the features of this case that were similar to those of published case reports as well as the course and outcome of treatment. This, to our knowledge, represents to first documented case of human granulocytic ehrlichiosis to occur outside the Upper Midwest. Because of the possible epidemiological association of Ehrlichia species with the deer tick Ixodes scapularis (dammini), this case raises additional concern for clinicians and patients in regions where Lyme disease is endemic.

Rapid detection of vancomycin-resistant enterococci.

Campylobacter blood agar with clindamycin incubated in 6% CO2 served as a medium to both screen for vancomycin resistance and select for presumptive enterococci. Colonies that grew on the medium were specifically identified as enterococci within 30 min by the pyroglutamyl-beta-naphthylamide and rapid bile esculin tests. The combination of a selective medium plus rapid enzyme substrate tests offered an inexpensive means to enumerate vancomycin-resistant enterococci from specimens by using readily available reagents.