To enable the comparison of antibiotics in a standardized, meaningful manner, a system that integrates the pharmacologic and microbiologic properties of β-lactam antibiotics has been developed. The ...system compares the duration of time that concentrations of both total and free drug exceed the 90% minimal inhibitory concentration (MIC₉₀) of various pathogens as well as the area under the concentration-time curve for both total and free drug, the latter measurement being an indication of potential for antibiotic diffusion to the periphery. Of the three cephalosporin(-like) compounds evaluated, moxalactam produced the longest duration of free drug above the MIC₉₀ for the Enterobacteriaceae as well as the largest free-drug area under the concentration-time curve following a standardized 2-g intravenous infusion. Both the duration of time cefotaxime was above the MIC₉₀ for the Enterobacteriaceae and the area under the concentration-time curve were significantly less because of its short elimination half-life, results indicating the need for more frequent dosing with cefotaxime than with moxalactam. Cefoperazone, because of its high degree of protein binding and higher MIC₉₀, develops the least duration of time above the MIC₉₀ for most pathogens. None of these new agents provides free-drug concentrations above the MIC₉₀ for Pseudomonas aeruginosa for longer than 0.6 hr, which suggests that they may be inadequate as single-agent therapy for many serious infections due to this pathogen. Because promotion of comparisons by this method relies on in vitro data for analysis, the conclusions relating to expected clinical efficacy are proffered and should be interpreted with caution. Nevertheless, this method of comparison fulfills its stated purpose of providing a standardized way of comparing new β-lactam antibiotics with diverse characteristics by integrating selected microbiologic and pharmacologic aspects of the drug.
Application of pharmacodynamic principles for interpretation of data generated by the Alexander Project is possible for beta -lactam, quinolone and macrolide antibiotics. For beta -lactams, the time ...that serum concentrations remain above the MIC of the pathogen (T > MIC) is the parameter most closely linked with outcome. It has been shown that T > MIC need be only 50-60% of a dose interval. Since the MIC has the greatest influence on this parameter, a conservative estimate of activity would use the MIC sub(90). The only beta -lactam antibiotics in the Alexander Project for which T > MIC sub(90) for the four major pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus) exceeded 50% of the dose interval were amoxycillin/clavulanate (500/125 mg) and ceftriaxone. For macrolides, T > MIC is relevant for erythromycin and clarithromycin, but not azithromycin, for which AUC is the parameter most closely linked to outcome. Erythromycin, clarithromycin and azithromycin showed efficacy against M. catarrhalis only at MIC sub(90). Quinolones (ciprofloxacin and ofloxacin), for which AUC is also the relevant pharmacodynamic parameter, had the greatest activity against H. influenzae and M. catarrhalis at MIC sub(90), but were less effective against S. pneumoniae and S. aureus. Susceptibility data such as those provided by the Alexander Project can aid clinicians in choosing appropriate treatment for LRTI based on pharmacodynamic principles.
Imipenem (formerly N-formimidoyl thienamycin) and ceftazidime were investigated for their postantibiotic effect on P. aeruginosa . Four strains of P. aeruginosa in the logarithmic phase of growth ...were exposed for 1 and 2 h to concentrations of antibiotics achievable in human serum. Recovery periods of test cultures were evaluated after dilution or addition of beta -lactamase. A consistent postantibiotic effect against all strains was obtained with imipenem but not with ceftazidime. Although ceftazidime did not have a postantibiotic effect, it did suppress the growth of theorganisms at concentrations equivalent to one-third of the MIC. The clinical implications of these effects need further evaluation.
Cyclosporin G (CSG) has produced less nephrotoxicity than cyclosporin A (CSA) at equivalent doses in animal models. Conflicting results have been reported concerning differences in the ...pharmacokinetics of CSA and CSG in preclinical studies, and no data exist regarding the effect of steady‐state oral administration of CSG on renal function in transplant patients or CSG‐induced release of endothelin and nitric oxide (NO) in vivo. The objective of the study was to examine steady‐state pharmacokinetic profiles of adult renal allograft recipients receiving CSA and CSG in relation to concentrations of endothelin‐1 and NO2/NO3 in urine and plasma, creatinine clearance (Clcr), and urinary excretion of N‐acetyl‐β‐D‐glucosaminidase (NAG) 9 months after transplantation. Concentrations of CSA and CSG were measured in whole blood over a 12‐hour dose interval by both a monoclonal and polyclonal fluorescence polarization radioimmunoassay for CSA. A metabolite fraction was defined as the numerical difference between the levels obtained at each time point by both assays. Patient groups were defined as follows: group 1: initial CSA (n = 6); group 2: initial CSG (n = 7); group 3: five of the seven patients in group 2 taking CSG subsequently undergoing conversion to CSA; group 4: the same five patients in group 3 restudied 1 month after 1:1 dosage conversion to CSA; and group 5: CSA groups 1 and 4 combined (n = 11). In group 1, the metabolite fraction accounted for 32% to 54% of the total measurable drug concentration at each time point, whereas in group 2, the metabolite fraction accounted for at most 10% to 15% of the total drug levels measurable by polyclonal fluorescence polarization radioimmunoassay. Although there were no significant differences in any of the mean pharmacokinetic parameters between groups using monoclonal fluorescence polarization radioimmunoassay, the normalized area under the concentration—time curve (NAUC) value was less in four of five patients after conversion from CSG to CSA, with a more variable and delayed time to reach peak concentration (tmax) but equivalent apparent oral clearance (Clpo) values. Clcr was found to change significantly with time in groups 1 and 5 but not in group 2, with CSA producing a more profound and sustained decrease than CSG. Endothelin‐1 and NO2/NO3 levels in plasma and urine remained relatively constant after administration of both CSA and CSG, and there were no significant differences between groups 3 and 4 regarding mean endothelin‐1 and NO2/NO3 concentrations in plasma, urinary release of endothelin‐1 and NO2/NO3, and mean AUC of endothelin‐1 and AUC of NO2/NO3. However, monoclonal NAUC correlated significantly with total urinary endothelin‐1 within CSA groups 1 and 5 but not within CSG group 2. Metabolite NAUC correlated significantly with total urinary NAG within CSA group 1. Although limited by the small number of patients, this study suggests that 1) CSG may produce less of a reduction in Clcr over time after oral administration at steady state than does CSA, and 2) this beneficial effect of CSG may be in part due to decreased intrarenal release of endothelin‐1, as urinary excretion of endothelin‐1 seemed to correlate better with CSA than with CSG exposure.
Following a 4-year controlled trial comparing early and later zidovudine treatment, we conducted an additional 3-year follow-up. Of the original 338 patients, 275 participated. Clinical outcome ...measures were AIDS and death. In the early therapy group (n = 170), 67 patients progressed to AIDS compared with 85 in the later therapy group (n = 168); the relative risk (RR) comparing early with later therapy was 0.72% (95% confidence interval CI 0.52-0.99; p = 0.044). The early therapy group had 74 deaths compared with 73 in the later therapy (RR = 0.98; 95% CI, 0.71-1.36; p = 0.91). The early group had a peak CD4+ count increase at 1-2 months and a delay of 1 year before CD4+ counts fell below baseline. For patients who received zidovudine for more than the median duration (20.3 months) before their first AIDS diagnosis, the RR for death was 2.08 (95% CI, 1.36-3.19, p = 0.001). Additional factors independently associated with poor prognosis following AIDS were a CD4+ count of < 100 cells/mm3 and increased severity of the first AIDS diagnosis, whereas use of another antiretroviral agent was associated with improved survival. We conclude that early zidovudine therapy delays progression to AIDS but does not affect survival. Patients who progress to AIDS while on prolonged zidovudine monotherapy many benefit from a change to other antiretroviral therapy(ies).
These guidelines describe the design and implementation of clinical trials to assess the safety and efficacy of anti-infective drugs for the treatment of infective endocarditis. Identification and ...enrollment of patients in clinical trials is based on a modification of traditional criteria. To accrue a sufficient number of patients, only those with streptococcal or staphylococcal endocarditis should be included in studies. Results of treatment with approved drugs allow for projection of expected bacteriologic cure rates and survival rates. Prospective randomized, double-blind studies are recommended. These guidelines are based on the premise that future protocols may include shorter courses of therapy, combinations of drugs, or progression from parenteral to oral therapy. Clinical response is judged as cure, failure, or indeterminate; there is no "improved" category. Microbiologic response is categorized as eradication, persistence, or relapse. When a patient has shown no clinical evidence of active disease for a protracted period, there may be no need to perform a posttreatment blood culture; for such patients, the microbiologic response is termed presumptive eradication. Several months of follow-up may be necessary to detect late relapses.
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