Comparisons between Antimicrobial Pharmacodynamic Indices and Bacterial Killing as Described by Using the Zhi Model

Various suggestions have been made for empirical pharmacodynamic indices of antibiotic effectiveness, such as areas under the drug concentration-time curve in serum (AUC), AUC>MIC, AUC/MIC, area under the inhibitory curve (AUIC), AUC above MIC, and time above MIC (T>MIC). In addition, bacterial growth and killing models, such as the Zhi model, have been developed. The goal of the present study was to compare the empirical behavior of the Zhi model of bacterial growth and killing with the other empirical pharmacodynamic indices described above by using simulated clinical data analyzed with the USC*PACK PC clinical programs for adaptive control of drug therapy, with one model describing a concentration-dependent antibiotic (tobramycin) and another describing a concentration-independent antibiotic (ticarcillin). The computed relative number of CFU was plotted against each pharmacodynamic index, with each axis parameterized over time. We assumed that a good pharmacodynamic index should present a clear and continuous relationship between the time course of its values and the time course of the bacterial killing as seen with the Zhi model. Preliminary work showed that some pharmacodynamic indices were very similar. A good sensitivity to the change in the values of the MIC was shown for AUC/MIC and also for T>MIC. In addition, the time courses of some other pharmacodynamic indices were very similar. Since AUC/MIC is easily calculated and shows more sensitivity, it appeared to be the best of the indices mentioned above for the concentration-dependent drug, because it incorporated and used the MIC the best. T>MIC appeared to be the best index for a concentration-independent drug. We also propose a new composite index, weighted AUC (WAUC), which appears to be useful for both concentration-dependent and concentration-independent drugs.     

Thrombotic thrombocytopenic purpura that is refractory to therapeutic plasma exchange in two patients with occult infection

BACKGROUND: The etiology of thrombotic thrombocytopenic purpura (TTP) remains undetermined. TTP has been associated with a number of secondary causes including infections, drugs, menses, pregnancy, autoimmune diseases, and bone marrow transplantation. Regardless of the inciting factors, it is widely accepted that endothelial injury and platelet aggregation are integral components. The morbidity and mortality have been significantly reduced with the use of plasmapheresis. However, refractory forms of TTP remain a clinical management challenge. Refractory TTP has not previously been associated with occult bacterial infection. CASE REPORT: Two patients had classic TTP that was refractory to daily plasma exchange with fresh-frozen plasma. Multiple attempts over a period of months to wean these patients off plasma exchange resulted in exacerbations of disease activity, as indicated by increased schistocytosis, decreased hematocrit, increased serum lactate dehydrogenase, and decreased platelet counts. Both patients were empirically treated for infections during hospitalization, although microbial cultures failed to isolate an organism. Discontinuation of antimicrobial therapy on multiple occasions in one patient was associated with recurrence of disease. In the other patient, dental extraction with drainage of an occult periodontal abscess resulted in sustained remission of disease. CONCLUSION: Occult bacterial infection may play a role in triggering and sustaining TTP that is refractory to conventional treatment. A careful search for such an infection and appropriate antimicrobial therapy should be considered in the management of these patients.     

Micro- and macro-consequences of ooplasmic injections of early haploid male gametes

This review refers to the evolution of ooplasmic injectionsof round spermatid nuclei ROSNI) or intact round spermatidsROSI). Conclusions from their preliminary application in thehamster, rabbit, mouse and human are discussed. Criteria foridentification of round spermatids and guidelines/quality controlfor application of ROSNI/ROSI techniques are emphasized. Althoughall the animal offspring and the human newborns delivered afterROSNI/ROSI are healthy additional research efforts are necessaryto confirm the safety of these procedures and improve theiroutcome     

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Objective: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. Methods: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined␣with positron emission tomography (PET) with [¹¹C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. Results: PET showed a high degree of binding of [¹¹C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. Conclusion: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals. Received: 21 August 1996 / Accepted in revised form: 22 November 1996     

Retroperitoneal foregut cyst

A foregut cyst is formed as a result of abnormal budding and pinching of the tracheobronchial tree when bronchial buds develop to form the primitive respiratory tree. Foregut cysts are clinically classified as bronchogenic, esophageal, enterogastric, or ciliated hepatic. We present a foregut cyst that occurred in the retroperitoneum and was difficult to distinguish from other retroperitoneal cystic mass lesions. Magnetic resonance imaging was useful in revealing the cyst's continuity to adjacent organs. Received: 19 June 1995/Accepted: 23 July 1995