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.     

World trends in infant feeding

Analysis of the dyadic nature (nutritional, psychological, and biological interaction between mother and infant with each affecting the other) and the economics of infant feeding strongly suggests the superiority of breastfeeding over artificial feeding, regardless of the socioeconomic status of societies. Universally, there are 3 main guidelines for scientifically guided biological infant feeding: 1) to feed the pregnant and lactating mothers with a mixed diet of locally available foods; 2) to breastfeed alone for 4 to 6 months, and 3) to introduce least cost weaning foods based on the concept of multimixes from 4 to 6 months onward, preferably prepared from locally available foods but with continuing lactation into the second year of life, particularly in poorer circumstances. Widespread increases in breastfeeding will protect some 10 million infants annually against marasmus and diarrheal diseases, some 1 million cases against infantile obesity and 100,000 cases against cow's milk allergy. The basic issue involved is the development of practical programs which would improve the pattern of breastfeeding or at least minimize its decline, and to optimize the quantity and quality of milk production, particularly by maternal feeding. This can be done by instituting changes in the emphasis in the education of health professionals, and in procedures at pediatric wards and maternity units in hospitals. The promotion and advertising of infant formulas, especially in poor areas, needs monitoring, and appropriate legislation and enforcement. Lactating mothers who are working should be provided with bonuses, creches, 'nursing pauses' in industry, and other methods which will encourage them to combine the roles of motherhood and salaried worker effectively. Interdisciplinary undertakings between economists, administrators and health professionals are needed in order to improve breastfeeding patterns on a community basis. Reappraisal of modern infant feeding practices should be based on modern scientific knowledge, awareness of successful traditional time-tested adaptation, and on man's ancient biological mammalian heritage.     

Pharmacokinetics of once-daily amikacin dosing in patients with cystic fibrosis

PURPOSE: To report the injection of tissue plasminogen activator into a retinal vein to treat central retinal vein occlusion. METHODS: An 81-year-old woman with visual loss of the right eye secondary to central retinal vein occlusion developed central retinal vein occlusion and visual loss in her left eye. Treatment of her left eye with topical ocular hypotensive medications, pentoxifylline, and laser chorioretinal anastomosis was without benefit. Thereafter, she underwent vitreoretinal surgery, including tissue plasminogen activator injection into a branch retinal vein of her left eye. RESULTS: The patient reported subjective improvement in the vision of her left eye. Ophthalmoscopic and fluorescein angiographic improvement were also noted. CONCLUSION: The feasibility of cannulating a retinal vein for treatment has been demonstrated.     

Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide

Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most important drugs for the treatment of tuberculosis (TB). The pharmacokinetics of all three drugs in the plasma of 24 healthy males were studied as part of a randomized cross-over phase I study of two dosage forms. Subjects ingested single doses of INH at 250 mg, RIF at 600 mg, and PZA at 1,500 mg. Plasma was collected for 36 h and was assayed by high-performance liquid chromatography. The data were analyzed by noncompartmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population modeling methods. Fast and slow acetylators of INH had median peak concentrations in plasma (C[max]) of 2.44 and 3.64 microg/ml, respectively, both of which occurred at 1.0 h postdose (time of maximum concentrations of drugs in plasma [T(max)]), with median elimination half-lives (t1/2) of 1.2 and 3.3 h, respectively (by the NPEM method). RIF produced a median C(max) of 11.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 3.4 h. PZA produced a median C(max) of 28.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 10.0 h. The pharmacokinetic behaviors of INH, RIF, and PZA were well described by the three methods used. These models can serve as benchmarks for comparison with models for other populations, such as patients with TB or TB with AIDS.     

Clinical Applications of Pharmacokinetics and Adaptive Control

FOR the great majority of drugs, it is generally true that the more drug one takes per day, the greater is the total amount of drug in the body, the greater are the serum and tissue concentrations, the greater is the rate of excretion of the drug, and also the greater is the incidence of adverse reactions. In general, most of these things, except the incidence of adverse reactions, are linearly related to each other, and the kinetic behavior of these drugs can be regarded as that of linear pharmacokinetic systems. The "well-stirred tank" concepts found in introductory courses in calculus apply, and compartmental models of drug behavior are the ones commonly used. Many drugs have been studied in this way, including digitalis glycosides, aminoglycoside antibiotics, lidocaine, procainamide, quinidine, and theophylline, to name only a few.     

Proper Orthogonal Decomposition for Time-Dependent Lid-Driven Cavity Flows

Proper orthogonal decomposition (POD) is employed to study a time-dependent lid-driven cavity flow. Ensembles of data are compiled from transient solutions computed with different grids and Reynolds numbers. The POD bases are used to reconstruct the constituents of the ensemble. Error measures are used to evaluate the effectiveness of the method. The geometric locations of major errors and their dependency on Reynolds number are also investigated. The POD technique proves capable of capturing more than 99.7% of the kinetic energy, using the first three eigenmodes. The errors were found to be uniformly bounded, which validates the theory derived.