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ID Week 2015, San Diego, CA. October 7-11, 2015 • Pseudomonas aeruginosa impacts overall PTA in the Gram-negative rod analysis • Prolonged infusion methodologies consistently outperform the bolus infusion equivalent regimen for both Pseudomonas aeruginosa and the Enterobacteriaceae • No regimen successfully reached 90% probability of pharmacodynamic target attainment for P. aeruginosa in all ICUs • Piperacillin-tazobactam, both intermittent bolus and prolonged infusion, did not reach 90% PTA in any analysis, suggesting that alternative agents should be used in all ICUs • Cefepime 1g q8h by both modalities was sufficient to reach 90% PTA for Enterobacteriaceae isolates (data not shown) Unit-specific Pharmacodynamic Modelling to Aid in Empiric Therapy Selection W. Cliff Rutter, PharmD1,2, Donna R. Burgess, RPh2 and David S. Burgess, PharmD, FCCP1 1 University of Kentucky, College of Pharmacy, Lexington, KY, 2 University of Kentucky HealthCare, Lexington, KY

It is well established that, at equilibrium, the concentrations of free drug on either side of a porous capillary are equal. However, the dynamic factors which operate on the way to achieving this equilibrium, while drug levels fluctuate in serum and extravascular sites, have been less well studied. This paper reviews some of the physical principles relating to diffusion through capillary pores and permeation through capillary membranes. Emphasis has been placed on the importance of the surface area-to-volume ratio in determining the time required to reach various stages of equilibrium. The effects of infection have been considered. At equilibrium, the AUC of free drug in serum and non-specialized extravascular compartments must be equal. Therefore, although the mode of administration (e.g. continuous infusion versus intermittent bolus) will affect the profile of the concentration-time curve in extravascular loci, it will not affect the overall AUC of drug in these sites. We have derived an equation to estimate the levels of drug within an abscess when bacteria are destroying the drug. Brief consideration has been given to transport in specialized sites with non-porous capillaries and with active transport systems. Throughout the analysis, we have focused on the application of these principles to in-vitro models and the potential use of in-vitro models to substantiate these principles.

To evaluate the dynamics of GH-secretion after infusion of growth hormone releasing factor, human pancreatic growth hormone releasing factor (hpGRF1-44) was infused over 2 and 5 h at a dosage of 100 μg hpGRF1-44/h into 11 healthy subjects. The infusion was started and terminated with a 50 μg hpGRF1-44 bolus injection. In 5 subjects 200 μg TRH was given 4 h after starting the infusion. In addition, 4 healthy subjects received 50 μg hpGRF1-44 bolus injection every 2 h. GRF, somatostatin, GH, Prl, and TSH were measured by radioimmunoassay. The initial 50 μg GRF bolus increased GH-levels in all 11 subjects with a maximum at 30 min (24.1 ± 5.1 ng/ml ± se). However, though hpGRF1-44 was continuously infused and GFR-levels remained elevated, GH decreased to a minimum 270 min after start of infusion (2.6 ± 0.6 ng/ml). The GH-response to the second bolus at the end of the infusion was lower compared to the first response (14.6 ± 3.4 ng/ml after 2 h and 7.6 ± 2.5 ng/ml after 5 h). TRH did not lead to a GH-increase during hpGRF1-44 infusion though Prl and TSH rose normally. The intermittent bolus injection of 50 μg hpGRF1-44 led to continuously decreasing GH-responses to the same GRF-dosage (I. bolus: 16.5 ± 1.6 ng/ml; II. bolus: 4.2 ± 0.8 ng/ml; III. bolus: 3.4 ± 0.5 ng/ml). No change in somatostatin levels was observed. These findings show that GRF infusion or bolus injection in short intervals does not sustain elevated GH-levels. Pituitary GH is either not readily available for continuous GRF-stimulation or GH-secretion may be antagonized by increasing portal somatostatin levels which are not reflected in the peripheral circulation.

The ordering of serum theophylline concentrations in a 900-bed university hospital was evaluated. Data were collected during the first week of three consecutive months from the records of adult inpatients who had serum theophylline assays performed. The appropriateness of ordering the serum theophylline determinations was evaluated on the basis of criteria including sampling at steady-state concentrations and sampling in proper relationship to the dosage schedule to represent a peak or trough concentration. A total of 113 determinations in 79 patients were reviewed. Pulmonary service patients accounted for 54 (48%) of the determinations. For the 56 concentrations ordered for patients receiving aminophylline continuous infusions, 25 (45%) of the determinations did not meet the criteria for appropriateness. For the 57 other determinations (oral theophylline products and intermittent bolus injections of aminophylline), 42 (74%) were not ordered according to the established criteria. Overall, 67 (59%) of 113 serum theophylline determinations were found to be ordered inappropriately. Corrective educational programs based on standard guidelines for ordering serum theophylline concentrations were established.