Determinations of single serum drug concentrations are useful in monitoring drug therapy. A mean serum level would supply more information but is expensive and laborious because of the multiple blood samples and assays, calculation of area under the curve (AUC) by the trapezoidal rule, and division of the AUC by the time interval during which the samples were drawn. A method was devised that pools aliquots from individual serum samples taken during the testing period to form on composite sample. A single assay of this sample provides the mean serum level of the testing period. The method was successfully tested with amaranth and then applied to valproic acid serum levels. AUC and mean serum levels were determined by the standard procedure of assays of multiple samples and the trapezoidal rule. Mean serum level was also determined by the pooled sample technique. The correlation coefficient for the comparison of the mean serum levels determined by the two techniques is 0.907 (p less than 0.001). There was no difference between the estimates of the mean serum levels by Student's paired t test (t = 0.693, p greater than 0.2). The good correlation and lack of difference between the conventional method and the pooled sample method indicates that the method is valid.

A high-performance liquid chromatographic method for the measurement of moxalactam concentrations in serum was modified to permit the simultaneous measurement of both moxalactam and cefazolin. We then studied whether the simultaneous administration of both moxalactam and cefazolin to nornal subjects would produce profiles of serum concentration versus time which were the same as those obtained after the administration of each drug individually. Six healthy adults received a 30-minfusion of cefazolin (10 mg/kg), followed in 2 days by the same dose of moxalactam. After 2 days, both antibiotics were administered together. A two-compartment model was found to adequately characterize the data, and the serum concentration curve for each drug when given alone was statistically identical to that obtained after simultaneous administration. Cefazolin was found to produce a significantly greater peak serum concentration (105 ± 14 versus 81 ± 21 ug/ml) and a significantly greater area under the curve (218 ± 42 versus 157 ± 19 lig.h/ml). The terminal half-life of moxalactam was not significantly longer than for cefazolin (2.2 ± 0.6 versus 2.0 ± 0.6 h, respectively). The method of simultaneous administration may have distinct advantages over conventional methods for studies of comparative tissue penetration.Studies which compare the penetration of two antibiotics into human tissue are often conducted in patients undergoing elective surgery, e.g., total hip replacement for bone penetration studies (7) or coronary vein bypass surgery for heart muscle penetration studies (4). The antibiotics are usually asigned randomly and are administered prophylactically before removal of the surgical specimen. The concentrations of the two drugs in tissue are then determined and compared. We describe here a method of simultaneous measurement and administration of moxalactam and cefazolin to normal volunteers which would appear to be adaptable to tissue penetration studies and which may have significant advantages over the conventional twogroup design. MATERIALS AND METHODSSubjects and drug administration. Six normal volunteers, three males and three females, ranging from 22 to 35 years in age and 51 to 84 kg in weight, participated in this study, with informed consent. Subjects were instructed to refrain from strenuous physical activity or alcohol ingestion during each study period. An indwelling heparin lock for infusion was placed in each volunteer on study day 1. Blood samples were also obtained from the heparin lock (after disposal of the first milliliter) except for the first and final samples, which were obtained by direct venipuncture.A 30-min infusion of 10 mg of cefazolin sodium per kg, dissolved in 50 ml of normal saline, was administered via an IVAC 530 constant-infusion pump (IVAC Corp., La Jolla, Calif.). At day 2 after the administration of cefazolin, each subject received a 30-min infusion of 10 mg of moxalactam disodium per kg, followed in 2 days by a simultaneous 30-min infusion of the same dose (as above) of both moxalactam...

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Single 600-mg capsules of rifampin were given orally to 26 patients as prophylaxis during cardiac valve replacement. Antibiotic concentrations were measured in blood (serum or plasma) and tissue (excised cardiac valve). The serum or plasma levels of rifampin in 18 patients who ingested this drug 2 h before they received preoperative opiates and anticholinergics intramuscularly were not significantly different from the levels in four normal volunteers who received the drug. These levels were 15.9 +/- 6.5 micrograms/ml (mean +/- standard deviation) 2 h after drug administration, 7.1 +/- 4.3 micrograms/ml 8 h after drug administration and 2 h after a mean of 1.4 h on cardiopulmonary bypass, and 1.6 +/- 1.6 micrograms/ml 24 h after drug ingestion. The valve tissue level was 3.8 +/- 2.7 micrograms/g (mean +/- standard deviation; n = 10). This value was 65% of the simultaneous serum and plasma levels and 31% of the peak serum and plasma levels. Eight patients who were given rifampin at the same time that they received other preoperative medications had significantly lower blood levels than the 18 patients who received rifampin 2 h earlier (P less than 0.001). No rifampin was detected in valves from seven of these patients. Decreased rifampin absorption due to simultaneous administration with opiates and anticholinergics was the probable reason for the low plasma and serum levels observed. These data suggest that, if properly dosed, rifampin administered orally gives high blood and valve tissue levels, which are affected minimally by cardiopulmonary bypass in patients undergoing cardiac valve surgery.

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