Serum bactericidal activity of ceftazidime: continuous infusion versus intermittent injections.

Since beta-lactam antibiotics have concentration-independent killing, bacterial eradication is a function of the time the serum drug concentration remains above the drug's MIC (T > MIC). We compared the serum bactericidal titers (SBTs) of ceftazidime given by continuous infusion (CI) or by intermittent bolus dosing (BD) against two clinical isolates each of Pseudomonas aeruginosa and Escherichia coli to determine if CI would allow lower daily dosing while still providing equal bactericidal activity compared with BD. This was an open-labeled, randomized, steady-state, four-way crossover study with 12 healthy volunteers. The ceftazidime regimens were 1 g every 8 h (q8h) BD, 1 g q12h BD, 3 g over 24 h CI, and 2 g over 24 h CI. The areas under the bactericidal curves were calculated by the trapezoidal rule using the reciprocal of the SBT. For all organisms the areas under the bactericidal curves for intermittent versus the CI regimens were the same for equal doses (P > 0.05). For both strains of E. coli all four regimens provided SBTs of > or = 1:2 over the dosing interval and 100% T > MIC. The 1-g q8h BD and q12h BD regimens provided T > MIC of 82 and 52%, respectively, for both P. aeruginosa isolates (MICs, 4 micrograms/ml). In comparison, the 2- and 3-g CI regimens always maintained SBTs of > or = 1:2 and T > MIC over the 24-h period as serum drug concentrations were 12.8 +/- 3.0 and 18.2 +/- 4.5 micrograms/ml, respectively. CI optimizes the pharmacodynamic and pharmacoeconomic profile of ceftazidime by providing adequate antibacterial activity over the 24-h dosing period with a reduction in the total daily dose of the antimicrobial agent.     

Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model.

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 micrograms/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime-susceptible P. aeruginosa. Continuous infusions of 10 and 20 micrograms/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 micrograms/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 micrograms/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 micrograms/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa. Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 micrograms/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.     

New schedule for tobramycin administration.

Ten patients received a loading dose of tobramycin of 60 mg/m2 intravenously over 0.5 h followed immediately by 60 mg/m2 over 2 h every 4 h. The highest mean serum concentration (at the end of the loading dose) was 6.0 +/- 0.3 microgram/ml (range, 3.2 to 10.9 microgram/ml). The mean serum concentration 2 h after the end of the initial 2-h infusion was 3.0 +/- 0.2 microgram/ml (range, 1.6 to 3.9 microgram/ml). This schedule of tobramycin was used to treat 117 patients with presumed or proven infection. There were no differences in the mean serum concentrations of tobramycin at comparable times on days 3 to 4 and 6 to 7. Only 60% of patients had serum levels between 3 micrograms/ml (trough) and 10 micrograms/ml (peak). This intermittent schedule of administration resulted in substantial fluctuations in serum concentrations of tobramycin and produced trough concentrations which were too low or peak concentrations which were too high in some patients.     

Clinical pharmacokinetics of aztreonam in cancer patients.

The pharmacokinetics of aztreonam were studied in 25 adult patients with hematological malignancies. Two groups of nine patients each received aztreonam (1 or 2 g every 8 h) prophylactically, and seven infected patients received a therapeutic regimen of aztreonam (1.5 g every 4 h). The mean peak serum concentration after a 1-g dose of aztreonam (given over 0.5 h on day 1) was 75.5 micrograms/ml; after a 2-g dose it was 177.2 micrograms/ml. The mean peak serum concentration after a 1.5-g dose of aztreonam (given over 2 h on day 1) was 68.5 micrograms/ml. The serum half-life ranged between 1.7 and 2.0 h for all regimens studied. The urinary concentration of the metabolite of aztreonam, SQ 26,992, increased during 1 week of administration of the drug; however, serum levels of the metabolite were barely detectable.     

Pharmacokinetic comparison of 5 g of azlocillin every 8 h and 4 g every 6 h in healthy volunteers.

To compare the multiple-dose pharmacokinetics of two dosage regimens of azlocillin, we studied 12 healthy volunteers via a randomized, crossover design with a 2-week washout phase between regimens. Serum and urine samples were collected for 8 h following the fifth dose of a regimen of 4 g every 6 h and the fourth dose of a regimen of 5 g every 8 h. Data for concentrations in serum were fitted to a two-compartment open model by nonlinear regression. Statistically significant differences (P less than 0.05) were observed in the following parameters (mean +/- standard deviation) for the 4- and 5-g regimens, respectively: area under the serum concentration-time curve during the dosing interval, 592 +/- 140 versus 772 +/- 151 micrograms.h/ml; terminal elimination rate constant, 0.5364 +/- 0.0912 versus 0.4758 +/- 0.0486 h-1; renal clearance, 87.6 +/- 16.1 versus 76.1 +/- 13.5 ml/min; maximum drug concentration in serum, 381 +/- 89 versus 473 +/- 90 micrograms/ml; and minimum drug concentration in serum, 19 +/- 10 versus 8 +/- 4 micrograms/ml. No significant differences were seen in the following parameters: V1, V beta, k10, k12, k21, total systemic clearance, and nonrenal clearance. These data support the presence of saturable renal elimination of azlocillin, as well as the feasibility of an 8-h dosing interval.     

Penetration of ceftazidime into the cerebrospinal fluid of patients with and without evidence of meningeal inflammation.

The concentrations of ceftazidime in the serum and cerebrospinal fluid of patients with and without meningitis were measured at various times after a 2- or 3-g dose. At similar concentrations in serum, ceftazidime concentrations in cerebrospinal fluid at a given time were substantially lower in patients without meningitis (mean, 0.8 micrograms/ml) than in those with meningitis (mean, 22.6 micrograms/ml).     

Multiple-dose pharmacokinetics of ceftazidime and its influence on fecal flora.

Eight healthy volunteers each received 2.0 g of ceftazidime by constant intravenous infusion over 20 min twice daily every 12 h for 8 days. Concentrations of ceftazidime in serum and urine were measured by a microbiological assay and by high-pressure liquid chromatography. Qualitative and quantitative studies on aerobic and anaerobic fecal flora were carried out before, during, and 2 weeks after the end of treatment. The mean (+/- standard deviation) maximum drug concentration in serum at the end of the 20-min infusion (day 1) was 185.5 +/- 28.5 micrograms/ml, decreasing to 0.8 +/- 0.4 microgram/ml after 12 h. The mean recovery of drug in urine at 12 h was 71.5 +/- 12.2%. Pharmacokinetic parameters calculated on the basis of a two-compartment model were as follows: elimination half-life, 110.5 +/- 15.2 min; volume of distribution at steady state, 21.2 +/- 2.6 liters/100 kg; volume of distribution by the area method, 26.2 +/- 4.0 liters/100 kg; area under the serum concentration-time curve, 293.3 +/- 47.8 micrograms X h/ml; total body clearance, 116.4 +/- 20.3 ml/min per 70 kg; renal clearance, 82.2 +/- 15.1 ml/min per 70 kg. The agar diffusion test and high-pressure liquid chromatographic analysis showed a good correlation of results. Metabolites of ceftazidime could not be detected by high-pressure liquid chromatography in serum or urine. No accumulation of ceftazidime could be observed during the 8-day study period. Mean maximum drug levels in serum were 185.5 to 214.5 micrograms/ml, and mean trough levels were 0.8 to 1.1 micrograms/ml (days 1 to 8). No severe side effects were noted. During ceftazidime treatment, anaerobes were left intact, whereas members of the family Enterobacteriaceae could be isolated from stool in only three of eight subjects. Two weeks after discontinuation of the drug, all stool specimens contained ampicillin- and cefazolin-resistant gram-negative rods.     

Biliary elimination of apalcillin in humans

Apalcillin was administered intravenously as a single 1-g dose on day 8 after surgery to 10 cholecystectomized patients with T-tube drainage. A peak of 2,093 +/- standard error of the mean 859 micrograms/ml of bile was attained at 3 h after dosage. Biliary recovery over a 12-h period amounted to 12.2% of the dose. In 20 patients undergoing biliary surgery, apalcillin concentrations 1 h after a 1-g dose were 65.5 +/- 5.0, 3,680 +/- 551, and 2,552 +/- 627 micrograms/ml in serum, choledochal bile, and gallbladder bile, respectively.     

Peritoneal transport of cefonicid

The pharmacokinetic characteristics of cefonicid, a highly protein-bound expanded-spectrum cephalosporin, were examined in six noninfected, clinically stable patients undergoing continuous ambulatory peritoneal dialysis. After a 1.0-g intravenous dose of cefonicid, the mean concentrations in serum were 105 +/- 25 and 35.6 +/- 14.4 micrograms/ml at 3 and 72 h, respectively. Despite a prolonged half-life in serum of 49.7 +/- 18 h, the penetration into peritoneal fluid was low. The average concentration in dialysate over the 72-h study period was 2.7 micrograms/ml. The serum clearance was 2.6 +/- 1.0 ml/min, and the distribution volume was 0.14 +/- 0.02 liter/kg. Dosage recommendations and clinical considerations for cefonicid use in continuous ambulatory peritoneal dialysis patients are discussed.     

Multiple-dose pharmacokinetics of amikacin and ceftazidime in critically ill patients with septic multiple-organ failure during intermittent hemofiltration.

The pharmacokinetic parameters of amikacin and ceftazidime were assessed in four patients undergoing hemofiltration for septic shock. The parameters were assessed during hemofiltration and in the interim period. The concentration-time profiles of these two drugs in plasma, urine, and ultrafiltrate were investigated after intravenous perfusion (30 min). In all cases a 1-g dose of ceftazidime was administered; for amikacin, the dosage regimen was adjusted according to the patient's amikacin levels (250 to 750 mg). Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection for ceftazidime and by enzyme multiplied immunoassay for amikacin. The elimination half-life (t1/2) and the total clearance of amikacin ranged from 31.1 to 138.2 h and from 5.4 to 8.9 ml/min, respectively, during the interhemofiltration period in anuric patients. Hemofiltration substantially decreased the t1/2 (3.5 +/- 0.49 h) and increased the total clearance (89.5 +/- 11.8 ml/min). The hemofiltration clearance of amikacin represented 71% of the total clearance, and the hemofiltration process removed, on average, 60% of the dose. During hemofiltration, the elimination t1/2 of ceftazidime (2.8 +/- 0.69 h) was greatly reduced and the total clearance increased (74.2 +/- 11.2 ml/min) compared with those in the interhemofiltration period (9 to 43.7 h and 7.4 to 16.8 ml/min, respectively). About 55% of the administered dose was recovered in the filtrate, and the hemofiltration clearance of ceftazidime was 46 +/- 14.3 ml/min. A redistribution phenomenon (rebound) in the amikacin and ceftazidime concentrations in plasma (35 and 28%, respectively) was reported after hemofiltration in two patients. The MICs for 90% of the most important pathogens were exceeded by the concentrations of the two drugs in plasma during the whole treatment of these patients.     

Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented gram-positive infections.

Ten patients were treated with conventional dosing (CD) and continuous-infusion (CI) vancomycin therapy in this prospective, randomized, crossover study. Patients were randomized to receive either CD or CI therapy for 2 consecutive days and then crossed over to receive the opposite regimen for 2 days. CD therapy consisted of 1 g of vancomycin every 12 h. CI therapy consisted of a 500-mg loading dose followed by 2 g infused over 24 h. Ten serum samples were obtained on the second day of each therapy for pharmacokinetic and pharmacodynamic analyses. Two clinical isolates of Staphylococcus aureus, one methicillin sensitive (MSSA 1199) and one methicillin resistant (MRSA 494), were chosen for pharmacodynamic evaluation of both regimens. The patient demographics (means +/- standard deviations [SD]) were as follows: sex, six males, four females; age, 36 +/- 11 years; and serum creatinine, 0.72 +/- 0.18 mg/dl. Mean pharmacokinetic parameters +/- SD for CD therapy were as follows: elimination rate constant, 0.16 +/- 0.07 h-1; half-life, 5.6 +/- 3.5 h; volume of distribution, 33.7 +/- 25 liters, 0.5 +/- 0.2 liters/kg; maximum concentration in serum, 53.4 +/- 19.3 micrograms/ml; and minimum concentration, 8.4 +/- 5.9 micrograms/ml. The steady-state concentration for CI was 20.2 +/- 11.1 micrograms/ml. Overall, both regimens resulted in the MIC being exceeded 100% of the time. The mean CD trough serum bactericidal titer (SBT) was 1:8, and the average CI SBTs were 1:16 for both isolates. Even though there was no statistically significant difference between CD trough and CI SBTs, the CI SBTs remained > 1:8 for 100% of the time versus 60% of the time for CD therapy. During CI therapy, 20 and 40% of the patients maintained SBTs of > 1:32 throughout the dosing interval for MSSA 1199 and MRSA 494, respectively. During CD therapy, however, only 10% of patients maintained SBTs of > 1:32 during the entire dosing interval for both isolates. The mean areas under the bactericidal titer-time curve (AUBC24s) +/- SD for MSSA 1199 were 528 +/- 263 for CD therapy and 547 +/- 390 for CI therapy. The mean AUBC24s +/- SD against MRSA 494 were 531 +/- 247 for CD and 548 +/- 293 for CI therapy. Similar to the AUBC24, the mean area under the concentration-time curve for a 24-h dosing interval divided by the MIC (AUC/MIC24) ratios +/- SD were 550.0 +/- 265.7 for CD and 552.6 +/- 373.4 for CI therapy, respectively. No statistically significant differences were found between any of the pharmacodynamic parameters for CD and CI therapy. In addition, no adverse effects with either CD or CI therapy were observed during the study. We conclude that CI and CD vancomycin therapy demonstrated equivalent pharmacodynamic activities. Although CI therapy was more likely to result in SBTs that remained above 1:8 for the entire regimen, the clinical impact of this result is unknown. Serum drug concentration variability was observed with both treatment regimens but to a lesser extent with CI administration. CI administration of vancomycin should be further evaluated to determine the clinical utility of this method of administration.     

Comparison of the pharmacokinetics of ceftazidime and moxalactam and their microbiological correlates in volunteers.

We compared ceftazidime with moxalactam, a commonly utilized, currently available drug. The microbiological activities of ceftazidime and moxalactam were studied. In addition, single-dose pharmacokinetics and serum bactericidal activity 1 and 6 h after a 2.0-g, 30-min infusion of each drug were determined in a crossover study in human volunteers. In vitro, both drugs had MICs for 90% of the isolates of less than 1.0 microgram/ml against the common members of the family Enterobacteriaceae and of 8.0 micrograms/ml against Staphylococcus aureus. Against Pseudomonas aeruginosa ceftazidime was more active than moxalactam, the respective MICs for 90% of the isolates being 8 and 128 micrograms/ml. Mean half-lives were 1.75 (+/- 0.21) h for ceftazidime and 2.5 (+/- 0.38) h for moxalactam. The serum bactericidal titers for both compounds against Escherichia coli and Klebsiella pneumoniae were high. Titers against S. aureus 6 h after infusion were negative. The mean (geometric) serum bactericidal titer of ceftazidime against 31 strains of P. aeruginosa (1:44) was higher than that of moxalactam (1:3.4).     

Pharmacokinetics of cefpiramide in volunteers with normal or impaired renal function.

The pharmacokinetics of a single 2.0-g intravenous dose of cefpiramide in patients with normal or impaired renal function were studied. Serial concentrations in serum and urine were measured by using high-performance liquid chromatography, and the effect of the concentration in serum on protein binding was assessed. Thirty patients (ten with creatinine clearances of greater than 80 ml/min, ten with creatinine clearances between 10 and 80 ml/min, and ten on dialysis) were studied. The concentration-time curve of cefpiramide was best described by an open two-compartment model. The elimination half-lives in patients with normal or impaired renal function or those on dialysis were 5.41 +/- 1.44, 8.3 +/- 2.82, and 8.38 +/- 4.06 h, respectively, and the serum clearances in the same groups were 2.0 +/- 0.84, 1.29 +/- 0.45, and 2.04 +/- 1.10 liters/h, respectively. There were no significant differences in any of the parameters among the three groups of patients. In patients with normal or impaired renal function, protein binding varied between 93.0 +/- 1.3% at 304.4 micrograms/ml and 99.3 +/- 0.8% at 41.1 micrograms/ml and was linearly and inversely related to the cefpiramide concentration in serum. In patients on dialysis, protein binding was significantly lower (P less than 0.05) and varied between 88.5 +/- 7.1% at 173.4 micrograms/ml to 94.9 +/- 4.8% at 46.8 micrograms/ml. In patients with normal or abnormal renal function, renal cefpiramide clearance decreased linearly with declining renal function, whereas plasma clearance was maintained. Therefore, nonrenal elimination becomes more important as renal impairment progresses.     

Pharmacokinetics of ceftizoxime in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of ceftizoxime were studied in 12 patients on continuous ambulatory peritoneal dialysis. After a 3-g intravenous dose, the steady-state volume of distribution was 0.23 +/- 0.05 liter kg-1, with an elimination half-life of 9.7 +/- 5.1 h. The peritoneal clearance of ceftizoxime (2.8 +/- 0.7 ml min-1) contributed modestly to the overall serum clearance of the drug (17.1 +/- 7.4 ml min-1) and was greater than the renal clearance (0.8 +/- 0.8 ml min-1). The peritoneal concentration rose to 91 +/- 29 micrograms ml-1 at 6 h, which was 0.61 +/- 0.17 of the serum concentration. A 3-g intravenous dose of ceftizoxime given every 48 h would result in adequate activity against most susceptible organisms, but more frequent dosing may be necessary for less susceptible organisms.     

Altered tobramycin pharmacokinetics during chemoprophylaxis in bladder surgery.

The effect of bladder surgery on the pharmacokinetics of tobramycin in hospitalized patients was studied. Fourteen patients with vesical neoplasia undergoing urinary tract surgery were given tobramycin in a dose of 2 mg/kg of body weight. Each patient received the dose at the induction of anesthesia, about 1 h before surgical incision. For seven patients, the drug was also administered 3 weeks later when nutritional conditions were normal. The pharmacokinetic parameters were determined by a two-compartment open model. Except for renal clearance, no significant difference appeared between pharmacokinetic parameters determined from serum data during peri- and postoperative periods. During this work, tobramycin excretion in urine was studied. Twenty-four hours after drug administration, the mean urine tobramycin levels were 25.5 +/- 9.06 and 41.6 +/- 21.5 micrograms/ml after peri- and postoperative administration, respectively; these values were higher than the MICs for most urinary tract pathogens. Seventy-two hours after perioperative administration, the mean value was still elevated (3.54 micrograms/ml), but 72 h after postoperative administration, the urinary tobramycin concentration was not detectable. The percentages of tobramycin recovered unchanged in urine were 54 and 79% after peri- and postoperative administration, respectively. When tobramycin was administered during surgery, a long terminal log-linear phase, with a mean half-life of 25.6 h, was detected. The ratio of renal clearance to total body clearance was 0.52 and 0.79 after peri- and postoperative administration, respectively.     

In vitro comparison of cefpirome and four other beta-lactam antibiotics alone and in combination with tobramycin against clinical isolates of Pseudomonas aeruginosa

In vitro susceptibility studies of cefpirome versus cefotaxime, ceftazidime, imipenem, and piperacillin alone and in combination with tobramycin were performed against 153 clinical isolates of Pseudomonas aeruginosa from four medical centers. The minimal inhibitory concentration (MIC) for each antibiotic alone was determined by a standardized dilution method. Antibiotic combination studies were performed using a modified checkerboard technique. Cefpirome alone was more active (MIC90 64 micrograms/ml) than piperacillin (MIC90 128 micrograms/ml) or cefotaxime (MIC90 256 micrograms/ml) but less active than imipenem (MIC90 2 micrograms/ml) or ceftazidime (MIC90 32 micrograms/ml). The addition of tobramycin reduced the MICs of all of the beta-lactam antibiotics except for imipenem. The MIC90 for cefpirome when combined with tobramycin was 8 micrograms/ml compared to 16 micrograms/ml for cefotaxime and piperacillin, 8 micrograms/ml for ceftazidime, and 4 micrograms/ml for imipenem. The combination of tobramycin and cefpirome proved to be additive or synergistic for 82% of the isolates (highest rate) compared to 31% with imipenem (lowest rate). The potent in vitro antipseudomonal activity of cefpirome alone and in combination with an aminoglycoside (tobramycin) suggests that this agent may play a useful role in the therapy of infections due to P. aeruginosa.     

Penetration of cefuroxime and ceftazidime into human lungs

We have studied the penetration of cefuroxime and ceftazidime into lung tissue of 40 patients subjected to pulmonary surgery. Samples of blood and lung tissue were taken 1 and 2 h after antibiotic administration. Patients were randomly assigned to four dosage schedule groups: group A received a single intravenous injection of 750 mg cefuroxime; the lung tissue levels at 1 and 2 h were 9.6 +/- 3.1 and 4.54 +/- 2.64 micrograms/g of cefuroxime; the percentage penetration from serum into the lung tissue was 33.7 and 34.6%, respectively. Group B patients received three doses of 750 mg cefuroxime; lung tissue levels were 17.1 +/- 7.7 and 14.7 +/- 5.4 micrograms/g, the percentage of penetration being 89.1 and 102.8% at 1 and 2 h. Group C received a single intravenous injection of 1 g ceftazidime; the lung tissue levels were 16.3 +/- 10.1 and 10 +/- 5.04 micrograms/g; the percentage of penetration from serum was 38.3 and 35.3%. Group D received three doses of 1 g ceftazidime; the lung tissue concentrations were 11.98 +/- 7.5 and 8.5 +/- 7.3 micrograms/g and the percentage of penetration 35.1 and 32.2% at 1 and 2 h after last dose.     

Multiple-dose pharmacokinetics of ceftazidime in cancer patients.

The pharmacokinetic parameters of ceftazidime were determined in 25 patients with neoplastic diseases. A group of 13 patients each received 1 g of ceftazidime over 15 min as a single intravenous dose. The mean peak drug concentration in serum was 77.4 micrograms/ml, and the serum half-life was 144 min. Urinary excretion at 12 h was 64.5%. These 13 patients also received 2 g of ceftazidime over 15 min at 8-h intervals for 7 or 8 days. The mean peak drug concentrations in serum were 103.6 micrograms/ml on day 1 and 87 micrograms/ml on day 7 or 8. A second group of 12 patients received 1 g of ceftazidime over 30 min, followed by 1 g over 2 h and every 4 h thereafter. The mean peak drug concentration in serum at 30 min was 57.5 micrograms/ml. Average peak and trough levels obtained on day 2 or 3 were 65 and 34.8 micrograms/ml, respectively, and remained in this range thereafter. The above-mentioned dose schedules produced high and adequate ceftazidime concentrations in serum.     

Imipenem concentrations in colorectal surgery and impact on the colonic microflora.

Twenty patients undergoing colorectal surgery were given, as prophylaxis, imipenem-cilastatin intravenously. Ten of them received a dose of 0.5/0.5 g of imipenem-cilastatin at induction of anesthesia, followed by subsequent doses of 0.5/0.5 g every 6 h for 48 h. The other 10 patients were given 1.0/1.0 g imipenem-cilastatin in the same way for 48 h. Samples from serum, intestinal mucosa, and feces were taken for analysis of imipenem concentrations during the day of surgery. The mean concentrations in serum at 1 h after the first imipenem dose were 15.9 +/- 1.7 micrograms/ml for the 0.5-g dose and 68.2 +/- 8.2 micrograms/ml for the 1.0-g dose. The mean half-lives were 1.5 and 1.4 h, respectively, and the mean areas under the serum concentration-time curve were 41.2 +/- 6.0 and 128.3 +/- 13.5 mg.h/liter, respectively. The imipenem concentrations in the intestinal mucosa varied between less than 0.1 and 3.6 mg/kg for the 0.5-g dose and 3.2 and 13.4 mg/kg for the 1.0-g dose. The concentrations in the fecal samples varied between less than 0.1 and 5.0 mg/kg for the 0.5-g dose and 0.7 and 11.3 mg/kg for the 1.0-g dose. Fecal samples were also collected during the investigation period for cultivation of aerobic and anaerobic bacteria. The aerobic bacteria--staphylococci, streptococci, enterococci, and enteroaerobic enterococci, and enterobacteria--were and anaerobic bacteria. The aerobic bacteria--staphylococci, streptococci, enterococci, and enterobacteria--were suppressed significantly during the imipenem prophylaxis period. Among the anaerobic bacteria, cocci, bifidobacteria, eubacteria, lactobacilli, clostridia, fusobacteria, and bacteroides decreased markedly during the same period. The microfloras were normalized after 2 weeks. There were no differences between the patients receiving 0.5-g doses of imipenem and those receiving 1.0-g of imipenem. No postoperative infections occurred.     

Intraoperative concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue.

To evaluate concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue after intravenous administration, patients greater than or equal to 16 years old diagnosed with acute cholecystitis were randomly assigned to receive ofloxacin (400 mg) intravenously every 12 h or ceftazidime (2 g) intravenously every 8 h. Doses of each regimen were given preoperatively. Serum, bile fluid, and gallbladder wall tissue samples of consecutive patients in the ofloxacin group were obtained intraoperatively. The samples were frozen at -70 degrees C until analyzed by high-pressure liquid chromatography. Twenty-three patients (6 males and 17 females) were evaluated. The mean (+/- the standard deviation) ofloxacin concentrations in serum, bile fluid, and gallbladder wall tissue were 2.9 +/- 2.4 and 6.0 +/- 7.9 micrograms/ml and 3.1 +/- 2.9 micrograms/g, respectively. The mean number of doses each patient received before surgery was 5.3 +/- 3.0, and the mean delta time (time elapsed between last antibiotic administration and when intraoperative samples were obtained) was 9.6 +/- 7.5 h. The mean tissue-to-serum ratio was 1.2 +/- 0.5, and the mean bile-to-serum ratio was 2.3 +/- 1.4. The mean serum ofloxacin concentrations were not statistically different from the concentrations in bile (P = 0.1) and tissue (P = 0.7) at the mean delta time. The study revealed that concentrations of ofloxacin in serum, bile fluid, and gallbladder tissue after intravenous dosing were adequate against susceptible organisms found in the biliary tract.