Different calcium and oxidative metabolic responses in human blood monocytes during exposure to various agonists.

It has become increasingly apparent that certain agonists of phagocytic cells exert their effects by using calcium as an intracellular messenger. Most studies have employed neutrophils for such analyses. We have investigated the requirement of calcium for respiratory burst activation in human blood monocytes by using three triggering agents, concanavalin A (Con A), N-formyl-methionyl-leucil-phenylalanine (FMLP), and phorbol myristate acetate (PMA). There was no overall correlation between the maximal extent of transient rise in cytosolic-free calcium (FMLP greater than Con A greater than PMA) and superoxide (O2-) release (PMA greater than Con A greater than FMLP). PMA, as the most effective agonist of respiratory burst activity, neither increased ionized cytosolic calcium [Ca2+]i nor plasma membrane 45Ca2+ permeability. FMLP evoked increments in [Ca2+]i occurred at lower concentrations than did respiratory burst activation, whereas with Con A a rise in [Ca2+]i and O2- release were parallel. Intracellular Ca2+ release into cytosol was blocked by 8-(N,N-diethylamino)octyl-3,4,5-trimethoxy benzoate, HCl (TMB-8). This caused a parallel inhibition of Con A or FMLP elicited [Ca2+]i transients and O2- release, while burst activity stimulated by PMA was unaffected. Our data thus suggest that a transient rise in [Ca2+]i is essential for Con A and FMLP activation in human blood monocytes. In addition to the calcium signal, other intracellular messengers are required for FMLP stimulation. Respiratory burst activation by PMA appears to act independently of [Ca2+]i transients.

Systemic and endotracheal antibiotic prophylaxis of nosocomial pneumonia in ICU.

Nosocomial pneumonias, especially in ventilated patients, are a continuing problem in modern medicine. Pathogens most commonly involved with these pneumonias are Enterobacteriaceae, Ps. aeruginosa and S. aureus. Several prevention measures for nosocomial pneumonia are possible such as parenteral and topical antibiotics--a very controversial issue. Several studies with parenteral antibiotics, starting as early as 1954, could not prove any benefit of parenteral antibiotics in pneumonia prevention. Topical antibiotics, starting with polymyxin or gentamicin via the endotracheal tube in the 70s, gave controversial results. In a prospective, randomized, double-blind placebo controlled study with gentamicin via the endotracheal tube in ventilated ICU patients we found no significant reduction of pneumonia rate and mortality. However, the combined approach (SDD) of oropharyngeal, gastrointestinal and parenteral use of certain antibiotics appears to give promising results in specific patient subgroups such as ventilated polytrauma patients in ICU.

Aminoglycoside dosage in hemodialysis patients.

Regulating aminoglycoside dosage in patients undergoing hemodialysis is difficult because its elimination depends entirely on renal function and because the therapeutic margin is narrow. Guidelines for aminoglycoside dosage were derived from published population-based kinetics and investigated in a prospective clinical study over a 12-month period in 50 consecutive patients undergoing hemodialysis with acute (70%) or chronic (30%) renal failure. Based on body weight, each patient received one loading dose (1.5 mg/kg) and a daily maintenance dose (0.5 mg/kg) of netilmicin. The dosage interval was 24 hours. On each hemodialysis day, the dose of netilmicin was given immediately after hemodialysis. Each posthemodialysis dose (1.3 mg/kg) was the sum of the daily maintenance dose plus a supplementary dose to replace the amount of the drug removed during hemodialysis. A blood sample was taken at the start and the end of each hemodialysis and one hour after the start of the posthemodialysis dosage. Netilmicin plasma concentrations were determined by substrate-labeled fluorescence immunoassay. The mean (+/- standard deviation) peak plasma concentration of the pooled data for all patients was 7.5 +/- 2.7 mg/L, and the mean trough level was 3.6 +/- 1.3 mg/L. The theoretically postulated range of therapeutic peak levels (5-10 mg/L) was the same as in patients with normal renal function, whereas the theoretically postulated range of therapeutic trough levels (2.2-5.0 mg/L) was considerably higher than in healthy persons. Peak and trough levels within the postulated range were achieved in 81% of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacokinetics of cefoperazone and cefotaxime.

The pharmacokinetics of cefoperazone and cefotaxime were compared in a crossover, randomized study in ten healthy volunteers (5 males, 5 females). Each subject received 2.0 gm of the study drug administered by an IV infusion over 30 minutes. Serum concentrations of cefoperazone and cefotaxime at the end of the infusion (zero time) were 254 mg/liter and 144 mg/liter, respectively. Comparative results at other times were the following: four hours, 20 mg/liter and 3 mg/liter; eight hours, 4.4 mg/liter and 0.3 mg/liter; and 12 hours, 1.2 mg/liter and 0.0 mg/liter. Twenty-one percent of the 2.0-gm single dose of cefoperazone was recovered in the urine during the first 24 hours following dosing, compared to 52% for cefotaxime. The renal clearance of cefoperazone was also determined in three patients during four hours. The results of the investigations will be discussed in view of the clinical relevance.

[Enzymatic quick determination of aminoglycoside antibiotics in serum]. / Enzymatische Schnellbestimmung von Aminoglykosidantibiotika im Serum

The therapeutic range of aminoglycoside antibiotics is relatively narrow; therefore short-term controls of serum concentrations can be recommended, particularly for high-dosage therapy and for renal insufficiency. For the aminoglycosides Amicacin, Gentamycin, Sisomicin and Tobramycin an enzymatic quick-determination test within 2 hrs is being described, which is based on the pH-deviation of a medium containing urea by hydrolytic activity of proteus mirabilis-bacteriae. In more than 180 measurements of patients' sera as well as of sera with known concentrations the method was tried out and compared with the conventional agar diffusion procedure. In strict compliance with the methodical directions, reproducable results could be achieved at any time within the range of1.0-30.0mug/ml; the number of faults in the quick-determination test was with +/- 8.4% about the same as in the agar diffusion test. In comparison with other microbiological or biochemical quick-procedures, the simplicity of the described method must be emphasized, thus it can be performed, too, in non-bacteriological laboratories.

[Comparative clinical pharmacology of gentamicin, sisomicin, and tobramycin].

Using a randomized crossover design involving 12 normal subjects, we studied comparatively the pharmacokinetics and tolerance of three aminoglycoside antibiotics, gentamicin, sisomicin, and tobramycin. Serum concentrations were determined during 8 h and the urine recovery rate was determined within 24 h after a 1-h intravenous infusion of the respective antibiotic in a dose of 1 mg/kg of body weight. Microbiological assay was performed with the agar diffusion test (Bacillus subtilis); pharmacokinetic calculations were performed by means of a digital computer on the basis of a mathematical model of an open, two-compartment system. Of the three antibiotics studied, gentamicin showed the lowest concentration in serum after termination of the 1-h infusion (3.85 +/- 0.67 mug/ml), and the serum-regression curve steadily lay below those of the two other antibiotics. Sisomicin had the highest serum concentrations (4,66 +/- 1.24 mug/ml) and the serum-level curve exceeded that of the two other antibiotics. Tobramycin occupied a position between sisomicin and gentamicin in form of its serum level characteristics. Corresponding to the serum kinetics we also found slight differences in the pharmacokinetic parameters, especially in serum half-lives, elimination constants, and areas under the serum level curves. The test of liver and kidney functions and the hematological systems, as well as the function of the stato-acusticus nerve, showed no pathological changes by any of the three antibiotics tested.

[Diagnosis and antibiotic treatment of infectious diseases in general practice. Results of an inquiry]. / Diagnostik und Antibiotikatherapie von Infektionskrankheiten in der Praxis. Ergebnisse einer Umfrage.

In February 1982 a questionnaire was sent to 2138 doctors in general practice in West Berlin, to obtain data relating to the incidence and treatment of infectious diseases. Replies were received from 453 (21%). Regular bacteriological tests were undertaken only for urinary tract infections, by 60% of those replying. The 453 doctors reported a total of 9280 cases of infectious disease during a one-week period, 6094 respiratory and 1723 urinary ones. Antibiotic prescriptions numbered 6118 during this period, 56.7% for respiratory and 27% for urinary tract infections. Indications for antibiotic treatment were predominantly decided on clinical grounds.

Comparative evaluation of ciprofloxacin, enoxacin, and ofloxacin in experimental Pseudomonas aeruginosa pneumonia.

The therapeutic activity of ciprofloxacin, enoxacin, and ofloxacin was evaluated in guinea pigs with acute and chronic experimental Pseudomonas aeruginosa pneumonia. Intratracheal instillations of P. aeruginosa resulted in fatal pneumonia in all untreated animals within 36 h. Among treatment groups (80 mg/kg [body weight] per day), cumulative survival rates were: 47%, ciprofloxacin; 55%, enoxacin; and 42%, ofloxacin. These rates were not significantly different. Intrapulmonary killing of P. aeruginosa was equivalent 3 h after a single dose of ciprofloxacin or ofloxacin (20 mg/kg) or enoxacin (40 mg/kg). The combination of ciprofloxacin with azlocillin, ceftazidime, or tobramycin did not increase the efficacy of intrapulmonary killing of P. aeruginosa over that of ciprofloxacin alone. A chronic, nonfatal bronchopneumonia was induced in guinea pigs by intratracheal instillation of microscopic agar beads impregnated with a mucoid strain of P. aeruginosa. Compared with no treatment, ciprofloxacin and enoxacin produced greater than or equal to 99.9% intrapulmonary killing, and ofloxacin sterilized the lungs completely, after 4 days of treatment. In no quinolone-treated animal did resistant strains of P. aeruginosa emerge during 4-day treatment periods. In further studies with the chronic model, oral and parenteral ciprofloxacin treatment were found to be equivalent in efficacy. We conclude that several quinolone derivatives may be effective for the treatment of P. aeruginosa pneumonia and that combinations of quinolones with beta-lactams or aminoglycosides may not increase efficacy against P. aeruginosa pneumonia.

Relation of cytosolic calcium to the microbicidal activation of blood monocytes by recombinant gamma interferon.

Oxygen metabolism and calcium ion (Ca++) handling in blood monocytes were greatly affected by treatment with recombinant gamma interferon (rIFN-gamma). Incubating the monocytes with rIFN-gamma resulted in increased basal production of superoxide anion, as well as a significantly enhanced respiratory burst in response to concanavalin A (Con A). A concomitant increase in microbicidal activity against Listeria monocytogenes was observed, and cell membrane permeability to Ca++ was enhanced by treatment with rIFN-gamma. Con A stimulation was also associated with acute rises in cytosolic-free calcium, and these calcium transients were greatly augmented in cells pretreated with rIFN-gamma. The enhanced respiratory burst and the increased calcium transients were completely neutralized by a monoclonal antibody to rIFN-gamma. Furthermore, enhancement of the respiratory burst and calcium transients occurred in a parallel dose-response range for rIFN-gamma. Blocking the intracellular release of calcium into cytosol by TMB-8 abrogated the capacity of rIFN-gamma to enhance the monocyte respiratory burst. Thus, not only was rIFN-gamma treatment of monocytes associated with altered calcium metabolism, but calcium from intracellular pools was essential to the expression of this activated state during Con A stimulation.

[Pharmacokinetics and clinical observations of sisomicin, a newly developed aminoglycoside derivative (author's transl)]. / Vergleichende Pharmakokinetik und klinische Erfahrungen mit einem neuen Aminoglykosid-Derivat: Sisomicin

In a randomized study of 12 healthy subjects the pharmacokinetics of gentamicin, sisomicin and tobramycin were determined after a one-hour infusion of each drug (1.0 mg/kg body-weight) four weeks apart. There were no pharmacokinetic differences of therapeutic significance between the three drugs. The mean serum concentrations at the end of infusion were 3.85 mug/ml for gentamicin and 4.66 mug/ml for sisomicin, falling to 0.12 and 0.26 mug/ml, respectively, after eight hours. The biological half-life varied between 96 and 122 min and the apparent volumes of distribution corresponded closely tothe size of the extracellular space. The antibacterial effectiveness, tolerance and modes of application were studied in 24 patients, most of them with urinary infection, at a dosage of 1.0 mg per kg body-weight two to three times daily. Good clinical results were achieved in 15, satisfactory ones in three, and in 16 the causative bacteria were eradicated. Sisomicin was well tolerated, except for minor and reversible renal (2 patients), hepatic (3 patients), and hearing (1 patient) disturbances.

[Pharmacologic studies or aminoglycoside antibiotics (amikacin, gentamicin, sisomicin, tobramycin)]. / Pharmakokinetische Untersuchungen von Aminoglykosid-Antibiotika (Amikacin, Gentamicin, Sisomicin, Tobramycin).

In a randomized study of 12 healthy subjects, the pharmacokinetics of gentamicin, sisomicin and tobramycin were determined after a one-hour infusion of each drug (1.0 mg/kg body-weight). There were no pharmacokinetic differences of therapeutic significance between the three drugs. The mean serum concentrations at the end of infusion were 3.85 microgram/ml for gentamicin and 4.66 microgram/ml for sisomicin, falling to 0.12 and 0.26 microgram/ml, respectively, after eight hours. The biological half-life varied between 96 and 122 min and the apparent volumes of distribution corresponded closely to the size of the extracellular space.--The pharmacokinetic data of amikacin were determined after a one-hour constant infusion, the mean amikacin serum concentration was 37.5 microgram/ml and, 8 hours later, decreased to an average of 1.3 microgram/ml. The biological half-life amounted to a mean of 114.2 +/- 16.7 min, and the apparent volume of distribution could be calculated with 18.1 +/- 1.81/100 kg body weight.

Comparative oxidative microbicidal activity of human blood monocytes and alveolar macrophages and activation by recombinant gamma interferon.

The relative oxidative and microbicidal activities of human blood monocytes compared with those of alveolar macrophages (AM) are poorly defined. Furthermore, the comparative efficiency of recombinant gamma interferon (rIFN gamma) to enhance microbicidal function of these 2 cell populations is uncertain. In this study, blood monocytes and AM were obtained concomitantly from 10 healthy, nonsmoking human subjects. Cells were adjusted to equivalent cell concentrations and assayed for respiratory burst activity (superoxide anion production) during soluble (Concanavalin A) or particulate (bacteria) stimulation. Microbicidal activity against Pseudomonas aeruginosa, Listeria monocytogenes, and Candida albicans was also determined for each cell type. Finally, the capacity of rIFN gamma treatment (200 U/ml for 24 h) to enhance these cellular activities was determined. Oxidative activity of AM was greater than that of blood monocytes (p less than 0.01, bacteria; p less than 0.02, Con A). Likewise, AM exhibited greater killing of P. aeruginosa (p less than 0.01) and L. monocytogenes (p less than 0.01) than did monocytes. Neither cell killed C. albicans. Treatment with rIFN gamma greatly enhanced both respiratory burst and microbicidal activity of blood monocytes, but had no effect on AM respiratory burst. Despite this, rIFN gamma-treated AM did exhibit some enhanced killing of L. monocytogenes (p less than 0.05). We conclude that oxidative microbicidal activity of resident AM greatly exceeds that of blood monocytes, but that blood monocytes are relatively more susceptible to activation by rIFN gamma.

Comparative evaluation of enoxacin, ofloxacin, ampicillin, and chloramphenicol for treatment of experimental Haemophilus influenzae pneumonia.

A murine model of bacteremic Haemophilus influenzae type b pneumonia was used to evaluate the therapeutic efficacies of the quinolone antimicrobial agents enoxacin and ofloxacin compared with those of ampicillin and chloramphenicol. Ampicillin-susceptible (AS) and ampicillin-resistant (AR) challenge strains were employed. Treatment with enoxacin or ofloxacin produced intrapulmonary killing of H. influenzae that was superior to that achieved with ampicillin (P less than 0.01 to P less than 0.001 for both AS and AR strains). Ofloxacin and enoxacin also provided killing greater than that with chloramphenicol for the AS strain (P less than 0.01 to P less than 0.001). For the AR strain, ofloxacin provided killing greater than that obtained with chloramphenicol (P less than 0.001). Survival from AS strain pneumonia was 60% in enoxacin-treated and 78% in ofloxacin-treated animals compared with 41% for chloramphenicol-treated and 23% for ampicillin-treated groups. We conclude that enoxacin and ofloxacin may be effective antimicrobial agents in treating either AS or AR strains causing H. influenzae pneumonia.

Comparative efficacies of ciprofloxacin, ampicillin and chloramphenicol in treatment of experimental Haemophilus influenzae pneumonia.

An experimental murine model of bacteraemic Haemophilus influenzae pneumonia was used to evaluate the therapeutic efficacy of ciprofloxacin, as compared with ampicillin and chloramphenicol. An ampicillin-sensitive (AS) and an ampicillin-resistant (AR) challenge strain were employed. Ciprofloxacin treatment produced intrapulmonary killing of H. influenzae which was superior to that achieved with ampicillin (P less than 0.001, both strains) and chloramphenicol (P less than 0.001, strain AS; P less than 0.005, strain AR). Likewise, survival from strain AS pneumonia was 61% in the ciprofloxacin-treated animals, as compared with 43% for the chloramphenicol-treated, and 22% for the ampicillin-treated groups. We conclude that ciprofloxacin may be an effective agent in treating pneumonia caused by either ampicillin-sensitive or ampicillin-resistant strains of H. influenzae.

[Cefoperazone--a new cephalosporin antibiotic with broader spectrum of activity]. / Cefoperazon--ein neues Cephalosporin-Antibiotikum mit erweitertem Wirkungsspektrum.

Concentration of Cefoperazone in serum and urine was determined after 1g (bolus injection) and 2g drip-infusion over a 30-minute-period in 10 healthy volunteers. The pharmacokinetic analysis was performed using an open 3-compartment model. Renal clearance was determined in three volunteers and indicates an expansive extrarenal elimination rate. 31 patients mainly with severe bronchopulmonary infections were treated with 2.0--6.0 g/day of Cefoperazone. The therapeutic results were favourable, the toleration of the drug was good.

Verapamil impairs human neutrophil chemotaxis by a non-calcium-mediated mechanism.

The in vitro effect of pharmacologic concentrations (10(-8) to 10(-6) mol/L) of verapamil on human neutrophil migration and response to chemotactic signals was examined. Human neutrophils were preincubated (15 minutes) in verapamil and then assayed for chemotactic response to formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe) (10(-8) mol/L). Cell viability was not affected by verapamil treatment. Verapamil-treated cells displayed 40% to 50% reductions in directed migration at all concentrations (P less than 0.02). Activated random migration (chemokinesis) was also impaired by verapamil treatment, but random locomotion was not affected except at a high concentration (10(-6) mol/L). This pharmacologic action of verapamil was not rapidly reversible by washing cells free of drug, but it was necessary that cells be exposed to drug before the chemotactic signal. In addition to f-Met-Leu-Phe, chemotactic response to activated human serum was also reduced for neutrophils. Several experiments were conducted to determine whether verapamil affected neutrophils as a calcium antagonist. Calcium antagonist binding-site assays using radiolabeled dihydropyridines provided no evidence for the presence of calcium channels in neutrophil membranes. Also, 45Ca2+ uptake assays demonstrated increased uptake of 45Ca2+ by f-Met-Leu-Phe-stimulated neutrophils, but no effect on uptake by verapamil exposures (10(-6) mol/L). Finally, the cytosolic calcium-chelating dye, quin 2 acetomethoxy ester (quin 2), was used as a fluorescent indicator to measure cytosolic Ca2+ concentrations, [Ca2+]i, in neutrophils. Verapamil exposures over a wide concentration range (10(-6) to 10(-4) mol/L) did not affect resting [Ca2+]i or [Ca2+]i transients after f-Met-Leu-Phe (10(-8) mol/L) stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Value of diagnostic procedures in fiberoptic bronchoscopy of pulmonary infections]. / Stellenwert diagnostischer Verfahren bei der Fiberbronchoskopie pulmonaler Infektionen.

Fibreoptic bronchoscopy has become an important means of diagnosing infections of the lower respiratory tract, since it a method with few complications, whereas, on the other hand, the conventional non-invasive methods are hardly reliable in respect of diagnostic relevance. Frequent oropharyngeal contamination severely limits the significant assessment of the pathogenicity of cultured microorganisms. The protected specimen brush (PSB) or quantitative cultures of bronchoalveolar lavage (BAL) might be useful in solving this problem. These methods were studied in two prospective trials comprising 123 patients with suspected bronchopulmonary infection and 54 control patients. Both methods were found to be disappointing in respect of sensitivity; moreover, quantitative cultivation did not yield any differences with regard to specificity.

Comparative pharmacokinetics of cefoperazone, cefotaxime, and moxalactam.

The pharmacokinetics of cefoperazone, cefotaxime, and moxalactam were compared in a cross-over randomized study in 10 healthy volunteers. Each subject received 1.0 g of the three drugs by bolus intravenous injection over 3 min. Serum and urine concentrations were assayed by a microbiological method and in addition by high-pressure liquid chromatography (HPLC) for cefotaxime in five subjects. Maximal concentrations in serum 5 min after the injection were 163 +/- 40.3 mg/liter for cefoperazone, 86.1 +/- 19.0 mg/liter for cefotaxime, and 95.5 +/- 21.1 mg/liter for moxalactam. After 12 h, 1.2 +/- 1.4 mg of cefoperazone per liter and 1.8 +/- 0.9 mg of moxalactam per liter could still be measured. Eight hours after the administration of cefotaxime, serum concentrations were below the detection limit of 0.3 mg/liter in most subjects. By HPLC analysis, the mean maximal concentration of desacetyl cefotaxime was 16.6 +/- 10.5 mg/liter 5 min after application; the metabolite exceeded the serum concentration of the parent compound after 1 to 2 h. Relevant pharmacokinetic parameters were calculated, using two- and three-compartment models. The terminal half-life was 144.1 +/- 37.3 min for cefoperazone, 76.1 +/- 32.0 min for cefotaxime, and 272.4 +/- 114.1 min for moxalactam. The apparent volume of distribution corresponded to the extracellular volume. Only 25.1 +/- 8% of cefoperazone could be detected in urine compared with 53.3 +/- 8.1% of cefotaxime and 61.0 +/- 9.2% of moxalactam in 24 h. A total of 89.6 +/- 11.4% of the cefotaxime dose could be recovered by HPLC in urine, 60.6 +/- 7.7% as cefotaxime and 29.1 +/- 7.0% as desacetyl cefotaxime.

Pharmacokinetics of multiple doses of ceftizoxime and their influence on fecal flora.

The pharmacokinetics of ceftizoxime, a new beta-lactam antibiotic, were studied in eight normal volunteers after single and multiple i.v. doses of 2 X 2 g daily for eight days. The mean maximum serum concentration after the first 20 min of infusion on the first day was 176.9 +/- 32.9 micrograms/ml decreasing to 11.0 +/- 4.1 micrograms/ml after 4 h and to 0.67 +/- 0.2 micrograms/ml after 12 h. Mean 12 h urine recovery was 78.8 +/- 9.0%. The half-life of ceftizoxime was 136 +/- 36 min. Volume of distribution was 22.9 +/- 8.1 1/100 kg body weight, AUCtot 208 +/- 33 micrograms/ml x h, total body clearance 151 +/- 33 ml/min, and renal clearance 110 +/- 23 ml/min. No ceftizoxime accumulation was registered during the administration period. Computed multiple-dose values were in good agreement with the measured values, and the pharmacokinetic parameters on the first, fourth and eighth days showed no significant differences. During the study period, the fecal flora displayed a reduction of sensitive gram-negative aerobic bacteria, a slight increase in the amount of enterococci (10(6) to 10(8)/g feces), and no change in the number of Bacteroides fragilis. Some resistant gram-negative strains increased during the administration period, but most of them could no longer be detected two weeks after administration. Tolerance of ceftizoxime was good in four volunteers. Four other volunteers had gastro-intestinal symptoms and mild fever reactions. One female volunteer was assumed to have an allergic drug reaction. Biochemical, hematological, virological and serological data showed no abnormalities in seven volunteers.

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.