Haemophilus influenzae prostatitis.
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Culture Media↗
Biomedical subjects
W A Craig
Publications and source records attributed to W A Craig.
[Experimental study of optimal dose interval in antibiotic therapy].
A postantibiotic effect (PAE) was demonstrated for various antibiotics which suppressed bacterial regrowth for at least two hours beyond the termination of a short drug exposure in vitro. Rifampin, tetracycline and erythromycin already exhibit a PAE at low concentrations. In contrast, in the case of beta-lactams high concentrations - higher than those obtained in serum during oral treatment - were needed to demonstrate a PAE of these antibiotics in vitro. The PAE phenomenon may be of clinical importance with regard to dosage regimens in antimicrobial chemotherapy.
Anti-Bacterial Agents↗
Pharmacokinetics of hydrochlorothiazide in fasted and nonfasted subjects: a comparison of plasma level and urinary excretion methods.
The bioavailability of hydrochlorothiazide from 50-mg oral tablet doses was examined in healthy male volunteers under fasting and nonfasting conditions. Bioavailability was examined from plasma levels and urinary excretion of unchanged drug. The pharmacokinetics of hydrochlorothiazide in plasma could be described in terms of a triexponential function, and the mean drug half-lives determined from the three exponents were 1.0, 2.2, and 9.0 hr. Changing the accompanying fluid volume has no significant effect on hydrochlorothiazide absorption in fasted subjects. Plasma drug levels were significantly reduced in non-fasted individuals, compared with those in fasted individuals. A similar trend was observed in the urinary excretion of hydrochlorothiazide, but differences between treatments were not significant (p greater than 0.05). Mean 48-hr urinary recovery of hydrochlorothiazide was 70.5% of the dose in nonfasted subjects, and 73.5 and 75.0% of the dose in fasted subjects receiving the drug with 20 and 250 ml of water, respectively. The cumulative urinary excretion of hydrochlorothiazide correlated poorly (r = 0.27) with areas under plasma drug level curves, although the correlation between the means of these values for each of the three treatments was high (r = 0.996).. Close similarity was observed between urinary excretion rates of hydrochlorothiazide and the time course of drug concentrations in plasma.
Adult↗
Oral hydrocortisone pharmacokinetics: a comparison of fluorescence and ultraviolet high-pressure liquid chromatographic assays for hydrocortisone in plasma.
Three fasted, male subjects received single 10-, 30-, and 50-mg oral doses of hydrocortisone tablets on separate occasions. Endogenous hydrocortisone was suppressed by giving 2 mg of dexamethasone 9 hr prior to dosing. Plasma samples obtained serially for 8 hr after hydrocortisone dosing were assayed by reversed-phase high-pressure liquid chromatography (HPLC) with UV detection and by normal-phase HPLC with fluorescence detection of the dansylhydrazine derivative of hydrocortisone. The two assay methods yielded equivalent plasma hydrocortisone concentrations. Metabolite interference was absent in both assay methods. Drug concentrations in plasma from all three doses of hydrocortisone were described by one-compartment open-model kinetics, with first-order absorption and elimination, and an absorption lag time. Mean Cmax values of 199, 393, and 419 ng/ml were obtained at 1.0, 1.0, and 1.7 hr following the 10-, 30-, and 50-mg doses, respectively. Hydrocortisone was cleared from plasma with an elimination half-life of approximately 1.5 hr. Within the dosage range studied, plasma levels of hydrocortisone were related, but not directly proportional, to dose size. This apparent lack of proportionality may be due to reduced drug availability or altered distribution with increasing dose.
Administration, Oral↗
An in vitro model for the study of antibacterial dosage regimen design.
A model was developed that is capable of simulating antibacterial agent concentration versus time profiles commonly observed following intravenous and intramuscular bolus injections, intravenous infusions, and oral doses, administered as single or multiple doses. The model consisted of two physical compartments separated by a membrane of a commercial hemodialyzer. The 1.08 m2 membrane surface area allowed rapid transmembrane passage of drugs and other small molecules, while membrane pore size prevented bacterial passage. These characteristics allowed bacteria in one of the two compartments of the model to be exposed to time-variant drug concentrations without affecting the number or concentration of bacteria. The model was used to study the effects of a multiple intravenous bolus dosage regimen of ampicillin on Escherichia coli ATCC 12407.
Administration, Oral↗
Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension.
The pharmacokinetics of hydrocortisone were examined following single doses of 5-, 10-, 20-, and 40-mg hydrocortisone suspensions to healthy male volunteers. Endogenous hydrocortisone was suppressed by giving 2 mg of dexamethasone the night before hydrocortisone administration. Plasma samples obtained serially for 12 hr after hydrocortisone administration were assayed by reversed-phase high-pressure liquid chromatography using a fixed-wavelength (254 nm) UV absorbance detector. Drug absorption was rapid, with mean maximum plasma hydrocortisone concentrations occurring within 60 min of dosing. Subsequent drug elimination was monophasic with mean elimination half-lives increasing from 1.2 hr for the 5-mg dose to 1.7 hr for the 40-mg dose. Increase in AUC and Cmax with increasing dose were linear but not directly proportional to dose size. This was attributed to dose-dependent absorption or to loss of drug the first-pass through the liver.
Adult↗
Bioavailability of tolazamide from tablets: comparison of in vitro and in vivo results.
The relative bioavailability of tolazamide was determined, in healthy male volunteers, from four different tablet formulations manufactured by direct compaction or granulation processes and the results were compared with in vitro disintegration and dissolution values. Serum tolazamide levels were determined by a high-pressure liquid chromatographic method developed in this laboratory. Serum tolazamide levels from the formulation that gave rise to rapid absorption were described by one-compartment model kinetics with a mean absorption half-time of 1.0 hr and an elimination half-life of 4.6 hr. Peak serum levels occurred at 3.3 hr after drug administration. Marked differences were observed in drug bioavailability from the four tablets, and the mean cumulative relative fraction of dose absorbed was 1.0, 0.42, 0.75, and 0.91 from Formulations A, B, C, and D, respectively. The hypoglycemic effect was closely related to serum tolazamide levels. Disintegration times did not predict in vivo tolazamide bioavailability. Dissolution rates provided an approximate rank order correlation with in vivo absorption but failed to be predictive among formulations. Currently available in vitro tests do not accurately predict tolazamide in vivo bioavailability characteristics among different formulations and manufacturing processes but may be useful to ensure lot-to-lot uniformity in bioavailability for a given formulation and specific method of manufacture.
Adolescent↗
Selection of aminoglycoside-resistant variants of Pseudomonas aeruginosa in an in vivo model.
The therapeutic failure of aminoglycosides in leukopenic mice was studied. Pseudomonas aeruginosa isolated from experimentally infected leukopenic mice was analyzed for susceptibility to gentamicin. Bacterial population analyses were performed before, during, and after therapy with high doses of gentamicin. Inocula from numerous strains, including P. aeruginosa strain ATCC 27853, harbored slowly growing aminoglycoside-resistant subpopulations. In leukopenic mice (in contrast to normal mice) receiving gentamicin, the breakthrough growth of these subpopulations occurred 6 hr after treatment. Resistance to gentamicin reversed in vivo when gentamicin treatment was stopped. The emergence of gentamicin-resistant subpopulations was successfully suppressed by a combined treatment regimen of gentamicin and ticarcillin. Gentamicin-ticarcillin synergy in these infections is due, in part, to antimicrobial suppression of slowly growing aminoglycoside-resistant subpopulations of bacteria.
Aminoglycosides↗
Influence of urinary pH on the pharmacokinetics of cinoxacin in humans and on antibacterial activity in vitro.
The impact of acidification and alkalinization of the urine on the pharmacokinetics of cinoxacin was examined after single 500-mg oral doses were administered to nine healthy male volunteers. Acidic and alkaline conditions were achieved by repeated oral doses of ammonium chloride or sodium bicarbonate, respectively. Plasma cinoxacin levels in all subjects were adequately described in terms of one-compartment-model kinetics with first-order absorption and elimination. Acidification and alkalinization treatment had no effect on cinoxacin absorption or distribution. The mean elimination half-life of cinoxacin in plasma was 1.1, 2.0, and 0.6 h in control subjects and with acidification and alkalinization of urine, respectively. Recovery of intact cinoxacin in samples of urine collected 0 to 36 h after cinoxacin administration represented 65% of the dose in control subjects and urine acidification and 80% of the dose with alkalinization of urine. The mean renal clearance of cinoxacin was 76, 118, and 278 ml/min with acidification, control, and alkalinization, respectively, and renal clearance was highly correlated with urinary pH. Urine concentrations of cinoxacin were significantly higher with alkalinization compared with control values during the first 4 h after drug administration. Urine cinoxacin concentrations were reduced somewhat by acidification, but these tended not to be significantly different from control values. Changes in cinoxacin elimination owing to urine pH are less pronounced in humans than in dogs. The antibacterial activity of cinoxacin against some common urinary tract pathogens was pH dependent. A four- to eightfold reduction in cinoxacin activity was generally observed at pH 8 compared with lower pH values. However, in view of the high levels of cinoxacin which are obtained in both acidic and basic urine, the impact of urine pH on cinoxacin antibacterial efficacy would be of minor clinical importance.
Adult↗
In vitro susceptibility of Clostridium difficile isolates to cefotaxime, moxalactam, and cefoperazone.
The in vitro susceptibility of 20 isolates of Clostridium difficile to cefotaxime, moxalactam, and cefoperazone was determined by a standard agar dilution method. The median minimal inhibitory concentrations were 64, 32, and 32 mug/ml for cefotaxime, moxalactam, and cefoperazone, respectively.
Anti-Bacterial Agents↗
Aminoglycoside-selected subpopulations of Pseudomonas aeruginosa: characterization and virulence in normal and leukopenic mice.
An attempt was made in vitro and in vivo to clarify the significance of aminoglycoside-resistant subpopulations that can be isolated from gentamicin-susceptible Pseudomonas aeruginosa. Population analyses revealed bacterial subpopulations resistant to greater than or equal to 8 micrograms/ml gentamicin in 23 of 24 gentamicin-susceptible strains tested. These subpopulations could easily be selected in a single exposure of high inocula of P. aeruginosa to two times the MIC of gentamicin for 24 to 48 hr. The increased gentamicin resistance was associated with slower growth and formation of smaller colonies. In serial subcultivations, most of the selected variants were unstable regarding gentamicin resistance and colony morphology. Stable SCV representing the extreme form of gentamicin-resistant subpopulations were further studied. In comparison to the corresponding PS, they were fourfold to sixfold less susceptible to five aminoglycosides tested; their susceptibility to eight antipseudomonal beta-lactam drugs, however, was usually retained. SCV proved to be less pathogenic than PS for normal and moderately leukopenic mice. Agranulocytic mice, in contrast, were invariably killed after i.p. injection of less than 20 organisms of PS or SCV, although death occurred 24 to 48 hr later in mice infected with SCV. After injection into the thigh muscle of agranulocytic mice, SCV were not affected by therapeutic plasma levels of gentamicin, whereas ticarcillin was highly effective. Aminoglycoside-resistant subpopulations of P. aeruginosa could contribute to the high number of treatment failures of Pseudomonas injections in agranulocytic patients and may account, in part, for the superiority of combined antipsuedomonal chemotherapy in this clinical situation.
Agranulocytosis↗
Effect of free fatty acids on protein binding of antimicrobial agents.
The effect of free fatty acids (FFAs) on the binding of antibiotics to human serum proteins was studied by addition of palmitic acid to albumin solutions and normal pooled serum. FFA reduced the binding of dicloxacillin, cefamandole, and sulfamethoxazole at molar ratios of FFA to albumin of greater than 2.0. In contrast, FFA enhanced the binding of benzylpenicillin, cephalothin, and cefoxitin at physiologic molar ratios of FFA to albumin. Elevated levels of FFAs induced in vivo by heparin produced similar results with dicloxacillin and benzylpenicillin. Addition of FFA to serum, but not to albumin, reduced the binding of clindamycin and trimethoprim. That the binding of these drugs was much lower in albumin than in serum suggested the presence in serum of another antibiotic-binding protein and that FFAs can modulate binding to this protein. Binding of chloramphenicol was unaffected by FFAs. The possible clinical significance of the changes in protein binding due to FFAs is discussed.
Anti-Bacterial Agents↗
Growth kinetics of respiratory pathogens after short exposures to ampicillin and erythromycin in vitro.
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Ampicillin↗
Pharmacokinetics of cefuroxime in normal and impaired renal function: comparison of high-pressure liquid chromatography and microbiological assays.
The pharmacokinetics of cefuroxime were studied after a single dose of 750 mg was given intravenously to each of 21 male volunteers grouped according to their creatinine clearances; these clearances were 60 to 120, 20 to 59, and less than 20 ml/min per 1.73 m,2 respectively, for groups 1 (12 subjects), 2 (4 subjects), and 3 (5 subjects). Cefuroxime obeyed two-compartment model kinetics in all three groups. Initial serum levels of cefuroxime were approximately 130 microgram/ml in group 1 and 2 and 80 microgram/ml in group 3. the levels then declined rapidly for 0.5 to 1 h after injection. After that time, cefuroxime levels declined more slowly, and the elimination rate became monoexponential. The mean serum half-lives for cefuroxime in groups 2, 2, and 3 were 1.7, 2.4, and 17.6 h, respectively. Mean cefuroxime levels in serum were greater than 8 microgram/ml for 3 h in group 1, for 6 h in group 2, and for 30 h in group 3. Cumulative 24-h urinary excretion accounted for essentially 100% of the dose in group 1 and 2, and for 40% in group 3. Urine levels exceeded the minimal inhibitory concentration for susceptible organisms for more than 12 h in all groups. Cefuroxime distribution characteristics were independent of renal function. In patients with creatinine clearances less than 20 ml/min per 1.73 m2, doses of cefuroxime needs to be reduced. A microbiological disk diffusion assay and a high-pressure liquid chromatography assay for cefuroxime yielded statistically identical results, except for serum levels in uremic patients (group 3).
Adult↗
Pharmacokinetics of cefoperazone: a review.
The pharmacokinetics of cefoperazone in normal subjects, and in patients with hepatic and renal dysfunction are reviewed. After intravenous administration of 2 g of cefoperazone, levels in serum ranged from 202 to 375 microgram/ml depending on the period of drug administration. After intramuscular injection of 2 g of cefoperazone, the mean peak serum level was 111 microgram/ml at 1.5 hours. At 12 hours after dosing, mean serum levels were still 2 to 4 microgram/ml. Cefoperazone was 90% bound to serum proteins. The apparent volume of distribution was 10 to 13L. The half-life of the drug varied from 1.6 to 2.4 hours; serum clearance was between 75 and 96 ml/min. Urinary excretion was rapid, but only 15 to 36% of the cefoperazone dose was recovered in the urine. Renal clearance ranged from 14 to 25 ml/min. Urine levels of cefoperazone in excess of 32 microgram/ml were maintained for at least 12 hours. Biliary levels of cefoperazone were many-fold higher than serum levels; peak bile concentrations from 675 to 6000 microgram/ml were obtained. Severe hepatic dysfunction was associated with a 2- to 4-fold increase in the half-life of cefoperazone. In patients with relatively complete biliary obstruction, over 90% of the dose was recovered in the urine. In contrast, the serum kinetics of cefoperazone were not significantly altered in patients with renal impairment. The human pharmacology of cefoperazone is similar to cephazolin in terms of serum concentrations, half-life, protein binding, and apparent volume of distribution, but markedly different in terms of biliary and renal excretion. Since biliary excretion is normally the primary route of cefoperazone elimination, dosage modification should only be required in the presence of severe biliary obstruction or concomitant renal and hepatic dysfunction.
Bile↗
Worldwide clinical experience with cefoperazone.
The safety and clinical efficacy of cefoperazone 1 to 2g 12-hourly was evaluated in clinical trials conducted in the United States, Europe, South and Latin America, and Japan. 1046 patients were treated in 4 comparative and 9 non-comparative studies. An overall satisfactory clinical response for cefoperazone therapy was achieved in 540 (88%) of the 615 evaluable patients. Cefoperazone was effective in 92% of lower respiratory tract infections, 81% of urinary tract infections, 98% of gynaecological infections and 90% of a mixture of intra-abdominal, wound and soft tissue infections. A satisfactory clinical response was obtained in over 90% of patients infected with organisms normally susceptible to cephalosporins, such as staphylococci, streptococci, Escherichia coli, Klebsiella and Proteus species. 50 to 90% of infections caused by organisms resistant to presently available cephalosporins, such as Enterobacter species, Proteus vulgaris, Providencia species, Morganella morganii, Serratia species, Pseudomonas aeruginosa, and Bacteroides fragilis responded satisfactorily to cefoperazone. In the 4 clinical trials comparing cefoperazone with cefamandole, cephazolin or carbenicillin, cefoperazone therapy resulted in a similar or higher rate of satisfactory clinical response. Adverse reactions related to cefoperazone occurred in 8% of patients and were mainly diarrhoea (4%), skin reactions (3%) and phlebitis (1%). Twice daily dosing with cefoperazone appears to be effective against numerous Gram-positive and Gram-negative bacteria in a variety of clinical infections.
Bacteria↗
Partial purification and characterization of the drug-binding-defect inducer in uremia.
The chemical basis of drug-binding defects in uremia was investigated by studying the effects of extraction of uremic sera with an organic solvent (n-butyl chloride). Extraction of uremic sera at acidic pH (3.0) with n-Butyl chloride fully corrected the binding defects for three acidic drugs (nafcillin, sulfamethoxazole, and salicylate), whereas binding of two basic drugs (trimethoprim and quinidine) was unaffected by similar treatment. When added to normal human serum or purified human serum albumin, the organic solvent layer was capable of inducing binding defects similar to those seen in uremia. Further fractionation of the organic solvent layer with purified human serum albumin at physiologic pH (7.4), followed by reacidification and extraction of the acidified albumin layer with the same solvent, gave a homogeneous fraction on thin-layer chromatography. This homogeneous fraction could induce the binding defects observed in uremia when added to normal human sera. This factor(s) is apparently a dialyzable and weakly acidic compound. It is lipid-soluble and tightly bound to albumin at physiologic pH, but extractable at acidic pH. Its molecular weight is approximately 500 or less. These findings strongly support the hypothesis that the drug-binding defect in uremia is due to accumulation of endogenous metabolic products rather than to an intrinsic structural abnormality in serum albumin.
Biological Products↗
Tissue binding of antimicrobial agents in vitro: a critical study focusing on the concentration of the tissue homogenate used.
In vitro tissue binding of clindamycin, trimethoprim and rifampin to serial dilutions of canine tissue homogenates was studied. For all three drugs tested, the percentage of bound drug tended to be linearly related to the logarithm of the percentage of tissue homogenate. Tissue binding studies of antimicrobials looking at a single concentration or tissue homogenate may give erroneous results that do not reflect tissue binding in vivo.
Animals↗