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Biomedical subjects

A U Gerber

Publications and source records attributed to A U Gerber.

45 records · Page 3Linked to original sources
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1981

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↗
PubMed1981

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↗
PubMedDate not supplied

Worldwide experience with bacampicillin administered twice a day.

The safety and clinical efficacy of dosing twice a day with bacampicillin was evaluated in clinical trials conducted at various locations in Latin America, Switzerland, and Scandinavia, Bacampicillin (200, 400, 600, or 800 mg) given twice a day was compared with bacampicillin (400 mg) or ampicillin (500 or 556 mg) administered three times a day in eight double-blind and six open randomized trials involving 750 patients with respiratory and urinary tract infections. In a noncomparative study, 47 additional patients were treated with 600 mg of bacampicillin twice a day. High rates of clinical cure or improvement were achieved for all types of infections investigated. Microbiologic cure was observed in greater than 90% of respiratory infections due to beta-hemolytic streptococci, Streptococcus pneumoniae, or Hemophilus influenzae. There were no significant differences between the responses of groups treated twice and those treated three times a day. Adverse effects of both regimens of bacampicillin were similar and occurred less frequently than in patients treated with ampicillin. Dosing twice daily with bacampicillin appears to be effective against numerous gram-positive and gram-negative bacteria in a variety of mild clinical infections. Studies comparing identical dosage regimens of bacampicillin and other aminopenicillins are needed to determine whether bacampicillin given twice a day has a therapeutic advantage.

Adolescent↗
PubMedDate not supplied

Postantibiotic suppression of bacterial growth.

Persistent suppression of bacterial growth following exposure of both gram-positive and gram-negative bacteria to numerous antimicrobial agents was studied. The persistent, or postantibiotic, effect was quantitated by periodic counts of colony-forming units after removal of the drug by washing, dilution, or inactivation with penicillinase. Although a postantibiotic effect was observed with all drugs studied, there were marked differences among drugs in their postantibiotic effects on certain organisms. With gram-positive organisms, concentrations of beta-lactam antibiotics near the minimal inhibitory concentration produced persistent effects lasting 1-3 hr. With gram-negative organisms much higher concentrations were required to elicit a postantibiotic effect. Inhibitors of protein and RNA synthesis produced the longest persistent suppression of growth, which was of comparable duration in gram-positive and gram-negative bacteria. Only a short persistent effect of gentamicin was observed with Staphylococcus aureus and Escherichia coli, but a postantibiotic effect lasting 1.6-2.6 hr was observed with Pseudomonas aeruginosa. The duration of the postantibiotic effect was related linearly to concentration of drug and duration of exposure up to a point of maximal response. Persistent effects following exposure to antibiotics were also demonstrated in 90% human serum.

Anti-Bacterial Agents↗
PubMedDate not supplied

Pharmacokinetics of cefoperazone in patients with normal and impaired hepatic and renal function.

The pharmacokinetics of cefoperazone in normal subjects and in patients with hepatic and renal dysfunction are reviewed. Peak serum concentrations and areas under serum level-time curves are linearly related to dose. The range of mean peak serum concentrations after a 2-g dose of cefoperazone is 202-375 micrograms/ml with iv injection or infusion and 111 micrograms/ml with im injection. The serum half-life is 1.6-2.6 hr. Urinary excretion is rapid, but only 15%-37% of the dose is recovered in urine. The drug is not metabolized significantly. Levels of drug in bile are many times higher than serum levels, and biliary excretion represents the major pathway of cefoperazone elimination. Serum kinetics of cefoperazone are not significantly altered by renal impairment. However, hepatic dysfunction is associated with a two- to fourfold increase in serum half-life. Even in these patients, drug accumulation was not observed after repeated administration of 1 g of cefoperazone at 12-hr intervals. Major dosage modification should only be required with concomitant renal and hepatic dysfunction.

Biliary Tract Diseases↗