Claude Regamey

Serum Protein Binding of the Aminoglycoside Antibiotics

The binding of four aminoglycoside antibiotics by human serum was investigated under controlled conditions of physiological pH and temperature, by means of an ultrafiltration technique. No serum binding was demonstrable for gentamicin, tobramycin, or kanamycin, whereas streptomycin was 35% bound. Previous conflicting studies are discussed, and some of the pharmacological implications are considered.

Comparative pharmacokinetics of tobramycin and gentamicin

Blood and urine concentrations of a new aminoglycoside, tobramycin, were compared with those of gentamicin after intravenous and intramuscular administration in healthy adult volunteers. Serum concentrations for the two antibiotics were the same after an intravenous infusion of 100 mg for the first haur (about 4.75 p.g per milliliter), during the steady state attained by infusing 30 mg per hour for the next 2 haurs (about 3.85 p.g per milliliter), and during the elimination phase after the antibiotics were stopped. After a single intramuscular injection of 100 mg, the blood level curves were equal and the peak concentrations at 20 to 45 minutes were the same as those obtained after intravenous infusion of the same dose for 1 hour. Between 80% and 90% of each of the two antibiotics was recovered in the urine within 24 hours. Plasma clearance was not significantly higher than renal clearance, and glomerular filtration seemed to be the main pathway of elimination. The two aminoglycosides had an apparent volume of distribution of about 30% total body weight. Each had a half‐life of 2 hours.

Comparative Clinical Pharmacology of Amoxicillin and Ampicillin Administered Orally

Ampicillin and amoxicillin (α-amino-p-hydroxybenzyl penicillin) were administered orally in 500-mg doses to eight fasting volunteers in a comparative study in which pharmacokinetic techniques were used. The absorption of amoxicillin was significantly better, as demonstrated by a higher mean peak serum concentration of 7.6 μg/ml as compared to 3.2 μg/ml for ampicillin, an average “area under the curve” that was approximately double that of ampicillin, and an 8-hr urinary recovery for amoxicillin of 60% as compared to 34% for ampicillin. Serum half-lives were the same for the two antibiotics, with values of 60.3 (±3.3) min for ampicillin and 61.3 (±5.6) min for amoxicillin. The latter drug gave measurable concentrations in the blood at 8 hr in all of eight volunteers, as compared to only three of eight with ampicillin.

Comparative pharmacokinetics of amikacin and kanamycin.

Pharmacokinetic parameters of amikacin and kanamycin were compared in a crossover study using healthy adult male volunteers. Following an intravenous infusion of 3.33 mg per kilogram for 1 hour, an infusion of 1.00 mg per kilogram per hour over the next 3 hours produced a steady state with serum levels of approximately 12 mcg per milliliter. The apparent volumes of distribution were about 28% of total body weight, a relatively large value consistent with the observation that neither antibiotic is protein‐bound. Amikacin and kanamycin had serum half‐lives of about 2 hours, and renal clearance of the antibiotics (84 ml per minute) was less than the creatinine clearance (120 per milliliter per minute), indicating tubular reabsorption. Although 94% of the total dose was eventually recovered in the urine, clearance of the antibiotics from the serum was greater than renal clearance (100 versus 84 ml per minute), implying a small component of unidentified distribution or elimination. After single intramuscular injections of 7.5 mg per kilogram (about 0.6 gm), peak blood levels of about 18 mcg per milliliter were found, and the serum half‐life of each antibiotic was again about 2 hours. Thus the pharmacokinetic parameters of amikacin and kanamycin were Virtually identical.

Inhibitory Effect of Heparin on Gentamicin Concentrations in Blood

In monitoring gentamicin concentrations in the blood of patients with renal insufficiency, the assayed antibiotic concentration was found to be lower when the sample was drawn as heparinized plasma rather than as serum. This lowering of gentamicin concentrations by heparin was studied further by adding increasing doses of heparin and various amounts of gentamicin to human serum. With a range of 2 to 100 units of heparin per ml, gentamicin concentrations in the serum were lowered by 9 to 14%; with higher heparin concentrations, an even greater and increasing inhibition was noticed, reaching 56% for 1,000 units/ml. This inhibitory effect of heparin on gentamicin was reversible by dilution, indicating that it was not due to degradation or to formation of an inactive chemical complex. Underestimation by the laboratory of gentamicin concentrations in blood is likely to be greatest with capillary tubes, with which the concentration of heparin is especially high. With clinical heparinization, the amount of active heparin in the blood does not exceed 10 units/ml and is for the most part under 3 units/ml; thus, therapeutically significant inhibition of the antibiotic is unlikely in patients receiving anticoagulation.

Synergism of Carbenicillin and Gentamicin Against Enterococci

Carbenicillin and gentamicin were tested for synergism against 25 strains of enterococci by two different methods. Killing curves were determined by doing serial colony counts of broth cultures containing the antibiotics separately and in combination. The combination was synergistic for all 25 strains with 75 and 4 μg of carbenicillin and gentamicin per ml, respectively. Reducing the concentrations to 50 and 3 μg of the antibiotics per ml with four strains significantly reduced the rate of killing of the combination. Synergism was also studied by constructing isobolograms, by using the standard two-dimensional broth dilution checker-board technique, and by measuring the end points both for minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs). Synergism was present for all 25 strains when bactericidal end points (MBCs) were evaluated, but was present for only 7 of the 25 strains when MICs were used to construct isobolograms. The time and effort involved were roughly the same for killing curves and for isobolograms, and it was concluded that neither had a distinct advantage over the other.

Pharmacokinetics of parenteral sodium cephalexin in comparison with cephalothin and cefazolin

SummaryIn four healthy adult volunteers, an intravenous infusion of 0.5 g of sodium cephalexin over a period of 20 minutes gave an average peak serum level of 41 mcg/ml as compared with 118 mcg/ml for cefazolin, and 70 mcg/ml for cephalothin administered in twice the dose (1 g). The serum half-lives were 0.9 hr for cephalexin, 0.5 hr for cephalothin, and 1.8 hr for cefazolin. During a steady state attained with a constant infusion of cephalexin the renal clearance (252 ml/min/1.73 m2) was the same as the serum clearance, and this was consistent with the recovery of almost 100% in the urine. Probenecid impaired the tubular secretion of cephalexin, prolonging the serum half-life from 0.9 to 1.7 hr and lowering the renal clearance to 124 ml/min/1.73 m2, similar to the creatinine clearance. The apparent volume of distribution was 16.4 liters/1.73 m2. In comparison, cephalothin had a similar renal clearance but a shorter half-life because of its partial metabolic breakdown in the body. Higher and more prolonged blood levels of cefazolin were due chiefly to a much lower renal clearance (62 ml/min/1.73 m2) and a smaller apparent volume of distribution (10 liters/1.73 m2). An intramuscular injection of 0.5 g of cephalexin gave a relatively constant blood level between 30 and 75 minutes with the peak averaging 9.5 mcg/ml, and the serum half-life was prolonged to 1.35 hr because of its depot effect.ZusammenfassungEin halbes Gramm Cephalexin wurde vier gesunden Erwachsenen innerhalb 20 Minuten infundiert. Am Ende der Infusion war der durchschnittliche Serumspiegel 41 mcg/ml, im Vergleich zu 118 mcg/ml für Cefazolin und 70 mcg/ml für Cephalothin, wobei aber für Cephalothin doppelt soviel verabreicht wurde (1 Gramm). Die Serum-Halbwertszeiten (T 1/2) waren 0,9 Stunden für das Cephalexin, 0,5 Stunden für das Cephalothin und 1,8 Stunden für das Cefazolin. Ein konstanter Serumspiegel („Steady State“) wurde mittels einer Infusionspumpe beibehalten. Während des „Steady State“ entsprach die renale Clearance des Cephalexins (252 ml/min/1,73 m2) der totalen oder Serum-Clearance, was mit der renalen Ausscheidung übereinstimmte: fast 100% der verabreichten Dosis wurde im Urin gefunden. Probenecid verlangsamte die tubuläre Ausscheidung des Cephalexins, die T 1/2 verlängerte sich von 0,9 Stunden auf 1,7 Stunden und die renale Clearance verringerte sich auf 124 ml/min/1,73 m2, was der Kreatinin-Clearance der Probanten entsprach. Das Verteilungsvolumen während des „Steady State“ war 16,4 1/1,73 m2. Im Vergleich dazu hat das Cephalothin eine ähnliche renale Clearance aber eine verkürzte T 1/2, da es zum Teil im Organismus metabolisiert wird. Die höheren und langsamer fallenden Serumkonzentrationen des Cefazolins sind hauptsächlich einer sehr verzögerten renalen Clearance (62 ml/min/1,73 m2) und einem kleineren Verteilungsvolumen (10 1/1,73 m2) zuzuschreiben. Eine intramuskuläre Injektion von 0,5 Gramm Cephalexin gibt einen relativ stabilen Serumspiegel von 30 bis 75 Minuten mit einer durchschnittlichen Spitzen-Konzentration von 9,5 mcg/ml. Die T 1/2 ist wegen eines Depot-Effektes auf 1,35 Stunden verlängert.

Pharmacokinetics of Cephanone in Healthy Adult Volunteers

Five volunteers received intramuscular injections of 7 mg (approximately 500 mg) of cephanone, a new cephalosporin for parenteral use per kg. Peak serum concentrations averaged 36 μg/ml, about four times as high as with the same doses of cephalothin, twice as high as with cephaloridine, and slightly lower than with cefazolin. With a constant intravenous infusion of 100 mg/h, a steady-state serum concentration of 31 μg/ml was attained in four volunteers. The serum half-life was similar for the intramuscular and intravenous studies, 2.4 and 2.6 h, respectively. Over 90% of the dose administered was recovered in the urine. The factor mainly responsible for the higher and more sustained serum concentrations of cephanone was its low renal clearance of 47 ml per min per 1.73 m2. Cephanone has a small apparent volume of distribution, probably related to its high serum protein binding of 88%.

Cephacetril-Konzentrationen im Perikardexsudat nach Herzoperation

ZusammenfassungBei 7 Patienten wurde bei einer Herzoperation die Diffusion von Cephacetril, einem Antibiotikum der Cephalosporin-Gruppe, im Perikarderguß (bei 6 Patienten) und im Pleuraerguß (1 Patient) während 24 Stunden gemessen. Den Patienten wurde vor der Operation, bei Operationsbeginn, dann alle 6 Stunden, 30 mg/kg (1,5–2,0 g) Cephacetril verabreicht. Im Serum ergab der mittlere Spitzenwert nach der 2. Injektion (1/2 Stunde nach Operationsbeginn) 159 (±28) µg/ml und nach der 3. Injektion 108 (±16) µg/ml. 4 Stunden nach Operationsbeginn konnten die 1. Cephacetril-Konzentrationen im Perikardexsudat gemessen werden. Die Spitzenwerte erreichten >30 µg/ml, und 4 Stunden nach Verabreichung waren meistens noch >6 µg/ml vorhanden. Die hohen Cephacetril-Konzentrationen im Perikarderguß konnten nicht einer Blutkontamination zugeschrieben werden. Unsere Ergebnisse zeigen, daß dieses Cephalosporin gut in ein Exsudat diffundiert. Die bei dieser Dosierung gefundenen Antibiotika-Konzentrationen im Perikarderguß sind höher als die minimalen Hemmkonzentrationen der meisten bei Herzoperationen gefürchteten pathogenen Keime.SummaryIn 7 patients undergoing heart sugery the diffusion of cephacetrile, an antibiotic of the cephalosporin group, was measured in the pericardial exudate (6 patients) and in the pleural exudate (1 patient) for 24 hours. The patients received 30 mg/kg (1.5–2.0 g) cephacetrile, before and at the start of the operation, and then at intervals of 6 hours.The highest mean serum level following the second injection (30 minutes after the start of surgery) was 159 (±28) µg/ml, and after the third injection 108 (±16) µg/ml. Four hours after beginning surgery it was possible to measure the first cephacetrile concentrations in the pericardial exudate. The maximum values were >30 µg/ml and 4 hours after administration >6 µg/ml was usually still observed. The high concentrations of cephacetrile in the pericardial exudate could not be attributed to seepage of blood into the pericardium. Our results show that this cephalosporin exhibits good diffusion in exudate. The concentrations of antibiotic substance in the pericardial exudate are higher than the minimal inhibitory concentrations valid for most of the pathogens which pose a threat in heart surgery.