Determination of cefalexin pharmacokinetics and dosage adjustments in relation to renal function.

Following oral administration of a single 500-mg dose of cefalexin, serum and urine levels of the antibiotic were determined comparatively in ten normal subjects, ten patients with renal impairment, and ten patients with chronic nephritis on maintenance hemodialysis. In normal subjects, mean serum peak levels (12.0 +/- 0.8 mcg/ml) were observed 2 hours after drug administration. Absorption half-time (Ta1/2) averaged 0.82 hour and mean serum half-life (T 1/2) was 1.03 hours. Urinary recovery of cefalexin over a 6-hour period amounted to 64 per cent of the ingested dose. The renal clearance of the drug was 214 ml/min. In patients with renal impairment and in patients on maintenance hemodialysis, total elimination rate constant (Ke) was markedly lower (CrCl=0; Ke=Km=0.0766), whereas serum half-life (T 1/2) was significantly increased, reaching theoretically 8.47 hours in patinets with creatinine clearance of 0 ml/min. A correlation was established between Ke values and the creatinine clearances of the patients under study (Ke=0.0766 + 0.0060 CrCl). Initial loading doses, maintenance doses, and intervals adjusted to creatinine clearances were calculated from these data; accurate dosage schedules well adjusted to the renal status of each individual patient were derived from the calculated values.

Pharmacokinetics of cefazolin in patients with renal failure; special reference to hemodialysis.

The pharmacokinetic constants of cefazolin were determined comparatively in ten normal subjects, 12 patients with renal failure, and ten patients on repeated hemodialysis. Significant correlations could be established between the creatinine clearance values and the overall elimination rate constants (Ke), serum half-lives (T 1/2), plasmatic areas (Ftot), urinary recoveries (uo-6 hr), and renal clearances of the antibiotic (Cr). The pharmacokinetic changes produced by extrarenal removal were also studied. On the basis of the obtained results, a dosage schedule adjusted to renal status was proposed.

Cefamandole pharmacokinetics and dosage adjustments in relation to renal function.

The pharmacokinetic characteristics of cefamandole were determined after intravenous administration of a 1-Gm dose to 10 subjects with normal renal function, 10 patients with stabilized renal failure, and five chronic nephritic patients included in a intermittent hemodialysis program. In normal subjects, biological half-life (t1/2) averaged 0.94 hour, the overall elimination rate constant (Ke) was 0.7378 (hr-1), total clearance (Ct) was 223 ml/min/1.73 m2, renal clearance (Cr) was 164 ml/min/1.73 m2, and urine recovery of cefamandole over the 6 hours following a dose amounted to 74 per cent of the administered dose. In patients with stabilized renal failure and in patients on hemodialysis, biological half-life was markedly increased, with a theoretical value of 10.4 hours in case of a creatinine clearance of zero. The amount of antibiotic extracted over a 6-hour dialysis period accounted for 29 per cent of the cefamandole present in the vascular compartment at the beginning of the dialysis procedure. A significant correlation was established between the values of Ke and creatinine clearances, Ccr: Ke = 0.0289 + 0.0063Ccr (r = 0.937). This relationship was used to calculate the loading dose (LD), maintenance doses (D), and dosage intervals (tau) with regard to renal function. From these data recommendations regarding the adjustment of cefamandole dosage to the renal status can be made.

Comparative pharmacokinetic profiles of cinoxacin and pipemidic acid in humans.

Serum and urinary levels of Cinoxacin and pipemidic acid were determined at 7-day intervals in the same 10 healthy volunteers after a single oral dose of respectively 500 and 400 mg of the drugs. Comparison of results shows that Cinoxacin was absorbed faster (absorption half-life, ta 1/2cin = 0.25 h) than pipemidic acid (ta 1/2pip = 0.37 h) and distributed in a smaller apparent volume (AVDcin = 23.5 1/1.73 m2; AVDpip = 60.1 1/1.73 m2). Biological half-lives were identical (tb 1/2cin = 2.10 h; tb 1/2pip = 2.15 h). On the other hand, serum levels for Cinoxacin at 1, 2 and 4 hours (8.1 +/- 1.5 micrograms/ml, 10.6 +/- 1.5 micrograms/ml, 5.6 +/- 1.3 micrograms/ml respectively) were higher than those for pipemidic acid (3.3 +/- 0.3 micrograms/ml, 3.4 +/- 0.5 micrograms/ml, 2.1 +/- 0.5 micrograms/ml respectively). Urinary excretion of the two derivatives during the 12 hours following their administration was similar (Ucin0-12h = 86%; Upip0-12h = 83%). Mean urinary concentrations were particularly high, still attaining respectively 90 +/- 29 micrograms/ml and 131 +/- 38 micrograms/ml in samples collected between the 9th and the 12th hours; these levels were well above the M.I.C. for the Gram-negative organisms included within the spectrum of activity of these two quinolones. In addition, predictive calculations of serum levels reached after multiple dosing indicate that at an administration rate of 500 mg every 6 or preferably every 4 hours, Cinoxacin concentrations should be sufficiently high to be of interest in the treatment of systemic infections by sensitive organisms.

[Methods for the appraisal of the safety of antiseptics (author's transl)]. / Hautentzündungstests zur Untersuchung der Toxizität antiseptischer Lösungen.

A procedure is described, topical applications for testing dermal toxicity of antiseptics. The tests for irritancy are made on Guinea pigs: a closed patch test giving us a primary irritation index, and prolonged applications over periods of 90 days giving a superficial aggressivity index. The standard method of testing animals for irritation of the skin is that given in the J.O. April 21, 1971 for cosmetics, changed in order to apply it to antiseptics.

Cephacetrile--application of pharmacokinetic data to dosage determination.

This pharmacokinetic investigation was based on the determination of serum and urinary levles of cephacetrile in 50 subjects given single intramuscular or intravenous doses of 0.5 or 1 gm of the antibiotic; 30 normal subjects, 10 patients with renal insufficiency, and 10 patients with chronic nephritis undergoing maintenance haemodialysis were included in this study. In normal subjects, mean serum half-life was 1.09 hours (Ke = 0.6337) after intramuscular injection of 0.5 gm cephacetrile, 1.31 hours (Ke = 0.5276) after intramuscular injection of 1 gm, and 0.89 hours (Ke = 0.7806) after intravenous injection of 1 gm. Absorption half-life was 0.45 hours after intramuscular injection of 1 gm cephacetrile. The urinary elimination of cephacetrile over the first 6 hours after injection was on the average 72.7% of the administered dose. After intravenous injection of 1 gm of the antibiotic, the plasma clearance of cephacetrile was 407 ml/min., and its renal clearance 313 ml/min. A linear correlation was found between the values of overall elimination rate constant (Ke) and creatinine clearance in the subjects under investigation (Ke = 0.0080 + 0.0061 ClCr). The established pharmacokinetic characteristics were used to calculate the maintenance and loading doses as well as the intervals between injections adjusted to creatinine clearance. These data constitute true dosage schemes adapted to the particular case of each patient according to his kidney function.

Dosage adjustments of cefazolin according to the pharmacokinetics of this new cephalosporin.

Serum and urine levels of cefazolin were studied: 1. following a single 500mg intra-muscular dose of the drug in normal subjects (n = 10), in patients with renal impairment (n = 12) and in patients undergoing maintenance hemodialysis (n = 10); 2. following a single 500 mg intra-venous dose of the drug in normal subjects (n = 10). In normal subjects, serum half-lives averaged 1.75 hour after intravenous injection (Ke = 0.395) and 2.22 hours after intra-muscular injection (Ke = 0.312); urinary recovery of cefazolin over a six hours period amounted to 61% after intra-venous injection and to 47.5% after intra-muscular injection. The renal clearance of the drug approximated 40 ml/mn. A linear correlation (Ke = 0.022 + 0.0028 CrCl) was established between the overall elimination rate-constants and the creatinine clearances in the subjects under investigation. The various pharmacokinetic constants thus obtained can be used to calculate the maintenance doses, loading doses and dosage intervals adjusted according to creatinine clearances. These data actually yield dosage regimes adapted to each individual case according to the degree of renal function.

Biliary excretion of a new semisynthetic cephalosporin, cephacetrile.

The biliary excretion of a new derivative of cephalosporin, cephacetrile (CIBA 36 278 Ba), was studied (i) in the isolated perfused rabbit liver, (ii) in humans with a duodenal tube, and (iii) in patients after cholecystectomy with a Kehr's drain in the common bile duct. The biliary excretion of the antibiotic was very low in the perfused liver, and no antibiotic activity was found in liver tissue at the end of the experiment. This observation, together with the finding of a rapid decline of the antibiotic concentration in the circulating blood serum, favors the assumption that a metabolic transformation of CIBA 36 278 Ba in liver tissue takes place. In humans, the antibiotic concentration was found to be low both in the duodenal juice and in the bile obtained by external drainage. The biliary concentrations found in these subjects seem to be inferior to those required for the inhibition of the common bacteria of biliary infections. In renal failure, however, the biliary excretion of CIBA 36 278 Ba increased considerably.

Ototoxicity of tobramycin in humans - influence of renal impairment.

The effects of prolonged tobramycin administration (given in repeated injections over a 15-day period) on auditory and vestibular functions were studied in normal subjects, in patients with renal impairment, and in chronic nephritic patients undergoing hemodialysis. With the doses used in this study, the repeated administration of tobramycin resulted in blood accumulation only in the group of patients with renal impairment. In one single case, administration of tobramycin was followed by a transient aggravation of a pre-existing renal impairment. Cochlear and vestibular functions were evaluated before treatment and repeated during and after drug administration. In normal subjects, a dosage of 50 mg/8 h failed to produce cochlear and vestibular dysfunction; but with dosages of 75 mg/8 h and 100 mg/8 h, changes in vestibular reflectivity occurred frequently, mostly of the irritative type. Generally moderate, but quite often slight changes persisted (5 of 10 cases). They were not accompanied by auditory or vestibular clinical signs. In patients with impaired renal function and in those undergoing chronic hemodialysis, vestibular impairment is customary and most often of the deficiency type. Half of the cases still showed detectable changes on follow-up evaluation that was performed 10 days after discontinuation of the drug.

[Experimental and clinical study of the biliary elimination of mezlocillin (author's transl)]. / Détermination expérimentale et étude clinique de l'élimination bilaire de la mezlocilline.

The biliary elimination of mezlocillin was studied in 5 perfused rabbit liver preparations. After adding 10 mg of mezlocillin to the perfusion medium, the biliary peak averaged 758 +/- 129 microgram/ml and total mezlocillin recovery within 3hr amounted to 20.3% of the administered dose. In 5 healthy subjects, the mean levels in the duodenal fluid collected during the 4 hrs following an infusion of 5 g of mezlocillin ranged from 440 to 637 microgram/ml. In cholecystectomized patients provided with a T-tube drainage, the maximal concentration after the same dosage (n = 10) was 505 +/- 158 microgram/ml and cumulative biliary excretion of mezlocillin over a 12 hr period corresponded to 1.3% of the administered dose. Under the same conditions, after intra-muscular injection of 1 g of mezlocillin to 10 subjects, the biliary peak averaged 292 +/- 58 microgram/ml and the total biliary recovery 2.6% of the administered dose. In 10 patients undergoing biliary tract surgery, the levels determined 1 hr after IV injection of 2 g of mezlocillin reached 896 +/- 196 microgram/ml and 402 +/- 133 microgram/ml in the main duct and in the gallbladder bile, respectively. These results were compared with the values obtained under identical conditions with 12 other beta-lactam antibiotics.

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.

The biliary excretion of cefazolin.

The biliary excretion of cefazolin was studied by perfusion of isolated rabbit livers. Under these conditions, 6.7 percent of the amount of cefazolin added to the circulating blood was excreted in bile, and concentrations of drug in bile were significantly higher than concentrations in serum. Biliary excretion of cefazolin was also studied in humans after the intravenous administration of 500 mg of the drug. In 10 normal subjects, maximal concentrations of cefazolin (17.10 plus or minus 8.5 mug/ml) in the fluid obtained by duodenal tubing were attained 1-2 hr after administration of cefazolin. Concentrations were similar in bile collected by external drainage from five cholecystectomized patients (maximal levels, 14.0 plus or minus 4.7 mug/ml) 1-2 hr after injection. Assays during cholecystectomy showed that 1 hr after injection, cefazolin levels were much higher in common duct bile (31 plus or minus 11 mug/ml) than in gallbladder bile (5 plus or minus 2 mug/ml).

[Biliary elimination of metampicillin. Experimental and clinical study (author's transl)]. / Elimination biliaire de la métampicilline. Etude expérimentale et clinique

Under the conditions of the isolated rabbit liver perfusion, metampicillin was found to be excreted at a high rate in the biliary tract : bile contains 46,5% of the administered dose. Hepatic uptake of metampicillin seems to be early and marked. In man, the biliary elimination of this antibiotic varies according to the route of administration. Only moderate biliary levels of metampicillin were obtained after oral administration ; on the contrary, extremly high biliary concentrations were found when antibiotic was injected intravenously. When parenteraly administered, metampicillin appears to be a particularly suitable penicillin for the treatment of biliary tract infections.

[Evaluation of the biliary excretion of penicillin G. (author's transl)]. / Evaluation du passage biliaire de la pénicilline G.

Biliary excretion of penicillin G was studied experimentally by perfusion of isolated rabbit liver. Under these conditions, bile recovery accounted for 5% of the amount of penicillin G added to the perfusing blood (10 mg); peak biliary level averaged 135.3 micrograms/ml. In man after intravenous administration of a 599 mg dose of penicillin G (1 MU) to patients provided with T-tube drainage (n = 10), the maximum biliary concentration averaged 18.0 +/- 8.0 micrograms/ml at 2 hours; biliary recovery of penicillin G accounts for 0.12% of the administered dose. The excretion of penicillin G in the juice collected through duodenal tubing in normal subjects averaged 0.07% of the administered dose (599 mg IV). Per-operative assays showed that the concentration determined at 1 hour after intravenous administration of the drug (599 mg) in the gallbladder bile (45.7 +/- 16.7 micrograms/ml) and common duct bile (93.5 +/- 16.3 micrograms/ml) were definitely higher (4.5--9 times) than the serum levels measured simultaneously. The biliary excretion of penicillin G is compared with the biliary elimination of a certain number of beta-lactam derivatives studied under the same conditions (ampicillin, metampicillin, carbenicillin, cefalothin, cefaloridine, cefacetrile, cefalexin, cefazolin).

[Infectious enterocolitis in intensive care patients fed by nasogastric tube]. / Entérocolites infectieuses chez des malades de réanimation alimentés par sonde nasogastrique.

Infectious enterocolitis sometimes spreads through intensive care units, the origin being contamination by "drips". A 9 month study concerning patients fed by nasogastric "drip" revealed 70 p. 100 of cases of severe diarrhea. Stool cultures confirmed the infectious origin of this diarrhea in 66 p. 100 cases. Virtually all of the suspect drip containers and fluids contained the organisms found in the stool culture, with a concentration of 10(6)-10(9) per ml/foodstuff. Enquiry revealed that contamination of these drips occurred above all in the kitchen at the time of preparation (poorly washed material, personnel often unaware of elementary hygiene). The great vulnérability of such intensive care patients predisposes them to infection of this type and the limit of danger for them is as low as 10(4) organisms per ml/foodstuff. Solutions concerning hygiene in preparation were tried with success (drips then containing only 50-100 organisms per ml/foodstuff.

[Mortality factors in infectious diseases in a surgical intensive care unit]. / Etude des facteurs de mortalité infectieuse dans un service de réanimation chirurgicale.

Among 350 patients admitted to a surgical intensive care unit between 1.1.77 and 31.9.77, their profile and septic course being defined, two populations were studied: -- the first involved 49 patients dying of infection during their stay in the department; -- the second involved 132 patients developing a non lethal infectious syndrome. Comparative study of these two patients groups made it easier to understand why, in the same department and apparently with the same kind of care, certain patients die of infection and others do not. It was thus attempted to demonstrate certain difference between the two groups in terms of biometric data, predictable risk factors, the type of underlying pathology and the nature and course of the infectious process. Finally, the role played by the intensive care unit in the onset of these deaths of infectious cause is considered.