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.

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.

[Exfoliatin in neonatal staphylococcal infections]. / L'exfoliatine dans les staphylococcies néonatales.

An outbreak of staphylococcal skin infection in neonates was investigated clinically, bacteriologically and epidemiologically with the following findings: (1) In 8 out of 13 cases, exfoliatin-producing staphylococci were present in the bullae, which is unusual with bullous lesions occurring at other ages; (2) exfoliatin producing staphylococci were present in all children with bullous lesions, as well as in carriers; (3) 39% of the phage II group staphylococci studied produced exfoliatin; (4) purulent lesions due to phage II staphylococci which did not produce exfoliatin were observed. The contaminating agent could be identified in most cases.

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.

Consequences of the chronic cutaneous application of iodinated antiseptics on the thyroid function in the guinea-pig.

The effect of the chronic cutaneous application of iodine-containing substances on the thyroid function was studied in the guinea-pig. Six iodinated products were daily applied at the rate of 2 g/kg/day for 90 days. We find a quasi-abolition in the thyroid 131I-uptake (reflecting the transcutaneous absorption of free iodine) and an important transient thyroidal hyperproduction during the first month. Then, this primary hyperthyroidism induces a strong pituitary negative feed-back so that the levels of the circulating hormones T3 and T4 are normalized at the end of the experiment; a new hormonal balance is reached with a TSH level reduced by half compared to its normal value.

[Comparative biliary excretion of mezlocillin and 12 other beta-lactam antibiotics (author's transl)]. / Excrétion biliaire comparative de la mezlocilline et de 12 autres bêta-lactamines.

The biliary excretion of mezlocillin was studied on an experimental in vitro model (perfused rabbit liver) and by various methods in man. After addition of 10 mg mezlocillin to blood perfusing isolated rabbit lever preparations (n = 5) during 3 hours, a mean biliary peak of 758 +/- 129 micrograms/ml was recorded between 30 and 60 minutes. The 0-3 h cumulative biliary excretion was 20.3 % of the dose administered. Following a 30 min intravenous infusion of 5 g mezlocillin to 5 healthy subjects, the mean maximal antibiotic activity in the duodenal aspiration fluid was 626.0 +/- 115.0 microgram/ml during the first hour. In 10 cholecystectomized patients with T-tube drainage who received 1 g mezlocillin intramuscularly, a mean biliary peak of 296 +/- 58 micrograms/ml was recorded. The 0-12 h cumulative biliary excretion of the antibiotic was 2.6 % of the dose injected. After intravenous infusion of 5 g mezlocillin, the corresponding values were 505 +/- 118 micrograms/ml and 1.3 % respectively. One hour after rapid intravenous injection of 2 g mezlocillin, the antibiotic activities in samples of serum, common bile duct bile and gallbladder bile collected during cholecystectomy were 28.9 +/- 5.3, 895 +/- 196.1 and 402 +/- 133.2 micrograms/ml respectively. These results were compared with those obtained in similar conditions with 12 other beta-lactam antibiotics.

Pharmacokinetics of mezlocillin in patients with kidney impairment: special reference to hemodialysis and dosage adjustments in relation to renal function.

The pharmacokinetics of Mezlocillin were determined after the intramuscular injection of a single 1-gram dose in 10 subjects with normal renal function, in 10 patients with stabilized renal impairment and in 5 patients with end-stage renal disease submitted to repeated hemodialysis. In normal subjects, biological half-life, Tb1/2, was equal to 0.9 h; total clearance (Ct) to 449 ml/min/1.73 m2; renal clearance (Cr) to 263 ml/min/1.73 m2.72.2% of the administered dose was excreted in the urine within 12 h. In patients with renal insufficiency and in patients undergoing long-term hemodialysis, the serum concentration decrease was markedly slower. During a 6-hour dialysis session, 62% of the Mezlocillin present in the central compartment at the start of hemodialysis was removed. In the 25 subjects under study, a significant correlation was found between the values of Ke and those of creatinine clearance, Ccr (Ke = 0.1973+0.0046 Ccr). This relation was used to calculate the loading doses, the maintenance doses and the dosage intervals adjusted to the degree of renal impairment, allowing assessment of useful dosage recommendations.

Biliary excretion of cefaclor. Experimental and clinical study.

Biliary excretion of cefaclor, a new orally active cephalosporin, was studied in vitro using an isolated rabbit liver preparation perfused for 3 h (n = 5). Under these conditions, bile recovery amounted to 2.3% of the cefaclor dose added to the circulating blood (10 mg). In humans, after oral administration of a 1-gram dose of cefaclor to cholecystectomized patients provided with a T tube (n = 10), a mean biliary peak concentration of 7.6 +/- 2.4 microgram/ml was observed at the 3rd hour. Cumulative biliary excretion amounted to 0.05% of the administered dose. Assays performed on samples collected during cholecystectomy in 10 patients 1 h after intake of a 1-gram dose of cefaclor showed mean concentrations of 13.7 +- 1.2 micrograms/ml in serum, 8.1 +/- 1.3 micrograms/ml in common duct bile and 5.9 +/- 1.4 micrograms/ml in gallbladder bile. These results were compared with the data obtained after administration of seven other cephalosporins studied under identical conditions.

[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.

[Experimental and clinical study of the biliary excretion of cefamandole (author's transl)]. / Etude expérimentale et clinique de l'élimination billaire du céfamandole.

Using the isolated rabbit liver perfusion model, it could be shown that 11.1% of 10 mg of cefamandole added to the circulating blood were recovered in the 3 hours collected bile. The maximal biliary antibiotic activity averaged 214 +/- 37 microgram/ml. In humans a peak concentration of 19.0 +/- 6.1 microgram/ml could be measured in the aspirated duodenal fluid (n = 5) 1 hour after a single intravenous injection of 1 g of cefamandole. In 10 patients provided with a Kehr's drainage, a mean biliary peak of 141.4 +/- 86.4 microgram/ml was observed at the 2nd hour after administration of the same dose of cefamandole. Assays performed during cholecystectomy showed 1 after the intravenous injection of 1 g of cefamandole mean values of 64.0 +/- 18.0 microgram/ml in the gallbladder bile and 87.2 +/- 16.1 microgram/ml in the common duct bile. These data are compared with those obtained by administration of 11 other beta-lactamines under similar experimental and clinical conditions.

Biliary excretion of cefuroxime. Experimental and human study.

The biliary excretion of cefuroxime was studied experimentally, using a preparation of isolated rabbit liver (n = 5) perfused in vitro during 3 h; 0.92% of the cefuroxime (10 mg) added to the circulating blood was found in the bile, while peak antibiotic activity reached a mean value of 8.0 +/- 1.1 microgram/ml. In man, 1 h after a single intravenous injection of cefuroxime (0.5 g), a maximum concentration of 4.0 +/- 1.6 microgram/ml was found in the duodenal aspiration fluid collected from 5 healthy subjects. In 10 patients with T-tube drainage, a mean biliary peak of 10.3 +/- 2.4 microgram/ml was observed 2 h after intravenous injection of the same dose; the biliary excretion of cefuroxime during the 12-hour experiment corresponded to 0.13% of the administered dose. Assays performed during cholecystectomy in 10 patients 1 h after cefuroxime intravenous injection of 0.5 g showed concentrations of 11.9 +/- 0.8 microgram/ml in the serum, 12.0 +/- 1.5 microgram/ml in the common duct bile and 7.4 +/- 1.1 microgram/ml in the gallbladder bile. These results were compared with those observed after administration of 11 other beta-lactam antibiotics in identical experimental and clinical conditions.

[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).

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.

Evaluation of the biliary excretion of pencillin 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). In man, after intravenous administration of a 599-mg dose of penicillin G (1,000,000 U) to patients provided with T-tube drainage (n = 10), the maximum biliary level averaged 18.0 +/- 8.0 microgram/ml at 2 h; biliary recovery of penicillin G accounted 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. Peroperative assays showed that the concentrations determined 1 h after intravenous administration 599 mg of the drug attained 45.7 +/- 16.7 microgram/ml in the gallbladder bile and 93.5 +/- 16.3 microgram/ml in the common-duct bile.

[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.

[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.