High haemodialysis clearance of ornidazole in the presence of a negligible renal clearance.

The pharmacokinetics of ornidazole was studied in 6 patients treated by haemodialysis and in 8 subjects with a creatinine clearance between 4 and 99 ml/min x 1.73 m2. Blood and urine collections were performed for 72 h after i.v. and oral administration of 1.0 g ornidazole. Total body clearance, half-life, volume of distribution and systemic availability were independent of renal function and did not differ from previously reported values in normal volunteers. The haemodialysis clearance of ornidazole was greater than 100% higher than the total body clearance. The renal clearance of ornidazole accounted for less than 7% of the total body clearance. The percentage of the dose of ornidazole recovered in urine as parent compound or as the biologically active metabolites [alpha-(chloromethyl)-2 hydroxymethyl-5 nitroimidazole-1 ethanol and 3-(2 methyl-5 nitroimidazole-1-yl)1,2 propanediol] decreased linearly with decreasing renal function. Although the sum of those three compounds recovered in urine accounted for less than 10% of the total dose of ornidazole administered, they yielded therapeutic concentrations (greater than 4 micrograms/ml) in urine over 24 h after dosing. Due to the peculiar pharmacokinetic behaviour of ornidazole, i.e. high haemodialysis clearance in the absence of significant renal clearance, no dosage adjustment is necessary while renal function declines, but an increased dose is mandatory while patients are on dialysis.

Pharmacokinetics of carumonam in patients with renal insufficiency.

The pharmacokinetics of carumonam after a single 1,000-mg intravenous infusion (20 min) were evaluated in four groups of subjects who had various degrees of renal impairment: group 1, CLCR greater than 60 ml/min; group 2, CLCR = 30 to 60 ml/min; group 3, CLCR = 10 to 30 ml/min; and group 4, CLCR less than 10 ml/min). The elimination half-life of carumonam increased with decreasing creatinine clearance (CLCR) from 1.7 h in group 1 to 11.3 h in group 4. Peak carumonam concentration (103 micrograms/ml) and steady-state volume of distribution (12.8 liters) did not change with decreasing CLCR. Total body clearance (r = 0.98), renal clearance (r = 0.98), and nonrenal clearance (r = 0.67) of carumonam correlated with decreasing CLCR. Mean nonrenal clearance was 21 ml/min in group 1 and 12 ml/min in group 4. With regard to dosage, patients with a CLCR above 60 ml/min should receive their standard maintenance dose of carumonam without any changes; patients with a CLCR between 30 and 60 ml/min should receive the dose every 12 h; and individuals with a CLCR between 10 and 30 ml/min should be given the dose once a day. Patients with a CLCR of less than 10 ml/min should receive one-half of the dose once a day. Our recommended dosage regimens should produce within the CLCR borderlines of each group average plasma concentrations that are between one and two times that achieved in normal subjects with a t.i.d. dosage regimen.

Antibacterial properties of Ro 13-99041, a long-acting new cephalosporin.

The antibacterial properties of the new cephalosporin RO 13-9904 were investigated in vitro and in vivo. The compound showed good activity against Entero-bacteriaceae and gram-positive cocci, except Streptococcus faecalis. Haemophilus influenzae, Neisseria gonorrhoeae and Neisseria meningitidis were extremely susceptible to Ro 13-9904. The bactericidal activity of Ro 13-9004 was comparable to that of cefotaxime. The new cephalosporin showed better therapeutic efficacy in mice against Pseudomonas aeruginosa than cefotaxime, cefoperazone, azlocillin, and piperacillin. Ro 13-9904 was highly effective in prophylactic studies, in contrast to cefotaxime, SCE-1365, cefoperazone and piperacillin. This indicates that Ro 13-9004 essentially differs from other beta-lactam compounds in showing unusually prolonged in vivo efficacy.

Ro 13-9904, a long-acting broad-spectrum cephalosporin: in vitro and in vivo studies.

Ro 13-9904, a new parenteral cephalosporin, was found to have high in vitro activity against Enterobacteriaceae and other gram-negative bacteria, including various isolates resistant to cefuroxime, cefamandole, cefoxitin, and cefazolin. It showed promising activity against Pseudomonas aeruginosa. Although inhibitory against Staphylococcus aureus at concentrations readily achievable in plasma, it was less potent against this pathogen than cefamandole, cefazolin, or cefuroxime. Isolates of Streptococcus faecalis were uniformly resistant to all the cephalosporins tested. Ro 13-9904 was more active than cefotaxime against Proteus mirabilis, Neisseria gonorrhoeae, Neisseria meningitidis, and Haemophilus influenzae, but less active against S. aureus. Ro 13-9904 was stable to various types of beta-lactamases. Its therapeutic efficacy against experimental septicemias in mice was equal to or slightly superior to that of cefotaxime and SCE-1365 when the antibiotics were administered in repeated subcutaneous doses after bacterial challenge. Cefoperazone, and particularly cefamandole nafate, cefazolin, and mezlocillin were less effective. Although structurally related to cefotaxime and SCE-1365, Ro 13-9904 was found to differ from them in one important respect, namely, in having a long duration of action; this was observed with single-dose treatment given before bacterial challenge. Its broad spectrum of activity coupled with favorable pharmacokinetic properties make Ro 13-9904 a promising compound for clinical studies.

Ro 13-9904/001, a novel potent and long-acting parenteral cephalosporin.

Ro 13-9904/001 is a novel parenteral cephalosporin antibiotic with potent in vitro activity against a wide range of beta-lactamase-producing and non-producing pathogens. In addition, Ro 13-9904/001 proved to possess a very long plasma half-life and, as a consequence, high prophylactic in vivo effectiveness.