Pipemidic acid, 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-pyrido [2,3- d ]pyrimidine-6-carboxylic acid, is a new derivative of piromidic acid. It is active against gram-negative bacteria including Pseudomonas aeruginosa as well as some gram-positive bacteria. Its potency is generally greater than that of piromidic acid and nalidixic acid. Cross-resistance is not observed between pipemidic acid and various antibiotics, and most of bacteria resistant to piromidic acid and nalidixic acid are moderately susceptible to pipemidic acid. The activity of pipemidic acid is scarcely affected by the addition of serum, sodium cholate, or change of medium pH, but is subject to the influence of inoculum size. Its action is bactericidal above minimal inhibitory concentrations.

The pharmacokinetis of AT-2266 (1-ethyl-luoro-1,4-dihydro-4oxo-7-(1-piperazinyl)

AT-2266, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3 -carboxylic acid, is a new pyridonecarboxylic acid derivative with broad and potent antibacterial activity. It inhibited some gram-positive bacteria, such as staphylococci and Bacillus subtilis, and most gram-negative bacteria, including Serratia marcescens, Pseudomonas aeruginosa, Haemophilus influenzae, and Campylobacter jejuni, at concentrations of 0.1 to 0.78 microgram/ml, and most gram-positive bacteria, glucose-nonfermenters, and Mycoplasma pneumoniae at concentrations of 1.56 to 12.5 micrograms/ml. Most of the clinical isolates tested were as susceptible to AT-2266 as were laboratory strains. The antibacterial potency of AT-2266 was higher than those of pipemidic acid and nalidixic acid and similar to that of norfloxacin. AT-2266 was not cross-resistant with antibiotics and inhibited most highly nalidixic acid-resistant bacteria at concentrations of 1.56 to 3.13 micrograms/ml. Its activity was barely affected by the addition of horse serum or sodium cholate but weakened by lowering the medium pH or increasing the inoculum size. AT-2266 was bactericidal at concentrations near its minimal inhibitory concentrations. Frequencies of mutants resistant to 10 micrograms of AT-2266 per ml were lower than 4.0 x 10(-9).

Primary mural endocarditis is an extremely rare infection in which nonvalvular endocardial involvement is seen without any cardiac structural abnormalities such as ventricular septal defects. The rapid and precise diagnosis of this disease remains challenging. We present 2 cases (67- and 47-year-old male patients) of pathologically confirmed primary mural endocarditis that could have been detected by initial transthoracic echocardiography in the emergency department. Transthoracic echocardiography and transesophageal echocardiography play critical roles in the early recognition and confirmation of primary mural endocarditis.

Pipemidic acid was absorbed well by the oral route. Its peak levels in plasma ranged from 4 to 12 ,ug/ml at an oral dose of about 50 mg/kg in mice, rats, dogs, monkeys, and men. The protein binding of pipemidic acid was about 20% in dog plasma and about 30% in human serum. Pipemidic acid was distributed to most of the organs and tissues tested at the concentrations comparable to or higher than the plasma level. Its concentrations in bile and urine were much higher than the plasma level. About 25 to 88% of orally administered pipemidic acid was excreted into urine in a bacteriologically active form, the percentage depending on the animals and doses employed. The remainder was excreted into feces in men. The main active principle in vivo was unchanged pipemidic acid itself. The mean lethal dose of pipemidic acid after a single oral dose was more than 16,000 mg/kg in mice. No abnormalities were observed in mice orally receiving pipemidic acid once a day for 4 weeks at doses of 1,000, 2,000, and 4,000 mg/kg per day, and in rats orally receiving the drug once a day for 2 weeks at doses of 400 and 1,600 mg/kg per day.Pipemidic acid is a new synthetic antibacterial agent structurally related to piromidic acid and nalidixic acid (unpublished data). It has some advantageous points over the latter two drugs, such as activity against Pseudomonas aeruginosa, activity against bacteria resistant to piromidic acid and nalidixic acid, the good distribution to organs and tissues, and the stability to metabolic inactivation. The present report is concerned with the pharmacological properties of pipemidic acid, together with some toxicological data.MATERIALS AND METHODS Drugs. Pipemidic acid trihydrate synthesized in this laboratory (unpublished data) was used for administration. The dose or concentration of the drug was always expressed as that of anhydrous compound.Pharmacological study. Animals used were female ddy-s mice weighing 30 to 46 g, male Wister rats weighing 191 to 262 g, male and female beagle dogs weighing 9.4 to 13.2 kg, male and female monkeys (Macaca mulatta) weighing 3.8 to 9.3 kg, and male healthy human volunteers (34 to 49 years old) weighing 47 to 70 kg. Pipemidic acid was orally administered to mice, rats, and monkeys as suspensions in 0.2% carboxymethyl cellulose, and to dogs and human volunteers as 250-mg tablets. Blood was withdrawn at the indicated times from mice and rats by cardiac puncture, and from dogs, monkeys, and men by venipuncture which was centrifuged to separate plasma. Rat bile was taken as described previously (5). Urine was pooled from 0 to 3, 3 to 6, and 6 to 24 h in mice and rats, from 0 to 24 h in monkeys, and from 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 h in men. Organs, tissues, and body fluids were harvested 2 h after the last dosing. The appropriate amount of the organs and tissues was weighed, homogenized with two times the weight of water with a Polytron homogenizer (Kinematica G.m.b.H.), heated at 80 C for 15 min, cooled, and centrifuged to separate the supernatant....