[Pharmaceutical aspects of creating an effective drug form of carfecillin]. / Farmatsevticheskie aspekty sozdaniia éffektivnoi lekarstvennoi formy karfetsillina.

Physical and technological parameters of carfecillin powder and carfecillin with auxiliary substances in the form of the powder mixture and granulate were studied comparatively. Possible preparation of carfecillin capsules characterized by high levels of the antibiotic dissolution was shown.

Clinical pharmacokinetics of carbenicillin, carfecillin, ticarcillin and BL-P 1654 in dairy cows.

The minimal inhibitory concentrations (MIC) of carbenicillin, ticarcillin and BL-P 1654 for gram-negative udder pathogens were determined using the agar plate dilution method. The MIC of the drugs for 50% and 90% of the isolates examined ranged for Escherichia coli and Aerobacter spp. from 1.56 to 25 micrograms/ml, and for Klebsiella spp. and Pseudomonas spp. from 3.12 to 50 micrograms/ml. The Serratia spp. were relatively non-susceptible for the drugs studied (MIC greater than 50 micrograms/ml). Each drug was administered intravenously at 5 g and 15 g per cow to different groups of cows with normal and inflamed quarters of the udder. Distribution and elimination kinetic parameters calculated from serum drug level data were very similar to those of other beta-lactam antibiotics. Although drug concentrations in milk from inflamed quarters were higher than in milk from normal quarters, they were considerably below the MIC for the majority of gram-negative udder pathogens. The data suggest that parenteral treatment of gram-negative udder infections with carbenicillin, carfecillin, ticarcillin and BL-P 1654 at the dose levels used in the present study is unlikely to result in a bacteriological cure and would probably be clinically ineffective.

The Assessment of Carfecillin in Acute Uncomplicated Urinary Tract Infection / 대한비뇨기과학회지

Fifty cases of acute uncomplicated urinary tract infection were selected and 3.0gm of Carfecillin was given for one day in two doses. The clinical and bacteriological results were compared with the results of 32 cases of the urinary tract infection who was given 200 mg of Doxycycline daily for 7 days. Of 50 patients receiving Carfecillin only 23 cases were sensitive to Carfecillin though 32 patients receiving Doxycycline were all sensitive to Doxycycline on prior to treatment urine culture. Carfecillin was effective in 34 cases among 38 cases of cystitis while Doxycycline was effective in 12 cases among 21 cases of cystitis. In 7 out of 12 cases of pyelonephritis Carfecillin was effective, while Doxycycline was effective in 9 out of 11 cases. Among 23 cases which were sensitive to Carfecillin, Carfecillin single day treatment was effective in 13 out of 17 cases of cystitis and 4 out of 6 cases of pyelonephritis. Both Carfecillin and Doxycycline showed good efficacy to E-coli, Staphylococcus aureus, Klebsiella, Streptococcus and Enterobacter. A single day treatment of Carfecillin was as effective as a conventional treatment of Doxycycline for the treatment of uncomplicated urinary tract infections.

Kinetics of drug decomposition. Part 66. Kinetics of the hydrolysis of carphecillin in aqueous solution.

The rates of hydrolysis of the beta-lactam ring in the pH range 1.77--9.22 at 294, 303, 313 and 233 K and of the ester bond in the pH range 0.43--8.78 at 273, 283, 294, 303, 313 and 323 K for carphecillin have been investigated. The rate constants were determined for the reactions catalyzed by H+ and OH- ions and moreover for the hydrolysis of the beta-lactam ring catalyzed by undissociated acids and anionic bases. The thermodynamic parameters were calculated for particular reactions. In the acidic medium carphecillin is significantly more stable than carbenicillin. In the alkaline medium the rate of inactivation of carphecillin and carbenicillin is the same because carbenicillin is formed from carphecillin as the result of the very fast hydrolysis of the ester bond.

Short-term antibiotic prophylaxis and prostatectomy.

Two hundred patients undergoing prostatic surgery at 2 hospitals were randomly allocated into 4 equal groups. The groups were a control, cephalexin, co-trimoxazole and carfecillin treated groups. The incidence of urinary tract infections and other complications of prostatic surgery were studied in each group after a short-term prophylactic regime of 3 doses of the antibiotic. The incidence of urinary infection was significantly improved from 28% in the control group to 8% and 16% in the co-trimoxazole and cephalexin groups respectively. Carfecillin was not effective in reducing urinary infection. However, all 3 antibiotics reduced the incidence of other infective sequelae.

Combination effect with some aminoglycoside antibiotics.

Strains of resistant species -- Staphylococcus aureus and Streptococcus faecalis -- isolated from material of nosocomial infections in the surgical department of a Prague hospital were tested for combined effect with further chemotherapeutics. The same concerned Ps, aeruginosa noted, at present, by a high degree of resistance. In Ps. aeruginosa it was the combination sisomicin-carfecillin that proved a success in 50 p. c. of cases as well as that of sisomicin-doxycyclin. At the same time the authors draw attention to the possibility of antagonistic action of the combination sisomicin-chloramphenicol in a third part of the strains tested. Potentiation of the effect in Staphylococcus aureus strains was observed also in the combination sisomicin-carfecillin in more than one half of the strains tested and in case of sisomicin-doxycyclin in one third of the strains. In Streptococcus faecalis strains sisomicin was combined with amoxycillin, carbenicillin, carfecillin and doxycyclin; synergistic action being observed with all those combinations in more than one half of strains tested. No antagonism was registered in those cases. (Ta.).

The availability of carfecillin and its phenol moiety in rat and dog.

1. Studies have shown that hydrolysis of carfecillin to carbenicillin and phenol in vitro occurs in blood, liver and gut tissues of rat and dog. Extremely rapid hydrolysis was observed in the blood and liver of the rat. 2. Absorption studies in intestinally-perfused rats showed that following administration of either [14C]phenol or [phenol-14C]carfecillin, the half-life values of radioactivity in the intestinal lumen were 6 min and 47 min respectively. 3. Following oral administration of phenol to rats and dogs at 300 mg/kg and 40 mg/kg respectively, maximum plasma concn. of phenol were 26 microgram/ml. However, following oral administration of carfecillin to rats and dogs at dose levels of 3000 and 800 mg/kg respectively, no significant amounts of free phenol or intact carfecillin were detected (< 1 microgram/ml). The very low concentrations of phenol found after carfecillin administration and the concomitant absence of acute phenol toxicity is explained by the slow absorption of carfecillin and its slow hydrolysis to phenol in the gut lumen. 4. In the dog, phenol which enters the portal circulation as carfecillin appears to undergo significant 'first pass' metabolism by the liver, while no such effect was observed if free phenol was administered.

The metabolism of carfecillin in rat, dog and man.

1. The absorption of the phenol moiety of [phenol-14C]carfecillin following oral administration to rat, dog and man was extensive, since 95%, 73% and 99% of the administered radioactivity respectively was recovered in the urine. In contrast, less than half of the carbenicillin moiety of carfecillin was absorbed after oral administration, as judged by excretion studies using [carbenicillin-14C]carfecillin in intact and bile-duct cannulated animals. 2. The patterns of radiometabolites in the urines of rat, dog and man following single oral administration of [phenol-14C]carfecillin were determined by chromatography and radioassay. In two men, the majority of a dose was excreted as phenylsulphate (71%) and phenylglucuronide (16%) with the sulphate and glucuronic acid conjugates of quinol representing small amounts of the urinary radioactivity. Similar metabolic patterns were observed in the rat and dog following oral administration of either [14C]phenol or [phenol-14C]carfecillin, although some saturation of sulphate conjugation was apparent at the dose levels employed.

[Effect of carfecillin on the body of animals in single and multiple administrations]. / Izuchenie vliianiia karfetsillina na organizm zhivotnykh pri odno- i mnogokdratnom vvedenii.

The effect of carfecillin on blood circulation, respiration, hepatic and renal functions, peripheral blood picture, growth and development of young animals was studied in acute and chronic experiments. The allergizating properties of the drug were also investigated. Carfecillin is low toxic. LD50 for albino mice on intravenous and oral administration of the drug is 782.5 and 3924 mg/kg respectively. When used repeatedly for treatment of rats in oral doses of 180 and 275 mg/kg corresponding to the daily doses for humans calculated for the body surface, carfecillin had no adverse effect on hepatic or renal function, cell composition of the blood, augmentation of the weight and relative weight of the organs of the growing animals. No detectable effect of carfecillin on arterial pressure, respiration, rhythm and amplitude of the systole was observed in acute experiments with anesthetized cats treated with the antibiotic intravenously in doses of 320 mg/kg. Histological examination of the internal organs of the rats treated with oral carfecillin during 2 months showed that the drug had an irritating effect on the gastrointestinal mucosa only in a dose of 540 mg/kg, which is 2 times higher than the equivalent daily dose for humans. Carfecillin possesses the allergizating properties and induces development of cross allergy to benzylpenicillin. The above properties were less pronounced in carfecillin than in benzylpenicillin.

Carbenicillin prodrugs: stability kinetics of alpha-phenyl and alpha-indanyl esters in aqueous solution.

Both ester and beta-lactam degradations of alpha-esters of carbenicillin disodium, carbenicillin indanyl sodium, and carbenicillin phenyl sodium in aqueous solution at 35 degrees and at 0.5 ionic strength were investigated. The reactions were followed by spectrophotometric assay, reversed-phase high-pressure liquid chromatography, and colorimetric assay. The degradation pathways were established, and the rate-pH profiles for ester and beta-lactam cleavage reactions are given for pH 1-11. Below pH 3, the beta-lactam degradation of the prodrugs proceeded exclusively. Above pH 7, the degradation was superseded by the ester hydrolysis to carbenicillin, beta-Lactams of both prodrugs are around three times more stable than carbenicillin disodium at pH 1, six times at PH 2, and 17 times at pH 3. The half-lives for carbenicillin production were predicted to be 17 hr for carbenicillin indanyl sodium and 8.5 hr for carbenicillin phenyl sodium at pH 7.0 and 37 degrees.

[Pharmacokinetic and clinical research of a new phenyl ester of carbecinillin: carfecillin]. / Ricerca farmacocinetica e clinica su un nuovo estere fenilico di carbenicillina: carfecillina.

Following a review of the latest methods of treating infections of the urinary ways, the pharmacokinetic and clinical results of a new antibiotic, Carfecillin, are reported. The examination was carried out on a total of 10 volunteers. The substance showed good serum levels and fair renal excretion with both the 250 mg and the 500 mg p.o. doses. The clinical study was carried out on a double blind basis versus a standard reference (indanyl ester of carbenicillin) in 26 patients and showed the electivity of the antibiotic in the oral treatment of urinary infections under well tolerated conditions.

[Acute toxicity and the cumulative properties of carfecillin]. / Ostraia toksichnost' i kumuliativnye svoistva karfetsillina.

Acute toxicity of oral and intraperitoneal carfecillin was studied on different species of laboratory animals, such as albino mice, rats and guinea pigs. The average lethal doses equal to 3040 (2393.7-3860.8) and 1325 (1104.2-1590) mg/kg for oral and intraperitoneal administration respectively allowed the authors to consider the antibiotic as a low toxic substance under conditions of a single administration. Higher toxicity of carfecillin as compared to carbenicillin may be due to production of free phenol on carfecillin hydrolysin in the animal organism. The different laboratory animals of both sexes had almost the same sensitivity to the antibiotic. On repeated administration of carfecillin to the albino mouse stomach (in portions of LD50) no cumulative properties of the antibiotic were observed.

Pharmacokinetic and clinical studies with carfecillin.

The pharmacokinetics of carfecillin (Carbenicillin-phenyl-ester) were studied in 10 healthy subjects, in 5 patients with hepatic cirrhosis and in 5 cases of renal insufficiency. In healthy subjects maximal carbenicillin serum levels attained by therapeutic doses were about 20 microgram/ml; concentrations in the urine surpassed 1000 mu/ml. The phenol moiety was detectable as free phenol in sera (less than 1 microgram/ml) and urine (less than 3 microgram/ml), but its major part was transformed to glucuronide and sulphate conjugates. Pharmacokinetics were not altered significantly by hepatic lesion. In renal insufficiency, serum levels of both carbenicillin and conjugated phenol were higher and their decrease delayed, while urine concentration was low. Carfecillin treatment was successful in 20 out of 30 patients with UTI.