The influence of uptake from the gastrointestinal tract and first-pass effect on oral bioavailability of (Z)-alkyloxyimino penicillins.

We have investigated the contribution of uptake from the gastrointestinal tract and first-pass effect to the poor oral bioavailability of a series of (Z)-alkyloxyimino penicillins in mice. Investigative studies in gut sacs and perfused small intestine demonstrated that these penicillins were able to pass across the mucosal epithelium although to a lesser extent than amoxycillin and cyclacillin, both of which exhibit excellent oral bioavailability in man and animals. In the jejunal gut sacs the mucosal to serosal flux for BRL 44154 was approximately half that of amoxycillin and four times less than that of cyclacillin, and for all, uptake was pH dependent. The serosal to mucosal fluxes were however similar for these compounds and significantly lower than mucosal to serosal fluxes, suggesting involvement of carrier mechanisms in uptake from the mucosal surface. The order of results for the alkyloxyimino penicillins paralleled that observed for oral bioavailability in the mouse. For the alkyloxyimino penicillins, between 5.5 and 9.9% was taken up from the perfused intestine, values which were significantly less than those for amoxycillin (13.2%) and cyclacillin (33.3%). However, uptake was concentration-dependent for BRL 44154 as it was for amoxycillin, thus confirming the possible use of carrier mechanisms in absorption. These observations suggest that the poor peripheral blood concentrations of the alkyloxyimino penicillins achieved after oral dosing were not a consequence of the inability of the compounds to cross the mucosal epithelium. The biliary clearance of the alkyloxyimino penicillins was, however, considerably greater than for amoxycillin and cyclacillin, a finding which may well have been a contributory factor to the comparatively low peripheral concentrations of BRL 44154 and its analogues achieved after oral administration.

Penetration of ciclacillin into bronchial secretions.

The penetration of ciclacillin into bronchial secretions was investigated in 105 patients undergoing bronchoscopy after a single oral dose of 500 mg ciclacillin. Comparison was made with 26 patients who received 500 mg ampicillin by mouth. Over a 6 to 8 hour period, ciclacillin achieved significantly higher levels in bronchial secretions but no statistically significant difference between serum ampicillin and ciclacillin levels was detected.

Oral cyclacillin interacts with the absorption of oral ampicillin, amoxycillin, and bacampicillin.

The relative bioavailabilities of single oral doses of ampicillin, amoxycillin, and bacampicillin were compared with and without concomitant administration of a six-times higher molar dose of cyclacillin. As the absorption of cyclacillin has been shown to involve a capacity-limited transport system in animals, it was selected as the reference compound for the study. The treatments were given to 14 fasting volunteers using a randomized, complete crossover design. The drugs in plasma and urine were determined by liquid chromatography. Renal clearance was 17%, 10% and 19% lower when ampicillin, amoxycillin, and bacampicillin were given together with cyclacillin. Consequently, differences in the relative bioavailability were based on urinary recoveries assuming constant non-renal clearance. When amoxycillin was given with cyclacillin there was a 67% delay in the time of the plasma peak concentration, and an 8% lower urinary recovery than when it was given alone. There was a 50% and 33% delay in the tmax of ampicillin and bacampicillin when combined with cyclacillin; the urinary recovery of ampicillin in the combination was 10% lower but that of bacampicillin was similar. There was also a 20% delay in the tmax of cyclacillin when combined with amoxycillin. The differences in renal clearance indicate an interaction in the renal elimination of the drugs, but the effect was probably not the explanation for the marked shift in time of the absorption of these rapidly absorbed drugs. The results support the existence of a capacity-limited transport system for aminopenicillins in the human gut.

Single-dose therapy for cystitis in women. A comparison of trimethoprim-sulfamethoxazole, amoxicillin, and cyclacillin.

We evaluated single-dose regimens of trimethoprim-sulfamethoxazole, amoxicillin, and cyclacillin as treatment for acute cystitis in 38 women. The trial was prematurely stopped because of frequent treatment failures. At two days after treatment, all 13 patients given trimethoprim-sulfamethoxazole were cured, while four (31%) of 13 given amoxicillin and four (33%) of 12 given cyclacillin had persistent bacteriuria. At two weeks, 11 (85%) of 13 patients given trimethoprim-sulfamethoxazole, six (50%) of 12 given amoxicillin, and three (30%) of ten given cyclacillin were cured. One patient with positive results of antibody-coated bacteria testing who was treated with cyclacillin had signs and symptoms of acute pyelonephritis three days after treatment, and two patients treated with amoxicillin and one treated with trimethoprim-sulfamethoxazole converted antibody-coated bacteria test results from negative to positive after therapy. We conclude that single-dose treatment of cystitis in unselected women with cyclacillin and amoxicillin may result in low cure rates and that progression to acute pyelonephritis may occur following ineffective single-dose therapy.

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics II: Michaelis-Menten kinetics of cyclacillin absorption and its pharmacokinetic analysis in rats.

The absorption of cyclacillin at pH 7.0 by the rat small intestine was investigated using in situ perfusion. At the lowest dose of 95 microgram/ml, the antibiotic disappearance was rapid and followed first-order kinetics, with the disappearance being 85% at 100 min. At the intermediate concentrations of 770 and 1200 microgram/ml, the disappearance after 100 min was 69 and 54%, respectively, and semilogarithmic plots clearly showed convex curvatures. At the highest concentration of 30 mg/ml, cyclacillin disappeared slowly from the perfusate, in an apparent first-order fashion. The disappearance was 26% after 100 min of perfusion and was similar in extent at 5.2 mg/ml. This concentration-time profile was satisfactorily fitted to the simultaneous Michaelis-Menten and first-order kinetic equations. The area under the blood concentration versus time curve (AUC) after a single intraduodenal dose of cyclacillin was almost consistent with the AUC after the equivalent intravenous dose (10 mg/kg). Additional evidence from a pharmacokinetic analysis of steady-state blood concentrations after constant infusion of cyclacillin through the portal vein and the small intestinal lumen indicated that cyclacillin absorption by the rat intestinal tissue at relatively low concentrations (less than 1 mg/ml) followed solely Michaelis-Menten kinetics. Cyclacillin may be transported by certain types of carrier-mediated mechanisms.

Pharmacological and in vitro evaluation of cyclacillin: assessment as potential single-dose therapy for treatment of Neisseria gonorrhoeae infection.

The pharmacokinetic properties of cyclacillin administered as a 3.0-g oral dose, with and without progenecid, have been studied and correlated with in vitro activity of the drug against 109 isolates of Neisseria gonorrhoeae. By 8 h after dosage, levels of cyclacillin in serum declined below the minimal inhibitory concentration and the inferior antibacterial activity of cyclacillin (compared with that of amipicillin) suggest that cyclacillin is not a promising alternative to ampicillin for single-dose treatment of gonorrhea.

[Comparative experimental study of cyclacillin and ampicillin]. / Sravnitel'noe izuchenie tsiklatsillina i ampitsillina v éksperimente.

Cyclacillin was compared with ampicillin by its bacteriostatic efficiency in vitro, chemotherapeutic efficiency in experimental infections of mice and rats and pharmacokinetic characteristics. It was found that cyclacillin was not superior to ampicillin by its antibacterial action. By a number of characteristics it was even significantly inferior. The pharmacokinetic advantages of cyclacillin were not considered significant.

[Studies on absorption and excretion of cyclacillin granules (vastcillin granules 'Takeda') (author's transl)].

Vastcillin granules 'Takeda', a cyclacillin (AC-PC) preparation for children were orally administered to nine children at a single dose of 10 mg/kg and its blood concentrations and urinary excretion were studied. From the results obtained, the following conclusions were obtained as to clinical dose and indications. (1) Absorption of AC-PC of Vastcillin granules is excellent . At 15 minutes after administration, 9.3 mcg/ml of AC-PC blood level was attained and its peak appeared 30 minutes after administration. The mean peak level was 17.6 mcg/ml.

Relationship between the chemotherapeutic effectiveness of ciclacillin and ampicillin and the time of their administration in experimental infections.

In an attempt to explain the discrepancy between the weak in vitro activity and good clinical efficacy of ciclacillin, a time-dosage-efficacy study was made in order to investigate the relationship of the effectiveness of this antibiotic to the interval between experimental infection and administration in comparison to ampicillin, which because of its similar antimicrobial spectrum and completely different pharmacokinetic properties was particularly suitable for use in the study. Various single oral doses of both antibiotics were administered once to NMRI (SPF) mice at various intervals (0, 1, 2 or 3 h) following experimental infection with E. coli WT 102, E. coli 3033 or E. coli 026:B6 and the CD50's determined and compared statistically. It was demonstrated that the chemotherapeutic effectiveness of both antibiotics was markedly dependent on the interval between experimental infection and administration. Whereas ampicillin was superior to ciclacillin when drug and infective organism were administered simultaneously (0 h), ciclacillin was superior to ampicillin when it was administered 3 h after experimental infection. Both antibiotics were about equally effective when administered 1 or 2 h after infection. The difference in the serum concentrations and rates of absorption and excretion of the two drugs is assumed to be the reason for this phenomenon, and the pharmacokinetic characteristics of ciclacillin, in particular its rapid and almost complete absorption and rapid attainment of high peak serum levels, are discussed as at least a partial explanation of the difference in its in vitro and in vivo activities.

[Ciclacillin therapy for diseases of the urinary tract]. / Ciclacillin-Therapie bei Harnwegserkrankungen

In our own controlled bacteriological investigations, ciclacillin showed a good effect in urological infections at a daily dosage of 3 g for 10 days. The efficacy is comparable to that of ampicillin and corresponds to that of the double blind trials bescribed in the literature. The specially good tolerance is worthy of note.