Bacampicillin (proposed international nonproprietary name), 1′-ethoxycarbonyloxyethyl 6-( d -α-aminophenylacetamido)penicillanate, is a new orally well-absorbed penicillin, highly active in vivo due to rapid transformation into ampicillin. The compound is stable in vitro at gastric pH and hydrolyzed slowly to ampicillin at neutral pH but very rapidly in the presence of biological fluids, e.g., tissue homogenates or serum. In vivo the transformation into ampicillin is so rapid that no unchanged compound could be detected in the blood after oral administration of bacampicillin to rats, dogs, and humans. On oral administration to mice, rats, and dogs, bacampicillin was found to be better absorbed than ampicillin, giving higher and earlier peak blood levels of ampicillin. The bioavailability of bacampicillin in rats and dogs was three to four times higher than that of an equimolar amount of ampicillin. On oral administration to rats, bacampicillin was found to give higher levels of ampicillin in organs such as the kidney, liver, and spleen than ampicillin itself. In “tissue cages” in rats, higher transudate levels of antibiotic were found after oral administration of bacampicillin than after ampicillin. On oral treatment of experimentally infected mice, bacampicillin was found to be more active than ampicillin.

Bacampicillin, a new oral prodrug which in vivo is rapidly transformed to ampicillin, was compared with ampicillin, pivampicillin, and amoxycillin in a randomized cross-over study on 11 healthy volunteers. All drugs were given in oral doses equimolar to 400 mg of bacampicillin (800 ,umol). The mean of the individual peak concentrations in serum was 8.3 jig/ml for bacampicillin, 7.1 ,ug/ml for pivampicillin, 7.7 ,ug/ml for amoxycillin, and 3.7 ,ug/ml for ampicillin. Furthermore, bacampicillin had a higher absorption rate than all the other drugs, although there were statistically significant differences only versus ampicillin. The peak serum levels of the individual subjects were more dispersed with ampicillin and amoxycillin, suggesting a more uniform absorption of bacampicillin and pivampicillin. The relative bioavailability of bacampicillin and pivampicillin was comparable, whereas ampicillin was only 2/3 that of the others.Ampicillin combines a low toxicity and broad antibacterial spectrum, but one disadvantage is its incomplete absorption. Small modifications of the molecule such as the insertion of a hydroxy group on the benzene ring in amoxycillin have improved absorption without essentially altering the antibiotic spectrum (27), although less activity in vitro against some species (3,21,32) and clinical inferiority (20) against Shigella have been noted in comparison with ampicillin. An improvement has been achieved by esterification of the carboxyl group with radicals which leads to increased lipid solubility and improved absorption. Upon uptake, the radicals are rapidly detached by hydrolysis, and free ampicillin is made available in blood and tissues. Examples of this class of compounds are pivampicillin (28, 29) and talampicillin (5, 25).A systematic search for a new ampicillin ester combining good bioavailability with virtual lack of gastrointestinal distress and diarrhea has led to bacampicillin [1'-ethoxycarbonyloxyethyl-6-(n-a-aminophenylacetamido)-penicillinate]. This is rapidly absorbed and transformed to ampicillin with a concomitant rapid breakdown of the ethoxycarbonyloxyethyl ester group to acetaldehyde, ethanol, and carbon dioxide. The hydrolysis proceeds so rapidly that no systemic bacampicillin has been detected (4). In animals, the new antibiotic is better absorbed than amp-iilin, giving higher and earlier peak blood,7evels of ampicillin (4, 9a).Studies with bacampicillin in healthy volunteers gave peak serum levels approximately 2.5 times higher than those after an equimolar dose of ampicillin. Mean individual peak serum levels after administration of 200, 400, and 800 mg of bacampicillin were 5.3, 8.9, and 16.5 ,ug/ ml, respectively (18). Bacampicillin has rendered bioavailabilities of 87 to 95% (26; T. Bergan, submitted for publication).With the various modifications of ampicillin and ampicillin-like antibiotics presently at the research stage, careful pharmacokinetic evaluations in controlled cross-over studies are important to reveal the points of distinction between them. The purpos...

Plasma levels and renal excretion of sulphonamide and trimethoprim following oral administration of co-trimazine (140 mg sulphadiazine + 90 mg trimethoprim) and co-trimoxazole (800 mg sulphamethoxazole + 180 mg trimethoprim) were monitored in healthy volunteers after a single dose and in the steady state after 12-hourly dosage. The plasma levels of free, non-protein bound components after co-trimazine were approximately half those after co-trimoxazole and thus correlated with the doses given. Urine recovery of trimethoprim was better after co-trimazine (70%) than after co-trimoxazole (58%). Sixty-six percent of the sulphadiazine was recovered as unchanged, active sulphonamide in the urine compared with only 13% of the sulphamethoxazole. Consequently, the sulphonamide levels of sulphadiazine were 2.5 times those of sulphamethoxazole. With respect to plasma half-life after the first dose, sulphadiazine with 8.0 hours was closer to trimethoprim with a half-life of 8.8 hours after cotrimazine and 9.6 hours after co-trimoxazole than to the half-life of sulphamethoxazole which was 7.7 hours. The distribution volume of sulphadiazine was closer to that of trimethoprim than was that of sulphamethoxazole. On the basis of these characteristics, it has been concluded that sulphadiazine is more suitable for a fixed combination tablet with trimethoprim than sulphamethoxazole, particularly for the treatment of urinary tract infections. Some renal tubular reabsorption occurs with both unchanged sulphonamides but is more pronounced with sulphamethoxazole. The solubilities of the sulphonamides and their acetylated metabolites at acid urinary pH indicate that therapy with co-trimazine is at least as safe as with co-trimoxazole. With the former drug, the result of scrutiny for crystals after dosage until the steady state was negative, whereas crystals of acetylated sulphamethoxazole were detected and verified chemically in two of eight subjects.

1 Erythromycin concentrations in serum and urine were determined in 24 healthy male, fasting subjects after oral administration of 250, 500, or 1000 mg of erythromycin base (250 mg capsules containing enteric‐ coated pellets). The subjects also received a film‐coated erythromycin stearate tablet (equivalent to 500 mg base). 2 The mean +/‐ s.d. maximal serum erythromycin concentrations were 1.9 +/‐ 0.8, 3.8 +/‐ 1.4, 6.5 +/‐ 2.9 and 2.9 +/‐ 1.7 mg/l for 250, 500, or 1000 mg base and 500 mg stearate, respectively. The serum peaks usually occurred after 2 h irrespective of dosage form given. 3 The mean +/‐ s.d. areas under the serum concentration v time curves (AUC0‐infinity) were 4.5 +/‐ 1.7, 11.2 +/‐ 4.3, 27.2 +/‐ 10.6 and 7.5 +/‐ 3.4 mg l −1 . h after 250, 500, or 1000 mg base, and 500 mg stearate, respectively. 4 The urinary recoveries were 5.0, 6.7, 8.6% of the base doses given and 4.4% of the stearate dose given. 5 Dose‐dependent excretion of erythromycin occurred. The increase in AUC was larger than multiples of the lowest base dose.

Ampicillin is often used in high oral doses due to its incomplete absorption. The objective of this study was to compare the bioavailability of bacampicillin, a new prodrug of ampicillin which is nearly completely absorbed, to that of high doses of oral ampicillin. Single oral doses of bacampicillin 400 mg or 800 mg and ampicillin 500 mg, 1 g, or 2 g were given to 12 male subjects according to a cross-over design after overnight fasting. The median time after administration till the peak serum level was 0.75 and 1.0 hour with bacampicillin 400 mg and 800 mg respectively, as compared to 1.5, 2.0 and 1.5 hours for the ampicillin doses. The mean of the individual peak serum level after bacampicillin 400 mg, was 7.7 mg/l, which is higher than that after ampicillin 500 mg, 5.2 mg/l, and about the same as that after ampicillin 1 g, 7.6 mg/l. A slightly higher mean peak level was seen after bacampicillin 800 mg, 12.2 mg/l, as compared to ampicillin 2 g, 10.5 mg/l. The absorption rate was highest with bacampicillin, for which 90% of the absorption had occurred 1 hour after administration as compared to 2.5 hours after administration of ampicillin. The relative bioavailability was about 2--3 times higher after bacampicillin as compared to ampicillin. The data imply dose-dependent absorption of oral ampicillin in high doses as there seems to be a less than proportional increase in AUC. The urinary recovery after bacampicillin was 68--75% as compared to 25--41% after ampicillin. Higher doses gave a lower percentage recovery and this phenomenon was more pronounced with ampicillin.