Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man

Five healthy fasting male subjects were each given single doses of intravenous ampicillin (471 mg), oral ampicillin tablets (495 mg), oral bacampicillin hydrochloride tablets (562 mg ampicillin equivalent), and oral pivampicillin hydrochloride capsules (491 mg ampicillin equivalent) in a crossover experiment. The resulting concentrations of ampicillin were determined in plasma and urine. The pharmacokinetic analysis was made according to a two-compartment open model. The total distribution volume of unbound ampicillin during the disposition phase was 0.247 ± 0.045 (sd) liter/kg, which is only slightly more than the extracellular fluid, suggesting that tissue binding and intracellular distribution of ampicillin are limited. The bioavailability of the esters bacampicillin (86 ± 11%) and pivampicillin (92± 18%) was significantly greater than that of ampicillin (62 ± 17%); however, the difference between the esters was not statistically significant. The absorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The absorption rate was highest for bacampicillin (0.89 ± 0.39% of dose absorbed per minute), followed by pivampicillin (0.64 ± 0.19) and ampicillin (0.58 ± 0.16). Bacampicillin also had the shortest lag time for the start of absorption (7.0 ± 0.9 min) under the present conditions. Thus, in comparison with ampicillin, the esters have a higher bioavailability, which, in fact, is close to the theoretically highest possible value by clearance concepts. The higher bioavailability in connection with higher absorption rates may be clinically important in ampicillin treatment by the oral route.This work was supported by the Swedish Medical Research Council, Project No. 522 (L. O. B.).     

Bacampicillin Hydrochloride: Chemistry,Pharmacology, and Clinical Use

Bacampicillin hydrochloride is an orally administered ester of ampicillin that is rapidly and completely hydrolyzed in vivo to ampicillin. The most notable advantage of bacampicillin over ampicillin is its superior bioavailability — bacampicillin achieves significantly higher blood and tissue levels and attains peak blood levels more rapidly than equimolar doses of oral ampicillin. In addition, the percentage of an oral dose of ampicillin that is absorbed decreases sharply as the size of the dose is increased from 500 mg to 2 g; this phenomenon is not observed with equipotent doses of bacampicillin. The enhanced absorption of bacampicillin in the upper gastrointestinal tract results in a frequency of diarrhea that appears to be markedly lower than that of ampicillin and similar to that observed with amoxicillin. Apart from the sizable differences between bacampicillin and ampicillin with regard to oral absorption, the pharmacokinetic and pharmacologic profiles of these two agents are essentially identical. Twice daily dosing (pulse dosing) with bacampicillin has been shown in numerous clinical trials to be of equivalent efficacy to ampicillin given four times daily or amoxicillin given three times daily in the treatment of infections of the upper respiratory tract, lower respiratory tract, skin and soft tissues, and urinary tract. The unanswered question is whether twice daily ampicillin or amoxicillin would yield similar results.     

The Oral Absorption of Ampicillin,Pivampicillin and Amoxycillin in Infants and Children

Abstract: The oral absorption of comparable doses of mixtures of ampicillin, amoxycillin and pivampicillin was studied in 38 children from 6 months to 6 years of age. Plasma concentrations following pivampicillin and amoxycillin were higher than those following the administration of ampicillin. No significant difference was found between amoxycillin and pivampicillin. The oral absorption of pivampicillin mixture was further studied in 12 infants, 0–1 month and 1–5 months of age. The absorption was faster in infants and children more than 6 months of age than in the 1–5 months group. The excretion, indicated by the slope of the plasma concentration curve, was delayed in infants less than one month of age. The oral absorption of amoxycillin and pivampicillin from tablets was also studied in 12 infants and children, 6 months-6 years of age, in the same doses as when mixtures were studied and was more complete with pivampicillin than with amoxycillin. The absorption of pivampicillin was more complete from tablets than from mixture. Also with amoxycillin there was a trend towards more efficient absorption from tablet than from mixture.     

The effect of sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin tablets

The effect of Sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin was investigated. The bioavailability of ampicillin was determined using the urinary excretion method. The urinary levels of ampicillin were measured chemically. Bacampicillin capsules were administered: (i) under different dietary conditions; and (ii) on an empty stomach together with chloroquine phosphate tablets. Unlike the case of ampicillin capsules, neither food nor chloroquine affected the bioavailability of ampicillin from bacampicillin capsules. The difference between ampicillin and bacampicillin capsules with respect to the effect of food and chloroquine on ampicillin bioavailability is discussed.     

Ampicillin in portal and peripheral blood and bile after oral administration of ampicillin and pivampicillin

Summary The concentration of ampicillin in serum and bile has been determined in 10 patients after oral administration of equivalent doses of ampicillin (500 mg) and pivampicillin (700 mg). Ampicillin produced maximum concentrations in bile twice as high as in serum, and, after pivampicillin, peak levels of ampicillin occurred earlier and were approximately four times greater than after ampicillin. In 11 other patients, ampicillin was determined simultaneously in peripheral and portal blood, collected from an umbilical vein catheter, following a dose of pivampicillin or an intravenous injection of ampicillin. The peak concentration of ampicillin after an oral dose was twice as high in portal blood as in peripheral blood. There appears to be passive transfer of ampicillin from blood to bile.     

Bacampicillin uptake is shared with thiamine in Caco-2 cells

Bacampicillin was developed as a prodrug to improve the intestinal absorption of its metabolite ampicillin. This study was undertaken to characterize bacampicillin transport in Caco-2 cells. The uptake of bacampicillin in Caco-2 cells was significantly greater than those of ampicillin and pivampicillin. An Eadie-Hofstee plot obtained from 5-min uptake of 0.2-5 mM bacampicillin was linear, indicating the presence of a saturable transport system for bacampicillin with K(m) and V(max) of 3.6 mM and 23.9 nmol/mg protein/min, respectively. Hydrophilic organic cations such as choline, cimetidine, guanidine, nicotinamide, 1-methylnicotiamide, and tetraethylammonium failed to modulate bacampicillin uptake in Caco-2 cells whereas diphenhydramine, procainamide, and thiamine significantly depressed it. Moreover, when thiamine was preloaded in Caco-2 cells, bacampicillin uptake was significantly increased, indicating that this cationic vitamin was capable of trans-stimulating bacampicillin transport across the apical membrane of Caco-2 cells. However, trans-stimulated bacampicillin uptake was not observed in the presence of diphenhydramine. Bacampicillin uptake increased with elevation of the medium pH, and the known modulators of thiamine transport such as amiloride and oxythiamine significantly inhibited bacampicillin uptake. Thiamine also significantly decreased the apical-to-basolateral transport of bacampicillin across Caco-2 cell monolayers. However, thiamine did not exert any modulating effect on pivampicillin uptake and its apical-to-basolateral permeation in Caco-2 cells. These results suggest that bacampicillin is transported in Caco-2 cells, sharing a carrier-mediated system with thiamine.     

Studies on the pharmacokinetic equivalence of pivampicillin base and hydrochloride in capsules and tablets (author's transl)

Absorption and urinary excretion of pivampicillin as hydrochloride and as base were studied following administration of four different formulations to 12 healthy volunteers in a cross-over study. A fluorimetric assay of ampicillin was adapted to be used with an Auto Analyzer system. The plasma concentrations observed are comparable to those reported in the literature. The amount of drug absorbed is the same for all four medications whereas absorption is more rapid from tablets than from capsules. Base and hydrochloride of pivampicillin are equivalent with respect to pharmacokinetic behaviour. So, the formulation itself seems to be more important for biological equivalence than the ionisation of the drug used in the formulation.     

Correlation between the bioavailability of microencapsulated bacampicillin hydrochloride in suspension and in vitro microcapsule dissolution

The relative bioavailability of microencapsulated bacampicillin hydrochloride in suspension was correlated with the in vitro dissolution half-lives of the microcapsules. Simultaneously, a sensory evaluation was performed to evaluate the taste acceptability of the suspension. The in vitro dissolution half-life is directly related to the coating thickness of the microcapsules. The four suspensions of bacampicillin hydrochloride, containing microcapsules with different coating thickness, were given as single 400-mg oral doses to 12 healthy volunteers after overnight fasting using a crossover design with balanced sequences. Bacampicillin is a prodrug of ampicillin, the concentration of which was determined in plasma and urine by bioassay. There were significant inverse linear relationships between the dissolution half-life and plasma peak concentration, area under the curve, and urinary recovery. The terminal exponential disposition phases of the curves were similar for all four suspensions. There was a significant direct linear relationship between the dissolution half-life and overall taste and bitterness. The results show that the mean bioavailability of bacampicillin hydrochloride from a microcapsule suspension can be predicted from an in vitro dissolution half-life. The results also suggest that bacampicillin hydrochloride can be given in a suspension with sufficient microcapsule film thickness to reduce the bitter taste of the drug and still retain adequate bioavailability.     

In vitro and in vivo evaluation of locust bean gum and chitosan combination as a carrier for buccal drug delivery

The object of the study was to evaluate locust bean gum and chitosan in ratios of 2:3; 3:2 and 4:1 (F1, F2 and F3) as a mucoadhesive component in buccal tablets and to compare the bioavailability of a propranolol hydrochloride buccal tablet with the oral tablet in healthy human volunteers. Propranolol hydrochloride buccal tablets containing various weight ratios of locust bean gum and chitosan were prepared and coated with 5% w/v ethyl cellulose on one face, and oral tablets containing 10 mg propranolol hydrochloride alone were formulated using a direct compression technique. The strength of mucoadhesion of the tablets was quantified based on the tensile force required to break the adhesive bond between a model membrane (porcine buccal mucosa) and the test polymer. The forces of detachment for the mucoadhesive buccal tablets were 14.61 +/- 0.14, 13.21 +/- 0.13 and 11.71 +/- 0.12. An in vitro study was carried out in pH 6.8 phosphate buffer and the cumulative percentage release of propranolol measured at 10 min intervals for 600 min was found to be 98.31 +/- 0.10, 92.24 +/- 0.41 and 90.18 +/- 0.76 respectively. A bioavailability study was conducted with the prepared formulation in 16 healthy human volunteers to determine the plasma concentration of propranolol at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. The bioavailability (AUC(0-t*) ng x h/ml) of the buccal propranolol hydrochloride tablets (F1, F2 and F3) and oral tablet (F4) was found to be 2244.18 +/- 210, 3580.69 +/- 460, 3889.19 +/- 290 and 1732 +/- 96 ng x hr/ml respectively. The study indicates that locust bean gum and chitosan in a weight ratio of 2:3 (F1) not only releases the drug unidirectionally from the dosage form, but also gives buccal tablets which are sufficiently mucoadhesive for clinical applications.     

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

Summary 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 t_max 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 t_max 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.     

Absolute bioavailability of mianserin tablets and solution in healthy humans

A pharmacokinetic study with mianserin . HCl was performed in six healthy male subjects. The subjects were treated on different occasions intravenously with a constant-rate infusion of 5 mg mianserin. HCl in 1 h, orally with a single dose of 60 mg as two tablets of 30 mg each and with 60 mg as an oral solution. The wash-out period between treatments was 1 month. Blood samples were taken at predetermined times over a period of 120 h following dosing. The mianserin concentration in the plasma samples was determined and the results were pharmacokinetically analyzed. The intravenous data could be adequately described by a 3-compartment model and the oral data by a 2-compartment model, both with first-order transfer and elimination rate constants. The mean plasma clearance of mianserin was found to be 19 +/- 2 l h-1 (mean +/- SEM), the kinetic volume of distribution 444 +/- 250 l, the steady-state volume of distribution 242 +/- 171 l and the elimination half-life 33 +/- 5 h. The absolute bioavailability in terms of extent of absorption was 22 +/- 3% for the solution and 20 +/- 3% for the tablets. The mean peak level for the solution was 79 +/- 11 ng X ml-1 and for the tablets 54 +/- 5 ng X ml-1; mean peak time for the solution was 1.1 +/- 0.2 h and for the tablets 1.4 +/- 0.2 h. The mean absorption half-life for the solution was 0.43 +/- 0.13 h and for the tablets 0.39 +/- 0.11 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Design and in vivo evaluation of a patch system based on thiolated polymers

A new oral patch delivery system has been designed to increase the overall oral bioavailability of drugs within the gastrointestinal tract. The patch system consists of four layered films: a mucoadhesive matrix layer, a water insoluble backing layer, a middle layer and an enteric surface layer. The separation layer between the two matrix layers contained lactose, starch and confectioners' sugar. The matrix layer, exhibiting a diameter of 2.5 mm and a weight of 5 mg, comprised Polycarbophil-cysteine conjugate (49%), fluoresceine isothiocyanate-dextran (26%), glutathione (5%), and mannitol (20%). A standard tablet formulation consisting of the same matrix served as control. Entire fluoresceine isothiocyanate-dextran (FD(4)) was released from the delivery system within 2 h. For in vivo studies patch systems were administered orally to male Sprague-Dawley rats. Maximum FD(4) concentration in blood of the patch system was 46.1 +/- 8.9 ng/mL and was reached 3 h after administration. In contrast c(max) of control tablets displayed 50.5 +/- 14.9 ng/mL after 2 h and the absorption of FD(4) after administration in oral solution was negligible. The absolute bioavailability of orally administered patch systems and control tablets was 0.54% and 0.32% respectively. Results of this study indicate that a prolonged and higher oral bioavailability of FD(4) is obtained with patches than with tablets.     

Talampicillin hydrochloride: Comparison with amoxicillin and ampicillin in the antibacterial activity and pharmacokinetics (author's transl)]

The antibacterial activities, absorption and excretion of talampicillin hydrochloride were compared with those of amoxicillin and ampicillin. Talampicillin hydrochloride showed a broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria as seen in amoxicillin and ampicillin. The antibacterial activities of talampicillin hydrochloride, amoxicillin and ampicillin were quite similar. In experimental murine infection with Staphylococcus aureus, protective effect of talampicillin hydrochloride was superior to ampicillin. For Escherichia coli infection, protective effect of talampicillin hydrochloride was similar to that of amoxicillin, while ampicillin was less active than both talampicillin hydrochloride and amoxicillin. The absorption and excretion of 250 mg equivalent doses of talampicillin hydrochloride, amoxicillin and ampicillin were compared in nine fasting healthy volunteers after oral administration of these antibiotics in randomized triple crossover study. In order to calculate the pharmacokinetic parameters, plasma levels were analyzed using an one-compartment open model, as well as area under the plasma concentration curve (AUC) and urinary excretion. Maximum plasma levels calculated were 2.8 times higher for talampicillin hydrochloride and 1.45 times higher for amoxicillin than for ampicillin. AUC was greater for talampicillin hydrochloride than for amoxicillin and lowest for ampicillin. Urinary excretion of talampicillin hydrochloride as penicillin determined in biological assay was comparable to that of amoxicillin and 1.55 times higher than that of ampicillin. Penicillins can be metabolized to penicilloic acids in the body. After taking into account the penicilloic acid contents in urine, total excretion in urine was 61% for talampicillin hydrochloride, 67% for amoxicillin and 42% for ampicillin during 6 hours after dosing. The absorption of the drugs was evaluated according to the plasma levels, the area under plasma concentration curve and the percentage of excretion in urine. The results obtained showed that talampicillin hydrochloride was well absorbed from the gastro-intestinal tract.     

Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers.

1 A mefloquine hydrochloride tablet (250 mg base equivalent to 4.8 +/- 0.6 mg kg-1; mean +/- s.d.) and deuterium labelled mefloquine hydrochloride solution (250 mg base) were given to six adult male Thai patients with acute falciparum malaria and six healthy Swiss adult male volunteers (equivalent to 3.5 +/- 0.1 mg kg-1). 2 The relative bioavailability of the tablet formulation derived from comparison of the areas under the plasma concentration-time curves was similar in both groups; 87 +/- 11% and 89 +/- 10% (mean +/- s.d.). 3 The rate of drug absorption appeared to be similar in the two groups but peak plasma mefloquine concentrations were approximately three times higher in the Thai patients (1004 +/- 276 ng ml-1 for the tablet and 1085 +/- 280 ng ml-1 for the suspension) compared with the Swiss volunteers (319 +/- 73 ng ml-1 for the tablet, and 369 +/- 121 ng ml-1 for the suspension). 4 Estimates of the oral clearance CLpo of unlabelled mefloquine were significantly lower (17.5 +/- 4.4 ml h-1 kg-1) in the Thai patients compared with 28.8 +/- 3.5 ml h-1 kg-1 in the Swiss volunteers; P less than 0.05). Terminal elimination half-lives were significantly shorter in the patients (10.3 +/- 2.5 days) than in the volunteers (16.7 +/- 1.9 days; P less than 0.005). Differences of a similar magnitude were observed when comparing the pharmacokinetic parameters derived from the deuteromefloquine plasma concentrations. 5 Both genetic and disease related factors are likely to account for the large pharmacokinetic differences between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum concentrations of ampicillin and probenecid and ampicillin excretion after repeated oral administration of a pivampicillin-probenecid salt (MK-356)

Summary Twenty male volunteers received oral doses (2100, 1050, and 525 mg) of a pivampicillin-probenecid salt in a 1 to 1 molar ratio (MK-356) at 12 hour intervals. After each dose peak serum concentrations of probenecid were observed 2 hours later than peak concentrations of ampicillin. Following the first dose of MK-356 the apparent elimination rate of ampicillin was dose-dependent and did not follow first order kinetics, as it showed a longer apparent half life after a higher dose. An equal dose of MK-356 administered 12 hours later caused an increase in the peak serum ampicillin level greater than expected from the concentration of ampicillin after the preceding dose. In twelve male volunteers who received at random 525 mg of MK-356 or 350 mg of pivampicillin, each three times daily for 4 days, the areas under the ampicillin concentration curve were the same after the first or last dose of either drug. When 2100 or 1050 mg of MK-356 was taken as an initial dose, 30 to 40 per cent of the ampicillin was recovered from urine in the ensuing 12 hours. The results indicate that when at least 400 mg probenecid was coadministered twice daily with 700 mg pivampicillin (MK-356), the peak serum concentrations of ampicillin were increased and its elimination rate slowed following successive doses.     

Bioavailability of hydrochlorothiazide from isomalt-based moulded tablets

The bioavailability of hydrochlorothiazide (HCT) from moulded isomalt-based tablets was evaluated after oral administration of 50 mg HCT to healthy volunteers as an oral moulded tablet and as a lozenge, in comparison with a conventional tablet formulation (Dichlotride 50 mg). Moulded tablets had a high relative bioavailability (F(rel)) as the pharmacokinetic parameters (C(max), t(max), t(1/2), AUC(0-->24 h)) determined from HCT plasma concentration versus time profiles were not significantly different (P>0.05; two-way ANOVA) in comparison with the conventional tablet. The relative bioavailability of the moulded tablet administered as a lozenge and as an oral tablet was 106.2+/-30.9% and 89.4+/-25.9%, respectively, in relation to the conventional tablet formulation. Direct moulding of isomalt tablets proved to be a suitable technique to administer a poorly soluble drug either as a conventional tablet or as a lozenge.     

Bioavailability and pharmacokinetic profile of dihydroergotoxine from a tablet and from an oral solution formulation

Dihydroergotoxine mesylate (DHETM, CAS 8067-24-1), the combination of the mesylates of four dihydrogenated ergot alkaloid derivatives (dihydroergocornine, dihydroergocristine, alpha-dihydroergocryptine and beta-dihydroergocryptine), is used mainly for age-related cognitive impairment. The bioavailability of DHETM was investigated in a cross-over study on 20 male healthy volunteers to whom two single doses of 9 mg DHETM were administered either in tablets (Orphol spezial) or in oral solution (Orphol forte). DHETM was assayed in serum with a double radioimmunoassay method displaying a satisfactory cross-reactivity with the principal components of DHETM. After administration of tablets the peak of DHETM was (mean +/- SE) 124 +/- 16 pg/ml, the tmax 1.15 +/- 0.21 h, the AUC 790 +/- 93 pg/ml x h and the terminal elimination half-life 7.54 +/- 1.23 h. After oral solution the peak of DHETM was 176 +/- 16 pg/ml, the tmax 0.50 +/- 0.04 h, the AUC 779 +/- 94 pg/ml x h and the terminal elimination half-life 6.13 +/- 0.76 h. The bioavailability of DHETM from tablets vs. that from oral solution differed only by a retard related to the dissolution time of DHETM from the tablets, but not for other pharmacokinetic parameters. The relatively high two single doses of 9 mg DHETM administered to the 20 subjects were well tolerated, causing only known and expected adverse reactions to DHETM (tiredness, headache and vertigo) that did not require discontinuation of the study.     

Bioavailability of enteral tramadol formulations. 1st communication: capsules

The absolute bioavailability of tramadol hydrochloride (rac-1(e)-(m-methoxyphenyl)-2-(e)-(dimethylaminomethyl)cyclohexan- 1(a)-ol hydrochloride, CG 315) after the oral administration of Tramal capsules was determined in a balanced cross-over study in 10 male volunteers. Each volunteer received two single doses of 100 mg tramadol hydrochloride, one by oral (2 Tramal capsules) and one by intravenous route (2 ampoules of Tramal 50 solution for injection). The formulations were administered in the morning on an empty stomach, and the interval between the two applications was one week. Serum concentrations of tramadol were determined by gas chromatography-mass spectrometry and the bioavailability was ascertained by calculation of the areas under the serum concentration curves. The absolute bioavailability of tramadol in Tramal capsules was 68 +/- 13% (means +/- SD; n = 10) with a range of 41-84% and a 95% confidence interval of 55.0-79.2%. The areas under the serum concentration curves of tramadol hydrochloride (AUC) were 2488 +/- 774 ng X h/ml (p.o.) and 3709 +/- 977 ng X h/ml (i.v.). Peak serum concentrations of 280 +/- 49 ng/ml were reached 2 h after oral administration of two Tramal capsules; a serum concentration of 100 ng/ml (assumed as the threshold value for analgesic efficacy) was reached after 0.68 +/- 0.17 h and was maintained for 9.0 +/- 2.2 h. The half-life of absorption was 0.38 +/- 0.18 h and the lag-time 0.48 +/- 0.14 h. In the terminal phase the biological half-lives of tramadol were 5.1 +/- 0.8 h (p.o.) and 5.2 +/- 0.8 h (i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Helicobacter pylori: treatment with combinations of pivampicillin and tripotassium dicitrato bismuthate

Fifty Helicobacter pylori- (H. pylori) positive patients entered an open study and were assigned to one of four treatment regimens comprising: pivampicillin (500 mg b.d.) for 2 weeks +/- tripotassium dicitrato bismuthate (tablet or liquid form) for one month. The 14C-urea breath test was used to evaluate clearance (negative at the end of treatment) and eradication (negative at 1 month post-treatment) of H. pylori. Clearance rates were 20% (2/10) after pivampicillin alone, 86% (12/14) after tripotassium dicitrato bismuthate tablets (240 mg b.d.) plus pivampicillin, 67% (6/9) after tripotassium dicitrato bismuthate tablets (120 mg q.d.s.) plus pivampicillin, and 100% (13/13) after tripotassium dicitrato bismuthate liquid (120 mg in 5 ml q.d.s) plus pivampicillin. The eradication rates were 0% (0/10), 13% (2/15), 0% (0/11) and 54% (7/13), respectively. Combination of the results from the 2 tripotassium dicitrato bismuthate tablet/pivampicillin groups gave an eradication rate of 7.7% (2/26) which was significantly lower than the 53.9% (7/13) obtained with tripotassium dicitrato bismuthate liquid/pivampicillin (P less than 0.02). In conclusion, a liquid tripotassium dicitrato bismuthate pivampicillin combination may be of special use in the treatment of H. pylori-positive patients when triple therapy is contraindicated (e.g. patient sensitivity/allergy to metronidazole) or when the H. pylori isolate is resistant to metronidazole.     

Randomised trial of pivampicillin plus pivmecillinam vs. pivampicillin in children and young adults with chronic obstructive pulmonary disease and infection with Haemophilus influenzae

A prospective, randomised, single-blind comparative trial was carried out to determine whether double beta-lactam treatment with pivampicillin plus pivmecillinam is more effective than pivampicillin alone in the treatment of recurrent and chronic lung infections with Haemophilus influenzae in patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). Fifty-six children and young adults with COPD or CF were randomised to the clinical study. The patients were allocated at random to receive perorally either pivmecillinam, 40 mg/kg/day, combined with pivampicillin, 50 mg/kg/day, or pivampicillin 50 mg/kg/day alone for 14 days. A cross-over pharmacokinetic study using the same drugs was carried out in 10 CF patients to determine the antibiotic concentrations in serum and sputum after a single dose of each drug. The clinical study showed no significant differences in clinical scoring, lung function tests or adverse events after treatment with pivampicillin plus pivmecillinam or pivampicillin alone. Follow-up microbiological evaluation 2 and 6 weeks after the end of treatment showed that the offending pathogen was eradicated in 68% of the patients treated with pivampicillin plus pivmecillinam and in 67% of the patients treated with pivampicillin alone. Reinfection with another biotype was more common in the combination group (50% vs. 21%) than in the pivampicillin group. In the pharmacokinetic study the median peak serum concentration occurred two hours after intake of tablets. The efficacy of double beta lactam treatment in lung infections with H. influenzae appears to be equivalent to that of ampicillin on clinical lung symptoms, lung function tests, adverse effects and bacteriology.