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Healthy adult volunteers received 1 g of sulphamethizole orally (n = 10) and later 400 mg of pivmecillinam (274 mg of mecillinam) (n = 9). All urine was collected in defined periods over 24 h, and the drug concentrations in urine were determined. For sulphamethizole, the maximum urine concentration for seven subjects was reached in 0-3 h, and for the remaining three in 3-6 h. For mecillinam, eight of the nine subjects attained a maximum urine concentration in 0-3 h, after which the concentration declined rapidly for six subjects in 3-6 h. Strains of Escherichia coli with different MICs for sulphamethizole and mecillinam were exposed to collected urine for 2.5 h and 5 h. The results indicated that a sensitive E. coli population should be suppressed by sulphamethizole in urine for two-thirds of the time (with 1 g twice-daily) and by mecillinam in urine throughout the 24-h period (with 400 mg three times a day). There was a slight but significant correlation between the ex-vivo effect (Delta log10 CFU/mL) and the log10 concentration/MIC ratio after exposure to sulphamethizole for 5 h (r2 = 0.27, p < 0.0001), and a significant correlation between the variables with mecillinam (r2 = 0.66, p < 0.0001).

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1. The pharmacokinetics of parenteral mecillinam (n = 27) and oral pivmecillinam (n = 12) were studied in pregnant (n = 27) and non-pregnant (n = 12) subjects. 2. In early pregnancy (9-14 weeks of gestation) the mean peak plasma drug concentration (Cmax = 19 +/- 9 micrograms ml-1) after an intravenous injection of 200 mg mecillinam was significantly lower (P less than 0.05) and the volume of distribution (V = 49 +/- 20.1) significantly larger (P less than 0.05) than in non-pregnant subjects (Cmax = 35 +/- 18 micrograms ml-1, V = 29 +/- 12.1). In late pregnancy (39-40 weeks of gestation) the plasma mean peak concentration (Cmax = (29 +/- 14 micrograms ml-1) after parenteral administration of 200 mg mecillinam was slightly lower and the volume of distribution (V = 65 +/- 29.1, V = 0.9 +/- 0.4 l kg-1) significantly larger than that in non-pregnant subjects (V = 0.4 +/- 0.3 l kg-1). Also after oral administration of 200 mg pivmecillinam, equimolar to 136.5 mg mecillinam, the mean peak plasma concentration in pregnant subjects (Cmax = 1.8 +/- 1.2 micrograms ml-1) was slightly lower than that in non-pregnant subjects (Cmax = 1.7 +/- 1.2 micrograms ml-1). 3. The mean half-life of elimination after parenteral administration of mecillinam was significantly longer during both early (t1/2,Z = 133 +/- 38 min, P less than 0.05) and late pregnancy (t1/2,Z = 107 +/- 41 min, P less than 0.05) as compared with the non-pregnant state (t1/2,Z = 75 +/- 21 min).(ABSTRACT TRUNCATED AT 250 WORDS)

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The bioavailability of amdinocillin was not altered when amdinocillin pivoxil was ingested 1 h before a standard breakfast, and it increased by 20% when amdinocillin pivoxil was ingested with or 1 h after a standard breakfast. Amdinocillin pivoxil would be convenient for patients since it may be taken with or without food.

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The maintenance of effective therapeutic concentrations of antibiotics within the renal parenchyma is an important issue in the management of acute and chronic pyelonephritis. Available clinical data indicate that an important clinical-therapeutic correlation exists between the physiologic state of the kidney and the antibiotic concentrations that can be achieved in the medulla and papilla. Using a healthy canine model, we evaluated the influence of hydration and the state of acid-base balance upon the intrarenal distribution and urinary clearance of the semisynthetic penicillin amdinocillin. Renal physiologic activity significantly modulates the intrarenal distribution pattern of this compound. During the production of maximally acid and concentrated urine, the highest renal parenchyma levels of amdinocillin are achieved. During the latter circumstances the antibiotic undergoes distal tubular nonionic diffusion, which appears to be an important contributing factor to the high medullary and papillary concentrations of the drug. Nonetheless, at all levels of tested renal physiologic activity tissue and urine drug concentrations are adequate for the treatment of sensitive urinary pathogens.

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Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14- to 18-h period. Although the clearance from plasma and the half-life of amdinocillin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis.

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The pharmacokinetics (i.e., blood level, biological half-lives and excretion) of bacmecillinam (KW-1100) was investigated. KW-1100 was orally administered to dogs at the dose of 20 mg/kg (as mecillinam). Biological half-lives (radioactivity) of 14C-KW-1100 in plasma were 1.2 hours (T1/2 alpha) and 52 hours (T1/2 beta). The Cmax and Tmax were 8.4 micrograms/ml and 2 hours. The biological half-life (microbiological activity) of KW-1100 in plasma was 0.9 hour. The Cmax and Tmax were 5.6 micrograms/ml and 1 hour. The urinary and fecal excretion of 14C-KW-1100 were approximately 46% and 49% (0 approximately 72 hours), respectively. The major metabolites in the urine (0 approximately 8 hours) were mecillinam, 5,5-dimethyl-2-(1'-formamidomethyl)-thiazolidine-1',4-dicarboxy lat e (M-1) and 6-beta-[(hexahydro-1 H-azepin-1-yl)-methyleneamino]penicilloic acid (M-6), each distribution ratio of which was 57.2, 24.2 and 12.0% of the total radioactivity in the sample, respectively. The major metabolite in the plasma at peak time (2 hours) was mecillinam (56.2%).

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Bacmecillinam (KW-1100) metabolites and their excretion in human urine were investigated in the 3 male volunteers. After administration of KW-1100 capsules containing 80 mg (2 X 40 mg) as mecillinam to men, the urine samples up to 8 hours were collected for every 2 hours and analysed by high performance liquid chromatography and gas chromatography. The major metabolites in the human urine were mecillinam and 6-beta-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicilloic acid (M-6), and minor quantities of M-4 and M-1 were also detected as the metabolites. Total recoveries of administered dose for the 3 volunteers were approximately 62, 81 and 73%, respectively. And M-1 excretion rate was lower than that in the case of rats and dogs. Hexamethyleneimine (HMI) as metabolite from the side chain was detected.

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Amdinocillin is a novel penicillin whose antibacterial activity is derived from its ability to bind specifically and avidly to Penicillin Binding Protein-2 (PBP 2). Other beta-lactams bind almost exclusively to PBPs 1 and 3. This unique feature has prompted many investigators to predict that amdinocillin would aggressively synergize with other antimicrobials, particularly other beta-lactams. Certain features of these predictions have been realized. Amdinocillin is active alone against many gram-negative organisms. Pseudomonas and non-fermenting gram-negative bacteria, however, are usually resistant. Amdinocillin, in combination with many beta-lactams, exhibits marked synergy against many enterobacteriaceae. No such synergy can be demonstrated for gram-positive organisms or pseudomonas species. Amdinocillin is not beta-lactamase stable. Organisms which produce high levels of plasma-mediated beta-lactamase are resistant to the drug. Amdinocillin is widely distributed to most tissues of the body. It is removed by renal tubular secretion which results in prodigious levels of the drug in the urine. Co-administration of probenecid results in markedly elevated plasma levels of amdinocillin and delays its excretion. Amdinocillin has a plasma half-life of about one hour in patients with grossly normal renal function. Its half-life increases to 3 to 6 hours in anephric patients. The spectrum of adverse reactions observed with amdinocillin is similar to that of other penicillins. Amdinocillin, as a single agent, is effective in the treatment of urinary tract infections caused by susceptible strains of E. coli and klebsiella and enterobacter species. When amdinocillin is used in concert with other antimicrobials, synergy can frequently be demonstrated but it is essentially limited to gram-negative aerobic organisms. At present, insufficient data are available to precisely profile the utility of amdinocillin, either alone or in combination, in the treatment of systemic infections.

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A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the determination of amdinocillin (formerly mecillinam) in human plasma and urine. The assay is performed by direct injection of a plasma protein-free supernatant or a dilution of urine. A 10 micrometer muBondapak phenyl column with an eluting solvent of water--methanol--1 M phosphate buffer, pH 7 (70:30:0.5) was used, with UV detection of the effluent at 220 nm. Azidocillin potassium salt [potassium-6-(D-(-)-alpha-azidophenyacetamido)-penicillanate] was used as the internal standard and quantitation was based on peak height ratio of amdinocillin to that of the internal standard. The assay has a recovery of 74.4 +/- 6.3% (S.D.) in the concentration ranges of 0.1-20 microgram per 0.2 ml of plasma with a limit of detection equivalent to 0.5 microgram/ml plasma. The urine assay was validated over a concentration range of 0.025-5 mg/ml of urine, and has a limit of detection of 0.025 mg/ml (25 microgram/ml) using a 0.1-ml urine specimen per assay. The assay was applied to the determination of plasma and urine concentrations of amdinocillin following intravenous administration of a 10 mg/kg dose of amdinocillin to two human subjects. The HPLC and microbiological assays were shown to correlate well for these samples.

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We investigated the effect of tissue and urine concentrations of ampicillin and mecillinam on bacterial bladder wall adherence in rats. Escherichia coli 02 labeled with 3H-1-leucine was inoculated into the bladder for 2 hr. With the ureters transected bilaterally, antibiotic was instilled into the bladder lumen or administered intravenously only. No bacteria survived after the presence of antibiotic in the bladder lumen for 1.5 hr. After intravenous administration of ampicillin, with no antibiotic in the bladder lumen, measured by viable counts, decreased significantly as compared to controls. Adherence, measured by radioactive counts, decreased significantly after intravenous administration of mecillinam, possibly indicating prevention of tissue invasion. This finding was explained by entrapment of bacterial debris in the bladder lumen and invasion of bacteria into the bladder wall. Our results support the importance of tissue concentrations in the treatment of urinary tract infections.

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Mecillinam is an amidino penicillinate derivative with a broad spectrum of activity against many gram-negative bacilli. Moreover, marked in vitro synergy against these organisms occurs when mecillinam is combined with other beta-lactam antibiotics. The purpose of this study was to determine the pharmacokinetic disposition of this antibiotic. A single dose of 10 mg/kg was administered to 12 healthy volunteers as a 15-min intravenous infusion. Multiple plasma and urine samples were collected at frequent intervals for 8 and 24 h, respectively. Plasma samples were assayed for mecillinam by using a specific high-pressure liquid chromatographic assay developed in our laboratory. Peak plasma levels ranged from 34 to 80 micrograms/ml, and after 4 h, plasma levels were 0.7 to 1.9 microgram/ml. The mean terminal plasma half-life was 51.1 +/- 8.6 min. The mean steady-state volume of distribution was calculated to be 0.23 +/- 0.04 liter/kg. The mean plasma and renal clearances were 3.5 +/- 0.4 and 2.5 +/- 0.4 ml/min per kg, respectively. The mean percentage of the dose excreted unchanged in the urine at 4 h was 67 +/- 5%; 71 +/- 6% was recovered in 24 h. Urine concentrations at 4 h were far above the minimum inhibitory concentration for susceptible gram-negative organisms.

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Mecillinam is a new amidinopenicillin which is taken orally as its ester pivmecillinam. 10 healthy volunteers were each given 200 mg of pivmecillinam hydrochloride four times daily and all urine was collected and cooled to -20 degrees C to minimize antibiotic degradation. 43% of the ingested antibiotic was recovered from the urine in its microbiologically active form, during the first 12 h and 34% during the subsequent 24 h. The corresponding figures for 10 volunteers receiving double this dose of antibiotic was 30 and 34%. The mean half life of mecillinam in urine due to spontaneous breakdown at 37 degrees C was 17 h. There was evidence that stearate-film-coated pivmecillinam hydrochloride tablets may be less likely to cause dyspepsia than gelatine capsules.

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