Levels of amdinocillin in human plasma and interstitial fluid following intravenous administration.

Amdinocillin levels in human plasma and interstitial fluid were studied in 12 human volunteers. The results showed that relatively high levels of amdinocillin were detected in the interstitial fluid. The fluid to plasma ratio of the area under the curve was 0.25. This is consistent with high diffusibility as seen in drugs with a low percentage of protein binding.

Efficacy, pharmacology, and safety of amdinocillin in treatment of neonates.

One hundred and nine neonates with complications conducive to lethal infections were investigated to determine the efficacy, pharmacokinetics, and safety of amdinocillin. Of these 109 neonates, 70 were participants in the clinical study and 39 in the pharmacokinetic study. Amdinocillin (40 mg/kg per day) and penicillin (60,000 units/kg per day) were administered separately in divided doses by intramuscular injection at six-hourly intervals for five days. Amdinocillin/penicillin proved to be a safe and effective alternative to gentamicin/penicillin; no adverse reactions were noted nor did the regimen adversely affect renal or hepatic function. Throughout the treatment period, amdinocillin maintained high therapeutic serum levels. Resistance to amdinocillin did not develop during treatment.

Morphologic changes produced by amdinocillin alone and in combination with beta-lactam antibiotics: in vitro and in vivo.

Scanning electron microscopy was used to study the morphologic effects of amdinocillin (mecillinam) when combined with several beta-lactam antibiotics in vitro (Escherichia coli, three isolates; Klebsiella pneumoniae, one isolate) and also in vivo (E. coli, one isolate). Ovoid forms were found in the cultures of E. coli and K. pneumoniae following in vitro exposure to amdinocillin. This characteristic in vitro effect was also produced in the amdinocillin-treated E. coli-infected mouse. Varying degrees of filament formation were seen both in vitro and in vivo with the other beta-lactam antibiotics tested. The in vitro combination of amdinocillin with the beta-lactam antibiotics produced morphologic effects on E. coli and K. pneumoniae (enhanced cell distortion and lysis) not seen with the individual agents at the doses tested. Amdinocillin was synergistic with ampicillin, carbenicillin, and cephalothin in mice challenged with E. coli 736; scanning electron microscopy of bacteria from peritoneal lavages of mice treated with these synergistic combinations indicated that the organisms were more enlarged and distorted than those from animals receiving the individual agents. The enhanced morphologic effect observed in vivo was in agreement with the in vitro effect. Viable counts of bacteria recovered from mice treated with ampicillin plus amdinocillin were appreciably less than those from mice treated with each agent alone. The morphologic results from the scanning electron microscopy study point to a synergistic or enhanced effect of amdinocillin in combination with beta-lactam antibiotics and are in accord with prior reports of the synergistic effects of amdinocillin.

Mecillinam in cerebrospinal fluid in children.

The penetration of mecillinam, a new beta-lactam penicillin-like antibiotic, into cerebrospinal fluid (CSF) was investigated in 11 children in whom all but 1 was presumed to have non-inflamed meninges. 30 minutes after a single intravenous dose of 30mg/kg, a concentration of approximately 0.30 micrograms/ml was achieved in the CSF (corresponding mean serum concentration 75 micrograms/ml), and this level was maintained during the next 4 hours in spite of rapidly declining serum concentrations, indicating a slow equilibration of mecillinam over the blood-liquor barrier. 1 child with suspected inflamed meninges showed a much higher CSF level of 12.1 micrograms/ml. It is concluded that mecillinam, as is the case for other penicillins, apparently crosses non-inflamed meninges poorly.

Concentrations of mecillinam and ampicillin determined in serum and renal tissue: a single-dose pharmacokinetic study in patients undergoing nephrectomy.

A study was carried out to determine serum and renal tissue concentrations of antibiotics after a single intravenous injection of 1.0 g ampicillin plus 0.4 g mecillinam, given up to 4 hours before surgery, in 13 patients with normal or near normal kidney function who were undergoing nephrectomy. Both antibiotics showed higher tissue concentrations than the corresponding serum levels. The mean kidney:serum ratio was 2.4 for ampicillin and 1.4 for mecillinam. Serum half-lives were calculated to be 57 minutes for ampicillin and 52 minutes for mecillinam. Corresponding elimination half-lives in the kidney were 45 minutes and 44 minutes, respectively.

Serum concentrations and penetration into prostate of mecillinam and ampicillin.

The absorption of the two antibiotic pro-drugs pivmecillinam and pivampicillin was investigated in 10 patients with normal or slightly impaired renal function. After a therapeutic dose of 200 mg pivmecillinam plus 250 mg pivampicillin, the mean peak concentration in serum was 2.3 micrograms mecillinam and 5.3 micrograms ampicillin per ml. The elimination half-life was approximately 2 hours for both antibiotics. Consequently, a ratio of 2:5 was maintained in serum during the excretion period and this ratio is within the range where optimal synergistic effect between the two antibiotics against many Gram-negative organisms is most likely to occur. Penetration of mecillinam and ampicillin into the prostate, determined in tissue homogenate obtained from 10 patients undergoing transurethral resection of the prostate showed that the antibiotics penetrated equally well with a serum tissue ratio of approximately 2:1.

Determination of bacmecillinam, an amdinocillin prodrug, in human and canine whole blood by reversed-phase liquid chromatography.

Bacmecillinam is an amdinocillin prodrug designed to be easily hydrolyzed in biological materials, so special procedures were developed for the collection of blood specimens. Whole blood was collected in tubes containing bacampicillin as an adsorption inhibitor and kept at -70 degrees; the extracting solvent, hexane-methylene chloride (9:1, v/v), was added to the cold tubes, and the extraction was performed during the thawing of the samples. The organic phase was partially evaporated before a reextraction to a small volume of acidic aqueous phase was made. The separation was performed on a microparticulate. C18-alkyl bonded silica packed in glass-lined stainless steel columns. Mobile phase was a buffer (pH 6)-acetonitrile mixture containing N-hexyl-N-methylamine as an adsorption inhibitor. The detection limit was 600 pg/ml of whole blood, and the within-run precision (srel%) was approximately 8% at the 5-ng/ml level.

Pharmacokinetics of mecillinam after a single intravenous dose in patients with impaired renal function.

Twelve male patients with impaired renal function and six healthy male volunteers were given a single i.v. dose of mecillinam (400 mg). Serum concentrations of mecillinam were determined by a microbiological assay. The pharmacokinetic parameters were obtained using an open, two-compartment model. Results showed that the median elimination t 1/2 (beta) of mecillinam was longer in patients (5 h) than in volunteers (3.4 h) (p less than 0.1). The median AUC0----infinity was greater in patients (72.44 micrograms ml-1.) than in volunteers (32.96 micrograms ml-1 X h) (p less than 0.001). Moreover, the median clearance was decreased in patients (5.5 L h-1) as compared with volunteers (12.17 L h-1) (p less than 0.001). Thus the study showed prolonged half-life and decreased elimination of mecillinam in patients with impaired renal function.

[Absorption, distribution, metabolism and excretion of bacmecillinam. I. Absorption, distribution, metabolism and excretion of 14C-bacmecillinam following oral administration to rats].

The pharmacokinetics of bacmecillinam (KW-1100), a new semisynthetic penicillin, was studied. Plasma levels, tissue distribution, metabolites and urinary and biliary excretion of mecillinam after oral administration of KW-1100 were studied in rats given a dose of 20 mg/kg (as mecillinam). The absorption of 14C-KW-1100 was so rapid that the level in blood was found to reach the peak 30 minutes after administration. 14C-KW-1100 was distributed widely into various tissues and relatively high distribution was noted in liver, kidney, adrenal gland and spleen. No accumulation of 14C-KW-1100 in any tissue was found. It was excreted rapidly from each tissue. Within 24 hours after administration of KW-1100, approximately 86% of the given dose was excreted. And within 72 hours, approximately 97% of the dose was excreted. Excretions in urine and feces within 72 hours after KW-1100 administration were 39.5 and 57.4% of the given dose, respectively. Biliary excretion was 2.0% of the given dose within 24 hours after administration of KW-1100. The major metabolite in the plasma at peak time (30 minutes) was mecillinam (50.5%). The major metabolite in the urine (0 approximately 8 hours) was mecillinam (52.2%), too. The minor metabolites were 5,5-dimethyl-2-(1'-formamidomethyl)-thiazolidine-1',4-dicarboxylat e(M-1), 6-beta-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicilloic acid (M-6) and M-4.

[Studies on the drug permeability of vesical walls. The permeability of mecillinam from the bladder].

When a drug is instilled into the bladder provided with experimental cystitis, the drug could be transferred into the serum. We studied the transfer of mecillinam into the serum, and found that the extent of transfer varied with the method to cause experimental cystitis and also occurred even in the normal bladder. It was suspected that in the inflamed bladder, a part of mecillinam excreted into the urine would possibly be transferred again into the serum through bladder wall.

Dialyzability of cefotaxime and mecillinam.

The dialyzability of cefotaxime and mecillinam was studied in 20 patients with end-stage renal failure maintained on regular hemodialysis in the Ain Shams Dialysis Unit. Cefotaxime was found to be a dialyzable antibiotic with a hemodialysis clearance rate of 60.3 +/- 10.4 ml/min. Mecillinam was found to be more dialyzable, with a clearance rate of 118.8 +/- 14.4 ml/min.

Determination of amdinocillin in plasma and urine by high-performance liquid chromatography.

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.

Serum levels of mecillinam in patients with severely impaired renal function.

12 patients with severe renal insufficiency were treated for urinary tract infection with 400 mg of mecillinam intravenously every 6 h. High serum concentrations of mecillinam were found 6 h after the first morning dose on day 2 and day 5 of the treatment period (mean values 11.4 and 14.5 microgram/ml respectively), and a serum half-life of 334 min. In spite of reduced elimination of the drug, a nearly steady state was achieved within the first few days of treatment. Side effects were not observed.

Influence of food on bioavailability of amdinocillin pivoxil.

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.

The pharmacokinetics of mecillinam and pivmecillinam in pregnant and non-pregnant women.

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)

Ceftazidime combined with mecillinam: serum bactericidal titres compared with in-vitro synergy against gram-negative bacilli.

In a study of the possible interaction between mecillinam and ceftazidime against Gram-negative bacilli, ten volunteers received on separate days: ceftazidime 20 mg/kg iv in 15 min, mecillinam 10 mg/kg iv in 15 min, or the combination. Blood samples were obtained before and 1 and 6 h after the end of the infusion. Ten strains each of Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Salmonella spp. and Yersinia spp. and nine strains each of Acinetobacter spp., and Pseudomonas aeruginosa were selected. Most of the strains were resistant to ampicillin and cefazolin. Serum levels of ceftazidime and mecillinam were measured by bioassay. Serum bacteriostatic (SBS) and bactericidal (SBA) titration was done in microtitre plates in cation supplemented Mueller-Hinton broth and 50% human serum. Chequerboard titration was also studied to assess in-vitro synergy between ceftazidime and mecillinam in Mueller-Hinton broth with or without 50% serum. The mean serum concentrations (SD) were for mecillinam: 6.1 (1.7) at 1 h, and less than 0.3 at 6 h and for ceftazidime: 36.3 (5.5) at 1 h and less than 5 at 6 h. Identical concentrations were measured for the combination. By chequerboard titration, no synergy occurred for Acinetobacter spp. and Ps. aeruginosa, whereas it was observed in 37/60 (FIC) and 33/60 (FBC) of the strains of other species in Mueller-Hinton; from the strains showing synergy, 28/37 (FIC) and 30/33 (FBC) showed also synergy in Mueller-Hinton with 50% human serum. In SBS and SBA, on the other hand, the combination of mecillinam with ceftazidime showed an additive effect against most Enterobacteriaceae tested, synergy being shown for only 10-35% of tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of mecillinam in calves.

The minimal inhibitory concentrations (MIC) of mecillinam, a novel beta-amidinopenicillanic acid derivative with unusual activity against Gram-negative bacteria, were compared with the MIC of cephazolin, cephalothin, amoxycillin, oxytetracycline, chloramphenicol, dihydrostreptomycin, neomycin, kanamycin, gentamicin and sulfadoxin/trimethoprim (TMP) against pathogenic Gram-negative bacteria recovered from neonatal calves. The MIC values of mecillinam ranged between 0.05 microgram/ml and 12.5 micrograms/ml, and the MIC90 values were 1.56 micrograms/ml and 3.12 micrograms/ml. The activity of mecillinam against salmonella, Escherichia coli and Pasteurella multocida was similar to or slightly greater than the activities of the first-generation cephalosporins, gentamicin and sulfa/TMP. Mecillinam concentrations less than or equal to 3.12 micrograms/ml inhibited the growth of the majority of isolates which were resistant (MIC90 greater than 100 micrograms/ml) to the other antibiotics studied. The minimum bactericidal concentration (MBC) values of mecillinam were two- to three-fold higher than the MIC values. The two-compartment open model was appropriate for the analysis of serum mecillinam concentrations measured after intravenous administration. The distribution half-life (t1/2 alpha) was 11.7 min, the elimination half-life (t1/2 beta) was 53.3 min, and the apparent volume of distribution (Vd (area)) and the distribution volume at steady state (Vd (ss)) were 0.568 and 0.896 l/kg, respectively. The drug was quickly absorbed after intramuscular (i.m.) injection; peak serum drug concentrations were directly related to the dose administered. They were obtained 30 min after treatment and the i.m. t1/2 was approximately 65 min.(ABSTRACT TRUNCATED AT 250 WORDS)