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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.
Distribution of ampicillin, amoxicillin, bacampicillin, mecillinam, pivmecillinam, carbenicillin, indanyl sodium was studied in the canine prostate, prostatic interstitial fluid, and prostatic secretion. All seven antibiotics were found in higher concentrations in the prostatic interstitial fluid than in the prostatic secretion. As expected for weak acids, drug concentrations in these fluids were always lower than the simultaneous serum concentrations. Tissue penetration was enhanced for the penicillin ester, pivmecillinam, as shown by its prostatic secretion/serum and tissue/serum ratios, which were higher than those of the other antibiotics, including the esters, bacampicillin, and carbenicillin indanyl sodium. This results may be due to pivmecillinam's long hydrolysis half-life. The concentrations for these penicillanic acid derivatives in prostatic interstitial fluid were above the minimal inhibitory concentrations for most of the commonly encountered gram-negative bacteria encountered in prostatitis. Therefore, these antibiotics should be effective in the treatment of bacterial prostatitis caused by susceptible organisms. Carbenicillin and carbenicillin indanyl sodium had the highest prostatic interstitial fluid/serum ratios of the compounds tested, and theoretically, therefore, they should be the most effective in the treatment of prostatitis. However, clinical trials should be carried out to confirm this.
Long-term treatment with pivalic acid prodrug results in impaired ketone-body production. Therefore, it was of interest to investigate whether short-term treatment had any influence on the fatty acid oxidation. In this study six healthy males were given 1200 mg per day of pivmecillinam for 12 days to induce carnitine deficiency. The concentration of free carnitine in serum was reduced from a mean of 42.8 mumol/liter (range, 31-48) to 11.6 mumol/liter (range, 7.0-24), but the muscle carnitine concentration was not reduced. A 36-h fasting test was performed before and after drug administration to study the effect on ketone-body production. After treatment, the two subjects with the lowest level of serum free carnitine at the end of the fasting period had impaired ketogenesis. This indicates a carnitine deficiency in the liver which was reflected in the free carnitine concentration for by mobilization of muscle carnitine. We conclude that there is a substantial risk to develop carnitine deficiency and impaired fatty acid oxidation in the liver during short-term treatment with drugs conjugated with pivalic acid.
Treatment with pivalic acid containing prodrugs has been shown to cause carnitine depletion by loss of pivaloyl carnitine in urine. A 7-day standard pivmecillinam treatment of adults lead to a marked decrease of the free serum carnitine concentration (44.6 to 12.9 mumol/liter), whereas no change was seen in those given norfloxacine (40.0 to 40.5 mumol/liter). In some patients irrespective of age the free serum carnitine concentration was decreased to levels (around 10 mumol/liter) at which an impaired ketone-body production may occur. Therefore, there is reason for cautious use of this type of drug irrespective of the age of the patients.
The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (+/- SD) peak levels of plasma mecillinam were 1.43 +/- 0.34, 2.73 +/- 0.43, and 4.62 +/- 1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38 +/- 0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21 +/- 0.19, 3.99 +/- 0.63, and 7.74 +/- 1.38 mg . h. l-1 for bacmecillinam and 5.35 +/- 0.93 mg . h. l-1 for pivmecillinam. The elimination half-lives were 0.8-1.1 h for bacmecillinam and 0.7 h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p less than 0.001), AUC (p less than 0.001) and urinary recovery (p less than 0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p less than 0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.
Thirty-one cases of pivmecillinam-associated oesophagitis or ulceration verified at endoscopy have been reported in Sweden between 1978 and 1987. There were 29 women and two men of average age 30 years (range 15-77 years). Dysphagia and retrosternal pain often developed within the first days of treatment and resolved without complications within days of stopping treatment. Based on sales and prescription data, this complication appears to be rare, with 25-36 reported cases per million treatment courses. Further galenical development of the tablets and better patient information should reduce the number of patients injured.
Three different pivmecillinam preparations, a conventional 200 mg tablet (P tablet) and two new formulations containing respectively pivmecillinam 200 mg and 400 mg plus Avicel (microcrystalline cellulose) as a disintegrator (PA tablet), were compared in vitro and in a gastroscopic study in 8 healthy volunteers. Disintegration of the PA tablet was significantly more rapid both in vitro and in the stomach. Following disintegration, the content of the PA tablet was spread over a larger area of the gastric mucosa (1088 mm2) than was observed with the P tablets (408 mm2). Three of the 8 volunteers taking the P tablet developed hyperaemia, interstitial bleeding or erosions of the mucosa of the stomach. No such reactions were seen with the PA tablets. Serum concentrations of mecillinam following ingestion of pivmecillinam tablets were determined in three groups of subjects; fasting volunteers, both supine and ambulant, and in ambulant subjects who took the preparation with a light meal. There was a tendency for the new PA tablets to produce a higher peak serum level as well as greater bioavailability of mecillinam. Administration of the PA tablets with a meal significantly increased the peak serum level and total bioavailability of the drug. On the basis of our observations we recommend adoption of the new PA tablet, because of its quick passage through the oesophagus and its more rapid and complete disintegration in the stomach.
Forty-three patients with a history of recurrent urinary infections, many of whom had renal involvement and had recently failed treatment, were then treated with pivmecillinam (400 mg 8-hourly for seven days). One week after the end of treatment the bacteriological cure rate was 72.1%. During the following four weeks, however, several of the cured patients relapsed, so that the cure rate five weeks after the end of treatment was only 46%. Thus, it is recommended that such patients should begin prophylactic treatment if found to be abacteriuric after the one week follow-up. Pivmecillinam was extremely well tolerated.
Forty hospitalized patients with mostly uncomplicated urinary tract infections received treatment for ten days with either pivmecillinam/pivampicillin of pivmecillinam alone. The bacteriological cure rate immediately after therapy was discontinued was 82% (18/22) in the combination group and 72% (13/18) in the pivmecillinam group. The causative organisms were Enterobacteriaceae in 89% of the cases. All but one were sensitive in vitro to mecillinam alone. No side-effects were recorded.
Twenty-eight patients with chronic urinary tract infections were treated with 400 mg pivmecillinam orally three times daily for 10 to 15 days. The diagnosis was confirmed by a history of cystitis or cystopyelitis four to six times annually, microscopy of urine sediment, and growth of pathogens in urine specimens obtained by suprapubic bladder puncture. Three days, three and six weeks after completion of therapy the success rates were 24/28, 20/28 and 19/28 respectively. Pivmecillinam was well tolerated. Two patients developed nausea and vomiting. Other side-effects were not observed. Pivmecillinam is a useful drug in the treatment of chronic urinary tract infections.
In a randomized, double blind, placebo-controlled study 36 patients aged 16-77 years who had been carriers of nontyphi Salmonella species for 10-21 weeks were given the combination pivampicillin/pivmecillinam or placebo for four weeks in order to eradicate the carrier state. 34/36 patients who fulfilled the criteria for inclusion in the study were evaluable for efficacy, 16 in the pivampicillin/pivmecillinam group and 18 in the placebo group. Seven patients in the pivampicillin/pivmecillinam group had to terminate the treatment after 10-25 days because of adverse reactions, mainly exanthema and nausea. After therapy 8/16 patients treated with pivampicillin/pivmecillinam and 4/18 patients treated with placebo had negative stool cultures for Salmonella species during a mean follow-up time of 13 and 20 weeks, respectively. No abnormalities could be found in those patients who did not respond to therapy except for earlier cholecystectomy in two patients, both in the pivampicillin/pivmecillinam group.
A comparative trial of pivmecillinam and ampicillin was performed on 100 women with bacteriuria of pregnancy. They received either 400 mg pivmecillinam four times daily or 500 mg ampicillin four times daily for seven days. Cure rates at two weeks were 88% in the pivmecillinam group and 85% in the ampicillin group. At six weeks the respective rates were 76% and 64%. Failure of therapy was not associated with the appearance of bacterial resistance in either treatment group. Side-effects, particularly vomiting and premature cessation of therapy, were significantly more frequent in the pivmecillinam group. No significant effects on liver function were found. In subsequent patients treated in a non-comparative manner with 200 mg pivmecillinam three times daily, the incidence of side effects was markedly reduced with no loss of efficacy.
Thirty-nine patients with acute enteric fever received the fixed-dose oral combination of pivmecillinam/pivampicillin. Thirty-seven (95%) subjects responded satisfactorily. No relapses or persistent faecal excretion of salmonellae were seen in the 29 patients followed up for 2 to 19 weeks. The treatment was well tolerated, no side-effects being recorded. In vitro studies revealed a synergistic interaction between mecillinam and ampicillin against isolates of Salmonella paratyphi A.
Pivmecillinam is a new penicillin-like compound belonging to the so-called amidinopenicillins and characterized by a high antibacterial activity against Enterobacteriaceae and by demonstrated synergism when combined with other beta-lactam antibiotics. In this prospective trial geriatric patients with a stationary indwelling catheter and significant bacteriuria caused by Enterobacteriaceae were treated for four weeks with pivmecillinam, pivampicillin or various combinations of the two compounds. Urine specimens were obtained weekly, and in eight patients receiving pivmecillinam 75% of the urine samples were free from Enterobacteriaceae during the period of treatment. The figure was 91% in 24 patients receiving combination therapy. In seven patients treated with an equimolar dose of pivampicillin alone 43% and 23% of the urine specimens, controlled during the first and the second havles of the treatment period respectively, Enterbacteriaceae was eradicated. In this group there was a marked and increasing tendency towards infections caused by more resistant strains of Enterobacteriaceae as the treatment progressed. The latter is keeping with the observation that pivmecillinam, as opposed to ampicillin, apparently does not cause any selection of resistant Enterobacteriaceae in the faecal flora which is the main source of urinary pathogens.
Typhoid fever is an infectious disease with multisystem involvement and is commonly seen in the tropics. Twelve patients with acute typhoid fever were successfully treated with a fixed dose combination of pivmecillinam and pivampicillin. The treatment results were compared to those obtained from the treatment of ten other patients with co-trimoxazole, which is the routine treatment of our Department. The two forms of treatment appeared to be equally effective, suggesting that the combination mecillinam/ampicillin may represent a valuable alternative to the antityphoidal drugs currently available. Eleven patients were infected with strains resistant in vitro to either ampicillin, chloramphenicol, or both. All clinical isolates were sensitive to co-trimoxazole and to the combination of mecillinam and ampicillin. MIC values for the combination ranged from 0.16 to 2.5 mg/l. No side-effects were recorded.
Long-term treatment with pivampicillin and pivmecillinam for 6-24 months in five adults and one child reduced the total serum carnitine concentration to 3.7-14 mumol/l (reference value: 25-66 mumol/l). Muscle carnitine was reduced to 0.3-0.7 mumol/g wet weight (reference value: 3-5 mumol/g) in two cases. All patients had muscle symptoms with weakness, asthenia and pains. One showed signs of carnitine depletion in the liver with increased secretion of dicarboxylic acids (C6, C8, C10) in urine and limited ketone body formation during prolonged fasting. Serum carnitine increased slowly after cessation of therapy and reached normal concentrations after 6-12 months. All symptoms caused by carnitine depletion disappeared. This was achieved on a normal diet without carnitine supplementation.
A case of endomyometritis associated with Capnocytophaga ochracea bacteremia following premature delivery is described. The patient, a 30 year old woman without immunological incompetence or other predisposing disease, responded to peroral pivmecillinam. Capnocytophaga spp. should be considered a possible cause of post-partum endometritis.
The pharmacokinetic parameters of amdinocillin and pivamdinocillin were studied in 12 normal volunteers. Plasma amdinocillin concentrations were determined by microbiologic assay and urine concentrations by high performance liquid chromatography. Pharmacokinetic parameters were calculated by a two-compartment open model for the intravenous infusion and by a one-compartment model with zero-order absorption for the oral doses. The mean peak serum level after the intravenous infusion of 500 mg was 39 micrograms/ml. At one and a half hours after the oral administration of 250 mg and 500 mg doses, mean peaks were 1.93 and 2.66 micrograms/ml respectively. Half-life was one hour for all doses. Maximal plasma concentration did not increase proportionally with dose. Bioavailability was 45 percent after the 250 mg dose and 38 percent after the 500 mg dose.