Carnitine deficiency induced by pivampicillin and pivmecillinam therapy.

Short-term administration of pivampicillin and pivmecillinam resulted in a reduction of serum carnitine concentration and an increase in excretion of acylcarnitine in urine. These changes persisted for more than ten days after cessation of therapy. In seven girls on long-term treatment with a mixture of pivampicillin and pivmecillinam the mean total serum carnitine concentration fell to 15% (7-27%) of pretreatment values. The acylcarnitine fraction was 11-57% of total carnitine, compared with less than 2% before treatment. Muscle carnitine concentrations in two girls treated with the antibiotics for 22 and 30 months were only 10% of the mean reference value. These concentrations in serum and muscle are in the range encountered in patients with carnitine deficiencies of other aetiologies in which life-threatening metabolic crises may arise. The risk of adverse effects from prodrugs that give rise to pivalic acid should be seriously considered, particularly in patients under metabolic stress.

Oesophageal injury associated with pivmecillinam tablets.

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.

Amdinocillin: a novel penicillin. Antibacterial activity, pharmacology and clinical use.

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.

Amdinocillin plus cefoxitin versus cefoxitin alone in therapy of mixed soft tissue infections (including diabetic foot infections).

In a randomized comparative trial, 45 patients were treated with amdinocillin plus cefoxitin or cefoxitin alone for bacterial soft tissue infections. Most patients were diabetic and had polymicrobial foot infections. The combination of amdinocillin plus cefoxitin was active in vitro against 71 percent of the isolates obtained before therapy as compared with 65 percent for cefoxitin alone. The combination demonstrated synergy for 29 percent of the isolates tested. A satisfactory clinical response occurred in 90 percent and 71 percent of patients treated with the combination regimen and cefoxitin, respectively, (p greater than 0.1). An increase in serum creatinine thought to be due to interstitial nephritis occurred in one patient treated with the combination regimen. The combination of amdinocillin and cefoxitin was effective in mixed soft tissue infections including diabetic foot infections.

Efficacy of amdinocillin and lack of nephrotoxicity when combined with a second beta-lactam antibiotic for therapy of serious gram-negative bacillary infections.

Seventy-eight patients with serious gram-negative bacillary infections were assigned at random to receive either amdinocillin or an aminoglycoside. In addition, each patient was also given a broad-spectrum penicillin or cephalosporin antibiotic. The clinical response to treatment was comparable in the two groups. Cures were effected in 35 (92 percent) of 38 patients treated with amdinocillin and a beta-lactam antibiotic, compared with 37 (93 percent) of 40 patients who were treated with an aminoglycoside/beta-lactam combination. For the entire group, only five (7 percent) of the 75 infecting organisms were resistant in vitro to the treatment beta-lactam or amdinocillin combination, and similarly only two (3 percent) organisms were resistant to the treatment aminoglycoside (p = 0.44). Although drug-related toxicity occurred with equal frequency in the two groups, six patients treated with an aminoglycoside experienced nephrotoxicity compared with none of the patients who received amdinocillin (p = 0.034). Thus, amdinocillin plus a broad-spectrum beta-lactam antibiotic may provide suitable empiric therapy for many patients with presumed gram-negative infection and so avoid the risk of aminoglycoside-induced nephrotoxicity.

Amdinocillin: use alone or in combination with cefoxitin or carbenicillin-ticarcillin.

One hundred fifty-five patients with 157 febrile episodes were treated with amdinocillin or amdinocillin and cefoxitin as second-line therapy, or amdinocillin and ticarcillin or carbenicillin as initial therapy in three separate studies. Overall responses were 57 percent, 55 percent, and 54 percent for amdinocillin, amdinocillin-cefoxitin, and amdinocillin-ticarcillin or amdinocillin-carbenicillin, respectively. In all three studies, patients with septicemia responded less often than patients with other infections. Most patients were profoundly neutropenic at the initiation of therapy, and both the initial neutrophil level and neutrophil trend during therapy influenced response. A significant number of superinfections occurred when amdinocillin alone was used. Although amdinocillin, alone or in combination with cefoxitin, appeared effective as second-line therapy in infections with organisms shown sensitive in vitro, the combination of amdinocillin and ticarcillin or carbenicillin was only moderately effective in initial therapy for neutropenic, febrile, cancer patients.

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.

Randomized trial of cefamandole plus amdinocillin versus cefamandole in serious pediatric infections.

In a randomized, prospective clinical trial cefamandole therapy was compared with cefamandole plus amdinocillin in infants and children with suspected bacterial infections. Fifty-two infections in 50 patients with bone and joint (19 infections), pulmonary (19 infections), soft tissue (eight infections), and urinary tract (6 infections) diseases were treated. Bacterial infection was documented in 31 patients. All isolates were susceptible to cefamandole except one strain of Serratia marcescens, which was susceptible to the combination. In vitro synergy was demonstrated in all coliform bacilli, in three of seven Haemophilus strains, and in six of 16 gram-positive cocci. No correlation between degree of serum bactericidal activity and presence or absence of synergy could be demonstrated. One patient treated with cefamandole died; all other patients responded promptly to therapy without serious adverse drug effects.

Management of enteric fever with amdinocillin.

Twenty-six patients with enteric fever treated with amdinocillin and/or its pivaloyloxymethyl ester in 1975 to 1978 were compared with 21 patients with enteric fever treated with trimethoprim-sulfamethoxazole in 1972 to 1974. Diagnosis was based on clinical illness and isolation of Salmonella typhi or S. paratyphi A/B from blood cultures or stool cultures. The dosage of pivamdinocillin in adults was 400 to 800 mg, every 6 hours, for 10 to 16 days; dosage in children was half this amount for 11 to 15 days. Of the 21 patients treated with trimethoprim-sulfamethoxazole, 18 (86 percent) showed a satisfactory clinical response; 13 of these 18 had negative stools immediately after therapy, and two more were negative at the time of discharge (total: 83 percent). Mean hospital stay of these patients was 34.5 days. Of the 26 patients treated with amdinocillin, 23 showed a satisfactory clinical response; 20 of those responding clinically were still excreting the causative organism at the end of therapy; seven of the group remained as convalescent patients who continued to excrete the causative organism in feces at the time of discharge. Mean hospital stay was 43 days. The results of initial trials of amdinocillin and ampicillin in combination suggest that such therapy may be preferable to use of amdinocillin alone, although the excretion of the causative organism during convalescence has not been adequately assessed.

Parenteral amdinocillin for treatment of complicated urinary tract infections.

Amdinocillin was administered to 55 male and female patients with complicated urinary tract infections. Forty-eight of these patients (28 men and 20 women) were evaluated to determine the safety and efficacy of amdinocillin. Therapy was instituted intravenously and concluded intramuscularly for a total of 7.8 mean therapy days. Toxicity was negligible and side effects were limited to presumed penicillin-allergic reactions. Escherichia coli was the infecting organism in 60 percent of the patients. In 79 percent of the patients, the infections were cured during therapy and from five to nine days following therapy. It was concluded that amdinocillin is a satisfactory antibiotic for the treatment of complicated urinary tract infections with susceptible organisms.

Combination amdinocillin and cefoxitin therapy of multiply-resistant Serratia marcescens urinary tract infections.

Amdinocillin has previously been shown to be synergistic with other beta-lactam antibiotics against many gram-negative bacteria. We evaluated the safety, efficacy, and microbiologic activity of combination amdinocillin and cefoxitin treatment in 17 patients with complicated urinary tract infections caused by multiply-resistant Serratia marcescens. Patients were treated with amdinocillin, 40 mg/kg per day, and cefoxitin, 100 mg/kg per day, for five to 14 days. In vitro synergistic activity was observed for 17 isolates using broth checkerboard testing and for nine isolates using combination disc diffusion testing. Of the 17 patients treated, 11 were bacteriologically cured, one failed to respond, and five patients had a relapse after initial improvement. Relapses followed short-duration therapy. Amdinocillin with cefoxitin was well tolerated. Combination amdinocillin and cefoxitin therapy was efficacious and safe in treating complicated urinary tract infections caused by multiply-resistant S. marcescens.

Systemic infections treated with amdinocillin in combination with other beta-lactam antibiotics.

Amdinocillin is a semisynthetic derivative of 6-beta-amidinopenicillanic acid, which has bactericidal activity against a broad spectrum of gram-negative bacteria. We report the results of a multicenter study evaluating the safety and efficacy of amdinocillin in combination with other beta-lactam antibiotics in the treatment of 120 serious gram-negative bacterial infections. Amdinocillin was safe and well tolerated and, in combination with other beta-lactam antibiotics, was effective in the treatment of a broad range of gram-negative bacterial infections. Therapy with amdinocillin and other beta-lactam antibiotics was often associated with a demonstrable synergistic effect. Thus, amdinocillin holds promise as an effective antibiotic with synergistic potential when used in combination with penicillins and cephalosporins.

Amdinocillin in combination with beta-lactam antibiotics for treatment of serious gram-negative infections.

Amdinocillin in combination with another beta-lactam antibiotic (ampicillin, cephalothin, cefamandole or cefoxitin) was used to treat 25 patients with pyelonephritis (with or without bacteremia), pneumonia, bacteremia secondary to intravenous devices, and urinary tract infections (with catheter in place) due to gram-negative organisms. The combination resulted in a clinical response in 96 percent of the patients and a bacteriologic response in 100 percent at 72 hours. Few toxic effects were seen. At long-term follow-up, relapse occurred in three of 10 patients with pyelonephritis who were treated with a combination regimen and completed their course of antimicrobial therapy with a beta-lactam antibiotic. Reinfection occurred in one patient who had a urinary tract infection with a catheter in place. In vitro testing showed that the cefamandole-amdinocillin combination most frequently produced synergy against the strains of Escherichia coli isolated. Synergy with the antibiotic combinations was also seen against strains of Klebsiella pneumoniae. It was difficult to correlate the in vitro test results with the in vivo therapeutic effect of these antibiotic combinations.

Pharmacokinetics of amdinocillin in healthy adults.

The pharmacokinetics of amdinocillin (mecillinam) were determined in 10 healthy volunteers. Single doses of 10 and 15 mg/kg of body weight were administered intravenously and intramuscularly in a crossover study. Plasma concentrations of amdinocillin were determined by microbiological assay. Mean peak plasma concentrations were 49 and 87 micrograms/ml after intravenous doses of 10 and 15 mg/kg, respectively. The terminal half-life value of 0.89 h was similar for both doses. After intramuscular injections, the mean concentration of drug in plasma was 26.2 micrograms/ml for the 10-mg/kg dose and 29.6 micrograms/ml for the 15-mg/kg dose, with terminal half-lives of 0.96 and 0.86 h, respectively. The mean apparent volumes of distribution at steady state were 18 and 16 liters/100 kg for the intravenous doses of 10 and 15 mg/kg, respectively. Drug concentrations in plasma at 4 h were above the minimal inhibitory concentrations for gram-negative organisms categorized as susceptible to this drug.

[Comparative study on clinical effectiveness of mecillinam and pivmecillinam versus ampicillin in acute urinary infections (author's transl)]. / Vergleich klinischer Wirksamkeit von Mecillinam und Pivmecillinam gegenüber Ampicillin bei Harnwegsinfekten.

30 outpatients suffering from acute urinary infections underwent oral treatment with pivaloyloxymethyl-(2S,5R,6R)-6-(perhydroazepin-1-ylmethylenamino)penicillinate (pivmecillinam) (n = 15) or ampicillin (n = 15) in a first study. In a second study 6-beta-(hexahydro-1H-azepin-1-yl)-methylenamino penicillanic acid (mecillinam) (n = 16) or ampicillin (n = 14) were applied i.v. to 30 patients with pretreated urinary infections. The tolerance of the drugs proved to be comparatively good in both studies. The clinical and antibacterial effectiveness were equally good in the first study. However, in the second study the effectiveness of mecillinam However, in the second study the effectiveness of mecillinam seemed to be comparatively inferior.