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Pharmacotherapy 1985Amdinocillin is a novel penicillin whose antibacterial activity is derived from its ability to bind specifically and avidly to Penicillin Binding Protein-2 (PBP 2).... (Review)
Review
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.
Topics: Amdinocillin; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Synergism; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Hydrolysis; Kinetics; Maternal-Fetal Exchange; Microbial Sensitivity Tests; Penicillin G; Pregnancy; Tissue Distribution; beta-Lactamases
PubMed: 3885172
DOI: 10.1002/j.1875-9114.1985.tb04448.x -
Annals of Internal Medicine Sep 1984
Topics: Amdinocillin; Bacterial Infections; Enterobacteriaceae; Humans; Penicillanic Acid
PubMed: 6087706
DOI: 10.7326/0003-4819-101-3-389 -
The American Journal of Medicine Aug 1983Amdinocillin has been shown to have broad coverage in vitro against many strains of Enterobacteriaceae. Synergy has been demonstrated in vitro with several other... (Review)
Review
Amdinocillin has been shown to have broad coverage in vitro against many strains of Enterobacteriaceae. Synergy has been demonstrated in vitro with several other beta-lactam antibiotics. The rabbit model of meningitis was used to study the in vivo effectiveness of amdinocillin when combined with other beta-lactams for serious infections. Organisms that showed an enhanced in vitro bactericidal effect from the combination of amdinocillin and another beta-lactam showed more rapid elimination of the organisms in vivo.
Topics: Amdinocillin; Animals; Anti-Bacterial Agents; Bacterial Infections; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Escherichia coli Infections; Klebsiella Infections; Klebsiella pneumoniae; Meningitis; Penicillanic Acid
PubMed: 6311005
DOI: 10.1016/0002-9343(83)90093-1 -
The American Journal of Medicine Aug 1983Activity against gram-negative bacilli and frequent synergism with other beta-lactam antibiotics were demonstrated by amdinocillin in urinary tract infections,... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial Review
Activity against gram-negative bacilli and frequent synergism with other beta-lactam antibiotics were demonstrated by amdinocillin in urinary tract infections, urosepsis, and in a variety of other infections. In a prospective study, 299 patients were assigned at random to receive amdinocillin or another antibiotic considered standard treatment for the infection. The majority of infections were of the urinary tract, and 58 of 59 patients treated with amdinocillin responded clinically, with cures in 49. Of the 52 patients treated with tobramycin or other comparative agents, 49 responded, and 42 were cured. Escherichia coli and other Enterobacteriaceae were the usual pathogens. Immediately after treatment, 90 percent of urine samples were negative in both treatment groups. At four to six weeks follow-up, relapse or reinfection rates were about 20 percent in either group. Miscellaneous infections were treated with either amdinocillin or a comparative agent. Eleven of 15 infections responded favorably to amdinocillin, and seven were cured. Adverse effects were usually mild and characteristic of the penicillins.
Topics: Adolescent; Adult; Aged; Amdinocillin; Anti-Bacterial Agents; Bacterial Infections; Child; Cholecystitis; Clinical Trials as Topic; Diarrhea; Endocarditis, Bacterial; Enterobacteriaceae Infections; Female; Humans; Male; Middle Aged; Penicillanic Acid; Sepsis; Typhoid Fever; Urinary Tract Infections
PubMed: 6311009
DOI: 10.1016/0002-9343(83)90098-0 -
Antimicrobial Agents and Chemotherapy Mar 2015Amdinocillin (mecillinam) is a β-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to...
Amdinocillin (mecillinam) is a β-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to identify mutations that confer amdinocillin resistance on laboratory-isolated mutants and clinical isolates of Escherichia coli and to determine why amdinocillin resistance remains rare clinically even though resistance is easily selected in the laboratory. Under laboratory selection, frequencies of mutation to amdinocillin resistance varied from 8 × 10(-8) to 2 × 10(-5) per cell, depending on the concentration of amdinocillin used during selection. Several genes have been demonstrated to give amdinocillin resistance, but here eight novel genes previously unknown to be involved in amdinocillin resistance were identified. These genes encode functions involved in the respiratory chain, the ribosome, cysteine biosynthesis, tRNA synthesis, and pyrophosphate metabolism. The clinical isolates exhibited significantly greater fitness than the laboratory-isolated mutants and a different mutation spectrum. The cysB gene was mutated (inactivated) in all of the clinical isolates, in contrast to the laboratory-isolated mutants, where mainly other types of more costly mutations were found. Our results suggest that the frequency of mutation to amdinocillin resistance is high because of the large mutational target (at least 38 genes). However, the majority of these resistant mutants have a low growth rate, reducing the probability that they are stably maintained in the bladder. Inactivation of the cysB gene and a resulting loss of cysteine biosynthesis are the major mechanism of amdinocillin resistance in clinical isolates of E. coli.
Topics: Amdinocillin; Bacterial Proteins; Drug Resistance, Bacterial; Escherichia coli; Laboratories; Mutation
PubMed: 25583718
DOI: 10.1128/AAC.04819-14 -
The Medical Letter on Drugs and... Mar 1985
Clinical Trial
Topics: Amdinocillin; Bacterial Infections; Clinical Trials as Topic; Gram-Negative Bacteria; Humans; Kinetics; Microbial Sensitivity Tests
PubMed: 3884992
DOI: No ID Found -
The American Journal of Medicine Aug 1983In the treatment of serious infections, combinations of beta-lactam antibiotics are being utilized in order to avoid aminoglycoside toxicity and to achieve antibacterial...
In the treatment of serious infections, combinations of beta-lactam antibiotics are being utilized in order to avoid aminoglycoside toxicity and to achieve antibacterial synergy. The pharmacokinetic disposition of amdinocillin and cephalothin was determined, when administered alone or in combination to healthy volunteers, as well as the penetration of amdinocillin into human cerebrospinal fluid. Six subjects received, on separate occasions, single intravenous doses of amdinocillin 10 mg/kg, cephalothin 15 mg/kg, or a combination of the two in the same doses. The elimination half-lives of amdinocillin and cephalothin are increased when these drugs are given simultaneously, compared with when they are administered alone. However, no significant differences were observed. When they were given in combination, no significant changes in plasma clearance, renal clearance, or steady-state volume of distribution were found. Eight patients undergoing lumbar puncture for various neurologic disorders without inflamed meninges received a single dose of 10 mg/kg amdinocillin intravenously. One to two hours later, simultaneous plasma and cerebrospinal fluid samples were obtained. The concentration of amdinocillin in the cerebrospinal fluid ranged from approximately 1 to 10 percent of concomitant plasma concentrations. Thus, amdinocillin penetrates in the cerebrospinal fluid in marginal amounts in the absence of meningeal inflammation.
Topics: Adult; Aged; Amdinocillin; Cephalothin; Drug Interactions; Female; Half-Life; Humans; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Penicillanic Acid
PubMed: 6311006
DOI: 10.1016/0002-9343(83)90094-3 -
Lakartidningen Aug 2020
Topics: Amdinocillin Pivoxil; Humans; Pyelonephritis
PubMed: 32852775
DOI: No ID Found -
The American Journal of Medicine Aug 1983One hundred fifty-five patients with 157 febrile episodes were treated with amdinocillin or amdinocillin and cefoxitin as second-line therapy, or amdinocillin and...
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.
Topics: Acute Disease; Adolescent; Adult; Aged; Amdinocillin; Bacterial Infections; Carbenicillin; Cefoxitin; Drug Therapy, Combination; Female; Humans; Leukemia; Leukocyte Count; Male; Middle Aged; Neutrophils; Penicillanic Acid; Penicillins; Sepsis; Ticarcillin
PubMed: 6310998
DOI: 10.1016/0002-9343(83)90105-5 -
The American Journal of Medicine Aug 1983The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have... (Review)
Review
The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections.
Topics: Amdinocillin; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Binding, Competitive; Carrier Proteins; Cell Wall; Drug Interactions; Hexosyltransferases; Muramoylpentapeptide Carboxypeptidase; Penicillanic Acid; Penicillin-Binding Proteins; Peptidyl Transferases; beta-Lactamases
PubMed: 6311012
DOI: 10.1016/0002-9343(83)90089-x