Showing papers on "Thienamycin published in 1982"
TL;DR: The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance, and despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK 0787 and its efficacy against experimental systemic infections in animals remain satisfactory.
Abstract: Thienamycin (THM), the N-formimidoyl thienamycin derivative MK0787, and related carbapenem antibiotics were metabolized extensively in mice, rats, rabbits, dogs, rhesus monkeys, and chimpanzees. Urinary recovery of THM ranged from a low of 5% in dogs to 58% in rhesus monkeys. Renal clearance rates in dogs and chimpanzees were unusually low, less than glomerular filtration rates. The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance. Degradation was detected only in kidney homogenates. The enzyme activity was membrane bound and sensitive to inhibitors of Zn-metalloenzymes such as EDTA. A renal dipeptidase, dehydropeptidase-I (DHP-I), EC 3.4.13.11, was found to be responsible for the metabolism of the THM-class antibiotics, which exhibit a structural homology to dehydropeptides. A parallel increase in specific activity against THM and the substrate of DHP-I, glycyldehydrophenylalanine, was observed during solubilization and purification of the enzyme from porcine and human renal cortex. DHP-I was found to catalyze the hydrolysis of the beta-lactam ring in THM and MK0787. The products of the enzyme reaction were identical by high-powered liquid chromatography to their respective metabolites found in the urine. Nonbasic N-acylated THM and natural N-acylated carbapenems (epithienamycins and olivanic acids) were degraded 4- to 50-fold faster than THM when exposed to the enzymatic hydrolysis of DHP-I. Good correlations were obtained between the increased susceptibility of the carbapenem antibiotics to DHP-I as measured in the in vitro enzyme assay and the generally lower recoveries of active antibiotic in the urine of test animals. Despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK0787 and its efficacy against experimental systemic infections in animals remain satisfactory.
326 citations
TL;DR: The purified penicillin beta-lactamase gave a single protein band on polyacrylamide gel electrophoresis, and showed a unique substrate profile, hydrolyzing N-formimidoyl thienamycin at a significant rate.
Abstract: Two types of beta-lactamase were found in the cell-free extract from Pseudomonas maltophilia GN12873. One was an inducible penicillin beta-lactamase, and the other was an inducible cephalosporin beta-lactamase. The purified penicillin beta-lactamase gave a single protein band on polyacrylamide gel electrophoresis. The isoelectric point was 6.9, and the approximate molecular weight was 118,000 by gel filtration and 26,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, suggesting that this enzyme consisted of four subunits. For the hydrolysis of penicillin G, the optimal pH was 8.0 and the optimal temperature was 35 degrees C. The enzyme activity was inhibited by cephamycin derivatives, carpetimycins A and B, iodine, and HgCl2, but not by clavulanic acid. Furthermore, beta-lactamase activity was almost completely inhibited by EDTA but was recovered by the addition of zinc ion. The enzyme showed a unique substrate profile, hydrolyzing N-formimidoyl thienamycin at a significant rate.
226 citations
TL;DR: N-Formimidoyl thienamycin inhibited the majority of organisms at concentrations below 1 microgram/ml and showed partial synergy with aminoglycosides against S. aureus, S. faecalis, and many Pseudomonas and Enterobacteriaceae.
Abstract: The in vitro activity of N-formimidoyl thienamycin was determined against 800 gram-positive and gram-negative aerobic and anaerobic bacteria and compared with the activity of cefoxitin, cefazolin, cefamandole, cefotaxime, moxalactam, ampicillin, cefoperazone, and gentamicin. N-Formimidoyl thienamycin inhibited the majority of organisms at concentrations below 1 microgram/ml. It inhibited methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus faecalis. It inhibited beta-lactamase-producing Haemophilus influenzae and Neisseria gonorrhoeae. Unlike other new beta-lactams, it inhibited Listeria. Escherichia coli, Klebsiella pneumoniae, enterobacters, Serratia, indole-positive Proteus, Acinetobacter, Pseudomonas aeruginosa, and Bacteroides resistant to other agents were inhibited. There was minimal effect of inoculum size and aerobic versus anaerobic conditions, and serum had no effect on activity. Most minimal bactericidal concentrations were two- or fourfold greater than the minimal inhibitory concentration. N-Formimidoyl thienamycin showed partial synergy with aminoglycosides against S. aureus, S. faecalis, and many Pseudomonas and Enterobacteriaceae. It was not hydrolyzed by plasmid-mediated and chromosomal beta-lactamases.
153 citations
TL;DR: In this article, a practical stereospecific synthesis of thienamycin 1 has been achieved using lead tetracetate oxidative decarboxylation and subsequent insertion of a four carbon diazo containing unit into a 3-acetoxy-2-azetidinene.
128 citations
TL;DR: An agar dilution method was used to measure the minimal inhibitory concentrations of 13 beta-lactam antibiotics against 868 recent human clinical isolates and N-Formimidoyl thienamycin was active against all of the species tested.
Abstract: An agar dilution method was used to measure the minimal inhibitory concentrations of 13 beta-lactam antibiotics against 868 recent human clinical isolates. Most members of the Enterobacteriaceae were susceptible to cefoperazone, ceftazidime, moxalactam, N-formimidoyl thienamycin, ceftriaxone, and ceftizoxime. Cephalothin was the most active antibiotic against Staphylococcus aureus. Most strains of Pseudomonas aeruginosa were inhibited by ceftazidime, N-formimidoyl thienamycin, and cefsulodin. N-Formimidoyl thienamycin was active against all of the species tested.
83 citations
TL;DR: The susceptibility of 26 isolates of Nocardia asteroides to several antibiotics was determined by the agar dilution technique, and Amikacin was the most effective agent tested.
Abstract: The susceptibility of 26 isolates of Nocardia asteroides to several antibiotics was determined by the agar dilution technique. Many currently available beta-lactam antibiotics were ineffective. Cefotaxime, cefmenoxime, and N-formimidoyl thienamycin were active against these strains, with 80% minimal inhibitory concentrations of 4, 4, and 2 micrograms/ml, respectively. Amikacin was the most effective agent tested.
59 citations
TL;DR: N-Formimidoyl thienamycin was significantly more active than the reference antibiotics against most organisms tested, especially Bacteroides sp.
Abstract: The susceptibilities of 462 clinical anaerobic bacterial isolates to N-formimidoyl thienamycin and 16 other currently available and investigational antibiotics were determined by the agar dilution technique. N-Formimidoyl thienamycin was significantly more active than the reference antibiotics against most organisms tested, especially Bacteroides sp., including clindamycin-resistant strains. All 462 isolates were inhibited by 4 micrograms of N-formimidoyl thienamycin per ml, and no resistant strains were found in the species tested. N-Formimidoyl thienamycin was less active (i.e., had a higher 50% minimal inhibitory concentration) against Fusobacterium sp. than clindamycin, SM-1652, and piperacillin, and less active against Clostridium difficile than metronidazole, but was equally active or more active than the other reference antibiotics tested.
47 citations
TL;DR: The in vitro activity suggests that SQ26,776 should prove useful in settings in which the most likely pathogens are gram-negative bacilli, and was superior to mezlocillin.
Abstract: A new monocyclic beta-lactam antibiotic, SQ26,776, was evaluated in vitro against clinical isolates, and its activity was compared with that of other cephalosporins, penicillins, and aminoglycosides. This compound was very active against the majority of the aerobic gram-negative bacilli tested, including 47 multiresistant strains. It had no activity against the gram-positive cocci. It also showed activity comparable to that of moxalactam, ceftazidime, ceftriaxone, thienamycin, and tobramycin. It was superior to mezlocillin. The in vitro activity suggests that SQ26,776 should prove useful in settings in which the most likely pathogens are gram-negative bacilli.
45 citations
44 citations
TL;DR: Moxalactam was less active than the other compounds tested, inhibiting only 9 of 13 strains at 50 micrograms/ml, while cefoxitin and cefotetan were more active.
Abstract: The comparative in vitro activity of N-formimidoyl thienamycin, cefmetazole, cefoxitin, cefotetan (YM-09330), and moxalactam against 13 isolates of Mycobacterium fortuitum was evaluated by agar dilution susceptibility testing. N-Formimidoyl thienamycin inhibited 10 to 12 strains at 6.25 micrograms/ml, cefmetazole inhibited 12 of 13 strains at 12.5 micrograms/ml, cefoxitin inhibited 11 of 13 strains at 25 micrograms/ml, and cefotetan inhibited 11 of 13 strains at 50 micrograms/ml. Moxalactam was less active than the other compounds tested, inhibiting only 9 of 13 strains at 50 micrograms/ml.
36 citations
TL;DR: A mild and efficient method of β-lactam alkylation has been achieved using 4-acetoxy-2-azetidinone and a variety of silyl enol ethers.
TL;DR: The effects of the combination of azlocillin with the beta-lactamase inhibitors clavulanic acid and sulbactam and with N-formimidoyl thienamycin against strains of Pseudomonas aeruginosa with R-factor-mediated carbenicillin resistance were investigated.
Abstract: We investigated the effects of the combination of azlocillin with the beta-lactamase inhibitors clavulanic acid and sulbactam and with N-formimidoyl thienamycin against strains of Pseudomonas aeruginosa with R-factor-mediated carbenicillin resistance. The 10 strains tested (1 R-, 9 R+) were isogenic, except for the presence of individual plasmids determining each of nine plasmid-mediated beta-lactamases found in P. aeruginosa. We utilized a checkerboard technique for testing antibiotic combinations. Low concentrations of clavulanic acid produced synergy with azlocillin against the strains producing the TEM-1, TEM-2, PSE-1, PSE-3, and PSE-4 beta-lactamases; for the strains producing the OXA-1, OXA-2, OXA-3, and PSE-2 beta-lactamases, such synergy was not found. With sulbactam, synergy was demonstrated in all strains except that producing PSE-2 beta-lactamase; for several strains, however, the concentration of sulbactam required to produce synergy was substantially higher than that for clavulanic acid. N-Formimidoyl thienamycin was highly active as a single agent against all of the strains, regardless of beta-lactamase production. The combination of N-formimidoyl thienamycin and azlocillin produced synergy against only two of the strains tested.
TL;DR: Kinetic analyses of the rate of enzyme — catalyzed hydrolysis of the antibiotic, N-formimidoyl-thienamycin, by purified renal dipeptidase demonstrated that the purified mammalian enzyme is responsible for the breakdown of the β-lactam antibiotic.
TL;DR: N-formimidoyl thienamycin may have therapeutic efficacy against respiratory infections with P. aeruginosa equivalent to that of tobramycin, and numbers of viable Pseudomonas organisms in lungs approximately 3 h after the first dose of drug were nearly 10-fold fewer.
Abstract: The therapeutic efficacies of disodium ticarcillin, tobramycin sulfate, and N-formimidoyl thienamycin (MK0787) were compared in guinea pigs with experimentally induced Pseudomonas aeruginosa pneumonia. Survival rates were 35% for ticarcillin, 80% for tobramycin, and 75% for N-formimidoyl thienamycin. Numbers of viable Pseudomonas organisms in lungs approximately 3 h after the first dose of drug were nearly 10-fold fewer in tobramycin- or N-formimidoyl thienamycin-treated animals than in ticarcillin-treated animals. Our data suggest that N-formimidoyl thienamycin may have therapeutic efficacy against respiratory infections with P. aeruginosa equivalent to that of tobramycin.
TL;DR: Of 43 isolates of methicillin-resistant Staphylococcus aureus, 90% were inhibited by 8 micrograms or less of N-formimidoyl thienamycin per ml by the agar-dilution technique.
Abstract: Of 43 isolates of methicillin-resistant Staphylococcus aureus, 90% were inhibited by 8 micrograms or less of N-formimidoyl thienamycin per ml by the agar-dilution technique. Cefamandole, cefotaxime, cefoperazone, moxalactam, and cefsulodin showed relatively poor activity. Vancomycin was the most active compound by weight, inhibiting 93% of strains at 1 microgram/ml.
TL;DR: Both methiillin-susceptible and (to a lesser degree) methicillin-resistant strains were generally susceptible to the antibiotic as judged from their minimum inhibitory concentrations.
Abstract: A total of 82 clinical isolates of methicillin-resistant Staphylococcus aureus and 21 isolates of methicillin-susceptible S. aureus were studied for in vitro susceptibility to N-forminidoyl thienamycin at incubation temperatures of 30 and 35 degrees C. The disk diffusion test results were correlated with the macrobroth dilution test by means of the error rate-bounded method of analysis. Both methicillin-susceptible and (to a lesser degree) methicillin-resistant strains were generally susceptible to the antibiotic as judged from their minimum inhibitory concentrations. The discrepancy between in vitro results obtained at 30 and at 35 degrees C was not very remarkable. However, tolerance of N-formimidoyl thienamycin was observed in 37% of methicillin-resistant strains and 24% of methicillin-susceptible strains at an incubation temperature of 30 degrees C; at 35 degrees C, the values were 54% (methicillin-resistant strains) and 14% (methicillin-susceptible strains).
TL;DR: Asymmetric induction provides a simple preparation of (+)-4-phentylthioazetidin-2-one, from which a key intermediate for (+)-thienamycin has been synthesised as discussed by the authors.
Abstract: Asymmetric induction provides a simple preparation of (+)-4-phentylthioazetidin-2-one, from which a key intermediate for (+)-thienamycin has been synthesised.
TL;DR: In this paper, a convenient synthesis of 3-(1′-hydroxyethyl)-2-azetidinone-4-yl acetic acid, one of the key intermediates in the thienamycin total synthesis, is described.
TL;DR: Chiral thienamycin intermediate (12) having the correct absolute configuration was synthesized from D-glucose as mentioned in this paper, which is the only known intermediate intermediate with the correct configuration.
Abstract: Chiral thienamycin intermediate (12) having the correct absolute configuration was synthesized from D-glucose.
TL;DR: N-formimidoyl thienamycin was the most effective drug as far as the spectrum of these bacterial groups and potency is concerned; ceftazidime was the second most effective agent.
Abstract: Thirty-one species (185 strains) of non-fermentative gram-negative rods (excludingPseudomonas aeruginosa) as well as 45 strains ofAeromonas spp., 15 strains ofPlesiomonas shigelloides and 68 strains ofEnterobacter agglomerans were tested in microdilution procedures against N-formimidoyl thienamycin, ceftazidime, cefotiam, ceftriaxone and cefotaxime. N-formimidoyl thienamycin was the most effective drug as far as the spectrum of these bacterial groups and potency is concerned; ceftazidime was the second most effective agent. Ceftriaxone and cefotaxime were similar in their activity (against a smaller spectrum), while cefotiam showed little effect. There were occasional differences between MBC and MIC values which were most notable with ceftazidime, cefotiam, ceftriaxone and cefotaxime againstE. agglomerans.
TL;DR: Renal dipeptidase purified from swine kidney hydrolyzed N-formimidoyl thienamycin, carpetimycins A and B, and Sch29482, but not azthreonam, penicillin G, or cephaloridine.
Abstract: Renal dipeptidase purified from swine kidney hydrolyzed N -formimidoyl thienamycin, carpetimycins A and B, and Sch29482, but not azthreonam, penicillin G, or cephaloridine.
TL;DR: The information obtained from this study suggests that the catalytic center of the P. vulgaris cephalosporinase is different not only from that of the penicillinase-type beta-lactamases but also fromthat of the cep HalosporInase- type beta- lactamase.
Abstract: Cefoxitin, N-formimidoyl thienamycin (MK0787), clavulanic acid, and penicillanic acid sulfone (CP45,899) were studied to determine their potency as suicide inhibitors of three very different kinds of beta-lactamases produced by Gram-negative bacteria: type Ib penicillinase (TEM-2 type), a typical cephalosporinase (the enzyme of Proteus morganii), and a cephalosporinase with broad substrate specificity (the enzyme of Proteus vulgaris). All these beta-lactams were confirmed to be quite stable to the three beta-lactamases. The absolute values of the turnover numbers (kcat) for these enzyme-catalyzed hydrolyses were determined, the values ranged from 0.25 minute-1 to 660 minute-1. All the beta-lactams studied, except cefoxitin, acted as suicide inhibitors of the typical cephalosporinase. Although cefoxitin did not exhibit such an effect, it was a powerful competitive inhibitor of this enzyme. Although the four beta-lactams acted as suicide inhibitors of the P. vulgaris cephalosporinase, the inactivated enzyme partially regained its activity after removing the effect of the free inhibitor. Type Ib penicillinase was also inactivated by the four beta-lactams, and the activity of the inactivated enzyme, except in the case of cefoxitin, was partially restored. The rate constants for enzyme inactivation or reactivation were calculated and are presented. The information obtained from this study suggests that the catalytic center of the P. vulgaris cephalosporinase is different not only from that of the penicillinase-type but also from that of the cephalosporinase-type beta-lactamases.
TL;DR: N-Formimidoyl thienamycin might prove to be useful for therapy of meningitis caused by E. coli and other susceptible bacteria.
Abstract: The pharmacokinetics and bacteriological efficacy of N-formimidoyl thienamycin were determined in rabbits infected with Escherichia coli K1. After a single intravenous dose of 25 mg/kg, a peak N-formimidoyl thienamycin concentration in cerebrospinal fluid (CSF) of 2.5 micrograms/ml was attained at 45 min. The penetration into CSF was calculated to be 31%. In animals that received continuous intravenous infusions of the drug for 9 h, the mean CSF concentration was 8.2 microgram/ml, and the CSF bactericidal titers against the E. coli K1 strain were from 1:16 to 1:32. This infusion produced a reduction in the numbers of E. coli in the CSF of 4 log10 colony-forming units per ml. N-Formimidoyl thienamycin might prove to be useful for therapy of meningitis caused by E. coli and other susceptible bacteria.
TL;DR: N-formimidoyl thienamycin was the most active drug against P. aeruginosa and Acinetobacter spp.
Abstract: The antibacterial activity of N-formimidoyl thienamycin (MK0787) was evaluated in 335 clinical isolates of ampicillin-resistant Enterobacteriaceae, 50 Pseudomonas aeruginosa strains, 28 Acinetobacter spp., 50 Streptococcus faecalis strains, and 7 oxacillin-resistant Staphylococcus aureus strains and was compared with the recently developed beta-lactam antibiotics mezlocillin, cefuroxime, cefazedone, cefoperazone, cefotaxime, and moxalactam. Among the gram-negative bacteria, N-formimidoyl thienamycin was less active than cefotaxime against Klebsiella, Serratia, and Proteus spp. but had comparable activity against Escherichia coli and Enterobacter strains. Activity of the thienamycin derivative was somewhat lower than that of moxalactam against most of the strains and superior to that of mezlocillin, cefuroxime, and cefoperazone. Moreover, N-formimidoyl thienamycin was the most active drug against P. aeruginosa and Acinetobacter spp. and had activity comparable to that of ampicillin against Streptococcus faecalis. N-Formimidoyl thienamycin was bactericidal at concentrations less than twice the minimal inhibitory concentration (MIC) in all gram-negative isolates tested. Oxacillin-resistant staphylococci (MIC of oxacillin, greater than 4 micrograms/ml) were inhibited at low concentrations of the thienamycin derivative (90% MIC, 0.25 micrograms/ml); however, N-formimidoyl thienamycin was not bactericidal at the 90% MIC. The antibacterial activity of N-formimidoyl thienamycin against all of the gram-negative bacilli was observed to be independent of beta-lactamase production.
TL;DR: The broad sensitivity spectrum of piperacillin, thienamycin, and the third-generation cephalosporins against non-fermentative gram-negative bacteria indicates their potential use in infections caused by these organisms.
Abstract: Susceptibility of 341 isolates of non-fermentative gram-negative bacteria to carbenicillin, piperacillin, cefoperazone, moxalactam, cefotaxime, ceftizoxime, and N-formimidoyl thienamycin was determined by the agar dilution and disc diffusion methods. Piperacillin was the most active agent againstPseudomonas aeruginosa, thienamycin the most active againstPseudomonas fluorescens andPseudomonas putida, and moxalactam the most active againstPseudomonas maltophilia. Piperacillin and thienamycin were the most active agents against the otherPseudomonas species studied. Thienamycin proved to have excellent activity againstAcinetobacter calcoaceticus − 90 % of strains were inhibited by ⩽ 1μg/ml. The two most active drugs againstAlcaligenes species were piperacillin and thienamycin, both of which inhibited 90 % of isolates at a concentration of 2μg/ ml. All drugs were active againstMoraxella species. The broad sensitivity spectrum of piperacillin, thienamycin, and the third-generation cephalosporins against non-fermentative gram-negative bacteria indicates their potential use in infections caused by these organisms.
TL;DR: In general, N-formimidoyl thienamycin was the most active, with all organisms inhibited by less than or equal to 0.5 microgram/ml.
Abstract: The in vitro activities of N-formimidoyl thienamycin, clindamycin, chloramphenicol, metronidazole, cefoperazone, cefotaxime, cefoxitin, moxalactam, penicillin G, and piperacillin were determined against 158 anaerobic bacteria isolated from endometrial wash cultures of women with pelvic infections. In general, N-formimidoyl thienamycin was the most active, with all organisms inhibited by less than or equal to 0.5 microgram/ml. Chloramphenicol, clindamycin, and metronidazole inhibited all organisms by less than or equal to 8 microgram/ml. The penicillins and cephalosporins exhibited variable activity of lesser degrees.
TL;DR: In this paper, a total synthesis of a key lactone intermediate in the synthesis of (+)-thienamycin is described, based on a strategy that uses "chiral templates" derived from D-glucose.
Abstract: A total synthesis of a key lactone intermediate in the synthesis of (+)-thienamycin is described, based on a strategy that uses "chiral templates" derived from D-glucose.
TL;DR: The in vitro activity of N-formimidoyl thienamycin (MK0787) was tested against 239 anaerobic bacteria clinical isolates and all were inhibited by less than or equal to 4 micrograms/ml.
Abstract: The in vitro activity of N-formimidoyl thienamycin (MK0787) was tested against 239 anaerobic bacteria clinical isolates: 70 of Bacteroides fragilis, 18 of B. distasonis, 16 of B. thetaiotaomicron, 10 of B. vulgatus, 24 of Bacteroides spp., 22 of B. melaninogenicus (all three subspecies), 26 of Fusobacterium spp., 10 of Peptococcus spp., 15 of Peptostreptococcus spp., 15 of Clostridium perfringens, and 13 of Clostridium spp. Ninety-five percent of the isolates were inhibited by less than or equal to 0.125 microgram/ml, and all were inhibited by less than or equal to 4 micrograms/ml.
TL;DR: The in vitro synergistic activity of N-formimidoyl thienamycin and amikacin was determined against gentamicin-resistant enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus.
Abstract: The in vitro synergistic activity of N -formimidoyl thienamycin and amikacin was determined against gentamicin-resistant enterobacteriaceae, Pseudomonas aeruginosa , and Staphylococcus aureus. N -Formimidoyl thienamycin showed synergism with amikacin against 19 of the gentamicin-resistant strains, 14 of the 49 strains of S. aureus , and only 1 strain of the 46 P. aeruginosa isolates.