In vitro activity of N-formimidoyl thienamycin (MK0787), a crystalline derivative of thienamycin.

N-Formimidoyl thienamycin (MK0787) is a derivative of thienamycin, a unique, new beta-lactam antibiotic. Its activity against 285 aerobic and facultatively anaerobic clinical isolates was compared with the activities of cephalothin, ampicillin, penicillin G, ticarcillin, and tobramycin. All of the 285 isolates, with the exception of 1 Staphylococcus epidermidis isolate, were inhibited by a concentration of N-formimidoyl thienamycin of less than or equal to 8 micrograms/ml. More than 50% of all isolates were inhibited by the lowest concentration of N-formimidoyl thienamycin tested (0.125 micrograms/ml); 98% of Staphylococcus aureus and 80% of S. epidermidis isolates were inhibited by N-formimidoyl thienamycin at a concentration of 0.125 micrograms/ml. Only 2 of 45 enterococci were not inhibited by 1 microgram of N-formimidoyl thienamycin per ml, and this drug was the most active agent tested against 162 gram-negative bacilli. It inhibited more than 95% of the gram-negative isolates at a concentration of less than or equal to 2 micrograms/ml. N-Formimidoyl thienamycin was as active or more active than tobramycin against Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis and substantially more active than ticarcillin. All 16 isolates of Klebsiella pneumoniae were inhibited by less than or equal to 0.5 micrograms of N-formimidoyl thienamycin per ml. The marked in vitro activity of this drug against a wide variety of clinical isolates makes it a promising new antibiotic.     

In vitro activity of newer beta-lactam agents in combination with amikacin against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Serratia marcescens

The in vitro activity of cefoperazone, ceftazidime, ceftizoxime, moxalactam, and N-formimidoyl thienamycin was evaluated alone and in combination with amikacin to assess possible synergistic activity against isolates of amikacin-resistant Pseudomonas aeruginosa and multidrug-resistant Serratia marcescens and Klebsiella pneumoniae susceptible to amikacin (one S. marcescens isolate was also resistant to amikacin). The checkerboard agar dilution method was used. Ceftazidime and thienamycin followed by moxalactam and cefoperazone were the most active agents versus the P. aeruginosa alone and in combination testing. Ceftazidime, moxalactam, and thienamycin showed the greatest activity against S. marcescens, and all agents except cefoperazone were active against K. pneumoniae. The finding of synergy or partial synergy in combination testing was found in the majority with all three genera, including levels below the breakpoint for both amikacin and the beta-lactam agents. This wide in vitro activity indicates that clinical evaluation of these agents in treatment of multidrug-resistant infections is warranted.     

In vitro susceptibility of cephalothin-resistant Enterobacteriaceae and Pseudomonas aeruginosa to Amikacin and selected new beta-lactam agents.

Amikacin was evaluated in vitro by agar dilution testing against 148 different clinical isolates of cephalothin-resistant Enterobacteriaceae and Pseudomonas aeruginosa in parallel with cephalothin, cefoxitin, moxalactam, N-formimidoyl thienamycin, ceftriaxone, and cefmenoxime. Cefsulodin was also evaluated against 39 isolates of P. aeruginosa. More than 80% of all isolates tested were also gentamicin resistant, as determined by disk testing. Moxalactam and amikacin had comparable high activities against Proteus species, Escherichia coli, Serratia species, and Providencia species, and both amikacin and N-formimidoyl thienamycin had comparably high activities against the Klebsiella-Enterobacter group. N-Formimidoyl thienamycin was the most active agent against P. aeruginosa, followed by cefsulodin and amikacin.     

Activity of N-formimidoyl thienamycin and cephalosporins against isolates from nosocomially acquired bacteremia.

The in vitro activity of N-formimidoyl thienamycin was compared with that of seven beta-lactam agents against bacteremic clinical isolates, including gentamicin-resistant, gram-negative bacilli, Staphylococcus aureus, Staphylococcus epidermidis, streptococci, and enterococci. N-formimidoyl thienamycin was the most active antibiotic against all of the gram-positive cocci studied, with the exception of Staphylococcus epidermidis, and the only agent active against the enterococci. N-formimidoyl thienamycin was less active than some of the other agents against Enterobacteriaceae, except for the strains of Serratia and Citrobacter studied. For Pseudomonas aeruginosa, N-formimidoyl thienamycin was the most active agent (4 micrograms/ml was the lowest concentration that inhibited 90% of the strains tested).     

In vitro comparison of N-formimidoyl thienamycin (MK0787) and Azlocillin with three aminoglycosides and ticarcillin against Pseudomonas aeruginosa

The activities of N-formimidoyl thienamycin and azlocillin were compared with those of tobramycin, gentamicin, amikacin, and ticarcillin against 175 Pseudomonas aeruginosa isolates, including 24 strains with known mechanisms of resistance to aminoglycosides. The 50% mean inhibitory concentration for azlocillin was lower than for ticarcillin, but the 90% mean inhibitory concentration was similar for both drugs. All susceptible and multidrug-resistant strains were susceptible to N-formimidoyl thienamycin.     

In vitro activity of moxalactam against pathogenic bacteria and its comparison with other antibiotics

843 isolates from clinical specimens were tested against moxalactam by disc agar diffusion. The bacteria used in this study consisted of Escherichia coli, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Klebsiella pneumoniae, Proteus mirabilis, Providencia rettgeri, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis and group B and group D Streptococci. In vitro activity of moxalactam was compared with the following antibiotics: ampicillin, amikacin, carbenicillin, cefamandole, cefoxitin, cephalothin, chloramphenicol, clindamycin, colistin, erythromycin, gentamicin, oxacillin, penicillin, tetracycline, tobramycin, trimethoprim-sulfamethoxazole and vancomycin. Of the 471 strains of Enterobacteriaceae tested, 466 (98.9%) were susceptible to moxalactam. Except for penicillin G, the gram-positive cocci were generally more resistant to moxalactam than the other beta-lactam antibiotics. Moxalactam was comparable to gentamicin, as far as its activity against P. aeruginosa was concerned, but was less effective than amikacin, tobramycin, carbenicillin or colistin.     

Influence of inoculum size on activity of cefoperazone, cefotaxime, moxalactam, piperacillin, and N-formimidoyl thienamycin (MK0787) against Pseudomonas aeruginosa.

Forty clinical isolates of Pseudomonas aeruginosa were tested for their susceptibility to cefoperazone, cefotaxime, moxalactam, piperacillin, N-formimidoyl thienamycin (MK0787), and gentamicin at three different inocula. At an inoculum of 5 x 10(3) colony-forming units (CFU) per ml, the minimum inhibitory concentrations (in micrograms per milliliter) for 90% of isolates (MIC90) were as follows: gentamicin, 1; N-formimidoyl thienamycin, 2; cefoperazone, 4; piperacillin, 8; moxalactam, 16; and cefotaxime, 16. When the inoculum was increased to 5 x 10(5) CFU/ml, the MIC90 for all drugs tested increased. Among the beta-lactam antibiotics, N-formimidoyl thienamycin and cefoperazone had the lowest MIC90 (8 micrograms/ml) at this inoculum. When the inoculum was increased further to 5 x 10(7) CFU/ml, an MIC90 could be determined only for gentamicin and N-formimidoyl thienamycin (4 and 8 micrograms/ml, respectively). Indeed, the MIC50 for moxalactam, cefotaxime, cefoperazone, and piperacillin was 128 micrograms/ml or more at this inoculum. The minimum bactericidal concentration for 90% of isolates (MBC90) at an inoculum of 5 x 10(5) CFU/ml ranged from 8 micrograms/ml for gentamicin and N-formimidoyl thienamycin to 128 micrograms/ml for cefotaxime. At the highest inoculum, however, whereas the MBC90 for gentamicin and N-formimidoyl thienamycin remained at 8 micrograms/ml, the MBC90 for each of the other drugs was greater than 128 micrograms/ml. N-Formimidoyl thienamycin was the only drug tested for which an MIC100 and MBC100 (MIC and MBC for 100% of isolates) could be determined, and these were not significantly different from the MIC90 and MCB90.     

A comparison of the antibacterial activities of N-formimidoyl thienamycin (MK0787) with those of other recently developed beta-lactam derivatives.

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.     

In vitro activity of N-formimidoyl thienamycin in comparison with cefotaxime, moxalactam, and ceftazidime.

The in vitro activity of N-formimidoyl thienamycin (N-f-thienamycin) was compared with the activities of other B-lactam antibiotics, using over 500 clinical bacterial isolates. N-f-Thienamycin inhibited 90% of the isolates of the common Enterobacteriaceae between 0.006 and 2 microgram/ml, regardless of their resistance to amoxicillin, ticarcillin, or cephalothin. It was, however, fourfold less active than moxalactam and ceftazidime and eightfold less active than cefotaxime. N-f-Thienamycin was nearly as active as ceftazidime against Pseudomonas aeruginosa (mean minimal inhibitory concentration, 3.0 microgram/ml) and eightfold more active than cefotaxime and moxalactam. In contrast to cefotaxime, moxalactam, and ceftazidime, N-f-thienamycin was highly active against enterococci (mean minimal inhibitory concentration, 1.3 microgram/ml) and staphylococci. The oxacillin-susceptible Staphylococcus aureus were inhibited between 0.03 and 0.12 microgram/ml, and the oxacillin-resistant S. aureus were inhibited between 0.12 and 2 microgram/ml. The high activity of N-f-thienamycin against both of the most important gram-positive and gram-negative organisms makes it a very promising new antibiotic.     

Comparative activities of 13 beta-lactam antibiotics.

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.     

Comparative activities of N-formimidoyl thienamycin, ticarcillin, and tobramycin against experimental Pseudomonas aeruginosa pneumonia.

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.     

Comparative in vitro activity of N-formimidoyl thienamycin against gram-positive and gram-negative aerobic and anaerobic species and its beta-lactamase stability.

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.     

Pseudomonas aeruginosa and Acinetobacter calcoaceticus: in vitro susceptibility of 150 clinical isolates to five beta-lactam antibiotics and tobramycin

The in vitro activities of azlocillin, carbenicillin, ceftriaxone, piperacillin, N-formimidoyl thienamycin (N-f thienamycin) and tobramycin have been compared against clinical isolates of Pseudomonas aeruginosa (n = 100) and Acinetobacter calcoaceticus (n = 50). An agar dilution method was employed for measurement of minimal inhibitory concentration (MIC). Tobramycin was the most active drug against P. aeruginosa (MIC less than or equal to 2 mg/l). Of the beta-lactam antibiotics, N-f thienamycin and tobramycin were highly active against A. calcoaceticus (MIC less than or equal to 2 mg/l), although one isolate was resistant to tobramycin (MIC greater than 16 mg/l). The other drugs were only moderately active against A. calcoaceticus.     

In Vitro Study of Netilmicin Compared with Other Aminoglycosides

Netilmicin (Sch 20569) is an ethyl derivative of gentamicin C(1a) that is active against most Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus isolates. Among 342 clinical isolates tested, all staphylococci; 92% of Escherichia coli, 93% of Klebsiella pneumoniae, and 92% of Enterobacter were inhibited by 0.8 mug or less of netilmicin per ml, but only 78% of P. aeruginosa were inhibited by 3.1 mug or less per ml. Most clinical isolates of enterococci, Serratia marcescens, and Providencia were not inhibited by 3.1 mug of netilmicin per ml. Like other aminoglycosides, the netilmicin in vitro activity was markedly influenced by the growth medium used, with activity decreased by sodium, calcium, and magnesium. Netilmicin was more active at alkaline pH. Addition of magnesium to Pseudomonas or Serratia pretreated with netilmicin produced inhibition of killing. Netilmicin was more active than gentamicin, sisomicin, tobramycin, or amikacin against E. coli and K. pneumoniae. Netilmicin inhibited growth of all gentamicin-resistant isolates of Klebsiella and Citrobacter tested, but only 73% of E. coli; Pseudomonas and Providencia were resistant to netilmicin. Most Serratia (95%) and indole-positive Proteus (83%) isolates were resistant to netilmicin but were inhibited by amikacin.     

Comparison of in vitro activity of FCE 22101, a new penem, with those of other beta-lactam antibiotics.

The in vitro activity of FCE 22101, a new semisynthetic penem derivative, was compared with that of ceftriaxone, moxalactam, imipenem (formerly imipemide, N-formimidoyl thienamycin, or MK 0787), cefuroxime, ceftazidime, and other beta-lactams, when appropriate, against 472 recent isolates and known beta-lactam-resistant strains. The minimum inhibitory concentrations of FCE 22101 against 90% of the members of the family Enterobacteriaceae, Haemophilus influenzae, Staphylococcus aureus, Lancefield group D streptococci, and Bacteroides spp. were between 0.5 and 4 micrograms/ml. Methicillin-resistant strains of Staphylococcus aureus were susceptible. Ninety percent of the Neisseria gonorrhoeae and Streptococcus pneumoniae strains were susceptible to 0.25 microgram of FCE 22101 per ml. Pseudomonas aeruginosa strains were resistant to FCE 22101 (minimum inhibitory concentration, greater than 128 micrograms/ml). The susceptibility of known, characterized beta-lactamase-producing strains of the Enterobacteriaceae suggested that FCE 22101 is resistant to many beta-lactamases. Generally, FCE 22101 was slightly less active than imipenem, moxalactam, ceftriaxone, and ceftazidime against members of the Enterobacteriaceae and considerably more active than the cephalosporins (including moxalactam) against Staphylococcus aureus. The human serum protein binding of FCE 22101 was about 40%, and human serum had little effect on the activity.     

In vitro activity of dactimicin, a novel pseudodisaccharide aminoglycoside, compared with activities of other aminoglycosides.

The in vitro activity of dactimicin, a new pseudodisaccharide aminoglycoside which possesses a formimidoyl group, was compared with those of gentamicin, tobramycin, and amikacin against 500 isolates. Dactimicin inhibited 90% of isolates from the family Enterobacteriaceae at a concentration of less than or equal to 4 micrograms/ml. It was more active than amikacin against Klebsiella pneumoniae, Serratia marcescens, Citrobacter diversus, Enterobacter agglomerans, Yersinia species, and Salmonella species, with an MIC for 90% of the strains (MIC90) of less than or equal to 4 micrograms/ml. The MIC90s for the Pseudomonas aeruginosa isolates were greater than 128 micrograms/ml. Dactimicin did not inhibit most methicillin-resistant Staphylococcus aureus isolates and coagulase-negative staphylococci but had an MIC50 (MIC for 50% of strains tested) of 2 micrograms/ml against methicillin-susceptible S. aureus isolates and coagulase-negative staphylococci. Dactimicin in combination with piperacillin acted synergistically against 75% of Escherichia coli, K. pneumoniae, S. marcescens, and S. aureus isolates. It exhibited an excellent postantibiotic suppressive effect on E. coli. Dactimicin was active against organisms possessing aminoglycoside-modifying enzymes including AAC(2')-b, AAC(3)-III, -IV, and -V, and AAC(6')-Ia, -Ib, Ic, -II, and -IV but was not active against isolates which contained AAC(3)-I and the bifunctional APH(2")-AAC(6')-I. Its lack of activity against P. aeruginosa appeared to be permeability related since in the presence of EDTA P. aeruginosa was susceptible, as were mutant isolates resistant because of permeability barriers.     

Comparative Activity of Tobramycin, Amikacin, and Gentamicin Alone and with Carbenicillin Against Pseudomonas aeruginosa

The effect of gentamicin against 130 clinical isolates of Pseudomonas aeruginosa was compared with that of two investigational aminoglycoside antibiotics, tobramycin and amikacin. Minimal inhibitory concentration data indicated that, on a weight basis, tobramycin was two to four times as active as gentamicin against most isolates. However, 14 of 18 organisms highly resistant to gentamicin (>/=80 mug/ml) were also highly resistant to tobramycin. Amikacin was the least active aminoglycoside on a weight basis, but none of the isolates were highly resistant to this antibiotic. When therapeutically achievable concentrations were used, adding carbenicillin to gentamicin or to tobramycin enhanced inhibitory activity against those isolates susceptible (相似文献   

Activities of New Beta-Lactam Antibiotics Against Isolates of Pseudomonas aeruginosa from Patients with Cystic Fibrosis

The in vitro activities of gentamicin, tobramycin, amikacin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, cefotaxime, ceftizoxime, cefoperazone, cefsulodin, moxalactam, ceftazidime, ceftriaxone, and N-formimidoyl thienamycin were measured against 62 isolates of Pseudomonas aeruginosa obtained from patients with cystic fibrosis. Ceftazidime and N-formimidoyl thienamycin were the most active of these agents.     

Superior activity of N-formimidoyl thienamycin against gentamicin-resistant Pseudomonas aeruginosa

N-Formimidoyl thienamycin (N-F-thienamycin), cefotaxime, moxalactam, and cefsulodin were tested by agar dilution against 125 isolates of Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, and Providencia stuartii. Against gentamicin-susceptible P. aeruginosa, N-F-thienamycin and cefsulodin were most active. Only N-F-thienamycin inhibited gentamicin-resistant P. aeruginosa at less than or equal to 4 microgram/ml. N-F-thienamycin's activity equaled or surpassed that of the other antibiotics tested against both the gentamicin-susceptible and -resistant Enterobacteriaceae.     

Activities of aztreonam and new cephalosporins against infrequently isolated gram-negative bacilli.

The susceptibilities of 159 clinical isolates of glucose nonfermentative gram-negative bacilli were determined for eight new monobactam or beta-lactam antibiotics. Imipemide (N-formimidoyl thienamycin) was effective against the largest number of species, although not against Pseudomonas maltophilia. Cefoperazone and ceftazidime, but not cefsulodin, were active against infrequently isolated Pseudomonas species. Aztreonam, moxalactam, cefotaxime, and ceftizoxime demonstrated selective activity against several species, including certain amino-glycoside-resistant isolates.