N-formimidoyl Thienamycin Research Articles

In vitro activity of N-formimidoyl thienamycin and other beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus.

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.

Cefoxitin, N-formimidoyl thienamycin, clavulanic acid, and penicillanic acid sulfone as suicide inhibitors for different types of beta-lactamases produced by gram-negative bacteria.

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.

N-formimidoyl thienamycin (MK0787): in vitro activity against anaerobic bacteria.

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.

Effect of atmosphere of incubation and inoculum size on the susceptibility of Eikenella corrodens.

The effect of atmosphere of incubation on the susceptibility of Eikenella corrodens to 13 antimicrobial agents was determined. Clindamycin, cefoxitin, cefotaxime, cefoperazone, moxalactam, meziocillin and piperacillin were more active in a 5% CO2 than in an anaerobic atmosphere. The activity of penicillin G, cefamandole, cefadroxil, ticarcillin, bacampicillin and N-formimidoyl thienamycin was not affected by environment. The effect of different inocula (103, 105, 108 and 109 cfu/ml) on the susceptibility of Eik. corrodens to penicillin G, clindamycin and cefoperazone was also tested. Penicillin G and clindamycin were equally active against all inoculum sizes, while cefoperazone was less active at the higher inocula.

The comparative activities of N-formimidoyl thienamycin (MK0787), moxalactam, cefotaxime and cefoperazone against Yersinia enterocolitica and Listeria monocytogenes

The comparative activities of <i>N</i>-formimidoyl thienamycin (MK0787), moxalactam, cefotaxime and cefoperazone against <i>Yersinia enterocolitica</i> and <i>Listeria monocytogenes</i>

The activity of N-formimidoyl thienamycin (MK0787) against Haemophilus influenzae and Streptococcus pneumoniae.

The activity of N-formimidoyl thienamycin (MK0787) against Haemophilus influenzae and Streptococcus pneumoniae.

In vitro susceptibility of Campylobacter fetus subsp. jejuni to N-formimidoyl thienamycin, rosaramicin, cefoperazone, and other antimicrobial agents.

The activities of 11 antimicrobial agents against 36 strains of Campylobacter fetus subsp. jejuni were studied by a broth microdilution method. All strains were susceptible to 7 of the 11 antimicrobial agents. Of the newer agents tested N-formimidoyl thienamycin (MK0787) and rosaramicin had very good activity, whereas cefotaxime, moxalactam, and cefoperazone had poorer activity.

Susceptibility of enterococci and Listeria monocytogenes to N-Formimidoyl thienamycin alone and in combination with an aminoglycoside.

The susceptibilities of 12 strains of enterococci and 10 stains of Listeria monocytogenes to N-formimidoyl thienamycin were determined by a standard broth dilution method. Minimal inhibitory concentrations for L. monocytogenes strains were less than 0.25 micrograms/ml. As a group, strains of Streptococcus faecium were less susceptible than Streptococcus faecalis strains, but even for the latter, the minimal inhibitory concentrations were slightly greater than those previously reported. Minimal bactericidal concentrations against all organisms were many-fold higher than the corresponding inhibitory concentrations. In time-kill studies, combinations of N-formimidoyl thienamycin with gentamicin were synergistic against (or they completely sterilized cultures of) all the enterococcal strains and nine to 10 strains of L. monocytogenes. The magnitude of killing by the combinations was comparable to that previously observed with penicillin-gentamicin combinations. N-Formimidoyl thienamycin-tobramycin combinations were synergistic against those strains of S. faecalis and L. monocytogenes tested, but not against those of S. faecium.

In vitro activity of N-formimidoyl thienamycin, moxalactam, and other new beta-lactam agents against Bacteroides fragilis: contribution of beta-lactamase to resistance.

N-Formimidoyl thienamycin (N-F-thienamycin) and moxalactam were compared with other currently available and investigational antibiotics against 100 clinical isolates of Bacteroides fragilis by an agar dilution method. N-F-thienamycin was the most active among the beta-lactam agents tested, with a minimal inhibitory concentration for 90% of isolates (MIC90) of 0.25 micrograms/ml. Moxalactam was next in activity, with an MIC90 of 4 micrograms/ml. N-F-thienamycin was somewhat more active, and moxalactam was slightly less active, than metronidazole and clindamycin. An increase in inoculum size caused an increase in the MIC of N-F-thienamycin, cefoperazone, and cefotaxime. This inoculum effect could influence the usefulness of these drugs in certain clinical conditions. The minimal bactericidal concentration was less than two times the MIC for most agents and less than four times the MIC for all beta-lactam agents at each inoculum size tested. Investigation of the mechanism of resistance to beta-lactam agents demonstrated a correlation between the level of resistance and beta-lactamase activity in each strain tested. N-F-thienamycin and cefoxitin were not hydrolyzed, and moxalactam was less susceptible to hydrolysis than the other beta-lactam antibiotics. Moxalactam and N-F-thienamycin may prove to be useful against infections with B. fragilis.

Effects of inducible beta-lactamase and antimicrobial resistance upon the activity of newer beta-lactam antibiotics against Pseudomonas aeruginosa.

The activity of carbenicillin, ticarcillin, piperacillin, cefotaxime, moxalactam, and N-formimidoyl thienamycin was evaluated against 262 clinical isolates of Pseudomonas aeruginosa. There were 242 (92%) of the isolates that were susceptible to carbenicillin or ticarcillin by an agar dilution method. Against this population of susceptible isolates, the median MICs were 1.56 microgram/ml of N-formimidoyl thienamycin, 3.13 microgram/ml of piperacillin, 25 microgram/ml of ticarcillin, 25 microgram/ml of cefotaxime, 50 microgram/ml of carbenicillin and 50 microgram/ml of moxalactam. N-Formimidoyl thienamycin was the only beta-lactam antibiotic not affected by an inducible beta-lactamase detected in 24 randomly selected susceptible isolates by a disk approximation assay, while cefotaxime was inactivated to a greater extent than any of the other beta-lactam antibiotics. Resistance to carbenicillin and ticarcillin was noted in 20 isolates (8%); these were susceptible to N-formimidoyl thienamycin, but cross-resistance with piperacillin, cefotaxime, and moxalactam was frequent. Only four of these resistant isolates were found to have a constitutive beta-lactamase. Gentamicin resistance occurred in 51 isolates (19%) and was an independent variable of resistance to the beta-lactam drugs.

In vitro activity of N-formimidoyl thienamycin (MK0787) against resistant strains of Pseudomonas aeruginosa, Staphylococcus epidermidis, Serratia marcescens, and Enterococcus spp.

The in vitro activities of N-formimidoyl thienamycin (MK0787) and nine other antibiotics were tested against 129 clinical isolates, including 71 of enterococci, 34 of Staphylococcus epidermidis, 17 of Pseudomonas aeruginosa, and 7 of Serratia marcescens. These isolates exhibited a variety of resistant patterns: 97% of the enterococci were resistant to moxalactam; 71 and 81% of the S. epidermidis isolates were resistant to methicillin and penicillin, respectively; 47, 53, and 53% of the P. aeruginosa isolates were resistant to carbenicillin, cefotaxime, and moxalactam, respectively; and all S. marcescens isolates were resistant to amikacin, gentamicin, and tobramycin. With respect to concentrations required to inhibit growth of 90% of the isolates, N-formimidoyl thienamycin was more active than any compound tested. Determination of the concentration required to inhibit growth of 50% of the isolates showed N-formimidoyl thienamycin to be more active than any other agent against S. epidermidis, S. marcescens, and enterococci, but against Pseudomonas isolates it was less active than amikacin, gentamicin, and tobramycin. This preparation is potentially useful for patients with serious infection caused by resistant bacteria; enterococcal and S. epidermidis endocarditis infections may be special situations which merit clinical trials.

The activity of gentamicin and N-formimidoyl thienamycin (MK 0787) on Pseudomonas aeruginosa at pH 7.4 and 7.0.

N-Formimidoyl thienamycin is a new β-lactam antibiotic which is active against Pseudomonas aeruginosa. This activity is neither significantly influenced by variations in inoculum density nor by changes in pH. Gentamicin, however, although it does not exhibit an inoculum effect, does lose activity with decreases in pH. It is argued that in order for a rational selection of antibiotics to be made on the basis of in-vitro activity, that the in-vitro system should simulate the in-vivo situation as closely as possible. This should take into account such variables as population densities and local tissue pH as well as cation content.

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.

Effect of N-formimidoyl thienamycin (MK0787) on beta-lactamases and activity against beta-lactamase-producing strains.

N-Formimidoyl thienamycin (MK0787) was active against beta-lactamase-producing strains and was an effective inhibitor of beta-lactamases extracted and purified from these strains except for plasmid-mediated penicillinase type IV.

Susceptibility of Eikenella corrodens to newer beta-lactam antibiotics.

In vitro susceptibility testing of 28 strains of Eikenella corrodens by the agar dilution technique showed that all strains were uniformly susceptible to penicillin, ticarcillin, cefoxitin, cefotaxime, N-formimidoyl thienamycin, and moxalactam and resistant to clindamycin and cefadroxil. Cefoperazone, piperacillin, and mezlocillin showed good activity, with some strains relatively resistant. Bacampicillin and cefamandole showed relatively poor activity.

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 N-formimidoyl thienamycin (MK0787).

The in vitro activity of N-formimidoyl thienamycin (MK0787), a stable congener of thienamycin, was determined against 200 species of aerobic and 84 species of anaerobic bacteria. The compound was highly active against resistant gram-negative bacilli, penicillin-resistant Staphylococcus aureus, enterococci, and anaerobic bacteria. The new derivative of thienamycin was more active than the parent compound, probably reflecting the stability of the analog.

MK0787 (N-formimidoyl thienamycin): evaluation of in vitro and in vivo activities.

The practical application of thienamycin, a novel beta-lactam antibiotic with a broad activity spectrum, was compromised by problems of instability. MK0787, N-formimidoyl thienamycin, does not have this liability. As reported, bacterial species resistant to most beta-lactam antibiotics, such as Pseudomonas aeurginosa, Serratis, Enterobacter, Enterococcus, and Bacteroides spp., are uniformly susceptible to MK0787, usually at one-half the inhibitory level of thienamycin. Bactericidal activity usually occurs at the minimal inhibitory concentration endpoint. Activity was reduced only at the highest inoculum densities tested and by a lessor factor than was observed with reference beta-lactam antibiotic active against P. aeruginosa and beta-lactamase-bearing strains. MK0787 exhibits a broad spectrum of in vivo activity when evaluated parenterally for efficacy against systemic infections in mice. The order of potency in vivo, 0.03 to 0.06 mg/kg for gram-positive species and 0.65 to 3.8 mg/kg for gram-negative infections including Pseudomonas, exceeded that of thienamycin and was at least 10-fold superior to reference beta-lactam antibiotics including two recently developed agents with antipseudomonal activity, cefotaxime and LY127935.

Antibacterial activities of a new stabilized thienamycin, N-formimidoyl thienamycin, in comparison with other antibiotics

The in vitro activity of a new crystalline derivative of thienamycin, N-formimidoyl thienamycin (MK0787), was tested against 46 laboratory reference strains and 2,158 clinical isolates of gram-positive and -negative bacteria, including anaerobes, and compared with cefoxitin, cefaxolin, carbenicillin, and amikacin. MK0787 was significantly more active than the reference antibiotics against most bacteria tests. MK0787 was 16- to 500-fold more active than the other antibiotics against Staphylococcus aureus, Streptococcus pneumoniae, and group A and group B streptococci, inhibiting most isolates at concentrations less than 0.031 micrograms/ml. The inhibition concentration against over 90% of 156 strains of Streptococcus faecalis was 1 micrograms/ml. MK0787 had slightly less activity than carbenicillin against Haemophilus influenzae. The minimal inhibitory concentrations of MK0787 against strains of Enterobacter spp., Citrobacter spp., Serratia marcescems. Pseudomonas aeruginosa, and Clostridium difficile that are resistant to currently available antibiotics were less than or equal to 4 micrograms/ml. The only species found resistant to MK0787 was Pseudomonas maltophilia, which was equally nonsusceptible to the other reference antibiotics.