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.     

Susceptibility of group B streptococci to 16 beta-lactam antibiotics, including new penicillin and cephalosporin derivatives

The susceptibility of 100 group B streptococci to 16 beta-lactam antibiotics was tested by agar dilution. Penicillin G and N-formimidoyl thienamycin were the most active agents tested, both having a 90% minimal inhibitory concentration (MIC90) of 0.06 microgram/ml. Ceftriaxone, cefotaxime, cefamandole, and SCH 29482 were almost as active, all having an MIC90 of 0.12 microgram/ml, and ampicillin, cephalothin, and mezlocillin all had an MIC90 of 0.25 microgram/ml. The MIC90 for piperacillin, cefoperazone, and ceftazidime was 0.5 microgram/ml. Least active were carbenicillin, ticarcillin, cefoxitin, and moxalactam, with MIC90s of 1, 2, 4, and 8 micrograms/ml, respectively. No penicillin-tolerant strains were detected.     

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.     

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.     

Susceptibility of penicillin-resistant pneumococci to eighteen antimicrobials: implications for treatment of meningitis

The minimal inhibitory concentrations (MICs) of 18 antibiotics including 16 beta-lactam antibiotics were determined by agar dilution on 70 strains of pneumococci (25 penicillin sensitive, 18 intermediate resistant and 27 resistant). The antimicrobials tested were penicillin G, ampicillin, carbenicillin, ticarcillin, piperacillin, mezlocillin, cephalothin, cefoxitin, cefamandole, latamoxef (moxalactam), cefotaxime, cefoperazone, ceftazidime, ceftriaxone, N-formimidoyl thienamycin, SCH 29482, chloramphenicol and vancomycin. Of these agents, only cefotaxime demonstrated greater activity than penicillin against intermediate penicillin-resistant strains while cefoperazone, ceftriaxone, N-formimidoyl thienamycin and vancomycin as well as cefotaxime demonstrated activity superior to penicillin against penicillin-resistant strains. Comparison of the MIC90s of these agents with the achievable cerebrospinal fluid levels suggests that meningitis caused by penicillin-resistant pneumococci should respond to treatment with cefotaxime, cefoperazone, ceftriaxone and vancomycin.     

In vitro activity of new beta-lactam antibiotics and other antimicrobial drugs against anaerobic isolates from obstetric and gynecological infections.

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.     

In vitro activity of cefpimizole sodium (U-63196E) and other antimicrobial agents against Haemophilus isolates from pediatric patients

In vitro activity of cefpimizole, an experimental third generation cephalosporin, and 10 other antimicrobials (ampicillin, azlocillin, cefamandole, cefoperazone, cefotaxime, mezlocillin, moxalactam, piperacillin, rifampin and sulfamethoxazole/trimethoprim) were determined for 181 isolates of Haemophilus obtained from pediatric patients. For 156 beta-lactamase-negative isolates, MIC50 values of cefoperazone, cefpimizole, and cefamandole were 4, 8, and 16 times greater than those of moxalactam and cefotaxime (0.06 micrograms/ml). 25 beta-lactamase-producing isolates were resistant to ampicillin, azlocillin, mezlocillin, and piperacillin, however, MIC50 of all third generation cephalosporin were similar to those obtained for beta-lactamase-negative organisms. Rifampin and SMX/TMP demonstrated low MIC50 values for all isolates.     

Evaluation of the in vitro activity of BMY-28142, a new broad-spectrum cephalosporin.

The in vitro activity of BMY-28142, a new cephalosporin, was tested by a broth microdilution system and compared with those of cefotaxime, ceftazidime, cefoperazone, moxalactam, and HR 810 against 747 bacterial isolates, one-third of which were resistant to one or more third-generation cephalosporins. BMY-28142 was the most active drug tested against 326 Enterobacteriaceae with an MIC for 90% of the organisms tested (MIC90) of 1.0 micrograms/ml. Against these Enterobacteriaceae the relative activities were: BMY-28142 greater than HR 810 greater than moxalactam and ceftazidime greater than cefotaxime greater than cefoperazone. For cefotaxime- and cefoperazone-resistant strains, the MIC90 of BMY-28142 was 4.0 micrograms/ml (compared with 0.13 micrograms/ml for susceptible strains). BMY-28142, with an MIC90 of 8.0 micrograms/ml for Pseudomonas aeruginosa, was about half as active as ceftazidime. The relative activities against P. aeruginosa were: ceftazidime greater than BMY-28142 greater than HR 810 greater than cefoperazone greater than moxalactam and cefotaxime. The MIC90 of BMY-28142 against staphylococci was 2.0 micrograms/ml, which was fourfold less active than HR 810, slightly less active than cefotaxime and cefoperazone, and fourfold more active than ceftazidime and moxalactam. BMY-28142 was very active against beta-lactamase-positive and -negative Haemophilus influenzae (MIC90, 0.06 micrograms/ml), Neisseria gonorrhoeae (MIC90, 0.015 micrograms/ml),aand nonenterococcal streptococci. Its activity against Streptococcus faecalis was poor (MIC90, 64 micrograms/ml). BMY-28142 was stable against the several beta-lactamases tested but exhibited little beta-lactamase inhibitory effect.     

Antibiotic susceptibility of community hospital blood culture isolates of gram-negative bacilli

The comparative in vitro activity of amikacin, cefamandole, cefoperazone, cefotaxime, cefoxitin, cephalothin, chloramphenicol, moxalactam, piperacillin, ticarcillin and tobramycin against 170 community blood culture isolates of gram-negative bacilli was investigated using the quantitative plate dilution method. Results showed that amikacin, cefoperazone, cefotaxime, moxalactam, piperacillin and tobramycin were most active on a weight basis. Tobramycin and amikacin were quite active against Pseudomonas aeruginosa but one isolate showed an MIC of 50 micrograms/ml to both. The order of activity of the remaining drugs for P. aeruginosa was cefoperazone greater than moxalactam greater than cefotaxime and piperacillin greater than ticarcillin.     

Piperacillin, tazobactam, and gentamicin alone or combined in an endocarditis model of infection by a TEM-3-producing strain of Klebsiella pneumoniae or its susceptible variant.

The efficacy of tazobactam, a beta-lactamase inhibitor, in combination with piperacillin, was studied in vitro and in rabbit experimental endocarditis due to a Klebsiella pneumoniae strain (KpR) producing an extended-spectrum beta-lactamase, TEM-3, or its nonproducing variant (KpS). In vitro, piperacillin was active against KpS (MIC = 4 micrograms/ml, MBC = 8 micrograms/ml with 10(7)-CFU/ml inoculum) but not against KpR (MIC = MBC = 256 micrograms/ml). Tazobactam (1 microgram/ml) restored the activity of piperacillin against KpR (MIC = 2 micrograms/ml, MBC = 4 micrograms/ml). Gentamicin was active against both strains (MIC = 0.25 and 0.5 micrograms/ml for KpS and KpR, respectively). The piperacillin-tazobactam-gentamicin combination was synergistic in vitro. The piperacillin/tazobactam ratio in plasma and in vegetations was always lower than the 4/1 injected dose ratio. In vivo, piperacillin (300 mg/kg of body weight four times a day [QID]) was active against KpS but not against KpR. Tazobactam (75 mg/kg QID) was able to restore the in vivo effect of piperacillin (300 mg/kg QID) against KpR (-3.0 log10 CFU/g of vegetation versus that of controls). Gentamicin (4 mg/kg twice a day [BID]) was active against both strains. Compared with controls, the combination of gentamicin plus piperacillin against KpS (-5.6 log10 CFU/g of vegetation), and the gentamicin-piperacillin-tazobactam combination against KpR (-4.4 log10 CFU/g of vegetation) achieved the greatest decrease in bacterial counts in vegetations and were the only regimens that significantly increased the proportion of sterile vegetations. It is concluded that (i) tazobactam was able to restore the effect of piperacillin against a TEM-3 extended-spectrum Beta-lactamase-producing strain of K. pneumoniae, both in vitro and in a severe experimental infection with high inoculum, when used in a 4/1 piperacillin/tazobactam dose ratio; (ii) gentamicin alone was effective because of the high peak/MBC ratio in plasma; (iii) piperacillin-tazobactam-gentamicin, probably because of the effect of gentamicin in reducing bacterial inoculum in vivo, as stressed by the results obtained by piperacillin-gentamicin against KpS, may be the most effective regimen against KpR.     

In Vitro Comparison of N-Formimidoyl Thienamycin, Piperacillin, Cefotaxime, and Cefoperazone

The antibacterial activity of N-formimidoyl thienamycin was compared with those of cefotaxime, cefoperazone, and piperacillin against 536 clinical aerobic isolates.     

In vitro activity of cefbuperazone compared with that of other new beta-lactam agents against anaerobic gram-negative bacilli and contribution of beta-lactamase to resistance.

Cefbuperazone was compared with other currently available and investigational antibiotics against 278 clinical isolates of anaerobic gram-negative bacilli by an agar dilution method. Cefbuperazone and cefotetan were equally active against Bacteroides fragilis, with 8% of the organisms tested found to be resistant to 32 micrograms of either drug per ml. Cefoperazone, cefotaxime, ceftriaxone, and cefmetazole were less active against these strains; cefoxitin, moxalactam, piperacillin, clindamycin, and metronidazole were more active. None of the agents were consistently active against any of the other anaerobic gram-negative bacilli except imipenem, for which the minimum concentration required to inhibit 90% of all strains tested was 4 micrograms/ml. A 10,000-fold increase in inoculum size caused an increase in the MIC of ceftriaxone, cefotaxime, and cefoperazone but not of cefbuperazone, cefotetan, or cefoxitin. Investigation of the mechanism of resistance to cephalosporin-like agents demonstrated a correlation between the level of resistance and beta-lactamase activity. Cefbuperazone, cefotetan, and cefoxitin were not hydrolyzed, had lower MICs, and were less affected by changes in inoculum size than were cefotaxime, ceftriaxone, and cefoperazone.     

Comparative in vitro antimicrobial activity of carumonam, a new monocyclic beta-lactam.

The antimicrobial activity of carumonam (formerly RO-17-2301), a monocyclic beta-lactam antibiotic, was compared with those of aztreonam, cefotaxime, cefoperazone, ceftazidime, piperacillin, and gentamicin against 455 bacterial isolates. Carumonam did not possess activity against gram-positive cocci and was generally comparable to aztreonam and ceftazidime for most gram-negative bacilli. However, carumonam was the most active beta-lactam against gentamicin-resistant Pseudomonas aeruginosa strains (90% MIC, 8 micrograms/ml).     

Pseudomonas aeruginosa: in vitro susceptibility to antimicrobial drugs, single and combined, with and without defibrinated human blood

Twelve clinical isolates of Pseudomonas aeruginosa of distinct pyocin type varied in susceptibility to 14 of 17 antimicrobial drugs. The 2 x MIC concentrations of 16 antimicrobial drugs combined with 55% (v/v) of fresh, defibrinated human blood yielded additive effects. Additive effects were noted with blood plus the MIC concentrations of all drugs tested except cefoperazone, gentamicin, and netilmicin. Blood combined with subinhibitory (1/2 MIC) concentrations of aztreonam, ceftazidime, ciprofloxacin, fleroxacin, imipenem, and tobramycin, respectively, yielded additive effects; indifferent effects were observed with the remaining 10 blood plus 1/2 MIC drug combinations. The following drug combinations additively augmented the antibacterial activity of 65% (v/v) of human blood against two selected isolates of P. aeruginosa: tobramycin (1 microgram/ml) plus the MIC or 2 x MIC concentrations of azlocillin, aztreonam, ceftazidime, ciprofloxacin, imipenem, norfloxacin, ofloxacin, piperacillin, and ticarcillin, respectively. Imipenem (8 micrograms/ml) combined with ceftazidime, cefoperazone, and piperacillin, but not aztreonam, enhanced the bactericidal activity of human blood. Rifampin (2 micrograms/ml) plus tobramycin (0.5-1 microgram/ml) combined with 8 or 16 micrograms/ml of azlocillin, aztreonam, cefoperazone, ceftazidime, imipenem, and piperacillin, respectively, enhanced blood-mediated killing of three representative multiple-drug-resistant P. aeruginosa isolates. Additional effective triple-drug combinations with human blood were rifampin + tobramycin + polymyxin B, rifampin + ciprofloxacin + imipenem, and rifampin + amikacin + imipenem. Ciprofloxacin (2 micrograms/ml) was the most potent intraphagocytic bactericidal drug of 16 tested agents (greater than or equal to 2 x MBC concentrations) against P. aeruginosa control strain ATCC 27853.     

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.     

Assessment of serum bactericidal activity after administration of cefoperazone, cefotaxime, ceftizoxime, and moxalactam to healthy subjects.

Bactericidal activity in serum produced after administration of 1-g intravenous doses of cefoperazone, cefotaxime, ceftizoxime, and moxalactam was ascertained in six healthy subjects. The assay organisms were a strain of Staphylococcus aureus which was moderately susceptible to the drugs (MBC, 2 to 8 micrograms/ml) and an isolate of Escherichia coli which was highly susceptible (MBC, 0.08 to 0.3 microgram/ml). Drug concentrations and bactericidal titers were measured from samples taken for up to 12 h after the dose. No bactericidal activity against the S. aureus strain was found at 4 to 6 h and beyond for any of the drugs. Ranking of the in vivo bactericidal activity of the drugs was cefoperazone = cefotaxime greater than ceftizoxime = moxalactam. Against the E. coli isolate, bactericidal activity was present for 8 h for cefotaxime, and for 12 h for the other drugs. Ranking of the drugs in terms of extent and duration of in vivo bactericidal activity versus E. coli was moxalactam = ceftizoxime greater than cefoperazone greater than cefotaxime. After administration of 1-g doses of these new beta-lactams, bactericidal activity in serum was maintained for 12 h against highly susceptible bacteria. More frequent (6 to 8 h) or higher (greater than or equal to 2 g) dosing appears to be necessary to achieve prolonged serum bactericidal activity against less susceptible isolates (MBC, greater than or equal to 2 to 8 micrograms/ml).     

In vitro susceptibility of Clostridium difficile to new beta-lactam and quinolone antibiotics.

The in vitro susceptibilities of 34 to 73 clinical isolates of Clostridium difficile to 24 antimicrobial agents, including 18 beta-lactams, 4 fluoroquinolones, clindamycin, and metronidazole were examined. Metronidazole was the most active (MIC for 90% of the isolates [MIC90], 0.5 microgram/ml), followed by the carbapenems (Sch 34343, 4 micrograms/ml; imipenem, 8 micrograms/ml) and the antipseudomonas penicillins (piperacillin, 8 micrograms/ml; ticarcillin, 32 micrograms/ml; carbenicillin, 32 micrograms/ml). A monobactam (aztreonam) and most cephalosporins were either highly inactive (cefoxitin, cefuroxime, cefotiam, cefsulodin, ceftizoxime, cefbuperazone, and cefotaxime), with an MIC90 of greater than or equal to 128 micrograms/ml, or moderately inactive (ceftriaxone, cefmenoxime, cefoperazone, ceftazidime, and moxalactam), with an MIC90 of greater than or equal to 32 micrograms/ml. Clindamycin (MIC90, 32 micrograms/ml) and the fluoroquinolones (ciprofloxacin, 8 micrograms/ml; A-56619, 8 micrograms/ml; A-56620, 8 micrograms/ml; norfloxacin, 32 micrograms/ml) were only variably active. These in vitro data per se may not necessarily predict the relative risks for C. difficile-associated diarrhea or colitis during therapy with these agents. However, these data, in concert with knowledge of drug bioavailability in feces and the broad-spectrum antimicrobial activity on the resident bowel flora, may provide additional insight into the mechanisms and predictability of this complication with these agents. Careful monitoring for the emergence of C. difficile and fecal cytotoxin and for diarrhea during therapy with these agents is clearly indicated.     

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.     

Comparative activities of piperacillin and tazobactam against clinical isolates of Legionella spp.

We evaluated the in vitro activity of piperacillin alone or in combination with the beta-lactamase inhibitor tazobactam against clinical isolates of Legionella species. At an inoculum of approximately 10(4) CFU, tazobactam, piperacillin, and the 8:1 combination had equivalent activities against Legionella spp. At an approximately 10-fold higher inoculum, the following results were obtained, expressed as MICs for 50 and 90% of strains tested (MIC range): piperacillin, 4 and 16 (0.25 to 32) micrograms/ml; tazobactam, 0.5 and 1 (0.125 to 2) micrograms/ml; and piperacillin-tazobactam (expressed in terms of MIC of piperacillin) 0.5 and 1 (0.03 to 2) micrograms/ml. Tazobactam alone and the combination with piperacillin were more active than piperacillin alone at the higher inoculum.     

In vitro activity of cefbuperazone, a new cephamycin, against anaerobic bacteria.

The 90% MIC of cefbuperazone (BMY 25182) was 32 micrograms/ml for Bacteroides fragilis and Bacteroides spp., 128 micrograms/ml for Fusobacterium and Clostridium spp., 64 micrograms/ml for Eubacterium and Peptococcus spp., 8 micrograms/ml for Actinomyces spp., and 32 micrograms/ml for Peptostreptococcus spp. The level of activity of cefbuperazone was higher against B. fragilis and lower against anaerobic cocci than those of related cephalosporins, i.e., cefoxitin, cefoperazone, cefotaxime, ceftizoxime, and cefmenoxime. However, the activity of cefbuperazone was comparable to that of moxalactam against all groups tested. Size of inoculum and type of media used did not alter the MICs of cefbuperazone for B. fragilis. Cefbuperazone showed synergistic activity when combined with cefoxitin against resistant strains of B. fragilis.