In Vitro Susceptibility of Nocardia asteroides to N-Formimidoyl Thienamycin and Several Cephalosporins

The susceptibility of N. asteroides to N-formimidoyl thienamycin, cefamandole, cefoxitin, and moxalactam was determined by agar dilution. N-Formimidoyl thienamycin was the most active, inhibiting eight of nine strains at 1.56 μg/ml.     

Comparative In Vitro Activities of N-Formimidoyl Thienamycin and Moxalactam Against Nonfermentative Aerobic Gram-Negative Rods

N-Formimidoyl thienamycin was the most active drug against strains of Pseudomonas aeruginosa with a 90% minimum inhibitory concentration of 1.25 mug/ml. With the exception of P. maltophilia, thienamycin was as active or more active than moxalactam against other species of pseudomonads and against other genera of nonfermenters.     

In Vitro Susceptibility of Clostridium difficile Isolates to Cefotaxime, Moxalactam, and Cefoperazone

The in vitro susceptibility of 20 isolates of Clostridium difficile to cefotaxime, moxalactam, and cefoperazone was determined by a standard agar dilution method. The median minimal inhibitory concentrations were 64, 32, and 32 mug/ml for cefotaxime, moxalactam, and cefoperazone, respectively.     

In Vitro Activity of Thienamycin

The in vitro activity of thienamycin was tested against 135 aerobic and anaerobic bacteria. The compound was highly active against resistant gram-negative bacilli and penicillin-resistant Straphylococcus aureus. The antianaerobic spectrum of the drug seemed to be comparable to that of metronidazole.     

Urinary Recovery of N-Formimidoyl Thienamycin (MK0787) as Affected by Coadministration of N-Formimidoyl Thienamycin Dehydropeptidase Inhibitors

N-Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N-formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N-formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N-formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20% with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N-formimidoyl thienamycin. Thus, at an N-formimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when N-formimidoyl thienamycin was given alone. The ratio of the N-formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N-formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular filtration only, possibly by competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.     

In Vitro Evaluation of N-Formimidoyl Thienamycin (MK0787) Combined with Amikacin Against Gram-Negative Bacilli and Staphylococcus aureus

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.     

Synergism Between N-Formimidoyl Thienamycin and Gentamicin or Tobramycin Against Enterococci

By the time-kill curve method, the combination of N-formimidoyl thienamycin and gentamicin showed synergism against 47 of 48 strains of enterococci, whereas the combination of N-formimidoyl thienamycin and tobramycin was synergistic against 46 strains.     

Piperacillin: In Vitro Evaluation

The in vitro activity of a new semisynthetic penicillin, piperacillin, was determined against 577 clinical isolates of gram-positive cocci and gram-negative bacilli. A concentration of 12.5 mug/ml inhibited 92% of isolates of Pseudomonas aeruginosa, 82% of Serratia marcescens, 73% of Escherichia coli, 61% of Klebsiella spp., and 42% of Enterobacter spp. Most Proteus spp. were extremely susceptible; over 85% were inhibited by 0.10 mug/ml. Piperacillin failed to inhibit the growth of gram-negative bacilli when large inocula were used. The type of media and pH had variable effects on the activity of piperacillin, depending upon the organism. Piperacillin was generally less active than PC-904 against gram-negative bacilli, but was consistently more active than carbenicillin and ticarcillin.     

Synergistic Effect of N-Formimidoyl Thienamycin with Gentamicin and Amikacin Against Streptococcus faecalis

The in vitro activities of N-formimidoyl thienamycin alone and in combination with amikacin and gentamicin were tested against 10 strains of Streptococcus faecalis. Synergy was demonstrated in 35% of the combinations tested by the microtiter checkerboard technique; 50% were found to be synergistic with time killing curves.     

In Vitro Studies of Piperacillin, a New Semisynthetic Penicillin

Piperacillin, a new semisynthetic penicillin, was compared with other semisynthetic penicillins, cephalosporins, and aminoglycosides by the agar dilution method against 3,600 isolates of facultative gram-negative bacilli, Bacteroides fragilis, and enterococci. At 64 μg/ml, piperacillin inhibited 90% of the isolates in each group of organisms tested except for Escherichia coli (83% inhibited by 64 μg/ml). Compared with carbenicillin, piperacillin had a 16-fold increase in activity by weight against Pseudomonas aeruginosa and the enterococcus, an 8-fold increase against Serratia marcescens, and a 4-fold increase against B. fragilis and Enterobacter species. Piperacillin was highly active against carbenicillin-resistant Klebsiella pneumoniae and inhibited many aminoglycoside-resistant organisms. Except for P. aeruginosa, the minimum bactericidal concentration of piperacillin was usually within one tube dilution of the minimum inhibitory concentration. Approximately one-third of the gram-negative bacilli were inhibited synergistically by piperacillin plus amikacin, but no synergy could be demonstrated against enterococci. Piperacillin's in vitro activity against gram-negative bacilli was similar to gentamicin's except that it also included B. fragilis, and piperacillin was decidedly superior to presently available penicillins against K. pneumoniae.     

In Vitro Activity of Cefotaxime Against Cephalothin-Resistant Clinical Isolates

Cefotaxime is more active than six other cephalosporins against 150 cephalothin-resistant Enterobacteriaceae strains and is the only drug which is more active than ampicillin against Haemophilus. It shows a potentially useful activity against Pseudomonas.     

Comparative In Vitro Appraisal of Piperacillin, Including Its Activity Against Salmonella typhi

Piperacillin was evaluated in vitro against 711 clinical isolates of aerobic and anerobic gram-positive and gram-negative bacteria, including 76 isolates of Salmonella typhi. Piperacillin minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were compared with those of a range of β-lactam, aminoglycoside, and other antimicrobial agents, and inoculum size effects were considered. The relationship between dilution and disk diffusion tests was studied by regression analysis. In addition, piperacillin was assessed in combination with aminoglycoside and other β-lactam drugs. This investigation has confirmed the activity of piperacillin against a broad range of bacteria, including Pseudomonas, Enterobacteriaceae, Neisseria, β-lactamase-negative Haemophilus influenzae, and Staphylococcus aureus as well as enterococci, Bacteroides fragilis, and other anaerobes. All strains of Pseudomonas aeruginosa were inhibited by ≤32 μg/ml or less, demonstrating again the potential usefulness of piperacillin in the treatment of pseudomonal infections. S. typhi proved susceptible to piperacillin, all isolates being inhibited by 1 μg/ml. Inoculum size experiments showed that inocula of 10⁸ CFU resulted in MICs and MBCs appreciably higher than those resulting from inocula of 10⁶ CFU, and inocula of 10² CFU resulted in MICs and MBCs appreciably lower than those resulting from inocula of 10⁴ CFU. Piperacillin was active against all gentamicin-resistant pseudomonads tested, but not against gentamicin-resistant klebsiellas and enterobacters. Combinations of piperacillin with tobramycin and amikacin were consistently synergistic against Pseudomonas and Serratia isolates. Less consistent results were shown when piperacillin was combined with aminoglycosides or cephalothin against Klebsiella and indole-positive Proteus isolates, although synergy was observed in most cases. Occasional antagonistic reactions were encountered with piperacillin-cephalothin or piperacillin-tobramycin combinations against the latter isolates.     

Comparison of the In Vitro Activity of Bay k 4999 and Piperacillin, Two New Antipseudomonal Broad-Spectrum Penicillins, with Other β-Lactam Drugs

Bay k 4999 and piperacillin, two new substituted ampicillins, were compared with other beta-lactam antibiotics, including carbenicillin, azlocillin, mezlocillin, benzylpenicillin, ampicillin, and cefoxitin, against a wide range of gram-positive and -negative organisms. Bay k 4999 and piperacillin were extremely active against Pseudomonas aeruginosa (50% inhibited by 2 mug/ml), being about 16-fold more active than carbenicillin. Bay k 4999 was the most active drug against Escherichia coli (50% inhibited by 0.5 mug/ml) and Klebsiella spp. (50% inhibited by 2 mug/ml). Piperacillin and Bay k 4999 were equally active against Proteus spp., and piperacillin had high activity against Bacteroides fragilis (50% inhibited by between 1 and 2 mug/ml).     

Comparative Evaluation of Piperacillin in Vitro

The minimal inhibitory concentrations of piperacillin and seven other betalactam antibiotics were determined against 407 bacterial isolates. Piperacillin was found to be more active than ampicillin against susceptible gram-negative bacilli and more active than either carbenicillin or ticarcillin against Pseudomonas aeruginosa and streptococci. Although piperacillin was active against Klebsiella pneumoniae, this activity was less than that of the cephalosporins. Piperacillin was not active against penicillin-resistant Staphylococcus aureus and Enterobacteriaceae that were resistant to the other test antibiotics.     

Comparative In Vitro Activity of Azlocillin, Ampicillin, Mezlocillin, Piperacillin, and Ticarcillin, Alone and in Combination with an Aminoglycoside

The in vitro activities of the newer semisynthetic penicillins azlocillin, mezlocillin, and piperacillin were compared with those of ampicillin and ticarcillin by using 290 clinical laboratory isolates. Piperacillin and mezlocillin were the most active against Escherichia coli, Proteus mirabilis, Klebsiella spp., and Enterobacter spp. When Pseudomonas aeruginosa was tested, piperacillin and azlocillin were more active than either mezlocillin or ticarcillin. Streptococcus pneumoniae and Haemophilus influenzae species were highly susceptible to all of the penicillins tested. Ticarcillin had relatively poor activity against enterococci. The rate of bacterial killing with multiples of the minimal inhibitory concentration of azlocillin, ampicillin, or ticarcillin was tested for E. coli, P. mirabilis, P. aeruginosa, and Klebsiella spp. Increasing concentrations increased the bactericidal effect. The effect of combining azlocillin, ampicillin, or ticarcillin with an aminoglycoside was studied by using both killing curves and checkerboards. The isobolograms constructed from the checkerboards showed a synergistic pattern for the organisms tested, which included E. coli, P. aeruginosa, Klebsiella spp., P. mirabilis, and enterococci. However, the rate of killing was increased by the combination only for P. aeruginosa and enterococci.     

In Vitro Comparison of Cefoxitin, Cefamandole, Cephalexin, and Cephalothin

The in vitro effect of cefoxitin, cefamandole, cephalexin, and cephalothin was tested against 645 strains of bacteria recently isolated from clinical sources. Against gram-positive organisms cephalothin and cefamandole were the most effective, generally being three- to fourfold more active than cephalexin or cefoxitin. Enterococci were not inhibited by less than 25 μg of any of the antibiotics per ml. Against Enterobacteriaceae, cefoxitin and cefamandole were the most active. An exception was the Enterobacter strains, against which cefoxitin was the least effective. None of the Pseudomonas aeruginosa strains were susceptible to 100 μg of any of the cephalosporins per ml. Cefamandole was the most active agent against Neisseria meningitidis and Neisseria gonorrhoeae. It was also the most effective agent against Haemophilus influenzae, even when taking into account a threefold inoculum effect.     

In Vitro Comparison of Gentamicin, Tobramycin, Sisomicin, and Netilmicin

The antimicrobial activity of gentamicin, tobramycin, sisomicin, and netilmicin (Sch 20569) was compared against 150 strains of organisms. Netilmicin was shown to be the least effective against Pseudomonas strains but to have slightly better activity against Staphylococcus aureus and Escherichia coli than the other agents. The effect of calcium and magnesium in enhancing the differences in activity of these aminoglycosides against Pseudomonas strains was also demonstrated.     

Comparison of In Vitro Activity of Cephalexin, Cephradine, and Cefaclor

Inhibitory activity of cephalexin, cephradine, and cefaclor was compared by the WHO-ICS agar dilution technique. Cefaclor was substantially more active against staphylococci, streptococci, gonococci, meningococci, Haemophilus, Escherichia coli, Klebsiella pneumoniae, Citrobacter diversus, Proteus mirabilis, salmonellae, and shigellae than was cephalexin, which in turn was more active than cephradine. Cefaclor appeared to be less resistant to staphylococcal penicillinase than did the other two agents. None of these cephalosporins was active against Enterobacter, Serratia, indole-positive Proteeae, Pseudomonas, or Bacteroides fragilis.