Search

The in vitro activity of FK-037, 5-amino-2-[[(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2- methoxyimino) acetyl] amino]-2-carboxy-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-(2-hydroxyethyl)-1H-pyrazoli um hydroxide, inner salt, sulfate (1:1), a new parenteral cephem, was compared with those of cefepime, ceftazidime, imipenem, and ciprofloxacin. FK-037 inhibited methicillin-susceptible staphylocci at < or = 4 micrograms/ml. Of 98 isolates of homogenous methicillin-resistant Staphylococcus aureus, 55 (56.1%) were inhibited by 8 micrograms of FK-037 per ml, compared to 3.1% for cefepime. Imipenem was the most active beta-lactam tested against staphylococci. The MIC of FK-037 for 90% of the strains tested (MIC90) was 0.06 micrograms/ml for hemolytic streptococci, Streptococcus pneumoniae, viridans group streptococci, and Streptococcus bovis. The MIC90 for many of the members of the family Enterobacteriaceae was 1 microgram/ml, similar to that of cefepime and lower than those of ceftazidime and imipenem. The MIC90 for Klebsiella pneumoniae and Enterobacter cloacae was 8 micrograms/ml, similar to that for cefepime, but all isolates were inhibited by 2 micrograms of imipenem per ml. K. pneumoniae isolates with cefotaxime and ceftazidime MICs of > 32 micrograms/ml with Bush type 2b' beta-lactamases were inhibited by 4 micrograms of FK-037 per ml. E. cloacae, Citrobacter freundii, and S. aureus stably resistant to FK-037 could be selected by repeated transfer in the presence of FK-037. The FK-037 MIC90 for Pseudomonas aeruginosa was 4 microgram/ml, compared to 32 microgram/ml for cefepime and ceftazidime and 8 microgram/ml for imipenem. Xanthomonas maltophilia, Pseudomonas cepacia, Acinetobacter anitratus, and Bacteroides species were resistant to FK-037 (MIC, more than or equal 32 microgram/ml). MBCs were identical to or within twofold of the MICs except for a 32-fold greater MBC for P. aeruginosa. Inoculum size and acid environment did not lower the activity of FK-037. FK-037 was not appreciably hydrolyzed by Bush group 1, 2a, 2b, and 2e beta-lactamases but was hydrolyzed by 2b' and 2d enzymes at rates comparable to that of ceftazidime. Nonetheless, FK-037 inhibited bacteria possessing TEM-3, -5, and -7 and SHV -5 at less than or equal 8 microgram/ml. Overall, FK-037 has lower MICs against staphylococci and P. aeruginosa than the currently available iminomethoxy aminothiazolyl cephalosporins and has activity against members of the family Enterobacteriaceae comparable to that of cefepime.

The in vitro activity of LJC 10,627, a new carbapenem, was compared with those of imipenem, cefotaxime, ceftazidime, and gentamicin. LJC 10,627 inhibited 90% of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Hafnia alvei, Citrobacter freundii, Citrobacter diversus, Proteus mirabilis, Morganella morganii, Proteus rettgeri, Serratia marcescens, Pseudomonas cepacia, salmonellae, shigellae, aeromonas, and yersiniae at less than or equal to 2 micrograms/ml. Haemophilus influenzae was inhibited by 0.5 microgram/ml, and moraxellae were inhibited by 0.12 microgram/ml. LJC 10,627 was twofold more active than imipenem against aerobic gram-negative organisms and inhibited ceftazidime-, cefotaxime-, and gentamicin-resistant members of the genera Klebsiella, Enterobacter, Citrobacter, and Serratia at less than or equal to 2 micrograms/ml. Xanthomonas maltophilia strains were resistant to the drug. Imipenem was two- to fourfold more active than LJC 10,627 against Staphylococcus aureus and Staphylococcus epidermidis. LJC 10,627 did not inhibit most methicillin-resistant Staphylococcus aureus or methicillin-resistant Staphylococcus epidermidis strains. LJC 10,627 inhibited Streptococcus pyogenes and Streptococcus pneumoniae at 0.06 and 0.12 microgram/ml, respectively. Bacteroides fragilis and other Bacteroides spp. were inhibited by 0.5 microgram of LJC 10,627 per ml. Serum (50%) did not affect the MICs. LJC 10,627 was not hydrolyzed by plasmid-mediated beta-lactamases of Bush types 2b, 2b', TEM-1, TEM-2, TEM-3, TEM-5, TEM-7, TEM-9, and SHV-1; the chromosomal beta-lactamases of Bush type 1; P-99; a Morganella enzyme; or a Citrobacter freundii enzyme. The Bush type 2c and 2d enzymes OXA-1, OXA-2, PSE-1, PSE-2, and PSE-4 did not hydrolyze LJC 10,627, nor did the beta-lactamases of Staphylococcus aureus, Moraxella spp., Bacteroides fragilis, and Proteus vulgaris. The beta-lactamase of Xanthomonas hydrolyzed LJC 10,627, albeit at approximately one-third the rate that imipenem was hydrolyzed.

HR 916B is a new orally absorbed cephalosporin. In tests its active metabolite, RU29246, inhibited Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus pneumoniae at less than or equal to 0.12 micrograms/ml, which is similar to the antibacterial activity of cefuroxime, and was more active than cefaclor. It was also more active (MIC 2 micrograms/ml) than cefixime, cefuroxime, cefaclor and cefotaxime against staphylococci. RU29246 inhibited Escherichia coli, Klebsiella pneumoniae, Citrobacter diversus, Klebsiella oxytoca, Proteus mirabilis, Providencia stuartii and Salmonella spp. at less than or equal to 1 microgram/ml, thus being more active than cefuroxime and cefaclor, but was less active than cefixime and cefotaxime. It did not inhibit Pseudomonas aeruginosa and other Pseudomonas spp., Enterobacter spp., Serratia marcescens or Bacteroides fragilis. RU29246 was not hydrolyzed by TEM-1, Staphylococcus aureus TEM-2 or Moraxella catarrhalis beta-lactamases, but was hydrolyzed by TEM-3 and the chromosomal beta-lactamases of Proteus vulgaris and Morganella morganii. Plasmid and chromosomal beta-lactamases were inhibited by RU29246.

GR69153, a new parenteral cephalosporin, inhibited 90% of Escherichia coli, Klebsiella oxytoca, Proteus mirabilis, Citrobacter diversus, shigellae, and salmonellae at less than 0.25 micrograms/ml (MIC90). It had activity comparable to those of ceftazidime, cefpirome, cefepime, and E-1040. Against cephalosporinase-producing Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens, MICs ranged from 0.12 to greater than 32 micrograms/ml, and cefpirome and cefepime were the most active agents against these species. Pseudomonas aeruginosa was highly susceptible to GR69153, and for this organism the MIC90 was less than or equal to 2 micrograms/ml, which was similar to the E-1040 MIC90, but most Pseudomonas cepacia and Xanthomonas maltophilia isolates were resistant. GR69153 inhibited Haemophilus influenzae and Moraxella branhamella at less than or equal to 0.5 micrograms/ml. For Staphylococcus aureus GR69153 MICs were similar to those of ceftazidime and E-1040. Enterococci and listeriae were resistant to GR69153, but Streptococcus pyogenes and Streptococcus pneumoniae were inhibited by 0.5 micrograms/ml. The activity of GR69153 was not affected by serum. GR69153 was not inactivated by the beta-lactamases of Staphylococcus aureus, TEM-1, TEM-2, SHV-1, and BRO-1, but it was hydrolyzed by TEM-3, TEM-9, and morganellae. GR69153 had overall activity comparable to those of commercially available parenteral cephalosporins or those found in clinical investigations. It is more active against bacteroides than most available aminothiazolyl parenteral cephalosporins are. GR69153 is hydrolyzed by the new plasmid beta-lactamases, and thus, its primary value may be related to its pharmacological properties.

BMY-28232, an aminothiazolyl imino methoxy cephalosporin which is available as an orally absorbed acetoxyethyl ester, inhibited strains of methicillin-susceptible Staphylococcus aureus, hemolytic streptococci, Streptococcus pneumoniae, Escherichia coli, Klebsiella species, and many strains of Proteus and Providencia stuartii at concentrations less than 1 microgram/ml, including isolates resistant to cephalexin and cefaclor. It had activity similar to that of cefixime, but was more active against methicillin-susceptible staphylococci. BMY-28232 was a poor substrate for beta-lactamases but was destroyed by the new TEM-3 enzyme, and had less activity against Enterobacter species, Citrobacter freundii, and Proteus vulgaris isolates. Methicillin-resistant staphylococci, Pseudomonas species, enterococci, Listeria monocytogenes, Corynebacterium jeikeium, Bacteroides fragilus and some strains of Clostridium species were resistant to BMY-28232.

The activity of the new oral cephalosporin Bay v 3522 was compared to that of six other beta-lactam agents. Bay v 3522 inhibited methicillin-susceptible Staphylococcus aureus and Staphylococcus epidermidis at less than or equal to 2 micrograms/ml, compared to MICs of greater than or equal to 8 micrograms/ml for the other cephalosporins tested. It was more active against Streptococcus pyogenes (MIC less than or equal to 0.06 microgram/ml) than cefuroxime, cefixime, cephalexin and cefaclor. Groups B, C and G streptococci were inhibited at less than or equal to 0.12 microgram/ml, while the MI"90 for Streptococcus bovis and viridans streptococci was 0.5 and 2 micrograms/ml, respectively. The MIC90 for enterococci and Listeria monocytogenes was 8 micrograms/ml. Clostridium perfringens was inhibited by 0.12 microgram/ml, but most Bacteroides spp. were resistant. The MIC90 for beta-lactamase positive Escherichia coli (producing primarily TEM-1) was greater than 64 micrograms/ml and for beta-lactamase negative strains 16 micrograms/ml. The MIC90 for high-level beta-lactamase producing Klebsiella pneumoniae was greater than 64 micrograms/ml versus 4 micrograms/ml for other isolates. The MIC90 for Moraxella catarrhalis was 2 micrograms/ml, for Haemophilus influenzae 1 micrograms/ml, and for Neisseria gonorrhoeae 4 micrograms/ml. Enterobacter cloacae, Citrobacter freundii, Proteus mirabilis, Providencia spp. and Pseudomonas aeruginosa were resistant. Bay v 3522 was destroyed by TEM-1, SHV-1, TEM-3 and P99 beta-lactamases.

beta-Lactamases have been known since the early 1940s when they were recognized as a major mechanism of resistance in Staphylococcus aureus. The synthesis of semisynthetic penicillins provided agents that overcame the resistance of staphylococci, but as gram-negative bacteria became increasingly important as the cause of infections, plasmid-mediated beta-lactamases were recognized in the Enterobacteriaceae, Haemophilus, and chromosomally mediated beta-lactamases in Klebsiella, and Bacteroides were found to be the mechanism of resistance of these species to ampicillin and related penicillins. Two approaches to the problem have been developed. One is to make stable compounds. This has been possible in the cephalosporin family. The other method has been to find inhibitors of beta-lactamases. Clavulanate is a beta-lactamase inhibitor that, in combination with amoxicillin, allows the combination to inhibit many of the organisms that are resistant to amoxicillin. Similarly, clavulanate has been combined with ticarcillin to provide a parenteral agent to inhibit beta-lactamase-producing bacteria and retain activity against Pseudomonas. Sulbactam has been combined with ampicillin. The combination of suicide inhibitors with other beta-lactams has provided agents that inhibit many of the bacteria present in mixed cutaneous infections. Clinical studies have established the efficacy of the clavulanate-amoxicillin and clavulanate-ticarcillin combinations in skin and skin-structure infections. These agents offer an alternative to other drugs when treating cutaneous infections.

Pyridinium-2-azo-p-dimethylaniline chromophore was evaluated as a test tube, filter paper and spectrophotometric assay for detection of beta-lactamases from gram-positive and gram-negative organisms. Although useful for detection of TEM beta-lactamases in Haemophilus influenzae and Neisseria gonorrhoeae, it was a poor agent for detecting TEM, OXA and PSE enzymes in Enterobacteriaceae. It also proved poor for detecting cephalosporinases in Pseudomonas aeruginosa and Enterobacteriaceae, and penicillinases in Staphylococcus aureus when compared to nitrocefin. As a spectrophotometric substrate it was equivalent to nitrocefin and cephaloridine with various beta-lactamases.

beta-Lactamases have proved to be extremely important in influencing therapy with penicillins and cephalosporins against gram-positive and gram-negative aerobic and anaerobic species. Both plasmid mediated beta-lactamases which are primarily of a constitutive penicillinase type and the inducible chromosomal enzymes which are primarily cephalosporinases are important. The use of penicillins to treat Haemophilus, Neisseria gonorrhoeae, Escherichia coli, Klebsiella, Salmonella, Shigella and Pseudomonas infections must be based upon the relative incidence of beta-lactamase producing strains. In the same manner cephalosporins can be used to treat infections due to Enterobacter, Serratia and Bacteroides only if the compounds are beta-lactamase stable and not good inducers of beta-lactamase activity. Although altered permeability is important in the resistance of some Pseudomonas and Enterobacter to beta-lactams, the resistance really is due to a combination of reduced entry of molecules and strategically placed beta-lactamases. It is only in some Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and Streptococcus faecalis strains that altered penicillin-binding proteins make a significant contribution to the resistance to beta-lactams. beta-lactamases will continue to be the most important factor in clinically significant resistance of bacteria to both penicillins and cephalosporins.

The beta-lactamase stability of cefoxitin, the second-generation cephamycin compound, was compared with that of cefamandole, cefoperazone, cefotaxime, moxalactam, carbenicillin, and piperacillin. Unlike cefamandole, cefoperazone, carbenicillin, and piperacillin, cefoxitin was not hydrolyzed by the common plasmid beta-lactamases, TEM-1, TEM-2, OXA-2, and SHV-1. Cefoxitin and moxalactam were the only agents stable to all chromosomal beta-lactamases, whereas cefamandole, cefoperazone, cefotaxime, carbenicillin, and piperacillin were destroyed by cephalosporinases of Proteus vulgaris and Bacteroides fragilis.

SM-7338, a new carbapenem, inhibited most members of the family Enterobacteriaceae at MICs of 0.015 to 0.25 microgram/ml, including Klebsiella oxytoca, Citrobacter freundii, Enterobacter cloacae, and Proteus vulgaris isolates resistant to cefotaxime, ceftazidime, piperacillin, and gentamicin. It was two- to eightfold more active than imipenem, but it inhibited Pseudomonas aeruginosa at 1 to 8 micrograms/ml, which was comparable to the activity of imipenem. Haemophilus, Neisseria, and Branhamella species were inhibited by less than or equal to 0.25 microgram/ml, which was superior to the activity of imipenem. SM-7338 inhibited Staphylococcus aureus and coagulase-negative staphylococci at 0.25 microgram/ml, but for methicillin-resistant isolates MICs were 4 to 16 micrograms/ml. Group A, B, and C streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.03 microgram/ml. Bacteroides species, including clindamycin-resistant isolates, were inhibited by 0.25 microgram/ml. There was no major inoculum size effect, and the MBCs were within a dilution of the MICs. SM-7338 was more active than imipenem at an acid pH under anaerobic conditions. Plasmid beta-lactamases of TEM-1, TEM-2, TEM-3, TEM-5, SHV-1, SHV-2, PSE-1, PSE-2, PSE-3, OXA-2, OXA-3, OXA-4, OXA-5, and OXA-7; Staphylococcus aureus enzymes; and the chromosomal beta-lactamases P-99 and K-1; Morganella species; and Proteus vulgaris did not hydrolyze SM-7338. The repeated transfer of organisms increased the MICs of SM-7338, as it did the MICs of imipenem.

SCE-129 [3-4-carbamoyl-1-pyridiniomethyl-7beta- (d-alpha-sulfophenylacetamido)-ceph-3-em-4-carboxylate] is a cephalosporin that inhibits Pseudomonas aeruginosa and Staphylococcus aureus. SCE-129 is tenfold more active than carbenicillin in inhibiting P. aeruginosa. SCE-129 has poor activity against Enterobacteriaceae compared with other cephalosporins and is 16-fold less active than the cephalosporins against streptococci. The activity of SCE-129 does not correlate with beta-lactamase stability, although SCE-129 is resistant to hydrolysis by gram-positive and gram-negative bacteria. The compound does not inhibit the hydrolysis of other cephalosporins. Although SCE-129 acts synergistically with gentamicin to inhibit some Pseudomonas, this cannot be predicted based on knowledge of resistance to one or more compounds.

The in vitro activity of ceftizoxime was compared with that of other beta-lactam antibiotics against 538 isolates. Ceftizoxime was the most active agent tested against Escherichia coli and Klebsiella, inhibiting 80% at 0.025 microgram/ml. It was more active than cefotaxime against Enterobacter cloacae and E. aerogenes. Ceftizoxime was more active than cefoxitin, cefotaxime, cefoperazone, and carbenicillin against Proteus mirabilis and indole-positive Proteus. It inhibited 97% of multiresistant Serratia isolates at 12.5 microgram/ml, whereas cefotaxime inhibited only 19%. Ceftizoxime was less active than cefotaxime and cefoperazone against Pseudomonas aeruginosa, but was more active than carbenicillin. It was more active than cefotaxime and cefoxitin against Bacteroides. It was not appreciably destroyed by beta-lactamases of Staphylococcus aureus, Enterobacteriaceae, or Pseudomonas.

The in vitro activity of cefazaflur, a parenteral cephalosporin, was determined against 590 clinical isolates. Cefazaflur inhibited the majority of gram-positive cocci at concentrations below 1 mug/ml except for enterococci. The agent was as active as cefamandole or cefoxitin against most Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. Although it inhibited a number of strains of Enterobacter, indole-positive Proteus, and Serratia resistant to cephalothin, it was much less active against these organisms than were cefamandole or cefoxitin.

The in-vitro activity and beta-lactamase stability of ceftazidime were evaluated against 700 Gram-positive and Gram-negative bacteria. Ceftazidime was less active than penicillins or older cephalosporins against Staphylococcus spp. and Streptococcus spp., and it did not inhibit Streptococcusfaecalis. However, ceftazidime was as active as moxalactam and cefoperazone against Escherichia coli, Klebsiella and Proteus mirabilis with MICs less than 0.2 mg/l. Ceftazidime also inhibited Enterobacter, Citrobacter, Salmonella and Shigella at concentrations below 0.2 mg/l. Most Morganella, Pr. rettgeri, Pr. vulgaris and Pr. inconstans were inhibited at concentrations below 1 mg/l similar to concentrations for moxalactam, cefoperazone, and cefotaxime. Ceftazidime was the most active agent tested against Ps. aeruginosa, with a mean MIC of 1.6 mg/l. It inhibited carbenicillin, piperacillin, cefoperazone, cefsulodin resistant Pseudomonas.

The in-vitro activity of BMY 28142, an iminomethoxy, aminothiazolyl cephalosporin containing a methyl pyrrolidinio C-3 was compared with that of cefotaxime, ceftazidime, aztreonam, imipenem and tobramycin against various bacteria. BMY 28142 was the most active agent tested against the Enterobacteriaceae inhibiting 90% at less than or equal to 1 mg/l. The in-vitro activity of BMY 28142 was equal to or superior to cefotaxime against the highly susceptible members of the Enterobacteriaceae and several-fold superior to ceftazidime and aztreonam. BMY 28142 inhibited many Enterobacter cloacae, Citrobacter freundii and Serratia marcescens resistant to cefotaxime, ceftazidime and aztreonam. BMY 28142 was more active than imipenem against Proteus, Providencia and Morganella species. Ceftazidime and imipenem were more active than BMY 28142 against Pseudomonas aeruginosa, but it inhibited piperacillin and tobramycin-resistant isolates. BMY 28142 inhibited beta-lactamase producing Haemophilus influenzae and Neisseria gonorrhoeae. BMY 28142 was more active than ceftazidime against streptococcal and staphylococcal species, but it did not inhibit or kill most methicillin-resistant Staphylococcus aureus. BMY 28142 did not inhibit most Bacteroides species. BMY 28142 was not hydrolyzed by common plasmid and chromosomal beta-lactamases, but it bound poorly to Enterobacter beta-lactamase, was a poor inhibitor of the TEM plasmid beta-lactamase and was a poor inducer of beta-lactamases.

The in vitro activity of cefpiramide, a new ureido cephalosporin antibiotic, was determined against 1128 gram-positive and gram-negative aerobic and anaerobic bacteria selected for resistance to ampicillin and cefazolin. Cefpiramide was less active on a milligram basis than cefotaxime, ceftazidime, moxalactam, and aztreonam against all of the members of the Enterobacteriaceae. Cefpiramide inhibited many Pseudomonas aeruginosa resistant to carbenicillin, piperacillin, and cefotaxime, but it was less active than ceftazidime and cefsulodin. Cefpiramide inhibited staphylococci and streptococci and had appreciable activity against Streptococcus faecalis and Listeria moncytogenes. It had less activity than cefoxitin against anaerobic species. Cefpiramide inhibited permeability mutants of Escherichia coli at lower concentrations than the parent strain, suggesting an effect of entry upon its activity. Although cefpiramide was resistant to attack by most chromosomal beta-lactamases, it was hydrolyzed by the common plasmid beta-lactamases TEM and SHV and by the chromosomal Proteus vulgaris, type Ic, cephalosporinase.

The in vitro activity of E-0702 was compared with the in vitro activity of cefotaxime, ceftazidime, moxalactam, and aztreonam against 600 gram-positive and gram-negative aerobic and anaerobic isolates. E-0702 had a minimal inhibitory concentration for 50% of isolates (MIC50) of 25 micrograms for Staphylococcus aureus, 50 micrograms for Staphylococcus epidermidis, and 1.6 to 3.1 micrograms for streptococci, with Streptococcus faecalis resistant. E-0702 had MIC50s against Escherichia coli, Klebsiella pneumoniae, and Enterobacter aerogenes comparable to those of cefotaxime, ceftazidime, moxalactam, and aztreonam, but MIC90S were higher than those of the other agents. It was as active as the other agents against Proteus mirabilis, Salmonella spp., and Shigella spp., but was four- to eightfold less active against Citrobacter freundii, Enterobacter cloacae, Providencia spp., Morganella spp., and Proteus vulgaris, with isolates in each species resistant. Activity against Bacteroides fragilis was fourfold less than that of cefoxitin. E-0702 was hydrolyzed by plasmid beta-lactamases and was only a weak inhibitor of plasmid and chromosomal beta-lactamases. There was an inoculum effect for E. cloacae, Serratia spp., Morganella spp., and Pseudomonas spp.

Ceftizoxime is an iminomethoxy aminothiazolyl cephalosporin that inhibits a wide variety of aerobic, anaerobic gram-positive and gram-negative bacteria. The majority of Enterobacteriaceae are inhibited by less than or equal to 1 microgram/ml as are streptococcal species with the exception of Streptococcus faecalis. Staphylococcus aureus are inhibited by 3-8 micrograms/ml, while methicillin-resistant. aureus are resistant. Bacteroides fragilis are inhibited by 16-64 micrograms/ml. It inhibits Pseudomonas aeruginosa at usually achievable concentrations. Ceftizoxime is overall similar in antibacterial activity to cefotaxime and moxalactam. Ceftizoxime is not hydrolyzed by common plasmid and chromosomal beta-lactamases. Serum levels of ceftizoxime after intramuscular and intravenous injection are similar to those of cefotaxime and moxalactam. The half-life is 1.6 to 1.9 hours in normal individuals. The compound is not metabolized and is cleared from the body by glomerular filtration. Ceftizoxime enters most body fluids, including the cerebrospinal fluid, to produce therapeutic concentrations against clinically important bacteria. Ceftizoxime accumulates in the presence of renal failure, but it is removed from the body by hemodialysis and peritoneal dialysis. Ceftizoxime has proved to be an effective chemotherapeutic agent when used as treatment for pneumonia, urinary tract infections, osteomyelitis, septic arthritis, meningitis, peritonitis, gonorrhea, including penicillinase-producing isolates, and gynecological infections. No major adverse reactions have been associated with the use of ceftizoxime and it has produced neither disulfram -like reactions nor bleeding.

Cefodizime, an iminomethoxy aminothiazolyl cephalosporin similar to moxalactam and ceftazidime, was less active (minimal inhibitory concentration, 1.6 to 12 micrograms) than cefazolin or cefotaxime against Staphylococcus aureus and Staphylococcus epidermidis. It inhibited Haemophilus and Neisseria spp. at less than 0.5 microgram/ml. It did not inhibit methicillin-resistant staphylococci, enterococci, or Listeria spp. and was 8- to 32-fold less active than cefotaxime, moxalactam, or ceftazidime against Escherichia coli, Citrobacter spp., Klebsiella pneumoniae, Providencia spp., and Serratia spp. Cefotaxime-resistant Enterobacter cloacae, Citrobacter freundii, and Proteus vulgaris were resistant to cefodizime. Cefodizime was less active than cefoxitin or moxalactam against Bacteroides fragilis. Cefodizime was not hydrolyzed by common plasmid or chromosomal beta-lactamases, and it inhibited type I beta-lactamases.

Resistance of bacteria to beta-lactam antibiotics has become a serious problem in the past several decades. Virtually all Staphylococcus aureus, many Haemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, many Enterobacteriaceae, many Pseudomonas aeruginosa and Bacteroides species possess beta-lactamases which hydrolyze to varying degree penems, penams, carbapenems, cephems, cephamycins and monobactams. The most common plasmid-mediated beta-lactamase is the so-called TEM beta-lactamase (Richmond Sykes type IIIa) which exists in Haemophilus, Neisseria and many of the Enterobacteriaceae. Techniques to overcome this resistance have been the development of beta-lactamase stable compounds and of beta-lactamase inhibitors. However, inducible chromosomally mediated beta-lactamases in species such as Enterobacter, Pseudomonas, Citrobacter and some Serratia have become an increasing problem with more widespread use of beta-lactamase stable cephalosporins.

Alteration of PBPs has proved an effective way for gram-positive bacteria to become resistant to beta-lactams. The gram-positive species have not been able to use decreased permeability or synthesis of novel beta-lactamases to overcome the advances by medicinal chemists. Nonetheless, altered PBPs have proved to be a formidable form of resistance for staphylococci, enterococci, and even some S. pneumoniae. Although isolated examples of resistance of gram-negative species to beta-lactams have been seen for E. coli, Serratia, or P. aeruginosa, in general this form of resistance has not been used by the gram-negative species except by N. gonorrhoeae. Conversely gram-negative bacteria have used beta-lactamases as an effective weapon to overcome the advances in medical chemistry that have provided beta-lactamase inhibitors and structurally stable cephalosporins, monobactams, and carbapenems. Derepression or induction of beta-lactamases has provided species such as E. cloacae and P. aeruginosa the ability to resist destruction by new cephalosporins. The original concept of beta-lactamase as a trap or sponge has been shown to be inaccurate, and we realize that the high concentration of beta-lactamase in the periplasmic space combined with a decreased or slow entry of the beta-lactam allows an efficient acylation of the so-called stable cephalosporins with hydrolysis of these compounds. Although the PBPs and beta-lactamases are clear problems, there is the potential for future modification of beta-lactam structures to increase affinity to PBPs and decrease beta-lactamase affinity. Bacterial populations do have the ability to create transferable resistance even to extended spectrum beta-lactams. It will be necessary to carefully monitor the development of resistance to new beta-lactams. However, advances in the chemistry of beta-lactams should offer solutions to these real but potentially controllable problems.

Foramidocillin is a 6-alpha-formamido penicillin with a 6-beta-acylureido side chain. The majority of the Enterobacteriaceae were inhibited by less than or equal to 1 microgram of foramidocillin per ml, and Pseudomonas aeruginosa was inhibited by 4 micrograms/ml. Foramidocillin had activity comparable to those of ceftazidime, imipenem, and aztreonam against beta-lactamase-producing members of the Enterobacteriaceae and P. aeruginosa, and it inhibited organisms resistant to piperacillin. Foramidocillin did not inhibit gram-positive species or anaerobic gram-negative bacteria. Foramidocillin was not hydrolyzed by the common plasmid-mediated beta-lactamases TEM-1, TEM-2, OXA-2, PSE-4, and SHV-1, by the chromosomal beta-lactamases P99 of Enterobacter cloacae and K1 of Klebsiella oxytoca, or by the Sabath-Abraham enzyme of P. aeruginosa.

FK482 is an oral aminothiazolyl hydroxyimino cephalosporin with a C-3 vinyl group. Its activity was compared with those of cephalexin, cefuroxime, cefixime, and amoxicillin-clavulanate. FK482 inhibited 90% of Staphylococcus aureus isolates at 1 micrograms/ml and 90% of Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus pneumoniae isolates at less than or equal to 0.012 micrograms/ml, superior to cephalexin and cefuroxime and similar to cefixime. It did not inhibit oxacillin-resistant S. aureus. FK482 inhibited 90% of Enterococcus faecalis isolates at 8 micrograms/ml. Although 90% of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella species, and Shigella species isolates were inhibited by less than or equal to 2 micrograms/ml, FK482 was less active than cefixime against Citrobacter, Enterobacter, Morganella, Serratia, and Providencia species, with MICs for many isolates of greater than 8 micrograms/ml. FK482 inhibited Haemophilus influenzae and Neisseria gonorrhoeae at concentrations comparable to that of cefixime and superior to those of cephalexin and cfaclor. Bacteroides and Pseudomonas species were resistant. FK482 was not hydrolyzed by the TEM-1 and TEM-2 beta-lactamases but was hydrolyzed by TEM-3 and the Proteus vulgaris enzyme. It had a high affinity for chromosomal beta-lactamases.

6315-S, a novel difluoromethyl thioacetamido oxacephem, had in vitro activity comparable to that of cefotaxime and moxalactam against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Klebsiella oxytoca, Citrobacter diversus, Salmonella spp., and Shigella spp., inhibiting 90% at less than or equal to 0.25 microgram/ml. It inhibited piperacillin- and cefoperazone-resistant isolates in these species. 6315-S did not inhibit cefotaxime- or moxalactam-resistant Citrobacter freundii, Enterobacter aerogenes, or Enterobacter cloacae (MICs for 90% of the strains tested were greater than or equal to 16 micrograms/ml). Proteus vulgaris resistant to cefotaxime was inhibited. Pseudomonas species and Acinetobacter species were resistant (MICs greater than 64 micrograms/ml). MICs for 90% of the Staphylococcus aureus and S. epidermidis isolates were 4 micrograms/ml. 6315-S was highly active against anaerobic species of Clostridium, Fusobacterium, Bacteroides, and peptostreptococci and was superior to other agents against these organisms. 6315-S was not hydrolyzed by the major plasmid and chromosomal beta-lactamases, but it induced chromosomal beta-lactamases in Enterobacter cloacae and Pseudomonas aeruginosa.

The in vitro activity of CGP 31608, a new penem, against aerobic and anaerobic organisms was evaluated and compared with those of other beta-lactams. CGP 31608 inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Citrobacter diversus, and Salmonella, Shigella, Aeromonas, and Yersinia spp. with MICs for 50% of the strains (MIC50s) of 2 to 4 micrograms/ml and MIC90s of 4 micrograms/ml, compared with cefotaxime, ceftazidime, aztreonam, and imipenem MICs of less than 0.25 microgram/ml. MIC90s were 8 micrograms/ml for Enterobacter species and C. freundii, for which other agents had MICs of 32 micrograms/ml, except imipenem, which had equal activity. The MIC90 for Proteus vulgaris, Morganella morganii, Providencia stuartii, and Providencia rettgeri was 8 micrograms/ml, compared with less than 2 micrograms/ml shown by the other agents. Acinetobacter species resistant to other agents except imipenem were inhibited by 4 micrograms/ml, as were Pseudomonas aeruginosa, including piperacillin-, ceftazidime-, and gentamicin-resistant isolates. The MIC for P. cepacia, P. fluorescens, and P. acidovorans was less than or equal to 8 micrograms/ml, but that for P. maltophilia was greater than or equal to 128 micrograms/ml. Hemolytic streptococci A, B, C, G, and F were inhibited by less than 1 micrograms/ml, but the MIC for Streptococcus faecalis was greater than or equal to 32 micrograms/ml. MICs for Staphylococcus aureus methicillin-susceptible and -resistant strains were less than or equal to 1 microgram/ml, as were those for methicillin-susceptible and -resistant S. epidermidis. Bacteroides fragilis and Clostridium species and Fusobacterium spp. were inhibited by less than or equal to 4 micrograms/ml. CGP 31608 was not hydrolyzed by plasmid beta-lactamases TEM-1, TEM-2, SHV-1, PSE-1, OXA-2, PSE-4, or by S. aureus. Chromosomal beta-lactamases of type Ia in Enterobacter cloacae P99 and Morganella morganii, Ic in P. vulgaris, K-1 in K. oxytoca, and Id in P. aeruginosa also did not hydrolyze CGP 31608. It inhibited TEM-1, but the 50% inhibitory concentration was 14.2 micrograms/ml compared with 0.15 micrograms/ml for the P99 enzyme. CGP 31608 induced beta-lactamases in P. aeruginosa, E. cloacae, C. freundii and Providencia rettgeri, but there was no increase in MICs for the isolates and it did not select strains derepressed for beta-lactamase production. Synergy of CGP 31608 and gentamicin was found against 90% P. aeruginosa, 60% Enterobacter cloacae, and 50% Serratia marcescens strains. No synergy was found with rifampin. A postantibiotic effect was found against E. coli.

The in vitro activity of cefoxitin, 3-carbamolyloxymethyl-7-alpha-methoxy-7[2-(2-thienyl)acetamido]-3-cephem-4-carboyxlic acid, was investigated. Activity against gram-positive organisms was less than that of cephalothin and cephloridine. It was highly active against gram-negative bacilli, with activity against Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae equal to that of currently available cephalosporins. In addition, it was active against certain Enterobacter strains, Serratia marcescens, indole-positive Proteae and Herellea. The strains of these latter bacteria were strains susceptible to carbenicillin and ticarcillin. Pseudomonas aeruginosa and other Pseudomonas species were resistant. Changes in pH, inoculum size, and type of growth medium had no significant effect on the activity of the antibiotic. Cefoxitin was highly resistant to hydrolysis by various types of gram-negative beta-lactamases. The precise role of resistance to beta-lactamase hydrolysis varied from strain to strain. Bacterial resistance to cefoxitin was not necessarily related to hydrolysis of the antibiotic. However, the resistance of cefoxitin to hydrolysis did contribute to its activity. Cefoxitin could function as an inducer of beta-lactamase activity and effectively bound to purified beta-lactamases.

Ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074), two new orally administered aminothiazolyl imimomethoxy cephalosporins, inhibited hemolytic streptococci and Streptococcus pneumoniae at less than or equal to 0.5 micrograms/ml but were less active against staphylococci than were cephalexin and cefaclor. They did not inhibit S. faecalis, S. faecium, Listeria monocytogenes, Corynebacterium JK species, or Pseudomonas aeruginosa. Haemophilus influenzae, Branhamella catarrhalis, and Neisseria gonorrhoeae, including ampicillin-resistant isolates, were inhibited at less than 0.25 micrograms/ml. Both agents inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Salmonella species, Shigella species, Citrobacter diversus, and Aeromonas hydrophila resistant to ampicillin, cephalexin, and cefaclor at less than or equal to 2 micrograms/ml, although many isolates of Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens resistant to cefotaxime were not inhibited by these agents. A marked inoculum effect was noted for Enterobacteriaceae carrying the Richmond-Sykes type 1A chromosomally mediated beta-lactamases, but plasmid-mediated beta-lactamases did not hydrolyze the compounds. Both drugs inhibited the chromosomally mediated beta-lactamase of E. cloacae, P99.

Carumonam is a monobactam with a beta-carbamyloxmethyl group at position 4. It inhibited 90% of Enterobacteriaceae at less than or equal to 8 mg/l and had in-vitro activity similar to that of cefotaxime, ceftazidime and aztreonam. Fifty per cent of Enterobacter, Citrobacter and Serratia isolates were inhibited by 4 mg/l, but isolates resistant to aztreonam and ceftazidime were not inhibited. Carumonam, like aztreonam, did not inhibit Gram-positive or anaerobic species. Carumonam was not destroyed by the common plasmid- and chromosomally-mediated beta-lactamases and was more stable than aztreonam to attack by the K-1 beta-lactamase of Klebsiella oxytoca. Carumonam inhibited Richmond-Sykes type Ia and Id beta-lactamases but was a poor inhibitor of type III enzymes. It did not induce beta-lactamases.

The beta-lactamase stability and inhibitory activity of 1-oxa cephalosporin, (6R,7R)-7-[[carboxy(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, was investigated and compared to that of cefoxitin and cefotaxime. There was no detectable beta-lactamase hydrolysis of 1-oxa cephalosporin, cefotaxime and cefoxitin when incubated with beta-lactamases of plasmid or chromosomal origin which were primarily cephalosporinases or enzymes which hydrolyzed both penicillins and cephalosporins. The beta-lactamase inhibitory activity of 1-oxa cephalosporin was comparable to that of cefoxitin and cefotaxime. At equal molar concentration of substrate and inhibitor, cefoxitin, cefotaxime and 1-oxa cephalosporin effectively inhibited cephalosporinase hydrolysis of cephaloridine. Cefoxitin and cefotaxime were more effective inhibitors than the 1-oxa cephalosporin against a Providencia enzyme, whereas cefotaxime and 1-oxa cephalosporin were more effective inhibitors of a Citrobacter cephalosporinase.

SQ 26,917 is a monobactam antibiotic. Its in vitro activity was compared with those of aztreonam, cefotaxime, ceftazidime, and moxalactam. SQ 26,917, which contains a beta-methyl configuration on the beta-lactam ring, was similar in activity to aztreonam with the exception of greater activity against Pseudomonas aeruginosa isolates. SQ 26,917 had no activity against gram-positive isolates or anaerobic bacteria. It was not hydrolyzed by common plasmid and chromosomal beta-lactamases.

The in vitro activity and beta-lactamase stability of SK&F 88070 (7-[[2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[ [1-(2-sulfaminoethyl)-1H-tetrazol-5-yl]thio]methyl]-3- cephem-4-carboxylic acid) a new parenteral cephalosporin was investigated against 780 types of bacteria. SK&F 88070 inhibited 90% of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella species, Shigella species, Morganella morganii, and Citrobacter diversus at less than or equal to 0.5 micrograms/ml. Its activity against these species was similar to cefotaxime and moxalactam and superior to cefoperazone and piperacillin. It was less active than cefoperazone against Pseudomonas aeruginosa and less active than cefotaxime or cefoperazone against Staphylococcus aureus. SK&F 88070 inhibited hemolytic streptococci and Streptococcus pneumoniae at less than or equal to 0.12 micrograms/ml. Enterobacter species, Citrobacter freundii, and Serratia, which were resistant to cefotaxime and moxalactam were resistant to SK&F 88070. It was not hydrolyzed by plasmid beta-lactamases, but was hydrolyzed by the Proteus vulgaris type 1c enzyme. SK&F 88070 inhibited Richmond-Sykes type 1a beta-lactamases.

The in vitro activity of CGP 31523A, an aminothiazolyl cephem, was compared to that of other cephalosporins--imipenem, aztreonam, carbenicillin, and gentamicin. CGP 31523A inhibited E. coli, K. pneumoniae, P. mirabilis, C. diversus, K. oxytoca, P. stuartii, Salmonella and Shigella at less than or equal to 0.25 micrograms/ml. It was equal or 2-fold more active than cefotaxime and ceftazidime, and 4-fold more active than imipenem against these organisms. It inhibited all carbenicillin and gentamicin-resistant isolates of these species. Neisseria and Haemophilus were inhibited by less than or equal to 0.12 micrograms/ml. Some C. freundii, E. cloacae, E. aerogenes, P. vulgaris, and P. penneri had MICs greater than or equal to 16 micrograms/ml similar to cefotaxime, ceftazidime and aztreonam. Pseudomonas were resistant, MIC 128 micrograms/ml. CGP 31523A inhibited streptococci at less than or equal to 0.25 micrograms/ml with the exception of S. faecalis, and staphylococci were inhibited by 0.5 micrograms/ml but methicillin-resistant isolates were resistant. Bacteroides and some Clostridium had MICs greater than or equal to 16 micrograms/ml. CGP 31523A was less stable than cefotaxime and ceftazidime to the plasmid TEM/SHV/PSE-4 beta-lactamases. Like cefotaxime it was hydrolyzed by the P. vulgaris type Ic beta-lactamase but not by the type Ia enzymes. CGP 31523A was not an effective beta-lactamase inhibitor nor did it induce beta-lactamases. It had overall activity comparable to available extended spectrum cephalosporins.

Resistance of bacteria to beta-lactam antibiotics has become a serious problem in the past several decades. Virtually all Staphylococcus aureus, and many Hemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, Enterobacteriaceae, and Bacteroides species possess beta-lactamases that hydrolyze penicillins and cephalosporins. The most common plasmid-mediated beta-lactamase is the TEM enzyme (Richmond-Sykes type IIIa), which is present in Hemophilus, Neisseria, and Enterobacteriaceae. One technique to overcome bacterial resistance has been the development of beta-lactamase inhibitors. Clavulanic acid is a beta-lactamase inhibitor that inhibits the beta-lactamases of S. aureus, Hemophilus, Neisseria, Branhamella, Eschericia coli, Klebsiella, and Bacteroides. Clavulanate acts as a "suicide" inhibitor, forming a stable enzyme complex that binds to serine at the active site of the enzyme. Clavulanate readily crosses the outer cell wall of most Enterobacteriaceae to interact with beta-lactamases in the periplasmic space. Clavulanate does not inhibit beta-lactamases such as the Richmond-Sykes type I enzymes found in Pseudomonas aeruginosa, Enterobacter, and Citrobacter species, which are inducible enzymes that function primarily as cephalosporinases.

FR 17027, a new orally absorbed cephalosporin ester, inhibited group A and B streptococci and Streptococcus pneumoniae at less than or equal to 0.1 micrograms/ml, which is similar to the inhibition concentration of amoxicillin and cefaclor, and was more active than cephalexin. It was less active (MIC, 25 micrograms/ml) against staphylococci than was cephalexin, and it did not inhibit Streptococcus faecalis or Listeria monocytogenes. FR 17027 inhibited beta-lactamase-producing isolates of Neisseria gonorrhoeae, Haemophilus influenzae, and Branhamella catarrhalis at less than 0.1 micrograms/ml and was more active than cefaclor or cephalexin against these bacteria. FR 17027 inhibited Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Klebsiella oxytoca, Providencia stuartii, Providencia rettgeri, and Citrobacter diversus at less than or equal to 1 microgram/ml, including isolated resistant to amoxicillin, cephalexin, and cefaclor, but it was less active than ceftizoxime. Some strains of Enterobacter cloacae, Enterobacter agglomerans, Citrobacter freundii, and Enterobacter aerogenes were resistant (MIC, greater than 25 micrograms/ml). FR 17027 did not inhibit Pseudomonas aeruginosa, other Pseudomonas species, Acinetobacter species, or Bacteroides species. Activity was minimally affected by growth conditions. FR 17027 was not hydrolyzed by the common beta-lactamases present in many of the pathogens causing respiratory and urinary tract infections in outpatients.

The in vitro activity and beta-lactamase stability of 7-[d(-)-alpha-(4-ethyl-2,3-dioxopiperazino-carbonylamino) -p-hydroxyphenylacetamido]-3-[(1-methyl)-5-tetrazolylthiomethyl] -Delta(3)-cephem-4-carboxylic acid (cefoperazone), a cephalosporin analog of piperacillin, were compared with the activities and stabilities of other cephalosporins and cephamycins. The compound was less active than cephalothin or cefamandole in inhibiting Staphylococcus aureus; it was as active as cefamandole and cefoxitin against most of the Enterobacteriaceae but less active than cefotaxime. It was more active than carbenicillin or piperacillin against Pseudomonas aeruginosa. In general, the compound was not active against Bacteroides. It was hydrolyzed by the beta-lactamases of some Escherichia coli which hydrolyzed cefamandole, but was stable to most plasmid-mediated, chromosomally mediated, inducible beta-lactamases in the Enterobacteriaceae and Pseudomonas.

We compared the in vitro activity and beta-lactamase stability of MDL 19,592, an orally absorbed cephalosporin, with that of cephalexin and cefaclor. It inhabited Staphylococcus aureus at less than or equal to 4 micrograms/ml, Streptococcus pyogenes at 0.25 microgram/ml, sero groups B, C and G streptococci at 1 microgram/ml, and Streptococcus pneumoniae at 2 micrograms/ml. It was slightly more active than cefaclor and cephalexin. MDL 19,592 did not significantly inhibit Enterobacteriaceae, enterococci, Listeria monocytogenes, Pseudomonas aeruginosa, and Acinetobacter spp. strains (MIC greater than or equal to 32 micrograms/ml). MDL 19,592 was not hydrolyzed by the plasmid beta-lactamases TEM-1 and SHV-1 of Klebsiella but was hydrolyzed by the TEM-3, Staphylococcus aureus beta-lactamase, and the chromosomal-mediated Enterobacter cloacae P99 enzymes.

The in vitro activity of U-63196E, a new broad-spectrum cephalosporin antibiotic, was studied against various gram-positive and gram-negative bacteria and compared with the in vitro activities of cefotaxime, moxalactam, cefoperazone, ceftazidime, and aztreonam. Although U-63196E inhibited many ampicillin-resistant bacteria and its activity against gram-negative species was similar to cefoperazone, it was much less active than the other agents. U-63196E was less active than cefazolin against gram-positive species, and it was less active than cefoxitin or moxalactam against Bacteroides fragilis. U-63196E did not inhibit most cefoperazone- or cefsulodin-resistant Pseudomonas aeruginosa. There was a difference between minimal inhibitory concentrations and minimal bactericidal concentrations for isolates which contained beta-lactamases. Plasmid beta-lactamases of the TEM, HSV, OXA, and PSE types hydrolyzed U-63196E. But U-63196E was relatively stable against hydrolysis by the chromosomal beta-lactamases.

Temocillin, a 6-alpha-methoxy penicillin, inhibited 90% of strains of Escherichia coli, Klebsiella pneumoniae, Citrobacter, Proteus, Providencia, Salmonella, and Shigella at a concentration of less than or equal to 16 micrograms/ml. Haemophilus influenzae and Neisseria gonorrhoea were inhibited by less than or equal to 1 microgram/ml. Changing the medium or pH of the cultures did not alter the minimal inhibitory concentrations, which were similar in broth and human serum, as were the minimal bactericidal concentrations. An increase in inoculum size from 10(5) to 10(7) colony-forming units increased concentration required for inhibition. Temocillin inhibited strains resistant to ampicillin, ticarcillin, cefazolin, cefamandole, and cefoxitin. Most Pseudomonas aeruginosa strains and other Pseudomonas spp. and Acinetobacter spp. were resistant, as were gram-positive organisms. Temocillin was not hydrolyzed by the common plasmid and chromosomal beta-lactamases but inhibited them. The resistance of certain gram-negative bacilli to temocillin seemed to be a result of failure of the molecule to enter through the cell wall, since combination of temocillin with EDTA made Pseudomonas, Acinetobacter, and Enterobacter strains susceptible to low concentrations of the compound.

The in vitro activity and beta-lactamase stability of ceftazidime were evaluated against 700 gram-positive and gram-negative bacteria. Ceftazidime was less active than penicillins or older cephalosporins against Staphylococcus spp. and Streptococcus spp., and it did not inhibit Streptococcus faecalis, Listeria, or anaerobic species. Ceftazidime was as active as ceftizoxime and moxalactam and more active than cefoperazone against Escherichia coli. Klebsiella, and Proteus mirabilis with minimal inhibitory concentrations of less than 0.2 mg/liter. Ceftazidime also inhibited Enterobacter, Citrobacter, Salmonella, and Shigella at concentrations below 0.2 mg/liter. Most Morganella, Proteus rettgeri, Proteus vulgaris, and Proteus inconstans were inhibited at concentrations below 1 mg/liter, similar to the concentrations for moxalactam, ceftizoxime, and cefotaxime. Ceftazidime was the most active agent tested against Pseudomonas aeruginosa, with a mean minimal inhibitory concentration of 1.6 mg/liter. It inhibited carbenicillin-, piperacillin-, cefoperazone-, and cefsulodin-resistant Pseudomonas. Minimal inhibitory and minimal bactericidal concentrations were similar, with the exception of some Pseudomonas values at 10(7) colony-forming units. Use of different media did not alter minimal inhibitory concentration values. Ceftazidime was not hydrolyzed by staphylococcal beta-lactamase or plasmid beta-lactamase of the TEM-1, TEM-2, SHV-1, OXA-1, PSE-1, PSE-2 types or by inducible beta-lactamases of the cephalosporinase type. Ceftazidime provides an extremely active agent against aerobic and facultative gram-negative bacteria.

LY163892 is a new orally absorbed carbacephem. It inhibited Streptococcus pyogenes and Str. pneumoniae at less than or equal to 1 mg/l, but was less active against group B streptococci and groups C, F, G and bovis streptococci with MICs of 1 to 2 mg/l for most but as high as 8 mg/l for some isolates. MIC90 of methicillin-susceptible Staphylococcus aureus was 8 mg/l, but greater than 128 mg/l for methicillin-resistant staphylococci. LY163892 had activity similar to cefaclor and cephalexin with MIC90 values of 16 mg/l for Escherichia coli, 8 mg/l for Klebsiella pneumoniae, Proteus mirabilis, Yersinia enterocolitica, but was more active against Haemophilus influenzae, and Branhamella catarrhalis. It had no activity against Enterobacter, Providencia, Serratia, and Pseudomonas and Bacteroides spp. LY163892 was more rapidly lytic than cephalexin. It was hydrolyzed by a number of plasmid and chromosomal beta-lactamases. For TEM-1, the Km = 354.7 microM, Vmax = 2.5 microMoles/min/mg of protein, P99 Km = 24.3 microM, Vmax = 28.9 microM/min/micrograms of protein, Staph. aureus PC Km = 47.4 microM, Vmax = 2.7 microMoles/min/mg of protein. Overall it had beta-lactamase stability similar to cefaclor, less than cephalexin, and markedly less than cefuroxime.

The activity of cefmenoxime, an aminothiazolyl cephalosporin, was studied against 650 bacteria. It was slightly less active than cefotaxime and more active than moxalactam against staphylococci. It had activity similar to that of cefotaxime and ceftizoxime against group A and B streptococci and Streptococcus pneumoniae. It did not inhibit Streptococcus faecalis or Listeria spp. Cefmenoxime had activity similar to that of cefotaxime, ceftizoxime, ceftazidime, and moxalactam against Escherichia coli, Citrobacter diversus, Klebsiella, Proteus mirabilis, Salmonella, and Shigella. It inhibited beta-lactamase-positive and -negative isolates at less than or equal to 0.4 microgram/ml. Cefmenoxime was somewhat less active than moxalactam or ceftizoxime against Enterobacter cloacae, Enterobacter aerogenes, and Enterobacter agglomerans, but was more active than cefotaxime, ceftizoxime, or ceftazidime against Morganella (minimum inhibitory concentration for 90% of isolates, 0.1 microgram/ml.), Proteus vulgaris and Providencia spp. It was as active as ceftizoxime was against Serratia. Pseudomonas spp. and Bacteroides spp. were relatively resistant (minimum inhibitory concentration for 90% of isolates, greater than 100 micrograms/ml). The compound was stable to the common plasmid beta-lactamases, such as that of TEM. It was stable to most chromosomally mediated beta-lactamases, which act primarily as cephalosporinases, but was hydrolyzed by Bacteroides and Acinetobacter.

The in vitro activity of cefotetan was assessed against beta-lactamase producing clinical isolates. The majority of Enterobacteriaceae were inhibited by less than or equal to 8 micrograms/ml with 50% of isolates inhibited by less than or equal to 1 microgram/ml. Cefotetan inhibited organisms resistant to cefazolin, cefonicid and cefoperazone, but not isolates of Enterobacter, Citrobacter or Serratia resistant to ceftizoxime. Cefotetan inhibited beta-lactamase producing Haemophilus influenzae and Neisseria gonorrhoeae at less than or equal to 1 microgram/ml, but it did not inhibit Acinetobacter or Pseudomonas aeruginosa. Cefotetan was as active as cefoxitin against anaerobic species such as Bacteroides fragilis and Clostridium. Cefotetan was not hydrolyzed by Richmond-Sykes plasmid beta-lactamases of type III such as TEM and SHV, nor by the OXA or PSE beta-lactamases. It also was not hydrolyzed by cephalosporinases of Richmond-Sykes type Ia or Id. Cefotetan inhibited beta-lactamases of the type Ia and Id, but it also induced these beta-lactamases in P. aeruginosa, E. cloacae and C. freundii.

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.