Clavulanic acid, Z-(2R,5R)-3-(β-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo-[3,2,0] heptane-2-carboxylic acid, has been shown to be an effective inhibitor of the β-lactamases of the Richmond types II, III, IV, and V. Inhibition is a time-dependent reaction and is irreversible. Clavulanic acid had poor antibacterial activity against Staphylococcus aureus, Enterobacteriaceae , and Pseudomonas aeruginosa , with minimal inhibitory levels greater than 25 μg/ml. It did inhibit the majority of Neisseria gonorrhoeae at 0.1 μg/ml and Haemophilus influenzae at 6.3 μg/ml. Clavulanic acid acted synergistically with penicillins and cephalosporins to inhibit β-lactamase-producing S. aureus and Enterobacteriaceae . Clavulanic acid combined with ampicillin inhibited β-lactamase-producing N. gonorrhoeae, H. influenzae, Escherichia coli, Salmonella typhi , and Shigella sonnei .

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The in vitro activity of piperacillin, a new semisynthetic piperazine penicillin derivative, was evaluated against 626 clinical isolates and compared with the activity of other ,-lactam antibiotics. At a concentration of 0.1 pg/ml, piperacillin inhibited all streptococci except enterococci. Non-f,-lactamase-producing staphylococci were inhibited by 1.6 pg or less per ml. Both f6-lactamase-and non-,8-lactamase-producing Haemophilus were inhibited by 0.1 ,ug/ml. Piperacillin inhibited non-,-lactamase-producing Escerichia coli, Salmonella, and Shigella at a concentration of 6.3 pg/ml, The superior clinical efficacy of,B-lactam compounds, as well as the toxicity inherent in the use of 2-deoxystreptamine derivatives such as gentamicin or tobramycin, has prompted a continuing search for penicillins with greater in vitro activity. Carbenicillin has proved highly successful in the treatment oflife-threatening infections in patients with compromised host defenses, and recently ticarcillin has been shown to have activity equal or superior to that of carbenicillin (3,7,8). However, the activity of both of these compounds against Kiebsiella and many members of the Enterobacteriaceae is poor. Furthennore, the large concentrations of these drugs used in treatment of infection require delivery of a large sodium load that can result in toxic reactions of bleeding and hypokalemic alkalosis (4). Piperacllin (Fig. 1)

The in vitro activity of (6R,7R)-7-{[carboxy(4-hydroxyphenyl)acetyl]amino} -7-methoxy-3- [[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-oxa-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid was tested against isolates of gram-positive and negative bacteria and compared with those of cephalothin, cefuroxime, cefamandole, cefoxitin, cefotaxime, and carbenicillin. The compound was less active than the other compounds when tested against Staphylococcus aureus and Staphylococcus epidermidis. It had equal or slightly less activity than did cefotaxime when tested against members of the Enterobacteriaceae, but was 8-to 32-fold more active than the other cephalosporins against the Enterobacteriaceae, inhibiting most isolates at concentrations less than 0.5 itg/ml. The compound was twofold more active than cefotaxime and cefoxitin against Bacteroides, and it was twofold more active than cefotaxime and fourfold more active than carbeniciin against Pseudomonas aeruginosa. In vitro activity did not correlate with either the presence or type of fi-lactamase in either Enterobacteriaceae or Pseudomonas. The compound showed minimal synergy when combined with aminoglycosides or carbencillin.There have been many new cephalosporin antibiotics developed in the past few years. Several of these agents, after extensive in vitro evaluation and clinical investigation, have become available commercially. Cefamandole, cefuroxime, and the cefamycin, cefoxitin, are agents which have significantly enlarged the antibacterial spectrum of the older agents such as cephalothin and cefazolin (2, 4-9). These agents, although they inhibit many strains of /3-lactamase-producing Enterobacteriaceae and many isolates of Bacteroides fragilis, have not inhibited Pseudomonas aeruginosa, which has become an increasingly important hospital pathogen. Cefotanime (HR 756) has been shown by a number of investigators to inhibit gram-positive and -negative aerobic and anaerobic bacteria at concentrations much lower than those required by other agents (1, 3, 8). The development of the oxa-cephalosporins has offered another type of compound which provides an in vitro activity equivalent to that of cefotaxime. For this reason we compared the in vitro activity of (6R,7R)-7-[[carboxy(4-hydroxyphenyl)-acetyl]amino]-7-methoxy-3-[ [(l-methyl-lHtetratol-5-yl)thio] methyl] -8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid ( Fig. 1) with the in vitro activities of cephalothin, cefamandole, cefoxitin, cefotaxime, and certain other /3-lactam compounds. MATERIAIS AND METHODSBacterial isolates utilized in the experiments were obtained from clinical specimens submitted to the diagnostic microbiology laboratory of the Columbia Presbyterian Medical Center, New York City. Organisms that were resistant to ft-lactam antibiotics and to aminoglycoside antibiotics and had been stored frozen were included in every species to provide a more realistic evaluation of the activity of this compound against multiresistant species.The compound, hereafter referred to as the "1-oxa cephal...

The in vitro activity of ceftriaxone (Ro 13-9904), a parenteral cephalosporin, was compared with that of other ,8-lactam antibiotics. The compound was less active against Staphylococcus aureus and Staphylococcus epidermidis than was cephalothin or cefamandole, but it was comparable to cefoxitin, cefotaxime, and moxalactam in inhibiting most isolates of S. aureus at 3.1 jig/ml. Ro inhibited Streptococcus pyogenes and Streptococcus pneumoniae at concentrations below 0.25 ,tg/ml, but Streptococcus faecalis required concentrations above 25 ,ug/ml. Neisseria gonorrhoeae and Haemophilus influenzae were inhibited at concentrations similar to those of cefotaxime, less than 0.1 ,ug/ml. Ro 13-9904 was as active as cefotaxime and moxalactam against most Enterobacteriaceae and was the most active agent tested against Proteus, inhibiting all strains tested at 0.006 ug/ml. Ro 13-9904 was slightly less active than moxalactam or cefoxitin against Bacteroides fragilis, requiring more than 100 ,ug/ml to inhibit 90% of isolates, and it was less active than cefoperazone against Pseudomonas aeruginosa. Presence of serum, alteration of pH, and use of various media did not change the inhibitory levels. Bactericidal concentrations were similar to inhibitory levels. Ro 13-9904 was stable to most plasmid-mediated ,B-lactamases, but was hydrolyzed by some Enterobacter, Proteus, and Bacteroides ,B-lactamases of chromosomal origin.An increasing number of fl-lactamase-stable cephalosporins have been synthesized within the past few years. However, each has had certain gaps in its overall spectrum of activity, and multiresistant Enterobacteriaceae and nonfermenting aerobic gram-negative bacilli continue to cause serious infections in hospitalized patients. The oxime cephalosporins (5, 7), as well as moxalactam (6), have been shown to be active both in vitro and in clinical trials. Thus any new agents which are developed must be evaluated in comparison with these agents.For these reasons we evaluated ceftriaxonehydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thiol methyl-8 oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid disodium salt (Fig. 1), a new cephalosporin, to determine its in vitro activity in comparison with the most recently developed agents.