Editor: George B. Whitfield, The Upjohn Company, Kalamazoo, Michigan Chapter 11. B-Lactam Antibiotics J. Alan Webber, Eli Lilly and Company, Indianapolis, Indiana Penicillins - An interesting new penicillin derivative, RIT 2214, bearing a 6-(2-amino-2-carboxy)ethylthioacetamido side chain, was discovered in a fermentation broth. RIT 2214 has broad-spectrum antibacterial activity, though less active than ampicillin, and was more active in vivo than ampicillin following subcutaneous administration to mice, possibly the result of higher blood levels.
Ticarcillin, 3-thienylmalonoyl 6-APA, has been closely compared to carbenicillin -in vitro. 2, 3,4 Although results vary, ticarcillin appears to be slightly more active against gram-negative pathogens, especially Pseudomonas aeruginosa. Clinical evaluation o f ticarcillin sug ests that it will be a useful drug in combating gram-negative infections,’~~*~ possibly at a lower dose than carbenicillin. In vitro examination of mezlocillin and azlocillin has shown them to have some superiority to carbenicillin against a number of species of gram-negative bacteria, including Bacteroides fragilis.’ The clinical evaluation of these two new penicillins suggests adequate tolerance and effectiveness. Mecillinam (FL 1060), the unusual amidino penicillanic acid derivative, has been shown to be synergistic with other B-lactam antibiotics (penicillins and Synergy with non-B-lactams in vivo. cephalosporins) both in vitro’ and -is less pronounced.12,13 Mecillinam itself has marked activit against The the more sensitive species of gram-negative aerobic bacteria. majority of ampicillin-resistant Enterobacteriaceae strains isolated from patients were susceptible to mecillinam.15
Several new penicillins with expanded gram-negative spectra including activity against p. aeruginosa have recently been evaluated. Pirbenicillin (1) is more active than carbenicillin against P. aeruginosa and Klebsiella species, but less active against Proteus sp.16717 A study of pirbenicillin pharmacokinetics in mice concluded that it has a larger distribution volume than carbenicillin. Compound PC 904 (2) has very in vitro activity against most bacteria including Pseudomonas, good -Serratia, Klebsiella, and B. fragilis; its efficacy in mouse infections compared very favorably wiFh that o f carbenicillin. Compound T-1220 ( 3 ) is also considerably more active than carbenicillin against a broad range of gram-negative bacteriae2’ It has low toxicity in animal tests and has proven effective in clinical trials.
Whitfield , Ed.
X = OH;
H; R R
OH; R = - Nn d E t 0
A class of penicillin derivatives in which the 3-carboxyl group is replaced by a tetrazole moiety is now known. The two analogues reported so far, CP-35,58722and CP-38,118,2 3 suggest that the tetrazole compounds have a somewhat broadened spectrum of antibacterial activity. A large series of lactonyl esters of penicillins have been prepared and examined for hydrolysis rates and oral absorption. In general, the esters of ampicillin were orally absorbed in varying degrees,2 4 * 2 5 while those of other penicillins were notez5 The phthalidyl ester of ampicillin, talampicillin, looked best in experimental animals and was chosen for examination in humans. Talampicillin compared favorably with amoxycillin and gave higher blood levels than ampicillin in a comparative Cephalosporins - Although cephalosporin C was the first naturally occurring cephalosporin derivative, and for many years remained the only one, recently several other derivatives of the cephem ring system have been isolated. A new compound in which the acetate of ceph C is replaced by a l,l-dimethyl-2-amino-2-carboxyethylthio moiety was elaborated by a Cephalosporium acremonium mutant strain.” Also observed in a fermentation broth was 4-carboxybutanamido-7-ADCAS -7-ACA, and the latter’s deacetyl analogue, all of which could have been accumulated through enzymatic action or de novo synthesis.2 8 A new cephamycin (7-methoxy cephalosporin), C2801X, being the 3,4-dihydroxycinnamoyl analogue of cephamycin A and B y has been isolated.2 9 , 3 0 Interest continued in cephalosporins of proven or potential clinical relevance. Valuable perspective on the relative $ vitro activity of clinically interesting cephalosporins has been p r o ~ i d e d . ~ The ~,~~ heaviest emphasis has been on candidates for parenteral administration. Cefazaflur (SKF 59962), for which human pharmacology had previously been reported, has excellent -in vitro activity,3 3 9 3 4 although its activity against more resistant gram-negative bacteria is not as great as that of other newer cephalosporins. Ceftezole (demethyl cefazolin) has comparable in vitro and mouse infection effectiveness to cefazolin.3 5 , 3 6 Although -lower in serum binding, ceftezole also shows a shorter half-life and lower peak serum level than cefazolin in humans. 3 6 * 3 7 Extensive animal
pharmacokinetic data have also been published.3 7 A large clinical trial has demonstrated the effectiveness of ceftezole.3 8 Cefamandole (4), cefoxitin (2) , and cefuroxime (6) are cephalosporins having expanzed gramnegative antibacterial spectra and are presently undergoin clinical trial. Cefamandole has been thoroughly examined -in ~ i t r o , ” - ~studied ~ for human harmacokinetic parameters,4 3 - 5 0 and shown to be clinically effective.” In vitro comparison studies including cefamandole and cefoxitin,5*-5Fcefamandole and cefuroxime, and cefoxitin and cef~roxirne~~ have been reported. The results of a broad trial have also demonstrated the clinical effectiveness of cefoxitin.5 7 Cefuroxime” has been examined for in ~ i t r 6oo and ~ ~ -in ~ vivo6’ characteristics. Favorable human pharmacokinezcs62nd clinical efficacy6 64 have been established, The -in vitro studies of these three cephalosporins have suggested some trends of relative activity against normally cephalosporin-resistant gramnegative bacteria. Cefamandole, cefoxitin, and cefuroxime are all active against a substantial percentage of indole-producing Proteus strains. Cefamandole and cefuroxime inhibit the growth of many Enterobacter strains, while cefoxitin has negligible activity. Cefamandole and cefuroxime are more active than cefoxitin against Hemophilus influenzae strains. Cefoxitin is somewhat more active against S. marcescens strains; and none of the three inhibits the growth of Pseudomznas.
Fewer cephalosporins have been of clinical interest for oral administration. Studies of cefatrizine (BLS-640; SKF 60771) (7) have continued to determine in vitro characteristics,65-67 human pharmacckinetics,66*68~6g and clinical effectiveness,69-7’ Extensive clinical trial data documented the effectiveness of cefadroxil (BLS-578; 2-OH cephalexin) . 7 2 Cefaclor (Lilly 99638) (8) has been shown in -in vitro studies to have better activity than cephalexin against gram-negative bacteria, especially H. The excellent oral absorption in mice, rats, and influenzae.56y60,73D74 dogs paralleled that of cephalexin.7 5 Metabolism was observed in dogs76 but not in rodents. Human pharmacology studies indicated that cefaclor gave acceptable blood and urine levels.7 7 The evaluation of FR 10612 (m-methanesulfonylamino cephalexin) indicated that it was comparable to ceFhalexin in vitro, but more effective orally against experimental mouse infections, presumably due to enterohepatic recirculation also leading to higher and longer blood levels,7 8 Although apparently dose related, human blood level curves for FR 10612 did show a longer half-life than did cephalexin. Oral cephalosporin candidate SCE-100 (tetrahydro cephalexin) has been examined extensively for in vitro and -in vivo properties.79 It is not as active as cephalexin.
CGP 9000 (9), a 3-methoxycephem derivative, is somewhat more active than -vitro and is efficiently absorbed orally in mice." cephalexinin The structure-activity relationship of a series of orally active cephalosporins
with phenyl- and hydroxyphenylglycyl side chains which led to the disAn impressive array of 3covery of cefatrizine has been published." heterocyclicthiomethylcephem nuclei were included in the study. The superior influence upon oral absorption in mice of E-OH phenylglycyl over o-OH-, "OH-, or phenyl-was demonstrated. The methyltetrazolethio and lJ2,3-triazolethioheterocyclic functions maximized -in vitro activity, BLS-786 (lo), a new cephalosporin with two hitherto unpublished side chains (ozminomethylphenylacetyl and carboxymethyltetrazolethio) , has in vitro acFivity comparable to cefamandole, with higher and longer blood levels similar to cefazolin.8 2 ~ 8 3 It has excellent effectiveness in mouse therapy studies. An extensive study was reported of structure-activity relationships among cephalosporins containing certain substituted heterocyclicthio groups, with emphasis on substituted methyltetrazolethio.8 4 Cefamandole analogues were stressed. The -in vitro and -in vivo activities were maximized in SKF 75073 (ll)." This analogue was comparable to cefamandole -in vitro (with , however, extraordinary Proteus mirabilis activity), had very high blood levels of long duration in mice, dogs, and squirrel monkeys, and cured experimental mouse infections very well. A series of 7-sulfonylacetamidocephems, which could be viewed as cefazaflur analogues, were synthesized." Although some were quite active, none matched cefazaflur. Two cephalosporins with a-ureidophenylacetyl side chains and having modest Pseudomonas activity were reported. Further refinements in the structure-activity relationships of a-sulfo cephalosporins have been published. Included were variations in the aryl (asulfo) acetyl moiety and a number of 3-heterocyclicthiomethylene functions. The latter do not match the excellent Pseudomonas activity of the pyridinium-methyl compounds. The data prompted the authors to suggest that it is the combination of an acidic 7-side chain together with a positive charge attached to the 3-methylene position that leads to increased Pseudomonas activity while reducing inhibition of other gramnegative bacteria. Synthesis of the 3-cyanocephem system and others in which the C-3 carbon is included in a heterocyclic ring have been accomAlthough the gram-positive activity in this series approached plished. that of cephalothin, the gram-negative activity was much lower.
Interest has continued in 7-methoxycephems. An improved 7-methoxylation route has been developed,” as well as modification of an earlier route leading to incorporation of substituents other than methoxy. The synthesis and evaluation of 7-methoxycephems related to cefazaflur were publi~hed.’~The new compounds displayed the same general trend seen in other 7-methoxy derivatives, i.e., less gram-positive activity, less activity against cephalosporizensitive gram-negative bacteria, and enhanced inhibition of resistant gram-negative strains compared to nonmethoxy analogues. A series of 7-methoxy-7-(2-substitutedthio)acetamidocephem derivatives were prepared and examined for in vitro activity. The best compound was slightly more active than cefoxitin. A new 7-methoxycephem derivative, (3-1170 (12), has been prepared and found to be more active than ~efoxitin.’~Extensive data have been presented on the structure-activity relationships leading to this compound, its -in vitro and -in vivo activityJg6and the absorption, distribution, excretion, and metabolism in several species,”
Naturally Occurring 6-Lactam Containing Compounds - Details of the discovery, isolation, and characterization of the unusual monocyclic B-lactam compound nocardicin A (13), previously known as FR 1923, have been published.9 8 ’ 9 9 The novel bicyclic ring-oxygen containing compound clavulanic acid (BRL 14151) (14) has been isolated from fermentation of a streptomycete.l o o Clavulanicacid, although having a low order of antibacterial activity, inhibits the action of certain 6-lactamases and has been shown to enhance the -in vitro and in vivo activity of selected penicillins.l o ’ An organism designated Streptomyces cattleya elaborates thienamycin, whose isolation was greatly complicated by instability. O 2 Thienamycin has low MIC values against bacteria, including problem organisms such as p. aeruginosa,-S. marcescens,-and B. fragilis and is very effective in curing mouse infections.1 0 3 Thienamycin - experimeKta1 has-been shown to contain a 1-carba penem system (15). - O4 OH
- Chemotherapeutic Agents
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p-Lactam A n t i b i o t i c s
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