Newer Cephalosporins

Cephalosporins currently undergoing clinical trials or recently being marketed in the United States fall into two categories: (a) orally active jS-lactamase-resistant cephalosporins and (b) parenteral j-lactamase-resistant antipseudomonal cephalosporins. The status of some of these compounds awaits more extensive clinical evaluation. Nonetheless, it appears that any advances they represent will be relatively modest.


Ceftibuten (Cedax) is a recently introduced, chemically novel analog of the oximino cephalosporins in which an olefinic methylene group (C=CHCH2-) with Z stereochemistry has replaced the syn oximino (C=NO-) group. This isosteric replacement yields a compound that retains resistance to hydrolysis catalyzed by many j-lactamases, has enhanced chemical stability, and is orally active. Oral absorption is rapid and nearly complete. It has the highest oral bioavailability of the third-generation cephalosporins.94 Ceftibuten is excreted largely unchanged in the urine and has a half-life of about 2.5 hours. Plasma protein binding of this cephalosporin is estimated to be 63%.

Ceftibuten possesses excellent potency against most members of the Enterobacteriaceae family, H. influenzae, Neisseria spp., and M. catarrhalis. It is not active against S. aureus or P. aeruginosa and exhibits modest antistreptococ-

cal activity. Ceftibuten is recommended in the management of community-acquired respiratory tract, urinary tract, and gynecological infections.


Cefpirome (Cefrom) is a newer parenteral, ß-lactamase-resistant cephalosporin with a quaternary ammonium group at the 3-position of the cephem nucleus. Because its potency against Gram-positive and Gram-negative bacteria rivals that of the first-generation and third-generation cephalosporins, respectively, cefpirome is being touted as the first fourth-generation cephalosporin.95 Its broad spectrum includes methicillin-sensitive staphylococci, penicillin-resistant pneumococci, and ß-lactamase-producing strains of E. coli, Enterobacter, Citrobacter, and Serratia spp. Its efficacy against P. aeruginosa is comparable with that of ceftazidime. Cefpirome is excreted largely unchanged in the urine with a half-life of 2 hours.


Cefepime (Maxipime, Axepin) is a parenteral, j-lactamase-resistant cephalosporin that is chemically and mi-crobiologically similar to cefpirome. It also has a broad antibacterial spectrum, with significant activity against both Gram-positive and Gram-negative bacteria, including streptococci, staphylococci, Pseudomonas spp., and the Enterobacteriaceae. It is active against some bacterial isolates that are resistant to ceftazidime.96 The efficacy of cefepime has been demonstrated in the treatment of urinary tract infections, lower respiratory tract infections, skin and soft tissue infections, chronic osteomyelitis, and intra-abdominal and biliary infections. It is excreted in the urine with a half-life of 2.1 hours. It is bound minimally to plasma proteins. Cefepime is also a fourth-generation cephalosporin.

Future Developments in Cephalosporin Design

Recent research efforts in the cephalosporin field have focused primarily on two desired antibiotic properties: (a) increased permeability into Gram-negative bacilli, leading to

enhanced efficacy against permeability-resistant strains of Enterobacteriaceae and P. aeruginosa, and (b) increased affinity for altered PBPs, in particular the PBP 2a (or PBP 2') of MRSA.31

The observation that certain catechol-substituted cephalosporins exhibit marked broad-spectrum antibacterial activity led to the discovery that such compounds and other analogs capable of chelating iron could mimic natural siderophores (iron-chelating peptides) and thus be actively transported into bacterial cells via the tonB--dependent iron-transport system.97,98 This provides a means of attacking bacterial strains that resist cellular penetration of cephalosporins.

A catechol-containing cephalosporin that exhibits excellent in vitro antibacterial activity against clinical isolates and promising pharmacokinetic properties is GR-69153. GR-69153 is a parenteral j-lactamase-resistant cephalosporin with a broad spectrum of activity against Gram-positive and Gram-negative bacteria.

The antibacterial spectrum of GR-69153 includes most members of the Enterobacteriaceae family, P. aeruginosa, H. influenzae, N. gonorrhoeae, M. catarrhalis, staphylococci, streptococci, and Acinetobacter spp. It was not active against enterococci, B. fragilis, or MRSA. The half-life of GR-69153 in human volunteers was determined to be 3.5 hours, suggesting that metabolism by catechol-O-methyl-transferase may not be an important factor. The relatively long half-life would permit once-a-day parenteral dosing for the treatment of many serious bacterial infections.

An experimental cephalosporin that has exhibited considerable promise against MRSA in preclinical evaluations is TOC-039.

TOC-039 is a parenteral, j-lactamase-resistant, hydrox-yimino cephalosporin with a vinylthiopyridyl side chain attached to the 3-position of the cephem nucleus. It is a broad-spectrum agent that exhibits good activity against most aerobic Gram-positive and Gram-negative bacteria, including staphylococci, streptococci, enterococci, H. influenzae, M. catarrhalis, and most of the Enterobacteriaceae family.99 A few strains of P. vulgaris, S. marcescens, and Citrobacter freundii are resistant, and TOC-039 is inactive against P. aeruginosa. Although the minimum inhibiting concentration (MIC) of TOC-039 against MRSA is slightly less than that of vancomycin, it is more rapidly bacteriocidal. Future clinical evaluations will determine if TOC-039 has the appropriate pharmacokinetic and antibacterial properties in vivo to be approved for the treatment of bacterial infections in humans.


The development of useful monobactam antibiotics began with the independent isolation of sulfazecin (SQ 26,445) and other monocyclic j-lactam antibiotics from saprophytic soil bacteria in Japan100 and the United States.101 Sulfazecin was found to be weakly active as an antibacterial agent but highly resistant to S-lactamases.

Structure Viagra

Extensive SAR studies102 eventually led to the development of aztreonam, which has useful properties as an antibacterial agent. Early work established that the 3-methoxy group, which was in part responsible for j-lactamase stability in the series, contributed to the low antibacterial potency and poor chemical stability of these antibiotics. A 4-methyl group, however, increases stability to ^-lactamases and activity against Gram-negative bacteria at the same time. Unfortunately, potency against Gram-positive bacteria decreases. 4,4-Gem-dimethyl substitution slightly decreases antibacterial potency after oral administration.


Aztreonam Disodium

Aztreonam (Azactam) is a monobactam prepared by total synthesis. It binds with high affinity to PBP 3 in Gramnegative bacteria only. It is inactive against Gram-positive bacteria and anaerobes. ^-Lactamase resistance is like that of ceftazidime, which has the same isobutyric acid oximi-noacyl group. Aztreonam does not induce chromosomally mediated S-lactamases.

Struktur Sugar

Aztreonam is particularly active against aerobic Gramnegative bacilli, including E. coli, K. pneumoniae, Klebsiella oxytoca, P. mirabilis, S. marcescens, Citrobacter spp., and P. aeruginosa. It is used to treat urinary and lower respiratory tract infections, intra-abdominal infections, and gynecological infections, as well as septicemias caused by these organisms. Aztreonam is also effective against, but is not currently used to treat, infections caused by Haemophilus, Neisseria, Salmonella, indole-positive Proteus, and Yersinia spp. It is not active against Gram-positive bacteria, anaerobic bacteria, or other species of Pseudomonas.

Urinary excretion is about 70% of the administered dose. Some is excreted through the bile. Serum half-life is 1.7 hours, which allows aztreonam to be administered 2 or 3 times daily, depending on the severity of the infection. Less than 1% of an orally administered dose of aztreonam is absorbed, prompting the suggestion that this jS-lactam could be used to treat intestinal infections.

The disodium salt of aztreonam is very soluble in water. Solutions for parenteral administration containing 2% or less are stable for 48 hours at room temperature. Refrigerated solutions retain full potency for 1 week.


Tigemonam is a newer monobactam that is orally active.103 It is highly resistant to jS-lactamases. The antibacterial spectrum of activity resembles that of aztreonam. It is very active against the Enterobacteriaceae, including E. coli, Klebsiella, Proteus, Citrobacter, Serratia, and Enterobacter spp. It also exhibits good potency against H. influenzae and N. gonorrhoeae. Tigemonam is not particularly active against Gram-positive or anaerobic bacteria and is inactive against P. aeruginosa.

In contrast to the poor oral bioavailability of aztreonam, the oral absorption of tigemonam is excellent. It could become a valuable agent for the oral treatment of urinary tract infections and other non-life-threatening infections caused by jS-lactamase-producing Gram-negative bacteria.

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