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In 1979, there were 10 cephalosporins available for use in the United States. Since then, the number has increased to about 30. Choosing from among these many similarly named antimicrobials has become a challenge for even the most knowledgeable internist.

The cephalosporins are synthetic or semisynthetic derivatives of products produced by the fungus Cephalosporium acremonium. The original compound, cephalosporin C, is closely related to penicillin in both structure and mechanism of action. The initial cephalosporins were recognized for their bactericidal activity against both gram-positive cocci and gram-negative bacilli, as well as their good safety profile. Cephalosporins have been developed during the past 10 years with increased intrinsic antibacterial activity and modified pharmacokinetic properties, so that drugs with a longer half-life and greater oral absorbability are available.
The conceptual organization of cephalosporins as first-, second-, or third-generation remains useful (Table 74-1). First-generation cephalosporins are similar, whereas third-generation cephalosporins must be appreciated for their unique differences.

Table 74-1. Classification of cephalosporins

First-generation cephalosporins remain active against most aerobic gram-positive cocci. They are resistant to hydrolysis by the penicillinase produced by Staphylococcus aureus. First-generation cephalosporins have been used extensively in staphylococcal infections with good success. They are not active against methicillin-resistant staphylococci. In the hospital setting, they are often used as second-line antimicrobials against staphylococci because oxacillin and nafcillin have a narrower spectrum and therefore are usually preferred for methicillin-sensitive organisms. In patients who have manifest allergy to penicillin, first-generation cephalosporins are drugs of choice for methicillin-sensitive staphylococcal infections. They are generally regarded as safer than clindamycin or vancomycin. In patients who have had anaphylactic reactions to penicillin, cephalosporins are not used.
First-generation cephalosporins are also widely used for streptococcal infection, excluding infections caused by enterococci. They are particularly useful to treat streptococcal cellulitis and pneumococcal pneumonia in patients who have had a rash in reaction to penicillin. First-generation cephalosporins are not preferred drugs for endocarditis caused by viridans streptococci. Because they penetrate the blood–brain barrier poorly, they cannot be used in pneumococcal meningitis.
Many strains of gram-negative bacilli, particularly Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, are sensitive to first-generation cephalosporins. When in vitro susceptibility tests are available and demonstrate susceptibility, first-generation cephalosporins are generally good choices against these agents because they are less expensive and induce less resistance than the second- and third-generation cephalosporins. The first-generation cephalosporins cannot be used as empiric therapy for life-threatening gram-negative bacillary infection because many of these bacilli (Pseudomonas and Serratia species in particular) are resistant. First-generation cephalosporins also cannot be used for infections caused by Haemophilus influenzae or for anaerobic infection.
The first-generation cephalosporins cephalothin, cephapirin, and cephradine can be considered interchangeable, and the same Kirby-Bauer disk is used to test susceptibility for all of them. Cefazolin has a longer half-life, and higher serum concentrations are obtained with IM injection. First-generation cephalosporins are still recommended for many types of IM injection and surgical prophylaxis; however, agents with better anaerobic activity are recommended for colorectal surgical prophylaxis. These drugs cannot be used for meningitis, as they do not penetrate inflamed meninges.
Second-generation cephalosporins are generally somewhat less active than first-generation cephalosporins against gram-positive cocci but have a broader spectrum against gram-negative bacilli, such as Enterobacter species, Citrobacter, and Morganella. More importantly, some provide excellent activity against H. influenzae, and others have added activity against anaerobic bacteria, particularly Bacteroides fragilis. The second-generation cephalosporins cefamandole, cefuroxime, and cefonicid and the oral drugs cefaclor, cefuroxime axetil, loracarbef, cefdinir, and cefprozil have become the antimicrobials of choice to treat infection with H. influenzae, both b-lactamase-positive and b-lactamase-negative strains. Other second-generation cephalosporins, such as cefoxitin, cefotetan, and cefmetazole, have little H. influenzae activity but are useful for mixed anaerobic and gram-negative bacillary infection.
The third-generation cephalosporins have the widest spectrum of gram-negative activity. Most have activity against both H. influenzae and anaerobes, although differences exist among individual members of the group. Ceftazidime has excellent activity against Pseudomonas aeruginosa and is one of the drugs of choice for infection with this organism. Other third-generation agents, such as cefoperazone, have moderate activity against Pseudomonas. Third-generation cephalosporins generally have lost activity against gram-positive cocci. Third-generation cephalosporins have been used to treat meningitis caused by H. influenzae, Neisseria meningitidis, Streptococcus pneumoniae, and many gram-negative bacilli. Treatment failure has recently been reported for pneumococcal meningitis caused by penicillin-resistant strains. Moxalactam, rarely used because of its tendency to cause gastrointestinal bleeding, was the third-generation cephalosporin of choice for anaerobic infection. Ceftizoxime has been considered a good anaerobic agent by some investigators.
In addition to the etiologic agent and spectrum of activity of the drug, the choice of a cephalosporin may depend on its side-effect profile. The major adverse reaction to all cephalosporins is hypersensitivity or allergic reactions. All can cause a drug fever, eosinophilia, and diarrhea. Gastrointestinal bleeding has occurred with all cephalosporins but is more common in those with a methylthiotetrazole ring at the R2 position. Such cephalosporins include moxalactam, cefoperazone, cefamandole, and cefotetan. These same cephalosporins can cause a disulfiram-like reaction in patients who have been drinking alcohol. Flushing, tachycardia, nausea, and vomiting are manifestations of this syndrome. Cephalosporins do not cause nephrotoxicity in themselves but may increase the likelihood of aminoglycoside nephrotoxicity when a cephalosporin and aminoglycoside are used together.
Cefixime, cefpodoxime proxetil, and cefetamet pivoxil are oral third-generation cephalosporins that have an additional spectrum of activity against gram-negative bacilli, but not Pseudomonas. They are generally less likely to be used for gram-negative bacillary infection than are quinolones. Cefpodoxime has better antistaphylococcal activity than the others, but none should be drugs of choice for gram-positive infection.
Cefepime is one of the newest cephalopsporins and has been considered by some to be a fourth-generation agent. Cefepime targets multiple penicillin-binding proteins and is resistant to many b-lactamases. The antibiotic covers many strains of Pseudomonas while maintaining activity against gram-positive cocci, including S. aureus.
The following considerations are important in choosing the right cephalosporin:

The first-generation cephalosporins such as cephalothin and cefazolin are good second-line drugs for staphylococcal (not methicillin-resistant S. aureus) or streptococcal infection. They can be used in patients with penicillin-induced rash but not in patients who have experienced anaphylaxis. They are useful in gram-negative bacillary infections when susceptibility tests show the organism to be sensitive.

Second-generation cephalosporins with H. influenzae activity (cefamandole, cefuroxime, cefonicid, cefaclor) are among the drugs of choice for lower respiratory infection. These antimicrobials are active against S. pneumoniae, H. influenzae, and Moraxella catarrhalis, the common respiratory pathogens in acute tracheobronchitis and community-acquired pneumonia.

Cefoxitin and cefotetan are second-generation cephalosporins with good anaerobic activity against Bacteroides fragilis. They cover some but not all gram-negative bacilli. For hospital-acquired gram-negative infection, broader-spectrum gram-negative coverage (to include P. aeruginosa) is necessary.

The third-generation cephalosporin ceftazidime is an excellent antipseudomonal agent with or without addition of an aminoglycoside. The other third-generation cephalosporins are generally not recommended for Pseudomonas infection.

Third-generation cephalosporins have become the drugs of choice for gram negative meningitis. They are also valuable in treating infection caused by resistant gram-negative bacilli, for which aminoglycosides might formerly have been necessary.

Ceftriaxone, the third-generation cephalosporin with the longest half-life, is commonly used to treat serious infections at home. The drug can be administered by a visiting nurse once or twice per day.

Ceftizoxime and cefotaxime, the third-generation cephalosporins with names that sound the most alike, actually are the most alike. They maintain coverage of gram-positive cocci better than do other third-generation cephalosporins but provide little Pseudomonas coverage. Some believe that ceftizoxime is a drug of choice for anaerobic infection. Moxalactam, which has the best in vitro activity against anaerobes, is no longer recommended because it causes gastrointestinal bleeding. (S.L.B.)
Cherubin CE, et al. Penetration of newer cephalosporins into cerebrospinal fluid. Rev Infect Dis 1989;11:526.
Compares cerebrospinal fluid concentrations of second- and third-generation cephalosporins. The most clinical data are available for cefotaxime.
Ehmann WC. Cephalosporin-induced hemolysis: a case report and review of the literature. Am J Hematol 1992;40:121.
Review of 13 cases of cephalosporin-induced hemolytic anemia.
Ennis DM, Cobb CG. The newer cephalosporins. Infect Dis Clin North Am 1995;9:687.
Describes structure, side effects, and activity of the newer second- and third-generation oral cepalosporins.
Finland M, Kaye D, Turck M. Clinical symposium on cefazolin. J Infect Dis 1973; 128:S312.
Includes 22 articles on the spectrum, pharmacology, uses, and adverse effects of a long-acting first-generation cephalosporin.
Fong IW, Tompkins KB. Review of Pseudomonas aeruginosa meningitis with special emphasis on treatment with ceftazidime. Rev Infect Dis 1985;7:604.
Ceftazidime has been successful in the treatment of Pseudomonas meningitis, making intraventricular aminoglycoside therapy rarely necessary.
Goldberg DM. The cephalosporins. Med Clin North Am 1987;71:1113.
Review article on cephalosporins, with more than 100 references.
Gorbach SL. The role of cephalosporins in surgical prophylaxis. J Antimicrob Chemother 1989;23(Suppl D):61.
For colorectal surgery, the choice of a cephalosporin should be based in part on its anaerobic activity.
Gustaferro CA, Steckelberg JM. Cephalosporin antimicrobial agents and related compounds. Mayo Clin Proc 1991;66:1064.
Bacterial resistance has developed to cephalosporins with respect to b-lactamase production, alterations in binding proteins, and modifications of the cell wall.
John CC. Treatment failure with the use of a third-generation cephalosporin for penicillin-resistant pneumococcal meningitis. Case report and review. Clin Infect Dis 1994;18:188.
Describes treatment failures of third-generation cephalosporins with minimum inhibitory concentrations greater than 2 mg/mL against pneumococci. Vancomycin is likely the drug of choice for these strains.
Kaiser AB. Overview of cephalosporin prophylaxis. Am J Surg 1988;155(5A):52.
Comprehensive review of cephalosporin prophylaxis in surgery that also stresses the difficulty in making definitive choices for prophylaxis.
Landesman SH, et al. Past and current roles for cephalosporin antibiotics in treatment of meningitis: emphasis on use in gram-negative bacillary meningitis. Am J Med 1981;71:693.
Describes role of cephalosporins in meningitis.
Meideros AA. Nosocomial outbreaks of multiresistant bacteria: extended-spectrum b-lactamases have arrived in North America. Ann Intern Med 1993;119:428.
Reports on a nosocomial outbreak of Klebsiella infection resistant to third-generation cephalosporins.
Neu HC. Cephalosporin antibiotics: molecules that respond to different needs. Am J Surg 1988;155(5A):1.
The presence of a methoxyl group at C7 of the cephalosporin nucleus confers activity against many anaerobes.
Neu HC, Prince AS. Interaction between moxalactam and alcohol. Lancet 1980;1:1422.
Description of Antabuse-like reaction with moxalactam and alcohol.
Quenzer RW. A perspective of cephalosporins in pneumonia. Chest 1987;92:3.
Describes an approach to cephalosporin therapy in patients with pneumonia.
Rankin GO, Sutherland CH. Nephrotoxicity of aminoglycosides and cephalosporins in combination. Adverse Drug React Acute Poisoning Rev 1989;8:73.
A review of cephalosporin potentiation of aminoglycoside nephrotoxicity.
Rouse MS, et al. Animal models as predictors of outcome of therapy with broad-spectrum cephalosporins. J Antimicrob Chemother 1992;29(Suppl A):39.
Suggests that animal models of endocarditis and meningitis may be most useful in assessing cephalosporin efficacy.
Sanders CC. Cefepime. The next generation? Clin Infect Dis 1993;17:369.
Cefepime has activity against many strains of Pseudomonas and also maintains good coverage of many gram-positive cocci. Hence, it is a broad-spectrum antipseudomonal antibiotic.
Sattler FR, Weitekamp MR, Ballard JO. Potential for bleeding with new b-lactam antibiotics. Ann Intern Med 1986;105:924.
Moxalactam is no longer recommended because of its propensity to cause gastrointestinal bleeding.
Scully BE, Neu HC. Clinical efficacy of ceftazidime: treatment of serious infection caused by multiresistant Pseudomonas and other gram-negative bacteria. Arch Intern Med 1984;144:57.
A proven role for ceftazidime in serious Pseudomonas infection.
Thoburn R, Johnson JE, Cluff LE. Studies on the epidemiology of adverse drug reactions. IV. The relationship of cephalothin and penicillin allergy. J Am Med 1966; 198:111.
A history of penicillin allergy or a positive skin test reaction with these drugs was a predisposing factor to cephalothin reactions.
Thompson RL. Cephalosporin, carbapenem, and monobactam antibiotics. Mayo Clin Proc 1987;62:821.
Part of the Mayo Clinic symposium on antimicrobials. Includes good summary of spectrum of activity and details on adverse reactions.
Weinstein L, Kaplan K. The cephalosporins: microbiological, chemical, and pharmacological properties and use in chemotherapy of infection. Ann Intern Med 1970;72:729.
Discussion of first-generation cephalosporins.
Wiedemann B. Selection of b-lactamase producers during cephalosporin and penicillin therapy. Scand J Infect Dis 1986;49 (Suppl):100.
Discusses the selection of cephalosporins with respect to their impact on b-lactamase production.


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