Some cephalosporium fungi yield antimicrobial substances called cephalosporins. These are β-lactam compounds with a nucleus of 7-aminocephalosporanic acid (Figure 1) instead of the penicillins’ 6-aminopenicillanic acid. Natural cephalosporins have low antibacterial activity, but the attachment of various R side groups has resulted in the proliferation of an enormous array of drugs with varying pharmacologic properties and antimicrobial spectra and activity. Cephamycins are similar to cephalosporins but are derived from actinomycetes.

Fig1. Basic structure of the cephalosporins. R, side chain. Various structures can be added at R1 and R2 to create the named derivatives.

The mechanism of action of cephalosporins is analogous to that of penicillins: (1) binding to specific PBPs that serve as drug receptors on bacteria, (2) inhibiting cell wall synthesis by blocking the transpeptidation of peptidogly can, and (3) activating autolytic enzymes in the cell wall that can produce lesions resulting in bacterial death. Resistance to cephalosporins can be attributed to (1) poor permeation of bacteria by the drug; (2) lack of PBP for a specific drug or alteration of a PBP that decreases affinity for the drug; (3) degradation of drug by β-lactamases, many of which exist; and (4) efflux mechanisms. Certain second- and third generation cephalosporins can induce special β-lactamases in Gram-negative bacteria. In general, however, cephalosporins tend to be resistant to the β-lactamases produced by staphylococci and common Gram-negative bacteria that hydrolyze and inactivate many penicillins.

For ease of reference, cephalosporins have been arranged into major groups, or “generations,” discussed in the para graphs that follow (Table 1). Many cephalosporins are excreted mainly by the kidney and may accumulate and induce toxicity in patients with renal insufficiency.

Table1. Major Groups of Cephalosporins

First-Generation Cephalosporins

 The first-generation cephalosporins are very active against Gram-positive cocci—except enterococci and MRSA—and are moderately active against some Gram-negative rods, primarily E. coli, Proteus, and Klebsiella. Anaerobic cocci are often sensitive, but Bacteroides fragilis is not.

Cephalexin, cefadroxil, and cephradine (no longer available in the United States) are absorbed from the gut to a variable extent and can be used to treat uncomplicated urinary tract infections and streptococcal pharyngitis. Other first-generation cephalosporins must be injected to give adequate levels in blood and tissues. Cefazolin is a choice for surgical prophylaxis because it gives the highest (90–120 μg/mL) levels with every 8-hour dosing. Cephalothin, cephapirin, and cephradine (these agents are no longer available in the United States) in the same dose give lower levels. None of the first-generation drugs penetrate the CNS, and they are not drugs of first choice for any infection.

Second-Generation Cephalosporins

The second-generation cephalosporins are a heterogeneous group. All are active against organisms covered by first-generation drugs but have extended coverage against Gram-negative rods, including Klebsiella and Proteus but not P. aeruginosa.

Some (not all) oral second-generation cephalosporins can be used to treat sinusitis and otitis media caused by H. influenzae, including β-lactamase-producing strains.

Cefoxitin and cefotetan used in mixed anaerobic infections, including peritonitis and pelvic inflammatory disease. However, resistance to these agents among the B. fragilis group has increased substantially.

Third-Generation Cephalosporins

 The third-generation cephalosporins have decreased activity against Gram-positive cocci except for S. pneumoniae; enterococci are intrinsically resistant to cephalosporins and often produce superinfections during their use. Most third-generation cephalosporins are active against methicillin-susceptible staphylococci, but ceftazidime is only weakly active. A major advantage of third-generation drugs is their enhanced activity against Gram-negative rods. When second-generation drugs tend to fail against P. aeruginosa, ceftazidime or cefoperazone may succeed. Thus, third-generation drugs are very useful in the management of hospital-acquired Gram-negative bacteremia. Ceftazidime may also be lifesaving in severe melioidosis (Burkholderia pseudomallei infection).

Another important distinguishing feature of several third-generation drugs—except cefoperazone—is the ability to reach the CNS and to appear in the spinal fluid in sufficient concentrations to treat meningitis caused by Gram negative rods. Cefotaxime, ceftriaxone, or ceftizoxime given intravenously may be used for management of Gram-negative bacterial sepsis and meningitis.

Fourth-Generation Cephalosporins

 Cefepime is the only fourth-generation cephalosporin now in clinical use in the United States. It has enhanced activity against Enterobacter and Citrobacter species that are resistant to third-generation cephalosporins. Cefepime has activity comparable to that of ceftazidime against P. aeruginosa. The activity against streptococci and methicillin-susceptible staphylococci is greater than that of ceftazidime and com parable with that of the other third-generation compounds. Cefpirome is a fourth-generation cephalosporin available outside of the United States.

Several new agents have recently been approved in the United States. Cefditoren is an oral third-generation cephalosporin with excellent activity against many Gram-positive and Gram-negative species. This agent has bactericidal activity and stability against many β-lactamase enzymes. Cefditoren is the most potent orally administered cephalosporin against S. pneumoniae. Two agents—ceftaroline and ceftobiprole— have activity against MRSA. Ceftaroline has enhanced anti-Gram-positive activity, including MRSA, ampicillin susceptible E. faecalis, and penicillin-nonsusceptible pneumococci. It is indicated for the treatment of acute bacterial skin and skin structure infections as well as community-acquired pneumonia. There are anecdotal reports of its successful use in more serious infections such as bacterial infections caused by MRSA. Ceftobiprole has a spectrum of activity similar to that of other cephalosporins but, in addition, is active against MRSA, ampicillin-susceptible E. faecalis, and penicillin resistant S. pneumoniae. It is not currently marketed in the United States. These latter two agents have been referred to as “MRSA-active cephalosporins.” However, it is important to note that these agents do not have good activity against P. aeruginosa, Acinetobacter species, or ESBL-producing Enterobacteriaceae.

Because of the growing numbers of β-lactamases, some cephalosporins are being combined with β-lactamase inhibitors. The most promising ones to date include ceftazidime and ceftaroline combined with avibactam, a novel β-lactamase inhibitor. These combinations have a spectrum of activity similar to the carbapenems. A novel cephalosporin with enhanced activity against P. aeruginosa ceftolozane has been combined with tazobactam in clinical trials to treat AmpC hyperproducing Enterobacter and KPCs. Both ceftazidime avibactam and ceftolozane–tazobactam have been cleared by the FDA.

Adverse Effects of Cephalosporins

The cephalosporins are sensitizing and can elicit a variety of hypersensitivity reactions, including anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia. The frequency of cross-allergy between cephalosporins and penicillins is approximately 5%. Patients with minor penicillin allergy can often tolerate cephalosporins, but those with a history of anaphylaxis cannot.

Thrombophlebitis can occur after intravenous injection. Hypoprothrombinemia is frequent with cephalosporins that have a methylthiotetrazole group (eg, cefamandole, cefmetazole, cefotetan, and cefoperazone). Oral administration of vitamin K (10 mg twice weekly) can prevent this com plication. These same drugs can also cause severe disulfiram reactions, and use of alcohol must be avoided.

Gastrointestinal side effects, mostly diarrhea, occur infrequently. Reversible biliary pseudolithiasis has been described with high-dose ceftriaxone administration.

Because many second-, third-, and fourth-generation cephalosporins have little activity against Gram-positive organisms, particularly enterococci, superinfection with these organisms and with fungi may occur.

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