Cephalosporin Antimicrobial Agents and Related Compounds
CYNTHIA A. GUSTAFERRO, M.D., JAMES M. STECKELBERG, M.D., Division of Infectious Diseases and Internal Medicine
Cephalosporins are broad-spectrum antimicrobial agents that are often used empirically to treat suspected bacterial infections and also to treat culture-proven infections due to selected gram-positive and gram-negative microorganisms. Cephalosporins differ widely in their spectrum of activity, susceptibility to ~-Iactamases, serum half-life, and penetration of the central nervous system. In general, the first-generation and second-generation agents are most active against staphylococci and streptococci, and the third-generation agents are most active against the Enterobacteriaceae and Pseudomonas, As a group, cephalosporins have a favorable profile of toxicity in comparison with other antimicrobial agents. The development of bacterial resistance has affected all steps of the cephalosporin mechanism of action, including production of ~-Iactamases, alterations in penicillin-binding proteins, and modification of the cell wall. New cephalosporins are among the most expensive pharmaceutical agents in use today. Maintaining expertise in the choice and use of these agents will remain a challenge to physicians as additional investigational cephalosporins continue to be developed and introduced into clinical practice. .
The cephalosporins are a widely used and rapidly expanding family of antimicrobial agents. These ~-lactam antimicrobial agents are derived semisynthetically from cephalosporin C, an antibacterial compound produced by the fungus Cephalosporium acremonium. The structure of the cephalosporins is similar to that of penicillin and consists of a fourmembered ~-lactam ring attached to a six-membered dihydrothiazine ring, which gives it inherent resistance to ~-lactamase degradation. Cephalosporins have the same mechanism of action as the penicillins-inhibition of synthesis of the cell wall. Modification of the basic structure has produced a variety of compounds with differences in spectrum of activity, pharmacokinetics, and potential toxicity. Because of their broad spectrum of activity, efficacy, and generally favorable profile of toxicity, these compounds are often used to treat numerous infections due to gram-positive and gram-negative bacteria. In this review, we will discuss Individual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 66:1064-1073,1991
the currently available cephalosporin agents as well as those likely to be available in the near future.
TYPES OF CEPHALOSPORINS Cephalosporin antimicrobial agents are traditionally divided into first-, second-, and third-generation agents. The distinction, originally used as a marketing tool, is more clinically useful when the agents are classified into generations on the basis of general spectrum of activity (see subsequent discussion). Considerable differences in spectrum of activity among cephalosporins of a given generation and also overlap in activity among generations have been noted. The cephamycins, closely related compounds, are most closely related to second-generation agents. The generic and trade names of currently available cephalosporin agents are listed in Table 1.
First-Generation Agents.-Currently available firstgeneration cephalosporins include the orally administered agents cefaclor, cefadroxil, cephalexin, and cephradine. The parenterally administered agents include cefazolin, cephapirin, and cephradine. The bacterial spectrum and activity of these agents are similar.
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Second-Generation Agents.-The currently available orally administered second-generation cephalosporin is cefuroxime axetil. Cefprozil, another agent for oral use, is currently under clinical investigation. The parenterally administered agents include cefamandole, cefonicid, ceforanide, cefuroxime, and three cephamycins---cefmetazole, cefotetan, and cefoxitin. Cefonicid, ceforanide, and cefotetan have the longest half-lives. Clinically important differences exist among second-generation cephalosporins in ability to penetrate the central nervous system, relative antistaphylococcal activity, and anaerobic activity. Third-Generation Agents.-The only orally administered third-generation cephalosporin currently available is cefixime. Agents for parenteral use include cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, and a cephamycin, moxalactam. Agents in clinical development include cefepime and cefpirome. Clinically important differences exist among third-generation cephalosporins in antipseudomonal and anaerobic activity.
PHARMACOLOGIC PROPERTIES Cephalosporins differ in their spectrum of activity, susceptibility to p-Iactamases, protein binding, peak serum concentration, serum half-life, route of excretion, penetration of the central nervous system, and toxicity.l-' These differences result from modification of the cephalosporin molecule in an effort to stabilize the p-Iactam ring. The structure of the cephalosporin molecule and side-chain substitutions of selected first-, second-, and third-generation agents are shown in Figure 1. Substitutions of the R 1 or R2 side chains result in changes in antimicrobial spectrum, potency, profile of toxicity, and half-life. R j substitutions affect resistance to bacterial plactamases and yield broader spectrum and greater activity. Cefazolin, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime all contain R 1 substitutions. Altering the R 2 side chain can provide the compound with a longer half-life. R2 substitutions are present in cefamandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, cefuroxime, and moxalactam. Substitution of the methylthiotetrazole side chain at the R2 position created new toxic effects that will be discussed subsequently herein. Examples of modifications of the cephalosporin nucleus include the addition of a carboxyl group on the acyl side chain to enhance antipseudomonal activity and the addition of a methoxy group at C7 to create the cephamycins. Carbapenems and monobactam drugs, the result of radical modification of the nuclear structure, are discussed elsewhere in this symposium. New agents with various properties will continue to be developed by further modifications. The pharmacologic properties of currently available and investigational cephalosporins are shown in Table 2. In
CEPHALOSPORINS
1065
Table I.-Classification of Cephalosporins for Oral or Parenteral Use Representative trade names
Route of administration*
First generation Cefaclor Cefadroxil Cefazolin Cephalexin Cephapirin Cephradine
Ceclor Duricef, Ultracef Ancef, Kefzol Keflex Cefadyl Anspor, Velosef
Oral Oral i.m., i.v, Oral i.m., i.v. Oral, i.m., i.v,
Second generation Cefamandole Cefmetazole Cefonicid Ceforanide Cefotetan Cefoxitin Cefuroxime Cefuroxime axetil
Mandol Zefazone Monocid Precef Cefotan Mefoxin Zinacef, Kefurox Ceftin
i.m., i.v. i.v. i.m., i.v. i.m., i.v. i.m., i.v. i.m.,i.v. i.m., i.v. Oral
Suprax Cefobid Claforan Fortaz, Tazidime, Tazicef Cefizox Rocephin
Oral i.m.,i.v. i.m., i.v. i.rn., i.v.
Generic name
Third generation Cefixime Cefoperazone Cefotaxime Ceftazidime Ceftizoxime Ceftriaxone Cefepimet Cefpirome']
i.m.,i.v. Lm.,i.v. i.m., i.v. i.m., i.v.
*i.m. = intramuscular; i.v. = intravenous.
t Investigational.
general, orally administered cephalosporins are rapidly and well absorbed. The agents vary, however, in their highest peak serum concentration depending on their administration in relationship to intake of food. Cefaclor, cefadroxil, cephalexin, and cephradine are best absorbed from an empty stomach. Cefuroxime axetil may be irregularly absorbed and may be associated with a higher frequency of gastrointestinal complaints than other agents. Its bioavailability increases when taken with food. No orally administered cephalosporin provides adequate concentrations in the cerebrospinal fluid, and none is highly protein bound. The firstand second-generation cephalosporins administered orally are excreted primarily by the renal route, whereas cefixime has increased biliary excretion. Cefadroxil and cefuroxime axetil have longer half-lives than the other agents and may be administered twice daily. A half-life of 3 to 4 hours for cefixime may allow once-daily administration.' Most parenterally administered cephalosporins have a half-life of 0.5 to 2 hours. A longer half-life is observed in cefonicid, ceforanide, cefotetan, and ceftriaxone because of their increased serum protein binding, low tubular secretion,
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Mayo Clin Proc, October 1991, Vol 66
CEPHALOSPORINS
Cephalosporin nucleus
1-1-1
R'_C7 )3-lactam ring
°
S
R 1 Substitutions
COOH
R2 Substitutions
/':N....... ~ N( tN-CH2C-
Celazolin
Dlhydrothiazine ring
N~R2
Celazolin
N=N /OCH 3 N Cefuroxirne
Celotaxlme Cellizoxime Cellriaxone H 2N
"° C-
("OyC
CYNTHIA A. GUSTAFERRO, M.D., JAMES M. STECKELBERG, M.D., Division of Infectious Diseases and Internal Medicine
Cephalosporins are broad-spectrum antimicrobial agents that are often used empirically to treat suspected bacterial infections and also to treat culture-proven infections due to selected gram-positive and gram-negative microorganisms. Cephalosporins differ widely in their spectrum of activity, susceptibility to ~-Iactamases, serum half-life, and penetration of the central nervous system. In general, the first-generation and second-generation agents are most active against staphylococci and streptococci, and the third-generation agents are most active against the Enterobacteriaceae and Pseudomonas, As a group, cephalosporins have a favorable profile of toxicity in comparison with other antimicrobial agents. The development of bacterial resistance has affected all steps of the cephalosporin mechanism of action, including production of ~-Iactamases, alterations in penicillin-binding proteins, and modification of the cell wall. New cephalosporins are among the most expensive pharmaceutical agents in use today. Maintaining expertise in the choice and use of these agents will remain a challenge to physicians as additional investigational cephalosporins continue to be developed and introduced into clinical practice. .
The cephalosporins are a widely used and rapidly expanding family of antimicrobial agents. These ~-lactam antimicrobial agents are derived semisynthetically from cephalosporin C, an antibacterial compound produced by the fungus Cephalosporium acremonium. The structure of the cephalosporins is similar to that of penicillin and consists of a fourmembered ~-lactam ring attached to a six-membered dihydrothiazine ring, which gives it inherent resistance to ~-lactamase degradation. Cephalosporins have the same mechanism of action as the penicillins-inhibition of synthesis of the cell wall. Modification of the basic structure has produced a variety of compounds with differences in spectrum of activity, pharmacokinetics, and potential toxicity. Because of their broad spectrum of activity, efficacy, and generally favorable profile of toxicity, these compounds are often used to treat numerous infections due to gram-positive and gram-negative bacteria. In this review, we will discuss Individual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 66:1064-1073,1991
the currently available cephalosporin agents as well as those likely to be available in the near future.
TYPES OF CEPHALOSPORINS Cephalosporin antimicrobial agents are traditionally divided into first-, second-, and third-generation agents. The distinction, originally used as a marketing tool, is more clinically useful when the agents are classified into generations on the basis of general spectrum of activity (see subsequent discussion). Considerable differences in spectrum of activity among cephalosporins of a given generation and also overlap in activity among generations have been noted. The cephamycins, closely related compounds, are most closely related to second-generation agents. The generic and trade names of currently available cephalosporin agents are listed in Table 1.
First-Generation Agents.-Currently available firstgeneration cephalosporins include the orally administered agents cefaclor, cefadroxil, cephalexin, and cephradine. The parenterally administered agents include cefazolin, cephapirin, and cephradine. The bacterial spectrum and activity of these agents are similar.
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Mayo CUD Proc, October 1991, Vol 66
Second-Generation Agents.-The currently available orally administered second-generation cephalosporin is cefuroxime axetil. Cefprozil, another agent for oral use, is currently under clinical investigation. The parenterally administered agents include cefamandole, cefonicid, ceforanide, cefuroxime, and three cephamycins---cefmetazole, cefotetan, and cefoxitin. Cefonicid, ceforanide, and cefotetan have the longest half-lives. Clinically important differences exist among second-generation cephalosporins in ability to penetrate the central nervous system, relative antistaphylococcal activity, and anaerobic activity. Third-Generation Agents.-The only orally administered third-generation cephalosporin currently available is cefixime. Agents for parenteral use include cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, and a cephamycin, moxalactam. Agents in clinical development include cefepime and cefpirome. Clinically important differences exist among third-generation cephalosporins in antipseudomonal and anaerobic activity.
PHARMACOLOGIC PROPERTIES Cephalosporins differ in their spectrum of activity, susceptibility to p-Iactamases, protein binding, peak serum concentration, serum half-life, route of excretion, penetration of the central nervous system, and toxicity.l-' These differences result from modification of the cephalosporin molecule in an effort to stabilize the p-Iactam ring. The structure of the cephalosporin molecule and side-chain substitutions of selected first-, second-, and third-generation agents are shown in Figure 1. Substitutions of the R 1 or R2 side chains result in changes in antimicrobial spectrum, potency, profile of toxicity, and half-life. R j substitutions affect resistance to bacterial plactamases and yield broader spectrum and greater activity. Cefazolin, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime all contain R 1 substitutions. Altering the R 2 side chain can provide the compound with a longer half-life. R2 substitutions are present in cefamandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, cefuroxime, and moxalactam. Substitution of the methylthiotetrazole side chain at the R2 position created new toxic effects that will be discussed subsequently herein. Examples of modifications of the cephalosporin nucleus include the addition of a carboxyl group on the acyl side chain to enhance antipseudomonal activity and the addition of a methoxy group at C7 to create the cephamycins. Carbapenems and monobactam drugs, the result of radical modification of the nuclear structure, are discussed elsewhere in this symposium. New agents with various properties will continue to be developed by further modifications. The pharmacologic properties of currently available and investigational cephalosporins are shown in Table 2. In
CEPHALOSPORINS
1065
Table I.-Classification of Cephalosporins for Oral or Parenteral Use Representative trade names
Route of administration*
First generation Cefaclor Cefadroxil Cefazolin Cephalexin Cephapirin Cephradine
Ceclor Duricef, Ultracef Ancef, Kefzol Keflex Cefadyl Anspor, Velosef
Oral Oral i.m., i.v, Oral i.m., i.v. Oral, i.m., i.v,
Second generation Cefamandole Cefmetazole Cefonicid Ceforanide Cefotetan Cefoxitin Cefuroxime Cefuroxime axetil
Mandol Zefazone Monocid Precef Cefotan Mefoxin Zinacef, Kefurox Ceftin
i.m., i.v. i.v. i.m., i.v. i.m., i.v. i.m., i.v. i.m.,i.v. i.m., i.v. Oral
Suprax Cefobid Claforan Fortaz, Tazidime, Tazicef Cefizox Rocephin
Oral i.m.,i.v. i.m., i.v. i.rn., i.v.
Generic name
Third generation Cefixime Cefoperazone Cefotaxime Ceftazidime Ceftizoxime Ceftriaxone Cefepimet Cefpirome']
i.m.,i.v. Lm.,i.v. i.m., i.v. i.m., i.v.
*i.m. = intramuscular; i.v. = intravenous.
t Investigational.
general, orally administered cephalosporins are rapidly and well absorbed. The agents vary, however, in their highest peak serum concentration depending on their administration in relationship to intake of food. Cefaclor, cefadroxil, cephalexin, and cephradine are best absorbed from an empty stomach. Cefuroxime axetil may be irregularly absorbed and may be associated with a higher frequency of gastrointestinal complaints than other agents. Its bioavailability increases when taken with food. No orally administered cephalosporin provides adequate concentrations in the cerebrospinal fluid, and none is highly protein bound. The firstand second-generation cephalosporins administered orally are excreted primarily by the renal route, whereas cefixime has increased biliary excretion. Cefadroxil and cefuroxime axetil have longer half-lives than the other agents and may be administered twice daily. A half-life of 3 to 4 hours for cefixime may allow once-daily administration.' Most parenterally administered cephalosporins have a half-life of 0.5 to 2 hours. A longer half-life is observed in cefonicid, ceforanide, cefotetan, and ceftriaxone because of their increased serum protein binding, low tubular secretion,
1066
Mayo Clin Proc, October 1991, Vol 66
CEPHALOSPORINS
Cephalosporin nucleus
1-1-1
R'_C7 )3-lactam ring
°
S
R 1 Substitutions
COOH
R2 Substitutions
/':N....... ~ N( tN-CH2C-
Celazolin
Dlhydrothiazine ring
N~R2
Celazolin
N=N /OCH 3 N Cefuroxirne
Celotaxlme Cellizoxime Cellriaxone H 2N
"° C-
("OyC
