Cephalosporins (Cephems)

Cephalosporin Antibiotics

The cephalosporins are the largest and most diverse family of beta-lactam antibiotics. They are structurally and pharmacologically related to the penicillins. Cephalosporins have a beta-lactam ring structure, infused to a 6-membered dihydrothiazine ring, thus forming the cephem nucleus.

Cephalosporin compounds were first isolated from cultures of bacteria Cephalosporium acremonium found in a sewage outfall off the Sardinian coast in 1948 by Italian scientist Giuseppe Brotzu. The first agent cephalothin (cefalotin) was launched by Eli Lilly in 1964.

Mechanism of action

Cephalosporins are bactericidal agents (which means that they kill bacteria) and have the same mode of action as other beta-lactam antibiotics (such as penicillins). All bacterial cells have a cell wall that protects them. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls, which causes the walls to break down and eventually the bacteria die.

Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan.

Cephalosporins mimic the structure of the D-Ala-D-Ala link and bind to the active site of PBPs, disrupting the cross-linking process. If the peptidoglycan fails to cross-link the cell wall will lose its strength which results in cell lysis.

Side Effects

Cephalosporins generally cause few side effects. Common side effects involve mainly the digestive system: mild stomach cramps or upset, nausea, vomiting, and diarrhea. Cephalosporins can also cause overgrowth of fungus normally present in the body.

Hypoprothombinemia is common with with cefoperazone, cefamandole, cefotetan.

Disulfiram-like reaction (flushing, sweating, headache, tachycardia) may occur with concomitant use of alcohol and methylthiotetrazole-containing cephalosporins (cefoperazone, cefamandole, cefotetan).

More serious but infrequent reactions include: black, tarry stools; painful or difficult urination; antibiotic-induced colitis (severe watery diarrhea, severe stomach cramps, fever, and weakness).

Allergic reactions: anaphylaxis (rare), rash (maculopapular, urticarial), serum sickness-like reaction, eosinophilia, interstitial nephritis.

Cross allergy with penicillins

Because the cephalosporins are structurally similar to the penicillins, some patients allergic to penicillins may be allergic to a cephalosporin antibiotic.

The overall cross-reactivity rate is about 1% when using first-generation cephalosporins or cephalosporins with similar R1 side chains. For penicillin-allergic patients, the use of third- or fourth-generation cephalosporins or cephalosporins with dissimilar side chains than the penicillin carries a negligible risk of cross allergy8.

Cephalosporins are generally not recommended patients with immediate allergic reactions to penicillins (eg. anaphylaxis, bronchospasm).

Classification of Cephalosporins

Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. Each newer generation of cephalosporins has significantly greater gram-negative antimicrobial spectrum than the preceding generation, and in most cases decreased activity against gram-positive organisms. Fourth generation cephalosporins, however, have true broad spectrum activity.

The newer agents have much longer half-lives resulting in the decrease of dosing frequency.

First-Generation Cephalosporins
  • cefadroxil (Duricef)
  • cefazedone
  • cefazolin (Ancef, Kefazol)
  • cephalexin (Keflex, Keftabs)
  • cephalothin (Keflin)
  • cephradine (Velocef, Intracef)
  • cephaloridine (Ceporin)
  • cephapirin

First generation cephalosporins have relatively narrow spectrum of activity focused mainly on the gram-positive cocci.

Spectrum of activity:
Good gram-positive cocci coverage: Streptococci, Staphylococci, Enterococci.
NOT effective against methicillin-resistant Staph. aureus, penicillin-resistant Strep. pneumoniae.

Modest gram-negative bacteria coverage: Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, though susceptibilities may vary. Poor activity against Moraxella catarrhalis and Hemophilus influenzae.

Active against most penicillin-susceptible anaerobes found in the oral cavity, except Bacteroides fragilis group.

Uses:
Uncomplicated skin and soft-tissue infections, uncomplicated urinary tract infections, streptococcal pharyngitis, surgical prophylaxis. Good alternatives to antistaphylococcal penicillins. NOT indicated for otitis media.

First generation cephalosporins do not penetrate well into the cerebral spinal fluid and are not good for CNS infections.

Cefazolin is the most commonly used 1st generation cephalosporin.

Second-Generation Cephalosporins

"True" second generation cephalosporins:

  • cefaclor (Ceclor, Raniclor)
  • cefamandole (Mandol)
  • cefprozil (Cefzil)
  • cefuroxime (Ceftin, Zinacef)
  • loracarbef (Lorabid), is a carbacephem, but it is sometimes grouped with the second-generation cephalosporins

Cephamycins:

  • cefmetazole (Zefazone)
  • cefotetan (Cefotan)
  • cefoxitin (Mefoxin)

Cephamycins have a 7-alpha-methoxy group that gives resistance to beta-lactamases and makes them different from other cephalosporins. Cephamycins are grouped with the second-generation cephalosporins because they have similar activity, with one important exception -- anaerobes.

The second generation cephalosporins have a greater gram-negative spectrum while retaining some activity against gram-positive bacteria. They are also more resistant to beta-lactamase.

Spectrum of activity:
Gram-positive cocci: "True" 2nd generation cephalosporins are almost comparable to 1st generation agents against Streptococci. Slight loss of activity against Staphylococci (NOT active against methicillin-resistant strains). Cephamycins are less active against gram-positive cocci than 1st generation agents.

Gram-negative aerobes: Hemophilus influenzae, Moraxella catarrhalis, Proteus mirabilis, E. Coli, Klebsiella, Neisseria gonorrheae.

Anaerobes: Unlike 2nd generation cephalosporins, cephamycins (cefotetan, cefoxitin, and cefmetazole) have activity against anaerobic Bacteroides.

No efficacy against Pseudomonas, enterococci.

Uses:
Upper and lower respiratory tract infections, acute sinusitis, otitis media, uncomplicated urinary tract infections.

Cephamycins are useful for mixed aerobic/anaerobic infections of the skin and soft tissues, intra-abdominal, and gynecologic infections, and surgical prophylaxis.

Second generation cephalosporins don't cross the blood-brain barrier and are NOT used for CNS infections.

Third-Generation Cephalosporins
  • cefcapene (Flomox)
  • cefdinir (Omnicef)
  • cefditoren (Spectracef)
  • cefetamet (Altamet)
  • cefixime (Suprax)
  • cefmenoxime (Bestcall, Bestron)
  • cefoperazone (Cefobid)
  • cefotaxime (Claforan)
  • cefpiramide
  • cefpodoxime (Vantin)
  • cefsulodin (Takesulin)
  • ceftibuten (Cedax)
  • ceftizoxime (Cefizox)
  • ceftriaxone (Rocephin)
  • latamoxef (or moxalactam) (Shiomarin), is an oxacephem
  • flomoxef (Flumarin), is an oxacephem7

The third generation cephalosporins have a marked activity against gram-negative bacteria due to enhanced beta-lactamase stability and the ability to penetrate the gram-negative cell wall. They have more favorable pharmacologic properties than previous generations.

Third-generation cephalosporins are notorious for inducing resistance among Gram-negative bacilli.

Spectrum of activity:
Gram-positive cocci: Limited activity against gram-positive cocci (particularly agents available in an oral formulation).

Cefotaxime, Ceftriaxone, and Ceftizoxime have the best gram-positive coverage of the third-generation agents: methicillin-susceptible Staphylococcus aureus (though less than 1st and some 2nd generation agents), very active against Groups A and B streptococci, and viridans streptococci. Cefotaxime and ceftriaxone are more active than ceftizoxime against Streptococcus pneumoniae.

Cefixime and Ceftibuten lack Staphylococcus activity.

NONE are active against methicillin-resistant Staphylococci, Enterococci, and Listeria.

Gram-negative bacteria: Very active against Hemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Enterobacteriaceae (Escherichia coli, Klebsiella species, Proteus (including strains resistant to aminoglycosides)), Providencia, Citrobacter, Serratia.

Anaerobes: Cefotaxime, ceftriaxone, and ceftizoxime have adequate activity against oral anaerobes.

Moxalactam has good activity against Bacteroides fragilis

No Pseudomonal activity.

Uses:
Gram-negative bacillary meningitis3, serious infections of Enterobacteriaceae, upper respiratory tract infections5, otitis media, pyelonephritis, skin and soft tissue infections.

Ceftriaxone is indicated for Lyme disease and gonorrhea.

Cefotaxime, ceftazidime, ceftriaxone, ceftizoxime, and moxalactam have excellent penetration into the cerebrospinal fluid.

Enterobacter species have a tendency to become resistant during cephalosporin therapy, and thus cephalosporins are not the drugs of choice for Enterobacter infections.

AntiPseudomonal Cephalosporins

Ceftazidime (Fortaz, Tazicef, Tazidime) and Cefoperazone (Cefobid) are the two third generation cephalosporins with antipseudomonal activity.

Spectrum of activity:
Pseudomonas aeruginosa - main indication.

Gram-negative nacteria: Enterobacteriaceae covered by the 3rd generation agents.

Poor activity against Gram-positive Cocci.

Fourth-Generation Cephalosporins
  • cefepime (Maxipime)
  • cefluprenam
  • cefozopran (Firstein)
  • cefpirome (Cefrom, Keiten, Broact, Cefir)
  • cefquinome

Fourth generation cephalosporins have the broadest spectrum of activity, with similar activity against gram-positive organisms as first generation cephalosporins. They also have a greater resistance to beta-lactamases than the third generation cephalosporins.

Cefepime and cefpirome are highly active against many resistant organisms that traditionally have been difficult to treat.

Spectrum of activity:
Gram-positive cocci: Streptococcus pneumoniae, Groups A and B streptococci, methicillin-susceptible Staphylococcus aureus (less potent than the 1st and 2nd generation agents).

Gram-negative bacteria: Increased activity compared to 3rd generation. Excellent activity against Enterobacteriaceae and Pseudomonas aeruginosa.

Minimal anaerobic coverage.

Uses:
Cefepime and cefpirome are highly active against nosocomial pathogens sand are primary used for nosocomial infections2.

Cefepime penetrate the CNS and can be used in the treatment of meningitis.

Fifth-Generation Cephalosporins
  • ceftaroline fosamil (Teflaro)
  • ceftobiprole (Zeftera, Zevtera)

Ceftaroline is unique in its activity against multidrug-resistant Staphylococcus aureus, including MRSA6, VRSA, and VISA. Ceftaroline is the ONLY beta-lactam with MRSA activity. it is also active against Enterococcus.

Ceftobiprole is a very broad-spectrum cephalosporin with activity against gram-positive cocci, including MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae, Enterococcus faecalis and many gram-negative bacilli including AmpC producing E. coli and Pseudomonas aeruginosa. It is investigated in the treatment of complicated skin and skin structure infections.

Ceftobiprole FDA approval continues to be delayed. This antibiotic will not likely reach the U.S. market.

Further reading
References & Resources

  • 1. The Merck Manual of Medical Information. Mark H. Beers et al., eds. 2nd Home Edition. Whitehouse Station, NJ: Merck; 2003.
  • 2. Tumah H. Fourth-generation cephalosporins: in vitro activity against nosocomial gram-negative bacilli. Chemotherapy. 2005 May;51(2-3):80-5.
  • 3. Prasad K, Kumar A, Gupta PK, Singhal T. Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis. Cochrane Database Syst Rev. 2007 Oct 17 PubMed
  • 4. Pizzo P. Use of third-generation cephalosporins. Pseudomonas. Hosp Pract (Off Ed). 1991;26 Suppl 4:18-21;
  • 5. Hedrick JA. Community-acquired upper respiratory tract infections and the role of third-generation oral cephalosporins. Expert Rev Anti Infect Ther. 2010 Jan;8(1):15-21. PubMed
  • 6. Duplessis C, Crum-Cianflone NF. Ceftaroline: A New Cephalosporin with Activity against Methicillin-Resistant Staphylococcus aureus (MRSA). Clin Med Rev Ther. 2011 Feb 10;3.
  • 7. Ito M, Ishigami T. The meaning of the development of flomoxef and clinical experience in Japan. Infection. 1991;19 Suppl 5:S253-7.
  • 8. Campagna JD, Bond MC, Schabelman E, Hayes BD. The use of cephalosporins in penicillin-allergic patients: a literature review. J Emerg Med. 2012 May;42(5):612-20. PubMed

Published: May 05, 2007
Last updated: November 02, 2013

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