• Information
  1. Overview
  2. First Generation
  3. Second Generation
  4. Third Generation
  5. Third Generation Cephalosporins for Resistant Organisms
  6. Fourth Generation
  7. Comparison of Different Cephalosporins
  8. Cephalosporin Allergy

A. Overview

1. Developed initially to overcome penicillin resistance
2. Increasing generations of agents
3. First generation are primarily for gram positive (G+) skin infections
4. Second generation have improved respiratory gram negative (G-) coverage
5. Third generation
   1. Parenteral 3rd generation primarily for G- infections
   2. Oral 3rd generation have somewhat variable G- coverage
   3. Specific anti-pseudomonal 3rd generation agents have been developed
6. Fourth generation for broad spectrum
7. Variable coverage of anaerobic organisms
8. No coverage of atypical organisms
9. Generally well tolerated
10. ~10% penicillin allergic patients are allergic to cephalosporins

B. First Generation

1. Coverage
   1. G+: Streptococci, Staphylococcus aureus (methicillin sensitive)
   2. G-: some E. coli and Proteus ssp.
2. Do not cross blood-brain barrier
3. Uses
   1. Skin and soft tissue infections
   2. Lymphangitis
   3. Antimicrobial prophylaxis in surgery [8]
4. Examples
   1. Cefazolin (Kefzol®): 0.5-2gm (usually 1gm) intravenous (IV), q8 hours
   2. Cephalexin (Keflex®): 250-500mg po qid
   3. Cefadroxil (Duricef®, Ultricef®): 500mg po bid (recommended oral agent)
   4. Cefaclor (Ceclor® CD): 375mg or 500mg po bid (increasing resistance)

C. Second Generation

1. Spectrum
   1. Gram + coverage reduced somewhat compared to first generation cephalosporins
   2. Better Gram - coverage: Klebsiella pneumonae, H. influenzae, E. coli
2. Uses: bronchitis in smokers, pneumonia (not atypicals), sinusitis, otitis, abdominal
3. Cefuroxime (Ceftin®)
   1. Excellent choice IV for community acquired pneumonia (CAP) in hospital
   2. Requires addition of agent for atypical coverage for complete CAP coverage
   3. Also for exacerbation of chronic obstructive pulmonary disease (COPD)
   4. No anaerobic coverage: should not be used for "below diaphragm" infections
   5. Cefuroxime axetil is oral agent of choice (500-750mg po bid), well tolerated
4. Cefoxitin (Mefoxin®)
   1. Good anaerobic coverage as well as G+/- (use in mixed infections)
   2. However, both induce high levels of ß-lactamase expression
   3. Frequently used in below diaphragm surgery for wound prophylaxis
   4. Cefoxitin may give false elevation of creatinine since is colorimetric agent
   5. Dose 1-2gm q6-8 hours IV only
5. Cefotetan (Cefotan®)
   1. Cefotetan has near third generation activities; 1-2gm IV or IM q12 hours x 5-10 days
   2. Cefotetan has significant incidence of inducing intravascular hemolysis [10]
6. Other Agents
   1. Cefprozil (Cefzil®) - borderline first generation; 250-500mg q12-24 hours po
   2. Loracarbef (Lorabid®) - borderline first generation; 200-400mg q12 hours po
   3. Cefamandole (Mandol®) - 1-2gm q4-6 hours (adjust for renal dysfunction) IV

D. Third Generation (Standard Agents)

1. Excellent Standard Gram Negative coverage
   1. Poor covereage of Pseudomonas, Acetinobacter, Citrobacter, Enterobacter
   2. Excellent G- coverage: E. coli, Proteus, Klebsiella, Haemophilus, Neisseria, Morexella
   3. Some Serratia coverage
   4. Moderate streptococcal and most have reduced staphylococcal coverage
2. Generally good anaerobic coverage
3. Ceftriaxone (Rocefin®)
   1. Usual 3rd generation agent of choice
   2. QD dosing because highly fat soluble / protein bound
   3. Excellent CNS penetration
   4. S. pneumoniae coverage unreliable
   5. Relatively contraindicated for gall bladder disease (increases sludging)
   6. Very low but reported incidence of intravascular hemolysis (may be severe / lethal) [10]
   7. Dose is 1-2gm IV or IM q24 hours
4. Cefotaxime (Claforan®)
   1. Children - especially for neonatal sepsis (dose adjust by age and weight)
   2. Slightly improved S. pneumoniae coverage compared with ceftriaxone
   3. Usual dosing is 1-2gm q8 hours IV or IM (maximum 2gm IV q6 hours)
   4. For gonococcal urethritis, dose is 500mg IM or IV x 1
   5. Overall spectrum and uses similar to ceftriaxone
5. Other parenteral third generation cephalosporins
   1. Cefoperazone (Cefobid®) - 1-2gm (max 4gm) IV or IM q12 hours
   2. Ceftizoxime (Cefizox®) - 1-2gm (max 4gm) IV or IM q8-12 hours
6. Oral Third Generation Cephalosporins [1,2,3]
   1. Cefixime (Suprax®): 400mg po qd (good pneumococcus, some staphylococcal coverage)
   2. Cefpodoxime (Vantin®): 100mg po bid (acitivity similar to cefixime)
   3. Ceftibuten (Cedax®): 400mg po qd (poor pneumococcus and staphylococcus coverage)
   4. Cefdinir (Omnicef®): 300mg po q12 hours (activity similar to cefpodoxime)
   5. Cefditoren (Spectracef®): 400mg po q12 (less expensive than others; good activity)
   6. Poor activity against resistant gram negatives (Pseudomonas, Serratia, Enterobacter)
   7. Used for oral treatment of gonorrhea (cefpodoxime and cefixime), otitis, bronchitis
   8. Active in acute exacerbations of COPD, tonsillitis, pharyngitis, simple skin infections
   9. Note: these agents really do not have full 3RD generation spectrum

D. Third Generation Cephalosporins for Resistant Organisms

1. Also called "Antipseudomonal" Cephalosporins
   1. Especially good Pseudomonas ssp coverage
   2. Stenotrophomonase (Xanthomonas) maltophilia coverage is poor
   3. Pseudomonas (Burkholderia) cepacia coverage is better than usual 3RD generation
2. Enterobacter coverage acceptable, though not much better than usual 3RD generation
3. In general, the following organisms should be treated with more than one antibiotic [7]:
   1. Pseudomonas
   2. Acinetobacter
   3. Citrobacter
   4. Enterobacter
   5. Serratia
   6. Mnemonic - "PACES"
   7. Increasing concern about Klebsiella species in some countries
   8. These organisms all produce ß-lactamase and also may alter cell wall binding proteins
4. Agents
   1. Ceftazidime (Fortaz®) - usual preferred agent, dosing1-2gm iv q8-12 hours
   2. Cefoperazone (Cefobid®) - less active than ceftazidime against Pseudomonas

E. Fourth Generation [4,6]

1. Agents which span spectrum of gram positive and negative, including resistant organisms
2. Excellent broad spectrum coverage
3. Agents
   1. Cefepime (Maxipine®) - 1-2gm iv q12 hours; may be given IM (for UTI)
   2. Cefpirome
4. Activity Spectrum
   1. As good as cefotaxime and first generation agents against Staphylococci, Streptococci
   2. Activity against Pseudomonas similar to ceftazidime
   3. Improved activity against Enterobacter, Citrobacter, Acinetobacter
   4. Poor activity against Xanthomonas maltophilia, Pseudomonas cepacia

F. Comparison of Different Cephalosporins [5]

1. Guidelines below are provided only for summary purposes
2. Individual patients and specific organisms should be assessed independently
3. Infectious disease consultation should be sought when questions arise
4. Cephalosporins have no activity against enterococci and most atypical organisms
5. Activities are shown as (+++) very active, (+) somewhat active and (--) no activity

   Organism	1st Gen	2nd Gen	3rd Gen	anti-Pseud	4th Gen
   Gram Positive
   Staphylococci	+++	++	+	--	+++
   Streptococci	+++	++	++	+	+++
   Gram Negative
   ß-Lactamase Negative
   Escherichia coli	+	++	+++	+++	+++
   Salmonella	+	+	+++	++	+++
   Other ß-lact neg	+	++	+++	+++	+++
   ß-Lactamase Positive
   Citrobacter freundii	-	-	+++	++	+++
   Enterbacter ssp	-	-	+++	++	+++
   Morganella morganii	-	-	+++	+++	+++
   Proteus vulgaris	-	+	+++	+++	+++
   Providencia ssp	-	-	+++	+++	+++
   Serratia ssp	-	-	+++	+++	+++
   Pseudomonas aeruginosa	-	-	-	++	++
   Pseudomonas cepacia	-	-	+/-	+	+/-
   Xanthomonas maltophila	-	-	-	-	+/-
   Acinetobacter ssp	-	-	+/-	+	++
   Neisseria gonorrhoeae	-	+	+++	+++	+++
   Haemophilus influenzae	-	++	+++	+++	+++

G. Cephalosporin Allergy [9]

1. Generally well tolerated
2. Dermatologic Side Effects 1.0-2.8%
   1. Maculopapular
   2. Morbilliform
3. Overall, ~10% of patients allergic to penicillin are allergic to cephalosporins

References

1. Cefditoren. 2002. Med Let. 44(1122):5
2. Thompson EM and Shaughnessy AF. 1994. Am Fam Phys. 50(2):401
3. Antibiotics. 1996. Med Let. 38(970):23
4. Sanders CC. 1993. Clin Infect Dis. 17:369
5. Jones RN. 1996. Am J Med. 100(sup6A):3S
6. Cefepine. 1996. Med Let. 38(983):84
7. Hanberger H, Garcia-Rodriguez JA, Gobernato M, et al. 1999. JAMA. 281(1):67
8. Antimicrobial Prophylaxis in Surgery. 1999. Med Let. 39(1060):75
9. Kelkar PS and Li JTC. 2001. NEJM. 345(11):804
10. Hemolysis from Ceftriaxone. Med Let. 44(1144):100