CEPHALOSPORIN DERIVATIVES AND RELATED COMPOUNDS
Copyright, Purdue Research Foundation, 1996
| BMS 445 Intro |
| Slides / Graphics |
| Drug Groups |
| Address |
| Cephalosporins (full text) |
Source:
- Cephalosporium acremonium
Classes of Cephalosporins and Related Drugs
- Cephems -- "true"cephalosporins
- Cephamycins -- cephems with methoxy at R3
- Oxacephms -- cephems with oxygen replacing the sulfur atom in the 7-aminocephalosporanic
acid nucleus
Modification of properties due to
- side chain alterations AND
- modifying substituents on position 3 of 6-membered ring.
Generations of Cephalosporins
- Four "generations" (Three mentioned here)
- Major differences in generations --
- Increasing activity vs. various gram negative bacteria
- Decreasing susceptibility to beta-lactamases
- AMADE5th: Use equally effective less expensive alternatives when appropriate
FIRST generation:
- Members
- cephalexin [KEFLEX] oral, q6h, t-half 0.9 h
- cefadroxil [DURICEF], oral, q12h, t-half 1.5 h
- cephalothin [KEFLIN] (IV/IM), q4h, t-half 0.6h
- cephapirin [CEFADYL], (IV/IM), q4h, 1.2 h
Mastitis -- Cattle
- Spectrum
- resemble amoxicillin but greater beta-lactamase resistance
- not as good as penicillins for Bacteroides spp.
- not good for CNS
SECOND generation:
- Members
- cefaclor [CECLOR], PO, q8h, t-half 0.6-0.8 h
- cefoxitin (cefamycin) [MEFOXIN], (IV/IM), q6h, t-half 0.7-1 h
- Spectrum
- To 1st generation adds more gram negative species, e.g.,
- E. coli, Proteus mirabilis
- Klebsiella, Haemophilus, Moraxella
THIRD generation:
- Members
- Ceftiofur [NAXCEL] -- veterinary only
- q12h. Approved for injection.
- Pasteurellaand Haemophilus somnus in cattle
- Salmonella spp. in hogs.
- Cefotaxime
Spectrum
- Most active cephalosporins against E. coli, Proteus mirabilis, Klebsiella,
indole-positive Proteus, and Enterobacter
- Increased activity (relative to earlier generations) against Pseudomonas
aeruginosa
Mechanism of Action
- Characteristic of beta-lactams
Pharmacokinetics
Absorption
- Highly variable
- Most parenteral due to poor PO F
- Cefuroxime axetil (gen 2, PO) F = 36-52%
- Food and/or milk effect on F variable
- Increase -- cefuroxime axetil (2).
- No change -- cefadroxil (1), cefaclor (2).
- Decrease -- cephalexin (1) and cephradine (1).
Distribution
- Resemble penicillins -- ECF
- Few useful for CNS infections--
- cefuroxime [2]
- of the few, most are third generation
- Biliary concentrations adequate
- Urinary concentrations -- most excellent
- Sample table from USPDI
Tissue Drug Concentration
--------------------- ----------------- -------------------
Bile &/or All Therapeutic
gallbladder
Bone & joints All parenteral Therapeutic
Cardiovascular All Therapeutic
CSF cefotaxime [3] Therapeutic
ceftazidime [3] Therapeutic
ceftriaxone [3] High
cefuroxime [2] Therapeutic
moxalactam [3] Variable
Others Low / unpredictable
NB: some variation
with ADMADE90
information printed
below
Eye ceftazidime [3] Therapeutic
ceftizoxime [3] Therapeutic
cefuroxime [2] Therapeutic
Others Low
Intra-abdominal Most Therapeutic
Kidneys All High; Therapeutic
Middle ear cefaclor [2] Therapeutic
cefoperazone [3] Therapeutic
cefotaxime [3] Therapeutic
cephalexin [1] (Large therapeutic doses)
cephradine [1] Therapeutic
Placenta All Cross readily
Respiratory tract Most Therapeutic
Skin & soft tissue Most Therapeutic
Urinary tract All High; Therapeutic
----------------------------
Data from UPDI8th, 1988. p632
Elimination
- Biotransformation -- Some deacetylated
cephalothin (1), cephapirin (1) and cefotaxime (3)
- Probenecid sensitivity varies[AMADE90,2:19-21]
- Sensitive -- All first and second generation except ceforanide.
- Third generation -- cefotaxime, ceftizoxime
- Not sensitive -- ceforanide - All third generation except
- Decrease dosage if decreased renal function of --
- Oral
- cephalexin (1), cephradine (1), cefadroxil (1), cefuroxime
axetil (2), and cefixime. Not cefaclor (2)
- All parenteral first and second generation
- Mixed
- Ceftriaxone (3)
- glomerular filtration -- 60%
- biliary secretion -- 40%
- 6-9h half-life is longest of third generation
- Q1D if non CNS infection.
Adverse Effects
Biological
- Not a notable problem with most
Hypersensitivity --
- Most common and similar to penicillins
- Mostly macropapular after few days
- More severe reactions rare
- Cross reactivity with penicllins
- Immunologic studies -- Up to 20%
- Clinical reports -- 5-10%
- AMADE90-2:15 -- 5%
Toxic
- HEMATOLOGIC reactions
- Bleeding related to --
hypoprothrombinemia,
thrombocytopenia, and/or platelet dysfunction
- More in patients that are --
- old
- poorly nourished or
- poor renal function
- Moxalactam (3), cefamandole (2), cefoperazone (3), and cefotetan (2)
- IRRITANTS
- PAIN at IM sites
- THROMBOPHLEBITIS at IV sites.
- Intrathecal NOT RECOMMENDED
- Interference with Laboratory Tests
- False positive for urine glucose with some types of tests
- False creatinine results if high concentrations of --
- cephalothin (1)
- cefoxitin (2), ceforanide (2)
- Renal toxicity
- generally not nephrotoxic
- pre-existing renal disesase --use care with aminoglycosides
- Disulfiram-like reaction
- Methylthiotetrazole side chain
- cefamandole (2, inj), cefoperazone (3, inj), moxalactam (3, inj), and cefotetan (2)
References
- [GG7th] Chapter 50, by Mandell, G.L., and M· Sande in Goodman &
Gilman's The Pharmacological Basis of Therapeutics, eds., A.G. Gilman,
L.S. Goodman, T.W. Rall, F. Murad. Macmillan, NY, 1985.
- [GG8th] Chapter 46, by Mandell, G.L., and M· Sande in Goodman &
Gilman's The Pharmacological Basis of Therapeutics, eds., A.G. Gilman,
T.W. Rall, A.S. Nies, P. Taylor. Pergamon Press, NY, 1990.
- [USP/DIxx] where xx = year of current edition. Drug Information for
the Health Care Professional, United States Pharmacopoeil Convention. FANTASTIC!
Updated annually.
- [AMADExx-nn:nn] AMA Drug Evaluations Subscription. xx = year for particular
monograph and nn:nn = section and page. Individual monographs updated at
irregular intervals. Published by the American Medical Association, Chicago.
Has introductory sections for groups of drugs followed by monographs for
each drug preparation. Excellent!
- Kagan, Ch. 3.
- Antimicrobial Therapy in Veterinary Medicine. Prescott, J.F. and Baggot,
J.Desmond, Blackwell Scientific Publications, Boston, MA, pp. 367. 1988.
Study Questions
- How do the cephalosporins compare to penicillin G with respect to mechanisms
of action, routes of elimination, psectrum of activity, etc., are concerned?
Note that first and second generation cephalosporins may more closely resemble
ampicillin's spectrum of activity.
- What is the difference betwen the various generations of the cephalosporins?
- Why is it so difficult to achieve therapeutic concentrations of first
generation cephalosporins in the CSF?
- Is there any reason to be concerned about hypersensitivity to cephalosporins
if a patient is highly allergic to penicillins? What about cross reactivity
betwen the penicillins?
- How do some of the third generation cephalosporins compare to penicillin
G in their affinity for the penicillin binding proteins of such organisms
as streptococci? Does this make them better or worse candidates for use
in therapy of these and other organisms sensitive to penicillin G?
- What is the significance of a disulfiram-like reaction? Give an example of a drug that can produce it.
- Which of the cephalosporins have been associated with producing a bleeding
tendency?
- What 4 cephalosporins are widely used and/or specifically indicated
for use in veterinary medicine?
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Gordon L. Coppoc, DVM, PhD
Professor of Veterinary Pharmacology
Head, Department of Basic Medical Sciences
School of Veterinary Medicine
Purdue University
West Lafayette, IN 47907-1246
Tel: 317-494-8633Fax: 317-494-0781
Email: coppoc@vet.purdue.edu
Last modified 9:18 AM on 4/5/96
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