Because the research leading to the development of the newer derivatives grew out of modifications of the basic cephem nucleus, other groups of drugs, e.g., the cephamycins and oxacephems, tend to be lumped with the cephems (cephalosporins).
MEMBERS OF GROUP
CLASSIFICATION -- STRUCTURAL & SPECTRUM
Cephems are the "true" cephalosporins, but the others are closely related. Cephamycins differ from cephems by having a methoxy group at position R3 of the 7-aminocephalosporanic acid structure shown below.
Source: Cephalosporium acremonium
All contain beta-lactam ring which is required for activity
Modification of properties due to
7-Aminocephalosporic acid
By modifying the side chain (position 7) and the substituents on position 3 of the ring.
Major differences in the three generations is increasing activity against a variety of gram negative species, decreasing susceptibility to beta-lactamases.
According to AMADE5th, the first and second generation analogues are "...not...regarded as antibiotics of first choice for treatment of most infections because of the availability of equally effective and less expensive alternatives." ... "The cephalosporins may be used as primary drugs in non-hospital acquired Klebsiella infections depending on organism susceptibility."
Dose intervals listed below are the LONGEST listed in any reference material and not necessarily that which might be recommended in a particular therapeutic application.
cephradine [ANSPOR], (PO,IV/IM), q6h, t-half 0.8 h
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
cefazolin [ANSEF], (IV/IM), q6h, t-half 1.8 h
Similar to "broad spectrum" (extended spectrum) penicillins, e.g., amoxicillin, except that they have greater beta-lactamase resistance.
Tend to be ineffective against "methicillin-resistant" Staphylococci. Low affinity for the "transpeptidase?"
Not as good as penicillins for Bacteroides spp, enterococci, and most indole-positive proteus.
Not good for CNS infections -- broken down too rapidly by deacetylase. (3-position)
High and consistently effective against Staphylococcus aureus and Streptococcus pneumoniae
Moderate activity against coli, Proteus mirabilis, and Klebsiella.
cefaclor [CECLOR], PO, q8h, t-half 0.6-0.8 h
cefamandole [MANDOL], (IV/IM), q4h, t-half 0.6-1 h
cefuroxime [ZINACEF,KEFUROX], (IV/IM), q8h, t-half 1.3-1.7 h
ceforanide [PRECEF], (IV/IM), q12h, t-half 2.7-3 h
cefonicid [MONOCID], (IV/IM), q24h, t-half 3.5-4.5 h
cefoxitin (cefamycin) [MEFOXIN], (IV/IM), q6h, t-half 0.7-1 h
cefotetan (cefamycin) [CEFOTAN], (IV/IM), q12h, t-half 3-4.6 h
Not good for meningitis because of poor and unpredictable concentrations in CSF. AMADE5th & USPDI.
In addition to gram negative organisms of first generation, have effectivness against E. coli, Proteus mirabilis, Klebsiella, and indole-positive Proteus. Cefamandole also adds moderate activity against Enterobacter.
Cefamycins have increased resistance to beta-lactamases of gram negative organisms relative other 2nd generation cephems. Cefoxitin similar to cefamandole except some activity against Bacteroides fragilis, and not useful for Enterobacter.
cefixime [SUPRAX], (PO), q12h, t-half 3-4 h
cefotaxime [CLAFORAN], (IV/IM), q4h, t-half 1.1 h
ceftizoxime [CEFIZOX], (IV/IM), q8h, t-half 1.4-1.8 h
cefoperazone [CEFOBID], (IV/IM), q12h, t-half 1.9-2.1 h
ceftazidime [FORTAZ], (IV/IM), q12h, t-half 1.8 h
ceftriaxone [ROCEPHIN], (IV/IM), q24h, t-half 6-9 h
Moxalactam (Oxacephem) [MOXAM, LAMOXACTAM, LATAMOXEF], (IV/IM) q8h, t-half 2.0-2.3 h
Most active cephalosporins against E. coli, Proteus mirabilis, Klebsiella, indole-positive Proteus, and Enterobacter
Increased activity (relative to earlier generations) against Pseudomonas aeruginosa
INEFFECTIVE against Enterococcus
ceftiofur [NAXCEL], q12h. Approved for injection. Pasteurella and Haemophilus somnus in cattle; Salmonella spp. in hogs.
cephapirin -- mastitis preparations
cephalexin -- oral
cephalothin -- injection
Characteristic of beta-lactams
Highly variable -- Many limited to parenteral adminstration because of poor bioavailability. A few are for PO administration.
Cefixime (3, po) -- F = 40-50%
Cefuroxime axetil (2, po) -- F = 36-52%; NB despite poor bioavailability, is intended for PO admin. Cefuroxime [2] is for parenteral use.
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
Considered useful for CNS infections: cefuroxime [2]; Most third generation (cefoperazone [3] variable).
Biliary concentrations adequate with third generation cephalosporins, especially Cefoperazone [3].
Urinary concentrations of most are excellent
Not a prominent feature of the group
Deacetylated: cephalothin (1), cephapirin (1) and cefotaxime (3), Less active metabolites eliminated via kidney
Probenecid sensitivity: [AMADE90,2:19-21]
Probenecid sensitive -- All first and second generation except ceforanide. Third generation -- cefotaxime, ceftizoxime. (Cefixime unknown)
Probenecid insensitive -- ceforanide, \sAll third generation except cefotaxime, ceftizoxime, and perhaps cefixime.
Decreased renal function requires decreased dosage of following oral cephalosporins: cephalexin (1), cephradine (1), cefadroxil (1), cefuroxime axetil (2), and cefixime. Not cefaclor (2).
Decrease renal function requires decreased dosage of all parenteral first and second generation cephalosporins.
Eliminated primarily by glomerular filtration: ceftazidime (3) and moxalactam (3).
Ceftriaxone (3) -- eliminated via glomerular filtration (60%) and biliary secretion (40%). Has longest half life of any third generation cephalosporin. Half-life = 6-9h; Dosage: Once per day if non CNS infection.
most common adverse effect and very similar to penicillins
Majority of reactions -- maculopapular rashes that appear after a few days of Rx. Frequently accompanied by fever and eosinophilia. Other, more severe types of reactions are uncommon or rare.
As many as 20% of patients demonstrate cross-reactivity between penicillins and cephalosporins in immunologic studies, but clinical reports indicate a lower frequency (5-10%).
AMADE90-2:15 says cross-hypersensitivity with penicillins is low. Less than 5% of patients with history of penicillin allergy are also allergic to cephalosporins.
Generally regarded as not nephrotoxic at recommended doses.
May temporarily increase BUN.
Cephalothin has caused acute tubular necrosis, but may be most important if pre-existing renal disease
Should be particularly cautious when mixing with aminoglycosides.
Alcohol intolerance -- characteristic of those that have methylthiotetrazole side chain. Cephalosporins with which one should avoid alcohol during and up to 3 days after a course of therapy include (n = generation): cefamandole (2, inj), cefoperazone (3, inj), moxalactam (3, inj), and cefotetan (2).
Disulfiram is an inhibitor of acetaldehyde dehydrogenase, the second step in metabolizing ethyl alcohol. This results in build-up of acetaldehyde which is very toxic.
Most often associated with MOXALACTAM in patients who are old, poorly nourished, or have poor renal function.
Also seen with cefamandole (2), cefoperazone (3), and cefotetan (2).
Cephalosporins are irritants and can cause PAIN at IM sites and THROMBOPHLEBITIS at IV sites.
First Generation: Least irritant is cefazolin
NOT RECOMMENDED for intrathecal injection
False positive for urine glucose with some types of tests.
High concentrations of cefoxitin (2), ceforanide (2), or cephalothin (1) may produce false results in creatinine measurements.
[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.
Smith and Reynard ...