cephalosporins

Rama Raju A.V.SPT/2010/04

Outline

• Introduction• Mechanism of action• Classification• Pharmacokinetics• Adverse effects• Drug interactions• Therapeutic uses• References

Cephalosporins

• B-Lactam antibiotics ( similar to penicillins)• Broad spectrum• Act by inhibition of cell wall synthesis• Bactericidal• Inactive against : enterococci, MRSA, legionella ,

mycoplasma, chlamydia spp. • Widely used in surgical procedures to reduce the risk

of post operative infections

• Cephalosporins are similar to penicillins, but more stable to many bacterial b-lactamases and therefore have a broader spectrum of activity.

• However, strains of E coli and Klebsiella species expressing extended-spectrum b-lactamases that can hydrolyze most cephalosporins are becoming a problem.

• Cephalosporins are not active against enterococci and

L. monocytogenes.

Mechanism of action• inhibit bacterial growth by interfering with

the transpeptidation reaction of bacterial cell wall synthesis

• Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide.Halting peptidoglycan synthesis, and the cell dies

• autolysins and disruption of cell wall morphogenesis are involved

E.Coli before and after treatment with cephalexin

Classifications of cephalosporins

FIRST GENERATION Cephalexin Cefazolin Cephalothin Cephradine

Active against G+ cocci ( except.enterococci & MRSA ): s.pneumoniae, s.pyogenes,s. aureus, s.epidermidis Indicated for streptococcal pharyngitis ( e.g. cephalexin) Commonly used ( eg. Cefazolin) as prophylactic for surgical

procedures.Modest activity against G- bacteria

Cefoxitin ( mefoxin )Cefuroxime ( zinacef ) Cef. axetil ( zinnat )Cefaclor ( ceclor ) Cefprozil ( cefzil ) Mainly effective against G- bacteriaModest activity against G+ bacteriaCefoxitin active against bowel anaerobes (B. fragilis ) Cefuroxim active against H. influenzae, M. catarrhalis, S. pneumoniaeCef. Axetil- oral form of cefuroximCefaclor active against H. influenzae, M. catarrhalis &E.coliCefprozil- similar to cefaclor, c. axetil and augmentin- Liked by childrenSecond Generations are used primarily for URTIs ( acute otitis media,

sinusitis) and Lower RTIs ( acute exacerbation of chronic bronchitis)

SECOND GENERATION

THIRD GENERATIONCeftriaxone ( rocephin )Cefotaxime ( claforan )Cetazidime ( fortum )Cefoperazone ( cefobid )Cefixime ( suprax )

They have enhanced G- activity, H. influenzae, N. meningitidis, N.gonorrhea, P. aeruginosae, M. catarrhalis, E.coli, most Klebsiella

Ceftriaxone has long half-life . Not advised in neonates (interferes with bilirubin metabolism )

Cefotaxime preferred in neonate ( does not interfere with bilirubin metabolism ), as may ceftriaxone.

Ceftazidime & cefoperazone have excellent activity against p. aeruginosae.Cefixime has similar activity to amoxicillin & cefaclor for actute otitis media

Fourth GenerationCefipimeActive against G+ bacteria than cefazolin against

s. pyogenes, s.pneumoniae but lower against s. aureus.Similar to cefotaxime against E.coli & K. pneumoniae but for p. aeruginosa.

Pharmacokinetics

Cephalosporins are given parenterally and orally.

Extent of binding to plasma protein vary from one to another. e.g. Cefazolin is 80% protein bound ( hence, long t1/2 ) Cephalexin is 10-15% protein bound

Relatively lipid insoluble ( like penicillins )Hence,do not penetrate cells or the CNS, except for third generations.

Mostly excreted unchanged by the kidney (glomerular & tubular secretion), except, ceftazidime & cefoperazone( glomerular filtration )

Probenecid slows their elimination and prolong their half-live ( except Ceftazidime & cefoperazone)

Half-life 30-90 min; ceftriaxone 4-7 hr

Metabolism

• Many cephalosporins aren’t metabolized at all.

Cefotaxime sodium is metabolized to the

nonacetyl forms, which provide less antibacterial

activity than the parent compounds.

• To a small extent, ceftriaxone is metabolized in the

intestines to inactive metabolites, which are

excreted via the biliary system.

Adverse effects

1. Hypersensitivity reactions- most common Anaphylaxis, bronchspasm, urticaria Maculopapular rash- more common2. Nephrotoxicity ; esp. cephradine3. Thrombophlebitis ( i.v admin. )4. Superinfections5. Diarrhea-oral cephalosporins, cefoperazone,

ceftriaxone & moxalactam.

6. cefamandole, moxalactam & cefoperazone may cause:

a) bleeding disorders b) Flushing, tachycardia, vomiting with

alcohol intake

Drug interactions

• The patient receiving cephalosporins who drinks alcoholic beverages with or up to 72 hours after taking a dose may experience acute alcohol intolerance, with such signs and symptoms as headache, flushing, dizziness, nausea, vomiting, or abdominal cramps within 30 minutes of alcohol ingestion. This reaction can occur up to 3 days after discontinuing the antibiotic

• Uricosurics (drugs to relieve gout), such as probenecid and sulfinpyrazone, can reduce kidney excretion of some cephalosporins. Probenecid is used therapeutically to increase and prolong plasma cephalosporin concentrations.

• Cephalosporins may also decrease estrogen absorption, leading to decreased efficacy of oral contraceptives containing estrogen and progesterone.

Therapeutic uses

1. Alternative to penicillin in allergic patients

2. Upper respiratory tract infections and otitis media cefaclor cefuroxime axetil cefixime cefprozil

3. Septicaemia caused by G- bacteria ( P.aeruginosae) A penicillin(eg.Piperacillin/ Ticarcillin) +aminoglycoside OR A cephalosporin(eg. ceftazidime ) + AG4. Urinary tract infections Cefuroxime, Cefixime

. 5. Prophlaxis in surgery Appendectomy ( bowel anaerobes ) eg. Cefoxitin Obstetrical &gynecological, urological, ( S. aureus & S.

epidermidis ) orthopedic procedures, etc eg. Cefazoline

6. Meningitis- N. Meningitidis Ceftriaxone Cefotaxime( pref. in neonate)

7. Gonococcal infections Ceftriaxone

Contd…

Recent advances in cephalosporins

• Ceftobiprole, a novel, broad-spectrum, parenteral cephalosporin,

inhibits the cell-wall synthesis of penicillin-binding proteins (PBPs)

PBP2a and PBP2x, responsible for the resistance in staphylococci

and pneumococci, respectively.

• Ceftobiprole has good activity against gram-positive aerobes and

anaerobes, and its activity against gram-negative aerobes and

anaerobes is species dependent. Ceftobiprole is relatively inactive

against Acinetobacter species

References

• ClinicalPharmacology MadeIncredibly Easy 3rdEdition

• Basic and clinical pharmacology by katzung 10th edition

• Lippincott’s illustrated reviews 4th edition Richard A Harvey and Pamela

• Rang&dales pharmacology 6th edition