Cephalosporins

Dr.Ramachandrudu

M.D(Pharma)

β-Lactam antibiotics (beta-lactam antibiotics)

• β-Lactam antibiotics (beta-lactam antibiotics) are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactamring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems.

Cephalosporin & Penicillin

penicillin

cephalosporin

HISTORY OF CEPHALOSPORINS

• ISOLATED FROM CULTURES OF CEPHALOSPORIUM ACREMONIUM

• IN 1945 –Italian scientist Brotzu

• Later cephalosporin-c is isolated in University of Oxford

• 7amino cephalosporinic acid(7ACA)which was derived from cephalosporin-c is analogous to penicillin nucleus(6APA)

CephalosporinsB-Lactam antibiotics ( similar to penicillins)Broad spectrumAct by inhibition of cell wall synthesisBactericidalInactive against : enterococci, MRSA, legionella , mycoplasma, chlamydia spp. Widely used in surgical procedures to reduce the risk of post operative infections Cephalosporins are less succeptable to penicillinasesDisrupt synthesis of peptidoglycon layerFinal step of synthesis of peptidoglycon layer is inhibited

Pharmacological actions

• Earlier generation cephalosporins are G-positive

Successive generations have increased G-negativity activity

• Cephalosporins reach poor conc. In c.s.f

• First generation (Moderate spectrum)• Cefazolin · Cephalexin · Cephalosporin C ·

Cephalothin • Second generation (Moderate spectrum)• With anti-Haemophilus activity• Cefaclor · Cefamandole · Cefuroxime • With anti-anaerobic activity• Cefotetan · Cefoxitin • Third generation (Broad spectrum)• Cefixime · Cefotaxime · Cefpodoxime ·

Ceftazidime · Ceftriaxone • Fourth generation (Broad spectrum)

Classification

• (With β-lactamase stability and enhanced activity against Gram-positive bacteria and Pseudomonas aeruginosa)

• Cefepime · Cefpirome

• Fifth generation* (Broad spectrum)

• (Antipseudomonal in addition to activity against MRSA and VRE. *Not universally accepted nomenclature. )

• Ceftobiprol & Ceftaroline

FIRST GENERATION

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 prophylacic for surgical procedures.

Modest activity against G- bacteria

SECOND GENERATION

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 cefuroxim

Cefaclor active against H. influenzae, M. catarrhalis &E.coli

Cefprozil- similar to cefaclor, c. axetil and augmentin- Liked by children

Second Generations are used primarily for URTIs ( acute otitis media, sinusitis ) and Lower RTIs ( acute exacerbation of chronic bronchitis)

THIRD GENERATIONCeftriaxone ( rocephin )Cefotaxime ( claforan )Cetazidime ( fortum )Cefoperazone ( cefobid )Cefixime ( suprax )Cefpodoxime(Mahacef-O)

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 GenerationCefipime

Active against G+ bacteria than cefazolin against S. pyogenes, S.pneumoniae but lower against S. aureus Similar to cefotaxime against E.coli & K. pneumoniae but forp.aeruginosa.

Fifth generation

• Ceftaroline & ceftobiprole

• Fifth-generation cephalosporins are effective against MRSA

• Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance. Ceftaroline has also been described as "fifth-generation" cephalosporin, but does not have the anti-pseudomonal effect.

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)

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

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

Mechanism of action

• Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins) but are less susceptible to penicillinases. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin-binding proteins (PBPs)

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Therapeutic uses

1. Alternative to penicillin in allergic patients

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

3. Septicaemia caused by G- bacteria( P.aeruginosae)A cephalosporin(eg.ceftazidime )

4. Urinary tract infectionsCefuroxime, Cefixime

Therapeutic uses contd---

. 5. Prophlaxis in surgeryAppendectomy ( bowel anaerobes ) eg. CefoxitinObstetrical &gynecological,urological, orthopedic procedures, etc ( S. aureus & S. epidermidis ) eg. Cefazoline

6. Meningitis- N. MeningitidisCeftriaxone Cefotaxime( pref. in neonate)

7. Gonococcal infectionsCeftriaxone

Preperations & Dosages

• Oral-1stgen-cephelexin250-500mg TID

• Cefadroxil-500mg-1gm BD

• Parenteral -1stgen-cefazolin500-1gm i.vTID

• Oral -2ndgen-cefaclor250-500mgTID

• Cefuroxime 250-500mgTID

• Parenteral-2ndgen-cefoxitin1-2gm i.vTID

• Oral -3rdgen-cefpodoxime200-400mgBD

• Parenteral-3rdgen-ceftrioxone & cefotoxime1-2gms i.v OD & BD

Adverse effects

1. Hypersensitivity reactions- most common Anaphylaxis, bronchspasm, urticariaMaculopapular rash- more common

10% of people who are sensitive to penicillins sensitive to cephalosporins also.

2. Nephrotoxicity ; esp. cephradine3. Thrombophlebitis ( i.v admin. )4. Superinfections5. Diarrhea-oral cephalosporins, cefoperazone,

ceftriaxone & moxalactam.

Adverse effects contd---

6. cefamandole, moxalactam & cefoperazone may cause:a) bleeding disordersb) Flushing, tachycardia, vomiting with alcohol

intake 7) Disulfiram like reactions when combined with

alcohol(newer)8) Drug fever.9)Blood Toxicity

includesHypoprothobenemia,abnormalities in platelet aggregation,false positive coomb’s test with certain cephalosporins likeCephalothin.

10) CNS irritation following intra thecal administration.

Bacterial Resistance

• Destruction of B-lactum ring by B-lactamases

• Altered affinity of cephalosporins

• Decreased penetration of antibiotic to penicillin binding protein

• (Applicable to G-negative bacteria)

Clinical applications

• Cephalosporins are used in the treatment of infections caused by bacteria

• Cephalosporins are used to treat infections in many different parts of the body. They are sometimes given with other antibiotics(Cefixime+Ofloxcillin )Some cephalosporins given by injection are also used to prevent infections before, during, and after surgery. However, cephalosporins will not work for colds, flu, or other virus infections

• cephalosporins are used in certain patients with the following medical conditions

• Amoxicillin-resistant sinusitis (treatment)—Cefaclor

• Bacterial endocarditis (prophylaxis)—Cefadroxil, cefazolin, and cephalexin

• Melioidosis (treatment)—Ceftazidime

• Melioidosis is an infectious disease caused by a Gram-negative bacterium, Burkholderia pseudomalle.