Cephalosporins

Beta Lactam Antibiotics- Cephalosporins

Contents

Cephalosporins

•       Mechanism of action

•       Classification

•       Pharmacokinetics

•       Adverse effects

•       Clinical uses

Objective

At the end of this lecture, the student will be able to:

•       Describe the antimicrobial spectrum of cephalosporins

•       Explain the mechanism of action of caphalosporins

•       Discuss the pharmacokinetics and adverse effects of cephalosporins

Cephalosporins

•       Cephalosporins chemical analogues – cefamycins

•       Dihydrothiazine ring fused to β-Lactam ring with an appropriate side chain on position-7

•       Isolated from Cephalosporinium acremonium and Streptomyces lactamdurans

Structure of Cephalosporins

Structure of Penicillin vs Cephalosporins

Mechanism of Action of Cephalosporins

•       Identical to penicillin

•       Inhibition of transpeptidation

•       Formation of imperfect cell wall

•       Osmotic changes

•       Activation of autolysin enzyme

•       Lysis of bacteria – Bactericidal

Classification and Antimicrobial Spectrum

•       According to their ‘generation’ and antibacterial spectrum, stability to β-Lactamase and year of production

•       First generation – 1960s

•       Second generation – 1970s

•       Third generation – 1980s

•       Fourth generation – 1997-1998

•       Fifth Generation- 2000-

First Generation Cephalosporins

•       Cephalexin, Cephapirin, Cefadroxil – Oral

•       Cephradine – oral & parenteral

•       Cephalothin & cefazolin – parenteral

•       β-Lactamase sensitive

•       Oral drugs- well absorbed from GIT

•       High serum level than tissues

•       Metabolism not significant

•       Excreted through urine

Antimicrobial spectrum

•       Sensitivity against gram positive cocci

•       Gram negative bacteria like E. coli, K. pneumoniea, Proteus mirabilis

•       Anaerobic cocci sensitive are – peptococcus and peptostreptococcus

Clinical uses

•       UTI, minor staphylococcus infections

•       Cefazolin – surgical prophylaxis before cardiac surgery, orthopaedic prosthesis procedures

•       Ineffective in meningitis

•       As an alternative to penicillins

Second Generation Cephalosporins

•       Cefaclor, Cefmetazole, Cefprozil – Oral

•       Cefoxitin Cefamandol, cefotetan – parenteral

•       Cefuroxime – oral or parenteral

Antimicrobial spectrum

•       Extended spectrum against gram negative organisms

K. Pneumonia

H. influenza

Bacteriodis fragilis

Pharmacokinetics

•       Well absorbed from GIT

•       Resistance to β- lactamase – except cefaclor

•       Protein binding is significant

•       Cefuroxime – cross BBB

•       Excreted unchanged in urine

Clinical uses

•       Sinusitis

•       Otitis

•       Lower respiratory tract infection

•       Effective against anerobes – peritonitis & diverticulitis

•       Cefuroxime – community acquired pneumonia

Third Generation Cephalosporins

Oral drugs	Parenteral drugs
Cefixime	Cefotaxime
Cefpodoxime	Cefitzoxime
Cefdinir	Ceftriaxone
Ceftibuten	Ceftazidime
	Cefoperazone

 

Advantages

•       Extended spectrum gram negative

•       Effective against β-lactamase producing haemophillus and nesseria

•       All can cross BBB

Disadvantage

•       Sensitive to constitutively produced β-lactamase in organisms like enterobacter

Pharmcokinetics

•       Oral – good bioavailability

•       Given i.v with anesthetic

•       Distribution is good – except cefoperazone

•       Reaches good level in CNS

Uses – Gonorrhae, meningitis and sepsis

Fourth Generation Cephalosporins

•       Cefipime

•       Cefpirome

•       Cefozoram

•       Extended gram negative coverage

•       Resistance to β-lactamase

•       Used in gonorrhae, meningitis and sepsis

Adverse effects

•       Super infection

•       Pain when injected IM

•       Thrombophlebitis may occur after i.v

•       Allergic reaction

•       Renal toxicity

•       Interstitial nephritis

•       Bleeding disorders and fall in prothrombin time

•       Ceftobiprole and Ceftaroline

•       Inhibit cell wall synthesis

•       Inhibit penicillin binding protein 2a produced by MRSA and penicillin resistant S. pneumoniae

•       Super infection, coagulation abnormalities and pseudolithiasis

Summary

•       Cephalosporins and their chemical analogues – cefamycins consists of dihydrithiazine ring fused to β-Lactam ring with an appropriate side chain on position-7

•       Isolated from Cephalosporinium acremonium and Streptomyces lactamdurans

•       Mechanism of action is similar to that of penicillins

•       Anti-Microbial spectrum-First generation cephalosporins: Sensitivity against gram positive cocci; Gram negative bacteria like E. coli, K. pneumoniea, Proteus mirabilis; Anaerobic cocci sensitive are – peptococcus and peptostreptococcus

•       Second generation cephalosporins: Extended spectrum against gram negative organisms- K. Pneumonia, H. influenza, Bacteriodis fragilis

•       Third and fourth generation cephalosporins: Gonorrhae, meningitis and sepsis

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