Pharmacology of Cephalosporins

Pharmacology of Cephalosporins

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  Anusha Shaji, B.Pharm,M.Pharm Assistant Professor Department of Pharmacology Nirmala College of Pharmacy, Muvattupuzha, Ernakulam
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  CONTENTS Introduction Classification Cefazolin Cephalexin Cefuroxime Cefuroxime axetil Cefotaxime Cefixime Cefpodoxime proxetil Cefepime Adverseeffects of Cephalosporins Uses of Cephalosporins
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  Cephalosporins Beta- lactam antibiotics Closelyrelated both structurally and functionally to the penicillins Most cephalosporins are produced semisynthetically Derived from cephalosporin- C Obtained from a fungus Cephalosporium Bactericidal MOA: Bacterial cell wall synthesis inhibition Nucleus consists of a beta- lactam ring fused to a dihydrothiazine ring
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  Classification
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  First Generation Cephalosporins Developedin 1960s Act as Penicillin G substitutes Have high activity against gram positive bacteria Weaker against gram negative bacteria They are resistant to the Staphylococcal penicillinase Cefazolin Prototype first generation cephalosporin Active against most Penicillin G sensitive organisms (eg. Streptococci, gonococci, meningococci, H. influenzae) Acivity against Klebsiella, Moraxella catarrhalis and E.coli is relatively high
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  It is thepreferred parenteral first generation cephalosporin, especially for surgical prophylaxis Dose: 0.5 g 8 hourly (mild cases) 1 g 6 hourly (severe cases) Children: 25-50 mg/kg/day i.m or i.v Cefalexin Most commonly used Effective orally Less active against penicillinase producing staphylococci and H. influenzae Plasma protein binding is low; it attains high concentration in bile Excreted unchanged in urine; Plasma half life: ~60 min
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  Second Generation Cephalosporins Developedsubsequent to the first generation compounds More active against gram negative organisms With some members active against anaerobes Weaker than first generation compounds against gram positive bacteria Their utility has declined in favour of the 3rd generation agents Cefuroxime Resistant to gram negative beta- lactamases: has high activity against organisms producing these enzymes including PPNG and ampicillin resistant H. influenzae Retaining significant activity on gram positive cocci and certain anaerobes but not B. fragilis
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  It is welltolerated by i.m. route Attains relatively higher CSF levels It can be employed for single dose i.m. therapy of gonorrhoea due to PPNG Dose: 0.75-1.5 g i.m. or i.v. 8 hourly Children: 30-100 mg/kg/day Cefuroxime axetil Ester of cefuroxime Orally effective Absorption is incomplete The activity depends on in vivo hydrolysis and release of cefuroxime Dose: 250-500 mg BD Children half dose
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  Third Generation Cephalosporins Introducedin the 1980s Have highly augmented activity against gram positive Enterobacteriaceae Few members inhibit Pseudomonas All are highly resistant to beta- lactamases from gram negative bacteria Less active on gram positive cocci and anaerobes Cefotaxime Prototype third generation cephalosporin Exerts potent action on aerobic gram negative as well as some gram positive bacteria Not active on anaerobes, Staph. Aureus and Ps. aeruginosa
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  Prominent indications aremeningitis caused by gram negative bacilli, life threatening resistant/ hospital- acquired infections, septicaemias and infections in immunocompromised patients. An alternative to ceftriaxone for typhoid fever Plasma half life: 1 hr Cefotaxime is deacetylated in the body Penetration into CSF is good Dose: 1-2 g i.m./ i.v. 6-12 hourly Children 50-100 mg/kg/day Cefixime Orally active third generation cephalosporin Highly active against Enterobacteriaceae, H. influenzae, Strep. pyogenes
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  Resistant to manybeta lactamases It is not active on Staph. aureus, most pneumococci and Pseudomonas Longer activity: Plasma half life- 3 hr Penetration into CSF is good Dose: 200-400 mg BD for respiratory, urinary, and biliary infections Side effects: Stool changes and diarrhoea Cefpodoxime proxetil Orally active ester prodrug of 3rd generation cephalosporin cefpodoxime Highly active against Enterobacteriaceae and streptococci It inhibits Staph. aureus Uses: Respiratory, urinary, skin and soft tissue infections Dose: 200 mg BD (max 800mg/day)
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  Fourth Generation Cephalosporins Thedistinctive feature of this last developed subgroup of cephalosporin is non- susceptibility to inducible chromosomal beta lactamases in addition to high potency against Enterobacteriaceae Cefepime Developed in 1990s Antibacterial spectrum similar to that of 3rd generation compounds Highly resistant to beta lactamases Plasma half life: 2 hours Higher concentrations are attained in the CSF Excreted by the kidney Use: Hospital acquired pneumonia, febrile neotropenia, bacteraemia Dose: 1-2 g i.v. 8-12 hourly
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  Adverse effects: Cephalosporins Painafter i.m. injection Diarrhoea Hypersensitivity reactions Nephrotoxicity, Neutropenia and thrombocytopenia Uses: Cephalosporins Respiratory, urinary and soft tissue infections Penicillinase producing staphylococcal infections Surgical prophylaxis and Meningitis Gonorrhoea caused by penicillinase producing organisms As alternatives to penicillin for ENT, upper respiratory and cutaneous infections