2. • Revision
• History and Chemistry
• Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
3. •Revision
• History and Chemistry
• Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
4. β- Lactam Antibiotics
• Common structure;
• Mechanism of Action Inhibition of synthesis of peptidoglycan
cell wall.
• Penicillins
• Cephalosporins
• Carbapenems
8. • Revision
•History and Chemistry
• Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
9. CEPHALOSPRINS
• Cephalosporium acremonium 1948 Giuseppe Brotzu
Sardinian coast.
• Crude filtrates inhibit in vitro S. aureus;
Cured staphylococcal and typhoid infections.
• Guy Newton & Edward Abraham Cephalosporin C.
10. CEPHALOSPRINS
• Nucleus 7- amino cephalosporanic acid analogous to 6-
aminopenicillanic acid.
• Modification in side chains
• First agent Cefalothin Eli Lilly 1964
11.
12.
13. • Revision
• History and Chemistry
•Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
14. CLASSIFICATION
• FIRST GENERATION: Cefadroxil, Cefazolin, Cephalexin,
Cephalothin
• SECOND GENERATION: Cefaclor, Ceforanide, Cefotetan,
Cefoxitin, Cefprozil, Cefuroxime, Cefuroxime axetil.
16. • Revision
• History and Chemistry
• Classification
•Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
17.
18. • Revision
• History and Chemistry
• Classification
• Mechanism of Action
•Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
19.
20. MECHANISM OF BACTERIAL RESISTANCE
• Inactivation of antibiotic by β- lactamase
• Modification of target PBPs
• Impaired penetration of drug to target PBPs
• Antibiotic efflux
21.
22. • Revision
• History and Chemistry
• Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
•General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
29. • Revision
• History and Chemistry
• Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
•Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
• Current Status
30. FIRST GENERATION CEPHALOSPORINS
• Gram positive cocci Streptococci, Staphylococci
• Gram negative Moraxella catarrhalis, E. coli, K. pneumonia, P.
mirabilis
• Penicillin susceptible anaerobes in oral cavity except B. fragilis.
• Exception Enterococci, MRSA, Penicillin resistant Streptococci,
S. epidermidis
32. SECOND GENERATION CEPHALOSPORINS
• Gram negative aerobes H. influenza, M. catarrhalis, P. mirabilis, E.
coli, Klebsiella, Neisseria gonorrhea
• Gram positive cocci less active
• Anaerobes- B. fragilis
• No efficacy against Pseudomonas, Enterococci
• Cefuroxime, Cefotetan, Cefmetazole lack activity against B. fragilis
33. SECOND GENERATION CEPHALOSPORINS
• Respiratory tract infections
• Acute sinusitis
• Otitis media
• Uncomplicated UTI
• Cephamycins mixed aerobic/anerobic infections
• Skin & soft tissues
• Intra abdominal
• Gynecological
34. THIRD GENERATION CEPHALOSPORINS
• Less active than 1st gen against Gram positive organisms.
• More active against enterobacteriaceae.
• Ceftazidime P. aeruginosa
35. THIRD GENERATION CEPHALOSPORINS
• With/without aminoglycoside infections by Klebsiella,
Enterobacter, Proteus, Hemophilus sp, Providencia
• Ceftriaxone all forms of gonorrhea; severe Lyme disease
• Cefotaxime & Ceftriaxone initial Rx of meningitis
• Ceftazidime+ aminoglycoside Pseudomonas meningitis
• Community Acquired Pneumonia
36. FOURTH GENERATION CEPHALOSPORINS
• Active against Gram positive, Enterobacteriaceae,
Pseudomonas.
• Uses Nosocomial infections
• No activity: penicillin-resistant S. pneumonia, MRSA, MRSE,
Staphylococci, Enterococcus, L. monocytogenes, Legionella
pneumophila, L. micdadei, C. difficile, Campylobacter jejuni.
38. • Revision
• History and Chemistry
• Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
•Adverse Reactions
• Current Status
40. ADVERSE EFFECTS
• Antibiotic induced colitis
• Intolerance to alcohol (disulfiram like reaction)
• Thrombocytopenia/ platelet dysfunction
• Rarely, bone marrow depression granulocytopenia.
41. • Revision
• History and Chemistry
• Classification
• Mechanism of Action
• Mechanism of Bacterial Resistance
• General features of Cephalosporins
• Antimicrobial Spectrum & Therapeutic Uses
• Adverse Reactions
•Current Status
42. AVYCAZ (CEFTAZIDIME+ AVIBACTAM)
• Feb 2015
• Complicated Intra-abdominal Infections; UTI
• Dose- 2.5g (2g/0.5g) 8 hrly IV infusion over 2 hrs
• ADR- nausea, vomiting, constipation, anxiety
43. ZERBAXA (CEFTOLOZANE + TAZOBACTAM)
• Dec 2014
• CIAI; UTI
• Dose: 1.5g (1g/0.5g) 8 hrly IV infusion over 1 hr
• ADR: nausea, diarrhea, headache, pyrexia
First source of cephalosporins isolated in 1948 by Italian scientist Giuseppe Brotzu from sea near sewer outlet off the Sardinian coast.
Crude filtrates from cultures inhibited invitro S aureus;
Guy newton & Edward Abraham at Sir William Dunn School of Pathology At Oxford University isolated Cephalosporin C.
Cephalosporins may be classified by their chemical structure, clinical pharmacology, resistance to β lactamase or antimicrobial spectrum. Well accepted system is classification by generations. It is based on antimicrobial activity.
Cefotetan and cefoxitin are cephamycins. They have a 7 alpha methoxy group tha gives resistance to betalactamases and makes them different from other cephalosporins. Grouped with second generation CS because of similar activity.
MC mechanism of bacterial resistance. Β lactamase hydrolyses β lactam ring and inactivates the drug.
Altered target proteins basis of MRSA and penicillin resistant pnemucocci and enterococci. These resistant organisms produce PBPs of low affinity for binding β lactam antibiotics; consequently not inhibited except at high clinically unachievable drug concentrations.
Impaired penetration Occurs in gram negative coz of the impermeable outer membrane which is absent in gram positive. Down regulation in production of porins impairs drug entry into the cell. Not sufficient to cause resistance. Becomes more resistant in the presence of β lactamase
Antibiotic efflux Gram negative produces an efflux pump which consists of cytoplasmic and periplasmic protein components that efficiently transports some β lactam antibiotics from periplasm back across cell wall outer membrane.
Cephalexin, Cefadroxil, Cefaclor, Cefpodoxime, Cefuroxime, Cefdinir orally
Excreted mainy in kidney
Dose to be altered I pts with renal insufficiency
Several CS penetrate CSF, cross placenta, synovial and pericardial fluids.
Penetration into aqueous humour is impo after administering systemic 3rd gen CS but poor penetrstion into vitreous humour
Cefazolin glomerular filtration; 64 micro/ml
Cefalexin 0.5g 16micro/ml not metabolused; excreted in urine
Cefoxitin IM 1g 22 micro/ml
Axetil acetyloxy ethyl ester
Cefotaxime desacetylcefotaxime
2g IV 126-193 micro/ml
Skin & Soft tissue infections owing to S. pyogenes and methicillin susceptible S. aureus
Single dose of cefazolin just before surgery is preferred prophylaxis for procedures in which skin flora are likely pathogens.
Cephamycins 7 alpha methoxy group that gives resistance to beta lactamases and makes them different from other CS. Grouped with 2nd generations cause they have similar activity with one important exception- anerobes. Example- cefmetazole, cefotetan, cefoxitin
Cefoxitin prohylaxis for intestinl anaerobes for colorectal surgery.
Cefotaxime and Ceftriaxone cause of good penetration into CSF; good antimicrobial activity, record of clinical success initial rx of meningitis in non immunocompromised adults and children > 3 months of age in combination with ampicillin/ vancomycin pending identification of causative agent)
Nosocomial infections by Enterobacter, Citrobacter, Serratia spp
Immunological studies 20% clinical studies 1% no skin tests
Cephalothin 8-12g/day acute tubular necrosis; ssynergistic effect when combined with gentamicin/tobramycin
Antibiotic-induced colitis (severe watery diarrhea, severe stomach cramps, fever, and weakness).
Disulfiram-like reaction (flushing, sweating, headache, tachycardia) CS with methylthiotetrazole group cefotetan, cefoperazone
CIAI caused by E. coli, Klebsiella, Citrobacter, Enterobacter, Proteus, Pseudomonas
