3. Introduction
• The cephalosporins are a class of β-
lactam antibiotics originally derived
from the Fungus Acremonium,
which was previously known
as Cephalosporium
5. History
• The aerobic mold which yielded cephalosporin
C was found in the sea near a sewage
outfall in Su Siccu, by Cagliari harbor in Sardinia,
by the Italian pharmacologist Giuseppe
Brotzu in July 1945
• The first agent, cefalotin (cephalothin), was
launched by Eli Lilly and Company in 1964
6. Chemical structure
• Most cephalosporins are produced
semisynthetically by the chemical
attachment of side chains to 7-
aminocephalosporanic acid (7-ACA).
Structural changes on the acyl side chain
at the 7-position alter antibacterial
activity and variations at the 3- position
modify the pharmacokinetic profile.
8. • Peptidoglycan layer is important for cell wall structure integrity
of bacteria
• The final step in synthesis of peptidoglycan (Transpeptidation) is
facilitated by transpeptidase (PBP-PenicillinBindingProtein)
• Cephalosporin competitively inhibit PBP as it mimics the structure
of D-Ala-D-Ala link to which PBP bind for cross-linking of
peptidoglycan
• As it disrupting the cross-linking process the cell wall will lose its
strength which results in cell lysis
9. • Bacteriostatic” means that the agent prevents the growth of bacteria
(i.e., it keeps them in the stationary phase of growth), and
“bactericidal” means that it kills bacteria.
10. Classification
• Cephalosporins have been classified as first, second, third, fourth, and
advanced generation, based largely on their
• Bacterial susceptibility patterns
• Resistance to β-lactamases
12. First generations
• First-generations compounds have
excellent activity against Gram-positive
organisms and some activity against
gram-negative organisms
13. Second generations
• The second-generation cephalosporins
display greater activity against gram-
negative organisms whereas activity against
gram-positive organisms is weaker
• Cephamycins (e.g.cefoxitin) included this
group, are active against anaerobic gram
negative bacilli
14. Third generations
• Third-generation cephalosporins have
enhanced activity against gram-negative
bacilli. For some (ceftazidime) it is
extended to include pseudomonas
15. Fourth generations
• Cefepime has a wide antibacterial spectrum, with activity against
streptococci and staphylococci
• Cefepime is also effective against aerobic gram-negative organisms,
such as Enterobacter species, E. coli, K. pneumoniae, P. mirabilis, and
P. aeruginosa
16. Fifth generations
• Fifth generations agents have an enhanced spectrum of gram-positive
activity that includes MRSA, and also have activity against gram-
negative bacteria
• Cefiderocol is a novel siderophore cephalosporin, which is also active
in the presence of extended spectrum beta-lactamase (ESBLs) and
carbapenamases
17. Resistance
• Resistance to the cephalosporins is either
• Due to the hydrolysis of the beta-lactam ring by β-lactamases or,
• Reduced affinity for PBPs
18. β-Lactamase inhibitor
• β-lactamase inhibitors are drugs that are co-administered with β-
lactam antimicrobials to prevent antimicrobial resistance by inhibiting
serine β-lactamases, which are enzymes that inactivate the beta-
lactam ring, which is a common chemical structure to all β-lactam
antimicrobials
• Currently available β-Lactamase inhibitors are:
• Clavulanic acid or clavulanate, usually combined with amoxicillin or ticarcillin
or cefuroxime
• Sulbactam usually combined with ampicillin or cefoperazone
• Tazobactam usually combined with piperacillin
• Avibactam approved in combination with ceftazidime
19. M/A of β-Lactamase inhibitor
• β-lactamase inhibitors work by one of two primary mechanisms.
• They may become substrates that bind the β-lactamase enzyme with high
affinity
• They may also become “suicide inhibitors,” which permanently inactivate the
enzyme through secondary chemical reactions in the active site
20. Indications of β-Lactamase inhibitor
• The most important use of beta-lactamase inhibitors is in the
treatment of infections caused by gram-negative bacteria
• Several bacteria have developed extended-spectrum beta-lactamase
enzymes (ESBLs) (Enterobacteriaceae and Pseudomonas aeruginosa) .
Beta-lactamase inhibitors can effectively treat ESBL-producing
organisms
21.
22. Pharmacokinetics
Administration : Many of the cephalosporins must be administered
IV or IM because of their poor oral absorption.
Distribution :
All cephalosporins distribute very well into body fluids.
Adequate therapeutic levels in the CSF, regardless of inflammation, are
achieved with only a few cephalosporins. For example, ceftriaxone and
cefotaxime.
Cefazolin, cefuroxime is commonly used for surgical prophylaxis due to their
activity against penicillinase-producing S. aureus, along with its good tissue
and fluid penetration
23. Elimination :
Cephalosporins are eliminated through tubular secretion and/or
glomerular filtration. Therefore, doses must be adjusted in renal
dysfunction to guard against accumulation and toxicity.
One exception is ceftriaxone, which is excreted through the bile into
the feces and, therefore, is frequently employed in patients with renal
insufficiency
24. Indications
• Antibiotic prophylaxis of surgical site infections
• Skin infections (erysipelas, cellulitis, complicated acne, drug eruption)
• GIT infections (Spontaneous bacterial peritonitis, acute cholecystitis, diverticulitis,
cholangitis)
• UTI
• Respiratory tract infection
• Enteric fever
• Meningitis
• Gonorrhea
• Septicemia
• Many more……………
26. Contraindications
• These drugs are contraindicated in patient with known
hypersensitivity to cephalosporin
• Known hypersensitivity to penicillin
• Renal failure (exception: ceftriaxone)
27. Drug interactions
• Cephalosporin can potentiate the effect of oral anticoagulant which
leads to increased risk for bleeding
• Combined use with aminoglycosides may leads to increased risk of
nephrotoxicity
• Concomitant intake of alcohol with cephalosporin may produce
disulfiram-like reaction (e.g. flushing, throbbing headache, nausea
and vomiting, chest pain, palpitations)
28. Pregnancy
• Cephalosporin is not associated with major birth defects, miscarriage
or adverse maternal or fetal outcomes
• Cephalosporin is excreted in human milk: there are no data on effects
of drug on breastfed child or on milk production
31. • Not categorized yet but available data have not established a drug-
associated risk of adverse maternal or fetal outcomes
• Cefazolin (1st)
• Cefuroxime (2nd)
• Cefoxitin (2nd)
• Ceftraixone (3rd)
• Cefixime (3rd)
• Cefipime (4th)
• No data in pregnant women available
• Cefaclor (2nd)
• Ceftaroline (5th)
