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CEPHALOSPORINS
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INTRODUCTION
• Antibacterial agents which inhibit bacterial cell wall synthesis
• Discovered from a fungal colony Cephalosporium acremonium in Sardinian sewer water (1948)
• Cephalosporin C identified in 1961
• These are β-lactam antibiotics that are closely related both structurally and functionally to the pencillins
• Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid
Why Cephalosporins?
• Broad spectrum of activity
• Stability to -lactamase
• Oral and parenteral preparations
• Widely accepted
• Treats ‘day to day’ as well as
‘serious infections’
• High safety profile
Cephalosporins-Limitations
• Emerging resistance patterns
• Some III & IV generation cephalosporins were
available only as parenteral formulations
• Pharmacoeconomics
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Dihidrothiazine ringPK
Β-lactam ring
Side chain Spect
Mechanism of action
• Identical to pencillins, i.e.,
– Binding to cephalosporin binding proteins
(PBP)
– Inhibition of transpeptidation process
– Activation of autolysin enzyme
Mechanism of action
Resistance
1. Bacteria produce -lactamase: -lactamases are either constitutive, or more commonly, are acquired by the transfer of plasmids.
2. Altered PBPs: Modified PBPs have a low affinity for -lactam antibiotics.
3. Decreased concentration of antibiotics in target site: altered porin (either in the number or function); increased active efflux system.
Classification
• Have been classified as first, second, third and fourth
generation, based on their bacterial spectrum and
resistance to β-lactamases
Note: Cephalosporins are ineffective against MRSA, L.
monocytogenes, Clostredium dificile and the
enterococci
Generation Parenteral Agents Oral Agents
First-generation(1960s) Cefazolin, CephalothinCefadroxil, cephalexin,cephradine
Second-generation (1970s)
Cefotetan, cefoxitin, cefuroxime
Cefaclor, cefprozil, cefuroxime axetil
Third-generation (1980s)
Cefotaxime, ceftazidime, ceftizoxime, ceftriaxone
Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime
Fourth-generation (1997-98)
Cefepime, cefpirome
Classification
First Generation Cephalosporins
Pharmacokinetics:• Oral cephalosporins are generally well absorbed• IM injection of cephalothin is very painful and hence
given by IV route• Except for cefazolin, which is 80-90% protein bound,
others exhibit a poor protein binding• Good distribution to most tissues except in CSF• Metabolism is not a major elimination path• Primarily excreted through kidney• Probenecid increases plasma half life• All are sensitive to β-lactamase enzyme degradation
Antimicrobial spectrum
Gram-positive bacteria Streptococcus pyogenes,Some viridans streptococci,Some Staphylococcus aureus,Some Streptococcus pneumoniae
Gram-negative bacteria Some Escherichia coli,Some Klebsiella pneumonia, Some Proteus mirabilis
Antimicrobial spectrum
Cocci > Bacilli > Bacilli > Cocci + - + -
Uses• UTI’s
• Minor staphylococcal infections
• Cellulitis or soft tissue abscess
• Ineffective in meningitis (do not cross BBB)• Cefazolin is drug of choice for surgical
prophylaxis before cardiac surgery and before orthopedic prosthesis procedures (has better penetration to tissues)
Second Generation Cephalosporins
Pharmacokinetics:• Cefaclor and cefuroxime can be given orally and have
good bioavailability• Cefuroxime axetil is an ester prodrug formulation in which
the ester is hydrolyzed during drug passage through the intestinal mucosa
• The free cefuroxime then enters the systemic circulation• Only cefuroxime crosses BBB among 2nd gen• Only cefoxitin is 80-90% protein bound; others have poor
protein binding
• More stable to β-lactamase degradation than 1st gen
• Their IM injections are painful and hence preferably
given administered by IV route
• These are excreted unchanged through kidney
• Probenecid increases plasma half life
Second Generation Cephalosporins
• The second-generation cephalosporins have a greater
Gram-negative spectrum while retaining some activity
against Gram-positive cocci.
Antimicrobial spectrum
Gram-positive bacteria
True cephalosporins have activity equivalent to first-generation agents. Cefoxitin and cefotetan have little activity
Gram-negative bacteria
Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Neisseria spp.
Anaerobic bacteria Cefoxitin and cefotetan have moderate anaerobic activity.
Antimicrobial spectrum
Cocci Bacilli > Bacilli, Cocci
Anaerobes
- - +
Uses
• Cefaclor: URTI’s
• Cefuroxime: commonly acquired pneumonia,
gonorrhoea and meningitis
• Cefoxitin & cefotetan: peritonitis and diverticulitis
and some gynecological infections (anaerobic
infection)
Third Generation Cephalosporins
Pharmacokinetics:• All these drugs distribute very well into body
compartments• Adequate levels in the CSF regardless of inflammation,
are achieved only with these 3rd gen• Thus these are used to treat meningitis• Ceftriaxone differs from others by its long plasma half
life(7-8hrs) and high protein bound (90%)- OD• Metabolism is not major path for elimination• Cefotaxime is metabolized to active metabolite –
desacetyl cefotaxime
• Cefoperazone and ceftriaxone are excreted through bile, so
no dose adjustment requied for renal insufficiency
• Urinary excretion is the major elimination route
• Probenecid may increase the plasma half life
• All are highly resistant to degradation by β-lactamases
from gram-negative bacteria
Third Generation Cephalosporins
Antimicrobial spectrum
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae, Modest activity against Staphylococcus aureus
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Some Enterobacteriaceae.
Anaerobic bacteria
Atypical bacteria
Spirochetes Borrelia burgorferi
Antimicrobial spectrum
-
Cocci, Bacilli > Bacilli, Cocci
anaerobic org.
+
Ceftriaxone:• Very effective in treating meningitis caused by N.
meningitidis, Pneumococci, H. influenza and susceptible enteric gram-negative rods but not by Listeria monocytogenes
• A single IM dose of 250mg is effective in gonorrhoae and chancroid
• Excellent for treatment of community acquired pneumonia caused by pneumococci, H. influenzae and staph aureus
• Lyme disease caused by Borrelia burgdorferi• Also efficacious in treating complicated UTI’s, abdominal
sepsis and septicaemias• Also used to treat multi drug resistant typhoid fever
(doses are high)
Cefotaxime:
• Like ceftriaxone, has been utilized effectively for treating
meningitis and community acquired pneumonia
• A single 0.5-1g IM dose is effective in treating
gonorrhoea
• Has been used in respiratory, genitourinary, abdominal
infections, septicaemia, anaerobic and hospital acquired
infections
Cefoperazone:
• More active than cefotaxime against pseudomonas (but
less active than ceftadizime)
• Good for Salmonella typhi and B. fragilis also
• Used for pseudomonal UTI’s, bactreamia, and infections
in immunocompromised patients
• Other uses like meningitis, gonorrhoae and septicaemia
are common to other drugs of this series
Ceftazidime:
• Has excellent activity against pseudomonas (better than
cefoperazone) and other gram-negative bacilli
• Ceftadizime+aminoglycosides is the treatment of choice
for pseudomonal meningitis
• Also useful for nosocomial infections also
Ceftizoxime:
• More active agaist B. fragilis than cefotaxime, otherwise
similar
Cefixime:
• Orally administered (200-400mg BD)
• Cefixime is used to treat respiratory, urinary, biliary
infections
• In a single 400mg oral dose it provides effective
treatment of uncomplicated gonorrhoea
• Not effective against Staph. aureus and Pseudomonas
Cefpodoxime:
• Is similar to cefixime but it is active against Staph. aureus
also
• Zwitterionic compounds
• Enhanced ability to cross the outer membrane of Gram
negative bacteria
• Given by IM /IV
• Plasma half life is 2hrs
• Protein binding is only 20%
• Widely distributed in tissues and body fluids
• Accumulates well in CSF
Fourth Generation Cephalosporins Oximinocephalosporins
Fourth Generation Cephalosporins
• It is eliminated 85-90% through kidney
• Pharmacokinetics of cefpirone is identical to cefepime
expect that its protein binding is only 10%
• Good affinity for the transpeptidase enzyme
• Low affinity for some β-lactamases
• Active vs. Gram +ve cocci and a broad array of Gram -
ve bacteria
• Active vs. P. Aeruginosa
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae. Modest activity against Staphylococcus aureus
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeroginosa.
Anaerobic bacteria
Atypical bacteria
Antimicrobial spectrum
Cocci, Bacilli > Cocci. Noanaerobic , No Bacilli- + +
IV Gen. Uses
• Hospital acquired pneumonia
• Bactreamia and septicaemia
• Also useful in UTI’s, RTI’s and as empiric therapy for
febrile neutropinic patients
Adverse effects
• Pain after IM inj. (cephalothin)
• Diarrhoea (cephradine and cefoperazone)
• Hypersensitivity reactions
• Nephrotoxicity (cephaloridine, cephalothin and few other)
• Bleeding (cefoperazone, ceftriaxone)(N-methyl
thiotetrazole side chain at R2 position
• Disulfiram like reaction (cefoperazone)