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)