CephalosporinsDR RAHUL

Inhibitors of Cell Wall Synthesis

Cephalosporins and cephamycins

Derivatives of 7-amino-cephalosporanic acid Cephamycins are fermented products of

streptomyces Closely related in structure to penicillin

(beta-lactam ring). They are highly resistant to penicillinase. Some bacteria can produce a beta

lactamase called cephalosporinase Many of them are resistant to the enzyme.

b-lactam Antibiotics

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Monobactams

All of the drugs in this group contain

a β-lactam ring in their structure

Penicillins

NO

S

Carbapenems

NO

NO

NO

S

Cephalosporins

share similar• features of chemistry,• mechanism of action, • pharmacologic and clinical effects.

Mechanism of action

Cephalosporins inhibit the peptido-glycan synthesis of bacterial cell wall in a manner similar to that of penicillin and are considered bactericidal.

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Cephalosporin

Divided into 4 major groups called “Generations”

Are divided into Generations based on Parallel their chronological development Their antimicrobial spectrum› First generation › Second generation › Third generation › Fourth generation

EXAMPLES: Cephalothin, Cefazolin, Cephalexin , Cephadroxil

They have a stronger antimicrobial action on G+ bacteria than that of the other generations, but they action on G- bacteria is relatively poor.

① These cephalosporins have nephrotoxicity to a certain degree.

② They are NOT effective against pseudomonas.

First Generation Cephalosporins

④ Comparatively, they are less stable for beta- lactamase (penicillinase ).

⑤ They are chiefly used in treating infection of the penicillinase-producing S.aureus and for surgical prophylaxis.

⑥ Cefazolin do not penetrate the central nervous system and can not be used to treat meningitis.

First Generation Cephalosporins

USES Treatment infection of the penicillinase-

productive S.aureus Minor staphylococcal lesions For surgical prophylaxis Cephazolin drug of choice for k. pneumonie

infections Treatment of staphylococcal or streptococcal

infection who have a h/o penicillin hypersensitivity.

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Second Generation Cephalosporin

Cefamandole, Cefaclor, Cefuroxime, Cefotetan, Cefoxitin (Cephamycins)

① Action of this generation on G+ bacteria is the same or a little less than that of the first generation.

② Their antimicrobial action on G- bacteria is obviously increased. (H. influenza, Klebsiella)

③ Cephamycins are effective against anaerobes such as B.fragilis, serratia

Second Generation Cephalosporin

④ Ineffective against p.aeruginosa.⑤ They are stable to many kind of beta-

lactamases and have less nephrotoxicity than the first generation.

⑥ Cefuroxime is the only second-generation drug that crosses the blood-brain barrier : used for the treatment of meningitis, especially H.influenzae meningitis, and sepsis.

USES :

Sinusitis, Otitis, LRTI, Community acquired pneumonia › caused by beta lactamase producing H.

influenza Meningitis Mixed infections :

› Peritonitis › Diverticulitis› pelvic infections

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Third Generation Cephalosporins

Cefotaxime, Ceftriaxone, Cefoperazone, Cefixime, Ceftizidime, Cefodoxime.

① The broadest spectrums of all cephalo-② The highest activities against G- bacteria.③ The lowest activities against G+ bacteria.④ The highest resistance to β-lactamase.⑤ Can cross blood brain barrier

Third Generation Cephalosporins

⑤ The best penetration into the CSF; almost no nephrotoxicity.

⑥ Ceftizoxime have good activity against B.fragilis.

⑦ Some of them are effective against P.aeruginosa and enteric bacilli. (cefoperazone and ceftizidime)

Third Generation Cephalosporins

There are also some unique properties of individual 3th generation.

Ceftriaxone has the longest half-life(8h) of any cephalosporin.

Cefixime is an oral preparation. Ceftazidime is the best anti-pseudomonal

cephalosporin. Cefoperazone is eliminated(70%) in the bile,

and is thus very useful in patients with renal failure.

Uses Used for serious infections caused by organisms

resistant to other drugs. Gonorrhea : cefixime / ceftriaxone Meningitis : Ceftriaxone, cefotaxime community acquired pneumonia: Ceftriaxone Septicemia Nosocomial infections UTI LRTI Soft tissue infections cellulitis Typhoid fever Mixed aerobic , anaerobic infections Urethral , biliary tract infections

uses

First line drug for Gonorrhea caused by Nisseria (ceftriaxone , Cefixime)

Meningitis caused by pneumococci, meningococci, H. influenza.

Empirical theraphy for sepsis of unknown cause

Urethral or biliary tract infections

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Fourth -Generations

Cefepime1. More resistant to hydrolysis by β-

lactamase2. Active against P-aeruginosa &

Enterobacteriaceace.3. Clinical use as third generations.

Generations First second Third

Drugs Cephalexin (O)Cefadroxil (O)Cefazolin (im, iv)Cephalothin (o,im)

Cefaclor (o)Cefuroxime (o)Cefoxatin (im, iv)Cefotetan (im)

Cefixime (o)Ceftriaxone (o)Cefotaxime (im, iv)Cefoperazone

Antibacterial spectrumG+Ve +++ ++ +

G -ve + ++ +++

Anaerobes Efective against B.Fragalis

Very effective (cefotetan &

cefoxitin)

Effective(Cefoperazone)

Pseudomonas - - -- effective

Salmonella -- - effective

Betalactamase Resistant to staphylococcal

H, resistant to G-ve

Highly resistant

BBB --- Only cefuroxime Most drugs

Adverse effects Relatively few and low The most common ones are Allergy-

hypersensitivity reactions (5%-10%)anaphylaxis, fever, skin rashes, nephritis,

granulocytopenia, and hemolytic anemia. During treatment with third-generation

drugs, these resistant bacteria, as well as fungi, often proliferate and may induce superinfections.

Adverse effects Nephrotoxicity: The first-generation cephalosporins

have certain nephrotoxicity. (Renal damage, including interstitial nephritis and even tubular necrosis )

The second-generation have slight nephrotoxicity.

The third-generation have no nephrotoxicity.

The Other Beta-lactam antibiotics

Monobactams - Aztreonam

① Aztreonam is highly resistant to beta-lactamases

② It is highly active against aerobic G- bacteria, including P.aeruginosa and penicillinase-producing strains of H. influenzae and gonococci. But it shows poor activity against G+ cocci and anaerobic bacteria.

③ The antimicrobial spectrum of aztreonam is similar to that of aminoglycosides

Other inhibitions of cell wall

synthesis

Mechanism of action Pharmacologic effects Clinical Uses Adverse Effects

VancomycinVancomycin

Vancomycin is an antibiotic

produced by Streptococcus

orientalis.

Pharmacologic effects

① Vancomycin is very effective against most staphylococci including those producing beta-lactamases， and other G+ cocci such as streptococcus viridans, enterococci, and pneumococcus.

② It is also active against clostridium species, Corynebacterium diphtheriae, and Bacillus anthracis.

Vancomycin: Clinical Uses

① Orally only for the treatment of antibiotic-associated Pseudomembranous colitis caused by C.difficile.

② Intravenous administration is mainly used for serious G+ coccal infections, such as enterocolitis, septicemia

› Especially for those caused by penicilin-resistant pneumococcus and staphylococci

Vancomycin: Adverse Effects

① Phlebitis› at the site of injection.

② Nephrotoxicity and Ototoxicity› rare with monotherapy, more common

when administered with other nephro- or ototoxins

› risk factors include renal impairment, prolonged therapy, high doses, high serum concentrations, other toxic meds

Vancomycin: Adverse Effects

③ “Red-Man”or “red neck” Syndrome › flushing, pruritus, erythematous rash on

face and upper torso› related to RATE of intravenous infusion;

should be infused over at least 60 minutes› resolves spontaneously after

discontinuation› Prevent: may lengthen infusion (over 2 to

3 hours) or pretreat with antihistamines in some cases

Beta lactamase inhibitors

They are available only in fixed combinations with specific penicillins:

Ampicillin + sulbactam Amoxicillin + clavulanic acid Ticarcillin + clavulanate potassium Piperacillin + tazobactam sodium

Sulbactam

(Amp/Sulbactam) Spectrum: Amp + most anaerobes + many

enteric G (-) rods, OSSA

Sulbactam alone is very active against Acinetobacter spp.

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Tazobactam

(Pip/Tazo) THE most broad-spectrum penicillin Tazobactam may improve the activity

of piperacillin vs. gram-negative rods, including anaerobes

4.5g IV q8h = 3.375g IV q6h 4.5g IV q6h for Pseudomonas

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