Inhibitors of cell wall synthesis (β- Lactam Antibiotics ) 1. PENICILLINS 2.Cephalosporins...
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Transcript of Inhibitors of cell wall synthesis (β- Lactam Antibiotics ) 1. PENICILLINS 2.Cephalosporins...
Inhibitors of cell wall synthesis (β-Lactam Antibiotics )
1. PENICILLINS 2.Cephalosporins
3.Carbapenems ( Imipenem ) 4. Monobactams ( Aztreonam)
Penicillins
Classification Narrow spectrum penicillins Antistaphylococcal penicillins
Extended –spectrum penicillins .
Mechanism of action
Like all β-lactam antibiotics , inhibit the synthesis of bacterial cell wall .
They are bactericidal on the actively growing bacteria.
Pharmacokinetics
Absorption Depending on acid stability Absorption of most oral penicillins is
impaired by food except amoxicillin .
Metabolism & Excretion
Not metabolized Excreted unchanged in urine Probenecid blocks their secretion Nafcillin is mainly cleared by biliary route Oxacillin by both kidney & biliary route.
Distribution
Relatively insoluble in lipid Poor penetration into cells and BBB
Inflammation permits entrance into CSF. Proteins binding vary from 20%-90%
Narrow spectrum penicillins
Penicillin G Short duration Acid unstable Penicillinase (β- lactamase ) sensitive Used in infections caused by streptococci,
meningococci, enterococci & non-β- lactamase – producing staphylococci.
Phenoxymethyl penicillin (P. V)
Less effective than penicillin G Acid stable Penicillinase sensitive Short acting ( four times/day) Used in minor infections
Procaine penicillin
Long acting (every 12 h ) . Acid unstable ( I.M.I ) Penicillinase sensitive Used to prevent subacute bacterial
endocarditis due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease .
Benzathine penicillin
Long acting (every 3-4 weeks ) Acid unstable Penicillinase sensitive Treatment of β-hemolytic streptococcal . Used as prophylaxis against reinfection with β-
hemolytic streptococci to prevent rheumatic fever .
Once a week for 1-3 weeks for treatment of syphilis (2.4 million units I.M.)
Penicillinase resistant to staphylococcal β-lactamase producer
Methicillin acid unstable Nafcillin its absorption is erratic Oxacillin, Cloxacillin,Dicloxacillin (acid
stable ). Used in minor & severe Stap. infections
Extended spectrum penicillins
Aminopenicillins Carboxypenicillins Ureidopenicillins
Retain the spectrum of Penicillin G, but having greater activity against gram –negative bacteria.
Aminopenicillins(Ampicillin &Amoxicillin)
Therapeutic uses H. influenza infections E. coli Ampicillin ( not amoxicillin) is effective for
shigellosis & complicated salmonella infections. Prophylaxis of infective endocarditis Urinary tract infections Effective against penicillin –resistant pneumococci
Carboxypenicillins(Ticarcillin)&Ureidopenicillin(Piperacillin)
Effective against pseudomonas aeruginosa & Enterobacter organisms.
Ampicillin , amoxicillin , ticarcillin & piperacillin are available in combination with β-lactamase inhibitors as clavulanic acid ,sulbactam or tazobactam.
Adverse effects of penicillins
Hypersensitivity reactions High dose in renal failure ---seizure Naficillin (neutropenia) Oxacillin (hepatitis) Methicillin(nephritis) Oral penicillins may lead to GIT upset.
Ampicillin has been associated with pseudomembraneous colitis
Cephalosporins
First-Generation
Cefazolin, Cephalexin, cephradin. Are very effective against gram- positive
cocci Are given orally ,except cefazolin given
I.V.I ,or I.M.
Excretion & Distribution
Through kidney Probenecid block tubular secretion and
increase plasma level . Can not cross B.B.B.
Clinical uses
Urinary tract infections Minor Staph.infections or minor
polymicrobial infections as cellulitis or soft tissue abscess.
Cefazolin is the drug of choice for surgical prophylaxis, also as alternative to antistaph.penicillin in allergic patients .
Second -Generations
Cefaclor ,Cefamandole, cefuroxime Less active against gram-positive bacteria
than first generation Have extended gram –negative effect No effect on P-aeruginosa or enterococci.
Pharmacokinetics
Given orally or parentrally
Can not cross B.B.B.
Excreted through kidney
Clinical uses
β -lactamase-producing H-influenza infections
Mixed anaerobic infections as peritonitis . Community acquired pneumonia
Third -Generations
Cefoperazone,Ceftazidime ,Ceftriaxone Have extended gram- negative spectrum. Some of them have an effect on P-
aeruginosa ( ceftazidime ) . No effect on E-coli.
Pharmacokinetics
Main route I.V.I.
Ceftriaxone has a long half- life (7-8h).can
be given once every 24h. Cross B.B.B. Excreted through kidney .(Ceftriaxone &
cefoperazone through bile ).
Clinical uses
Serious infections Cceftriaxone is first line for treatment of
gonorrhea & drug of choice in meningitis. P-aeruginosa infections ( ceftazidime ).
In penicillin-resistant pneumococci
Fourth -Generations
Cefepime More resistant to hydrolysis by β-
lactamase Active against P-aeruginosa & E-coli Clinical use as third generations.
Adverse Effects of cephalosporins Allergy Thrombophilibitis Interstitial nephritis and tubular necrosis Cephalosporins that contain a
methylthiotetrazole group as cefamandole ,cefoperazone cause :hypoprothrombinemia & bleeding disorders
Methylthiotetrazole ring causes severe
disulfiram-like reaction ( alcohol or alcohol medication must be avoided ).
Superinfections. Diarrhea.
Carbapenems
Imipenem Bctericidal, inhibit bacterial cell wall
synthesis. Has a wide spectrum of activity Resistant to most β lactamases except
metallo-β lactamase .
Pharmacokinetics
Not absorbed orally, taken by I.V.I. Inactivated by dehydropeptidases in renal
tubules, so it is given with an inhibitor cilastatin for clinical use.
Penetrates body tissues and fluids including C.S.F.
Clinical uses
Mixed aerobic and anaerobic infections Is the β lactam of choice for treatment of
enterobacter infections. Pseudomonal infections Intrabdominal infections Febrile neutropenic patient Septicaemia.
Meropenem
Highly active against gram-negative aerobes .
Not degraded by renal dehydropeptidase
Adverse effects
Nausea, vomiting, diarrhea Skin rash and reaction at the site of
infusion High doses in patients with renal failure
may lead to seizures Patients allergic to penicillins may be
allergic to carbapenems .
Monobactams
Aztronam Active only against gram-negative aerobic
bacteria. Given I.V. Similar to β-lactam in mechanism of action Penicillin-allergic patients tolerate aztronam Skin rash & elevation of liver enzymes may
occur