Inhibitors of cell wall synthesis (β- Lactam Antibiotics ) 1. PENICILLINS 2.Cephalosporins...
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Inhibitors of cell wall synthesis (-Lactam Antibiotics )1. PENICILLINS 2.Cephalosporins 3.Carbapenems ( Imipenem ) 4. Monobactams ( Aztreonam)
PenicillinsClassificationNarrow spectrum penicillinsAntistaphylococcal penicillins
Extended spectrum penicillins .
Mechanism of actionLike all -lactam antibiotics , inhibit the synthesis of bacterial cell wall .
They are bactericidal on the actively growing bacteria.
PharmacokineticsAbsorptionDepending on acid stability Absorption of most oral penicillins is impaired by food except amoxicillin .
Metabolism & ExcretionNot metabolized Excreted unchanged in urineProbenecid blocks their secretionNafcillin is mainly cleared by biliary routeOxacillin by both kidney & biliary route.
DistributionRelatively insoluble in lipid Poor penetration into cells and BBB Inflammation permits entrance into CSF.Proteins binding vary from 20%-90%
Narrow spectrum penicillinsPenicillin G Short duration Acid unstablePenicillinase (- lactamase ) sensitiveUsed in infections caused by streptococci, meningococci, enterococci & non-- lactamase producing staphylococci.
Phenoxymethyl penicillin (P. V)Less effective than penicillin GAcid stable Penicillinase sensitive Short acting ( four times/day)Used in minor infections
Procaine penicillinLong acting (every 12 h ) .Acid unstable ( I.M.I )Penicillinase sensitiveUsed to prevent subacute bacterial endocarditis due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease .
Benzathine penicillinLong acting (every 3-4 weeks )Acid unstable Penicillinase sensitive Treatment of -hemolytic streptococcal .Used as prophylaxis against reinfection with - 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 -lactamase producerMethicillin acid unstableNafcillin its absorption is erraticOxacillin, Cloxacillin,Dicloxacillin (acid stable ).Used in minor & severe Stap. infections
Extended spectrum penicillinsAminopenicillinsCarboxypenicillinsUreidopenicillins
Retain the spectrum of Penicillin G, but having greater activity against gram negative bacteria.
Aminopenicillins(Ampicillin &Amoxicillin)Therapeutic usesH. influenza infectionsE. coliAmpicillin ( not amoxicillin) is effective for shigellosis & complicated salmonella infections.Prophylaxis of infective endocarditisUrinary tract infectionsEffective against penicillin resistant pneumococci
Carboxypenicillins(Ticarcillin)&Ureidopenicillin(Piperacillin)Effective against pseudomonas aeruginosa & Enterobacter organisms.
Ampicillin , amoxicillin , ticarcillin & piperacillin are available in combination with -lactamase inhibitors as clavulanic acid ,sulbactam or tazobactam.
Adverse effects of penicillinsHypersensitivity reactions High dose in renal failure ---seizureNaficillin (neutropenia)Oxacillin (hepatitis)Methicillin(nephritis)Oral penicillins may lead to GIT upset. Ampicillin has been associated with pseudomembraneous colitis
CephalosporinsFirst-GenerationCefazolin, Cephalexin, cephradin.Are very effective against gram- positive cocciAre given orally ,except cefazolin given I.V.I ,or I.M.
Excretion & DistributionThrough kidney Probenecid block tubular secretion and increase plasma level .Can not cross B.B.B.
Clinical usesUrinary tract infectionsMinor 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 -GenerationsCefaclor ,Cefamandole, cefuroximeLess active against gram-positive bacteria than first generationHave extended gram negative effect No effect on P-aeruginosa or enterococci.
PharmacokineticsGiven orally or parentrally
Can not cross B.B.B.
Excreted through kidney
Clinical uses -lactamase-producing H-influenza infectionsMixed anaerobic infections as peritonitis .Community acquired pneumonia
Third -GenerationsCefoperazone,Ceftazidime ,CeftriaxoneHave extended gram- negative spectrum.Some of them have an effect on P-aeruginosa ( ceftazidime ) .No effect on E-coli.
PharmacokineticsMain 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 usesSerious infectionsCceftriaxone is first line for treatment of gonorrhea & drug of choice in meningitis. P-aeruginosa infections ( ceftazidime ).
In penicillin-resistant pneumococci
Fourth -GenerationsCefepimeMore resistant to hydrolysis by -lactamaseActive against P-aeruginosa & E-coliClinical use as third generations.
Adverse Effects of cephalosporinsAllergyThrombophilibitisInterstitial nephritis and tubular necrosisCephalosporins 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.
CarbapenemsImipenemBctericidal, inhibit bacterial cell wall synthesis.Has a wide spectrum of activity Resistant to most lactamases except metallo- lactamase .
PharmacokineticsNot 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 infectionsIs the lactam of choice for treatment of enterobacter infections.Pseudomonal infections Intrabdominal infections Febrile neutropenic patientSepticaemia.
MeropenemHighly active against gram-negative aerobes .Not degraded by renal dehydropeptidase
Adverse effectsNausea, vomiting, diarrheaSkin rash and reaction at the site of infusionHigh doses in patients with renal failure may lead to seizuresPatients allergic to penicillins may be allergic to carbapenems .
MonobactamsAztronamActive only against gram-negative aerobic bacteria.Given I.V.Similar to -lactam in mechanism of actionPenicillin-allergic patients tolerate aztronam Skin rash & elevation of liver enzymes may occur