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 & protein binding Absorption of most oral penicillins is impaired by food except amoxicillin .

Metabolism & Excretion Not metabolised 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 ( I.M.I ) Penicillinase sensitive Treatment of β-hemolytic streptococcal pharyngitis. Used as prophylaxis against reinfection with β- hemolytic streptococci so 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, Cefonicid, 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 parenterally Can not cross B.B.B. Excreted through kidney Cefonicid is highly protein binding

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 ( ceftazidme ) . 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 mainly with cephaloridine. Cephalosporins that contain a methylthiotetrazole group as cefamandole ,cefoperazone cause :hypoprothrombinemia & bleeding disorders

Vitamin K twice weekly can prevent this. . 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 Similar to imipenem but it is 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