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