β-Lactam Antibiotics

1. PENICILLINS 2.Cephalosporins

3.Carbapenems ( Imipenems ) 4. Monobactams ( Aztreonam)

Penicillins

Classification Narrow spectrum penicillins Antistaphylococcal penicillins Broad spectrum penicillins Extended –spectrum penicillins

( antipseudomonal penicillins).

Mechanism of action

Like all β-lactam antibiotics , inhibit the synthesis of bacterial cell wall .

Through inhibition transpeptidase enzyme 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 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 sensitive Used in enterococcal endocarditis usually

with aminoglycosides To prevent gonorrheal opthalmia in new

born .

Procaine penicillin

Long acting (every 12 h ) . Acid unstable 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

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 milloion units I.M.)

Phenoxymethyl penicillin (P. V)

Less effective than penicillin G Acid stable Penicillinase sensitive Short acting Used in minor infections

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

Broad &Extended spectrum penicillins

Aminopenicillins Carboxypenicillins Ureidopenicillins

Aminopenicillins(Ampicillin &Amoxicillin)

Therapeutic uses 1)H.influenza 2)E.coli 3)Salmonella&Shigella infections only ampicillin 4)Prophylaxis of infective endocarditis 5) Urinary tract infections 6) Effective against penicillin –resistant

pneumococci

Carboxypenicillins(Ticarcillin)&Ureidopenicillin(Piperacillin)

Effective against pseudomonas aeruginosa & Enterobacter.

Penicillinase sensitive Can be given in combination with β-

lactamase inhibitors as clavulanic acid ,sulbactam, tazobactam.

Adverse effects

Hypersensitivity reactions High dose in renal failure ---seizure Naficillin (neutropenia) Oxacillin (hepatitis) Methicillin(nephritis) B.S.P.(pseudomembraneous colitis ) Secondary infections

Problems relating to use & misuse of penicillins

1- 90% of staphylococcal strains both in hospital or community are β-lactamase producers

2- New generations of microorganisms as H.influenzae , N.gonorrhoeae or pneumococci are resistant to penicillins

3- Broad spectrum penicillins eradicate normal flora causing superinfections

Cephalosporins

First-Generation Cefazolin, Cephalexin, cephradin. They are very effective against gram-

positive cocci They are given orally ,except cefazolin

given I.V.I ,or I.M.

Excretion

Mainly through kidney Probenecid block tubular secretion and

increase plasma level . They 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 Less active against gram-positive bacteria

than first generation They have extended gram –negative

effect No effect on P-aeruginosa or E-cocci.

Pharmacokinetics

Given orally or parenterally Can not cross B.B.B. Excreted through kidney Cefonicid is highly protein binding

Clinical uses

H-influenza infections Mixed anaerobic infections as peritonitis . Community acquired pneumonia

Third -Generations

Cefoperazone,Cefixime,Ceftriaxone They have extended gram- negative

spectrum. Have an effect on P-aeruginosa . No effect on E-coli.

Pharmacokinetics

Main route I.V.I. Cefixime can be given orally Ceftriaxone has a long half- life (7-8h).can

be given once every 24h. Cross B.B.B. Excreted through kidney .Ceftriaxone

through bile.

Clinical uses

Serious infections Cefixime ,first line in treatment of

gonorrhea. Meningitis P-aeruginosa infections.

Fourth -Generations

Cefepime More resistant to hydrolysis by β-

lactamase Active against P-aeruginosa & E-coli Clinical use as third generations.

Adverse Effects

Allergy Thrombophilibitis Interstitial nephritis and tubular necrosis

mainly with cephaloridine. Cephalosporins that contain a

methylthiotetrazole group as cefamandole ,cefperazone cause hypoprothrombinemia

And bleeding disorders . Vit.K twice weekly can prevent this . Methylthiotetrazole ring causes severe

disulfiram-like reaction. Superinfections. Diarrhea.

Carbapenems

Imipenem Bctericidal, inhibit bacterial cell wall

synthesis. Has a wide spectrum of activity Sensetive to 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 of renal dehydropeptidases,cilastatin for clinical use.

Penetrates body tissues and fluids including c.s.f.

Clinical uses

Mixed aerobic and anaerobic infections Carbapenem is the β lactam of choice for

treatment of enterobacter infections. Pseudomonal infections Intraabdominal 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 dose with imipenem in renal failure

cause seizure Patients allergic to penicillin 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

and adverse effects.

Macrolides(MACROCYCLIC LACTONE RING 14-16 ATOMS)

Erythromycin(14 atom lactone ring ) Is effective against Legionella,cornybacteria,gram-positive

cocci,chlamydia,helicobacter Less effective on gram-negative

organisms.

Mechanism of action

Inhibit protein synthesis via binding to 50 S ribosomal RNA subunit.

Bactericidal at high conc.and bacteriostatic at low conc.

Pharmacokinetics

Destroyed by stomach acid and must be administered with enteric coating .

Food interferes with absorption Half-life 1.5h Excreted mainly through bile,5%only in

urine. Cross placenta not B.B.B.

Clinical uses

Drug of choice of corynebacterial infections

Chlamydial infections Community acquired pneumonia Mycoplasma Legionella Penicillin allergic patients.

Adverse effects

Anorexia,nausea,vomiting,diarrhea. Liver toxicity especially with the estolate

coat produce acute cholestatic hepatitis Drug interactions as it is cytochrome p450

inhibitor. Hypersensitivity reactions .

Clarithromycin(14 atom lactone ring)

Acid stable Mechanism of action as erythromycin Spectrum as erythromycin but more active

against Mycobacterium avium complex.m.leprae.Toxoplasma gondii.

Half –life 6h. Metabolised in liver (active metabolites ).

Partially excreted in urine

Drug interactions similar to erythromycin Has a lower frequency of gastric upset And less frequent dosing More tolerable More expensive

Azithromycin(15 lactone ring )

Same mechanism of action Similar spectrum as clarithromycin,but

more active on H-influenza &chlamydia. Half-life 3 days . Rapidaly absorbed and well tolerated . Free of drug interactions Excreated in bile and urine

Clinical uses

Upper and lower respiratory tract infections

Skin infections Alternative to penicillin in allergic patients Urethritis or cervicitis mainly by chlamydial

infections .

Adverse effects

Gstric upset (less than erythromycin ) Allergic Superinfections Liver affection

Tetracyclines

Broad spectrum antibiotics Bacteriostatic,inhibits protein synthesis

reversibly by binding to 30 S ribosomal subunits .

Pharmacokinetics

Absorption: Poorly absorbed 30% as chlortetracycline Medialy absorbed 60-70% as

tetracycline ,oxytetracycline and demeclocycline

Highly absorbed 95-100% as doxycycline and minocycline.

Absorption is impaired by food except

Doxycycline and minocycline

Absorption of all preparations is impaired by divalent cations,milk and its products ,antacids and alkaline pH.

Plasma protein binding 40-80%. Minocycline reaches very high conc. In

tears and saliva, makes it useful in eradication of meningococcal carrier.

They cross placenta barrier .

Excreated through bile and urine Doxycycline is eliminated by nonrenal

route . According to half-life : Long acting; doxycycline &minocycline (16-18h once daily ). Intermediate (12h) demeclocycline

Short acting (6-8h)oxy,tetracyclines.

Clinical uses: Mycoplasma pneumonia Chlamydial infections Rickettsial infections Spirocates Brucellosis Anthrax

Clinical uses

Cholera Traveller,s diarrhea Helicobacter pylori Acne(minocycline&doxycycline) Bronchitis Protozoal infections Minocycline to eradicate meningococci carrier

Not used in:

Streptococcal & staphylococcal infections . Gonococcal infections Meningococcal infections Typhoid fever

Adverse effects

I.M.(pain & inflammation) I.V.(thrombophilbitis) Gastric upset (N.,V.,D.) Enterocolitis Super infections Damage growing bone &teeth.

Adverse effects

Yellowish brown discolorationof teeth &dental caries.

Liver toxicity Kidney toxicity (tubular necrosis). Photosensitization(demeclocycine) Vestibular reaction(vertigo,dizziness,) (Doxycycline &minocycline).

Contraindications

With milk or its products,or antacids. Pregnancy Children under 8 years.

Chloramphenicol

Broad spectrum antibiotics Bacteriostatic,inhibits protein synthesis by

binding to 50S ribosomal subunits. Rapidly &completely absorbed Rapidly distributed Cross placental barrier &B.B.B. Metabolised in liver Excreted mainly through urine Enzyme inhibitor(p450)

Clinical uses

Serious rickettsial infections In children whom tetracyclines are

contraindicated Meningitis In allergic patients to penicillin Topically in bacterial eye infections except

in chlamydial infections.

Adverse effects

Gastric upset (N.,V.,D.) Super infections Bone marrow depression Gray baby syndrome Hypersensitivity reactions Drug interactions

Aminoglycosides

Bactericidal antibiotics Inhibits protein synthesis by binding to

30S ribosomal subunits. Active against gram negative aerobic

organisms. Poorly absorbed orally Given parenterally (I.M,I.V.) Not freely cross BBB

Aminoglycosides

Excreted mainly unchanged in urine More active in alkaline medium Have common adverse effects : Ototoxicity Nephrotoxicity Neuromuscular blocking effect CNS (not common ).

Clinical uses

Streptomycin T.B. in combination with other

antituberculous drugs. Enterococcal endocarditis with penicillin. Severe brucellosis with tetracycline

Gentamicin

Severe infections caused by gram negative organisms as sepsis ,urinary tract infections & pneumonia caused by pseudomonas.

Topically for the treatment of infected burns,wounds,skin lesions,ocular, ear infections.

Tobramycin

More active against pseudomonas than gentamicin.

Ineffective against mycobacteria Less nephrotoxic and ototoxic than

gentamicin. Used in treatment of bacteremia,

osteomyelitis and pneumonia.

Amikacin

Has the broadest spectrum Used for serious nosocomial infections by

gram negative organisms. In T.B. as alternative to streptomycin Atypical mycobacterial infections

Neomycin

Highly nephrotoxic ,used only orally for gut sterilization before surgery or topically in skin infections,burn or eye infections.

Contraindications of aminoglycosides

Renal dysfunction Pregnancy Diminished hearing Myasthenia gravis Respiratory problems

Precautions with:

Loop diuretics Cephalosporins Monitor plasma level is useful. Neostigmine reverses respiratory

depression.

FLUOROQUINOLONES(Ciprofloxacin,ofloxacin,norfloxaci

Mechanism of action: Block bacterial DNA synthesis by inhibiting

bacterial topoisomerase11(DNA gyrase ) and topoisomerase 1V.

Antibacterial activity : Highly active against gram-negative aerobic

bacteria. Active against gram-positive bacteria. Mycoplasma,chlamydia,legionella,mycobacteria.

Pharmacokinetics

Well absorbed orally. Widely distributed in body fluids & tissues. Half-life(3-10h). Absorption is impaired by antacids. Concentrated mainly in

prostate,kidney,neutrophils ,macrophages. Excreted through kidney.

Clinical uses

U.T.I.caused by multidrug resistance organisms as pseudomonas.

Bacterial diarrhea. Soft tissues,bones,joints,intra-abdominal,

respiratory infections caused by multidrug resistance organisms.

Gonococcal infections. Legionellosis. Chlamydial urethritis or cervicitis T.B & atypical T.B.

Adverse effects

N.V.D. Headache,dizziness,insomnia Skin rash ,abnormal liver enzymes. QT prolongation Damage growing cartilage causing

arthropathy. Tendinitis in adults

Drug interactions & contraindications

With antacids Elevate serum levels of theophyline

increase the risk of seizure. Contraindicated in

children ,adolescents ,pregnancy ,lactation ,epileptic patients.

Miscellaneous Antibiotics

Polymyxins Active against gram-negative including

pseudomonas. Polymyxin B is only available. Bactericidal inhibits cell wall synthesis. Used only topically . Highly nephrotoxic.

Spectinomycin

Bactericidal,inhibits protein synthesis by binding to 30S ribosomal subunits.

Given I.M.I.as a single dose in treatment of gonorrhea.

Pain at the site of injection. Excreted through kidney . Nephrotoxicity is rare.

Clindamycin

Active against gram-positive and anaerobic bacteria.

Inhibits protein synthesis by binding to 50S ribosomal subunits.

Given orally or parenterally Widely distributed Cross placenta not BBB. Metabolised in liver giving active metabolites.

Excreted in bile & 10% in urine.

Clinical uses: Anaerobic infections minly in bones and joints . Conjunctivitis. In combination with aminoglycosides or cephalosporin is

used to treat penetrating wounds of the abdomen & the gut.

Female genital tract e.g. septic abortion ,pelvis abscess. Instead of erythromycin for prophylaxis of endocarditis. Adverse effects : Diarrhea,Pseudomembranous colitis,hepatotoxicity,bone

marrow suppression.

Other inhibitors to cell wall synthesis

Vancomycin Bactericidal Active only on gram +ve bacteria. Poorly absorbed orally Given by I.v.I Not freely cross BBB Excreted mainly through kidney

Clinical uses

Endocarditis mainly caused by methicillin –resistant staphylococci.

Alternative to penicillin in enterococcal endocarditis( in combination with gentamicin).

Meningitis( in combination with ceftriaxone or rifampin in highly resistant pneumococcus strains).

Orally in antibiotic associated enterocolitis

Adverse effects

Irritation at the site of injection Ototoxicity & nephrotoxicity . Red man or red neck syndrome. Gastric upset.

Bacitracin

Bactericidal No cross resistance between it and other antimicrobial

drugs. Active against gram +ve organisms Used only topically in skin ,eye ,nose infections . Highly nephrotoxic producing proteninuria, hematuria Hypersensitivity reactions As ointment in combination with polymyxin or neomycin

for mixed bacterial infections. As solution in saline for irrigation of joints, wounds or

pleural cavity.

Teicoplanin

Glycopeptide antibiotic Bactericidal Inhibits bacterial cell wall Active against gram positive organisms Given I.M. or I.V. Has a long half-life(45-70 h). Given once daily.

Cycloserine

Bactericidal Inhibits bacterial cell wall Broad spectrum antibiotic Effective on gram positive & gram negative organisms as well as

M.tuberculosis. Unstable in acid or neutral medium When given orally 70%- 90% of the drug is rapidly absorbed. Widely distributed in body tissues & fluids. Excreted as active form in urine Used in treatment of pulmonary & extrapulmonary tuberculosis Causes serious dose related C.N.S. toxicity ( headaches, tremors,

acute psychosis, convulsions) Contraindicated in epileptic & psychotic patients