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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