Transcript β-Lactam Antibiotics

β-Lactam Antibiotics
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1. PENICILLINS
2.Cephalosporins
3.Carbapenems ( Imipenems )
4. Monobactams ( Aztreonam)
Penicillins
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Classification
Narrow spectrum penicillins
Antistaphylococcal penicillins
Broad spectrum penicillins
Extended –spectrum penicillins (
antipseudomonal penicillins).
Mechanism of action
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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
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Absorption
Depending on acid stability
Absorption of most oral penicillins is
impaired by food except amoxicillin .
Metabolism & Excretion
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Not metabolised
Excreted unchanged in urine
Probenecid blocks their secretion
Nafcillin is mainly cleared by biliary route
Oxacillin by both kidney & biliary route.
Distribution
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Relatively insoluble in lipid
Poor penetration into cells and BBB
Inflammation permits entrance into CSF.
Proteins binding vary from 20%-90%
Narrow spectrum penicillins
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Penicillin G
Short duration
Acid unstable
Penicillinase sensitive
Used in enterococcal endocarditis usually
with aminoglycosides
To prevent gonorrheal opthalmia in new
born .
Procaine penicillin
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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
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Long acting (every 3-4 weeks )
Acid unstable
Penicillinase sensitive
Treatment of β-hemolytic streptococcal
pharyngitis.
Used as prophylaxis against reinfection with βhemolytic 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)
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Less effective than penicillin G
Acid stable
Penicillinase sensitive
Short acting
Used in minor infections
Penicillinase resistant to
staphylococcal β-lactamase producer
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Methicillin acid unstable
Nafcillin its absorption is erratic
Oxacillin, Cloxacillin,Dicloxacillin (acid
stable ).
Used in minor & severe Stap. infections
Broad &Extended spectrum
penicillins
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Aminopenicillins
Carboxypenicillins
Ureidopenicillins
Aminopenicillins(Ampicillin
&Amoxicillin)
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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)&Ur
eidopenicillin(Piperacillin)
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Effective against pseudomonas
aeruginosa & Enterobacter.
Penicillinase sensitive
Can be given in combination with βlactamase inhibitors as clavulanic acid
,sulbactam, tazobactam.
Adverse effects
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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
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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
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First-Generation
Cefazolin, Cephalexin, cephradin.
They are very effective against grampositive cocci
They are given orally ,except cefazolin
given I.V.I ,or I.M.
Excretion
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Mainly through kidney
Probenecid block tubular secretion and
increase plasma level .
They can not cross B.B.B.
Clinical uses
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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
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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
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Given orally or parenterally
Can not cross B.B.B.
Excreted through kidney
Cefonicid is highly protein binding
Clinical uses
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H-influenza infections
Mixed anaerobic infections as peritonitis .
Community acquired pneumonia
Third -Generations
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Cefoperazone,Cefixime,Ceftriaxone
They have extended gram- negative
spectrum.
Have an effect on P-aeruginosa .
No effect on E-coli.
Pharmacokinetics
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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
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Serious infections
Cefixime ,first line in treatment of
gonorrhea.
Meningitis
P-aeruginosa infections.
Fourth -Generations
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Cefepime
More resistant to hydrolysis by βlactamase
Active against P-aeruginosa & E-coli
Clinical use as third generations.
Adverse Effects
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Allergy
Thrombophilibitis
Interstitial nephritis and tubular necrosis
mainly with cephaloridine.
Cephalosporins that contain a
methylthiotetrazole group as cefamandole
,cefperazone cause hypoprothrombinemia
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And bleeding disorders .
Vit.K twice weekly can prevent this .
Methylthiotetrazole ring causes severe
disulfiram-like reaction.
Superinfections.
Diarrhea.
Carbapenems
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Imipenem
Bctericidal, inhibit bacterial cell wall
synthesis.
Has a wide spectrum of activity
Sensetive to metallo-β lactamase .
Pharmacokinetics
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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
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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
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Similar to imipenem but it is highly active
against gram-negative aerobes .
Not degraded by renal dehydropeptidase
Adverse effects
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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
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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)
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Erythromycin(14 atom lactone ring )
Is effective against
Legionella,cornybacteria,gram-positive
cocci,chlamydia,helicobacter
Less effective on gram-negative
organisms.
Mechanism of action
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Inhibit protein synthesis via binding to 50
S ribosomal RNA subunit.
Bactericidal at high conc.and
bacteriostatic at low conc.
Pharmacokinetics
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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
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Drug of choice of corynebacterial
infections
Chlamydial infections
Community acquired pneumonia
Mycoplasma
Legionella
Penicillin allergic patients.
Adverse effects
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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)
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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
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Drug interactions similar to erythromycin
Has a lower frequency of gastric upset
And less frequent dosing
More tolerable
More expensive
Azithromycin(15 lactone ring )
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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
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Upper and lower respiratory tract
infections
Skin infections
Alternative to penicillin in allergic patients
Urethritis or cervicitis mainly by chlamydial
infections .
Adverse effects
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Gstric upset (less than erythromycin )
Allergic
Superinfections
Liver affection
Tetracyclines
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Broad spectrum antibiotics
Bacteriostatic,inhibits protein synthesis
reversibly by binding to 30 S ribosomal
subunits .
Pharmacokinetics
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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
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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 .
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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 (68h)oxy,tetracyclines.
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Clinical uses:
Mycoplasma pneumonia
Chlamydial infections
Rickettsial infections
Spirocates
Brucellosis
Anthrax
Clinical uses
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Cholera
Traveller,s diarrhea
Helicobacter pylori
Acne(minocycline&doxycycline)
Bronchitis
Protozoal infections
Minocycline to eradicate meningococci carrier
Not used in:
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Streptococcal & staphylococcal infections .
Gonococcal infections
Meningococcal infections
Typhoid fever
Adverse effects
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I.M.(pain & inflammation)
I.V.(thrombophilbitis)
Gastric upset (N.,V.,D.)
Enterocolitis
Super infections
Damage growing bone &teeth.
Adverse effects
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Yellowish brown discolorationof teeth
&dental caries.
Liver toxicity
Kidney toxicity (tubular necrosis).
Photosensitization(demeclocycine)
Vestibular reaction(vertigo,dizziness,)
(Doxycycline &minocycline).
Contraindications
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With milk or its products,or antacids.
Pregnancy
Children under 8 years.
Chloramphenicol
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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
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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
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Gastric upset (N.,V.,D.)
Super infections
Bone marrow depression
Gray baby syndrome
Hypersensitivity reactions
Drug interactions
Aminoglycosides
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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
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Excreted mainly unchanged in urine
More active in alkaline medium
Have common adverse effects :
Ototoxicity
Nephrotoxicity
Neuromuscular blocking effect
CNS (not common ).
Clinical uses
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Streptomycin
T.B. in combination with other
antituberculous drugs.
Enterococcal endocarditis with penicillin.
Severe brucellosis with tetracycline
Gentamicin
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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
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More active against pseudomonas than
gentamicin.
Ineffective against mycobacteria
Less nephrotoxic and ototoxic than
gentamicin.
Used in treatment of bacteremia,
osteomyelitis and pneumonia.
Amikacin
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Has the broadest spectrum
Used for serious nosocomial infections by
gram negative organisms.
In T.B. as alternative to streptomycin
Atypical mycobacterial infections
Neomycin
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Highly nephrotoxic ,used only orally for gut
sterilization before surgery or topically in
skin infections,burn or eye infections.
Contraindications of
aminoglycosides
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Renal dysfunction
Pregnancy
Diminished hearing
Myasthenia gravis
Respiratory problems
Precautions with:
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Loop diuretics
Cephalosporins
Monitor plasma level is useful.
Neostigmine reverses respiratory
depression.
FLUOROQUINOLONES
(Ciprofloxacin,ofloxacin,norfloxaci
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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
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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
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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
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N.V.D.
Headache,dizziness,insomnia
Skin rash ,abnormal liver enzymes.
QT prolongation
Damage growing cartilage causing
arthropathy.
Tendinitis in adults
Drug interactions &
contraindications
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With antacids
Elevate serum levels of theophyline
increase the risk of seizure.
Contraindicated in children ,adolescents
,pregnancy ,lactation ,epileptic patients.
Miscellaneous Antibiotics
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Polymyxins
Active against gram-negative including
pseudomonas.
Polymyxin B is only available.
Bactericidal inhibits cell wall synthesis.
Used only topically .
Highly nephrotoxic.
Spectinomycin
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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
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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.
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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 :
Other inhibitors to cell wall
synthesis
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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
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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
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Irritation at the site of injection
Ototoxicity & nephrotoxicity .
Red man or red neck syndrome.
Gastric upset.
Bacitracin
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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
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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
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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