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Beta lactam antibiotics
Beta lactam antibiotics
Classes
These antibiotics have beta lactam ring.
1. Penicillins
2. Cephalosporins
3. Carbapenem (e.g. imipenem)
4. Monobactam (e.g. aztreonam)
in addition β lactamase inhibitors (clavulanic acid, sulbactam )also have β lactam
structure but are not antibacterial.
1. The Penicillins
Chemistry
These are derivative of 6 amino penicillanic acid. 6APA nucleus is essential for biological
activity.
Penicillin G (benzyl penicillin) is the only natural penicillin used clinically.
Semisynthetic penicillins are prepared from penicillium chrysogenum.
Unit of penicillin
1 international unit = 0.6μg of penicillin G sodium.
1 million units= 0.6 gm
Semisynthetic penicillins are prescribed by weight.
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Penicillins
Mechanism of action
• They are bactericidal. They inhibit cell wall synthesis.
• The peptidoglycan is composed of glycan chains which are
linear strands of two alternating amino sugar (N
acetylglucosamine and N acetylmuramic acid) that are cross-
linked by peptide chains.
• Penicillins bind to PBPs which catalyse transpeptidase reaction.
The interaction between penicillin and PBP is covalent.
• They inhibit transpeptidation (final stage in the synthesis
of cell wall).
• The lysis of bacteria that usually follow the use of beta lactam
antibiotic is dependent on cell wall autolytic enzymes.
Autolysins or murein hydrolases usually work in the process of
cell division. Penicillins activate autolysins.
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Penicillins: Mechanism of bacterial resistance
Broad spectrum Good No Listeria monocytogenes, enterococci. Similar to penicillin G, destroyed by β lactamase but acid stable and
penicillins: Proteus mirabilis, Escherichia coli, more active against gram –ve bacteria
Ampicillin salmonella, shigella, H. influenzae,
and Helicobacter pylori.
Amoxicillin Excellent Similar to ampicillin but greater absorption, gives high blood
concentrations, most effective of all β lactams for penicillin resistant
strep pneumoniae.
Antipseudomonal Above plus. Pseudomonas Inferior to ampicillin, against gram positive cocci and L.
penicillins: Poor, not Enterobacter species, Proteus (indole monocytogenes
i. Carboxypenicillins: given orally No positive)
Ticarcillin
Ureidopenicillins: Poor (not No Pseudomonas species, Enterobacter Resembles ticarcillin against gram –ve aerobes
Extended spectrum given species, mainly Klebsiella and Piperacillin effective against gram positive cocci and listeria
penicillins: orally) bacteroids. monocytogenes (like ampicillin)
Piperacillin
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ADME of Penicllin G
Absorption
Benzylpenicillin G- Only 1/3rd abs.from duodenum. Destroyed by gastric juice,
Absorption better in achlorhydriac.
Distribution
Widely distributed
65% is reversibly protein bound.
Therapeutic conc in most tissues except prostatic fluid.
Penetration in CSF more if meninges are inflammed (normally 1% but in meningitis 5%-
adequate for susceptible organisms). Fever increases penetration.
Excretion
Through kidneys. 10% by GF and 90% by tubular secretion. Probenecid decreases
excretion.
T½ -30 minutes.
Clearance low in neonates and infants and in renal failure.
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Uses of Penicillin G
Drug of choice (DOC) for:
• N. meningitidis (meningococcal meningitis, septicemia).
• Bacillus anthracis- anthrax
• Clostridium perfringens (gas gangrene)
• C. diphtheriae (diphtheria)
• T. pallidum (syphilis)
• Leptospira (leptospirosis)
• Actinomyces israelii (actinomycosis).
• Borrelia burgdorferi (lyme disease) in children.
• Prophylactic uses of the penicillin:
– Recurrences of rheumatic fever - 1.2 million units of benzathine
penicillin G once a month.
– Syphilis - prophylaxis for a contact with syphilis
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II. The penicillinase resistant penicillins-
antistaphylococcal penicillins.
Agents used for staphylococccal infection. No of isolates have developed
resistance- MRS. Vancomycin is drug of choice for MRS.
Resistance to methicillin is due to high molecular PBP which has very
little affinity to beta lactam antibiotics.
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3. Aminopenicillins- broad spectrum penicillins
III. Aminopenicillins
• Examples: ampicillin, amoxicillin and their congeners.
• Destroyed by beta lactamase (produced by both gram-positive and
negative organisms)
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Ampicillin and Amoxicillin
Ampicillin
Well absorbed orally. Probenecid increases plasma conc. Appears in bile,
undergoes enterohepatic circulation - excreted in feces and urine . T ½-
80 minutes. Given 4 times daily.
Adverse reactions of ampicillin
• Diarrhea.
• Macular rash- in patients with AIDS, EB virus infection (infectious
mononucleosis)
or lymphatic leukemia, and also in patients with renal failure, or taking
allopurinol.
• Pseudomembranous enterocolitis (clostridium difficile diarrhea), secondary
infection with candida
Amoxicillin
• Antimicrobial spectrum identical to ampicillin with the exception that
amoxicillin appears to be less effective than ampicillin for shigellosis.
• Plasma conc. are 2-2.5 times more and also lasts twice as long than
ampicillin when given in the same dose, half life is same. This is
because it is more rapidly and completely absorbed from the
gastrointestinal tract than ampicillin. Because of its more complete
absorption, the incidence of diarrhea is also less. It is given three 11
times daily.
Therapeutic indications broad spectrum
(amino)penicillins
1. Upper respiratory tract infection: Effective for sinusitis otitis media, acute
exacerbation of chronic bronchitis and epiglotitis. Amoxicillin is more
effective against Strep. pneumoniae.
Piperacillin
• More active than ticarcillin for Pseudomonas aeruginosa.
• Effective for Klebsiella, Enterobacteriaceae and bacteroides
spp.
• High biliary concentrations are achieved.
• Available in combination with tazobactam.
•
Therapeutic uses
• Serious infections caused by gram negative bacteria-
bacteremia, pneumonias, infections following burns, urinary tract
infections due to organisms resistant to penicillin G and ampicillin
give with aminoglycosides.
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• For severe infections in neutropenic patients.
Untoward reactions to penicillins
• Hypersensitivity reactions: most common adverse reactions with
penicillins. Penicillins are cross sensitizing and cross reacting.
– Type I :Anaphylactic shock - most serious, urticaria, pruritus.
– Type II: hemolytic anemia, neutropenia (nafcillin), thrombocytopenia.
– Type III: Serum sickness (rare- urticaria, fever joint swelling, angioneurotic
edema, pruritus, bronchospasm- 7-12 days after), interstitial nephritis
(methicillin).
– Type IV: contact dermatitis.
Cross allergenicity: Complete between penicillins, Can occur but rare
between cephalosporins and penicillins, Can occur with carbapenems
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Beta lactamase inhibitors
Examples
1. Clavulanic acid
– Amoxicillin + clavulanic acid= Augmentin, or Co-amoxiclav- an oral
preparation. Clavulanic acid may cause cholestatic jaundice. Used for
refractory otitis media, sinusitis, bite wound infections.
2. Sulbactam
– Sulbactam + ampicillin = unasyn (parenteral), used for mixed
intra-abdominal and pelvic infections. Also used for CAP in
combination with macrolide.
3. Tazobactam
– Tazobactam+ piperacillin=zosyn (parenteral)- uses similar to timentin.
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2. Cephalosporins and cephamycins
Mechanism of action
• Like penicillin, these are bactericidal drugs. They all inhibit cell wall
synthesis in the susceptible organisms.
• These are more stable than penicillins for many bacterial beta
lactamase – hence they have broad spectrum.
• These are not good for enterococci, E. faecium, MRSA, listeria
monocytogenes.
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General features
ADME
A. Some (cephalexin, cephradine, cefaclor and cefuroxime axetil
and cefixime are absorbed after oral administration. Others can
be administered either IM or IV.
Spectrum:
• Gram –ve organisms, Klebsiella (resistant to 1st generation), H. influenzae
(including β lactamase producers).
• Not against serratia, enterococci, pseudo.
• Cefoxitin, cefotetan- cephamycin- effective against anaerobes (B. fragilis).
Uses:
Oral:
• Beta lactamase producing H. influenzae, M. Catarrhalis producing upper respiratory
tract (sinusitis, otitis) and lower respiratory tract infections.
• Alternative for UTI
Parenteral:
• Cefoxitin: - for prophylaxis in GIT surgery, diabetic foot, mixed anaerobic
infections- peritonitis, diverticulitis 21
• Cefuroxime-CAP (community acquired pneumonia)
3rd generation
More for gram –ve, effective for serratia, citrobacter, destroyed by beta lactamase
from enterobacter.
Oral- cefixime
Parenteral- ceftriaxone, cefotaxime, ceftazidime, cefoperazone, ceftizoxime ( for B.fragilis ).
• Cefoperazone and ceftazidime are good for pseudomonas.
• Except for oral and cefoperazone all achieve conc. in CNS for –ve rods except
pseudomonas.
• Ceftriaxone has long half life- 8 hours, may be given once daily.
• Cefoperazone and ceftriaxone are excreted in bile, others are excreted in urine by GF
and TS.
Clinical uses
Oral - Cefixime- respiratory tract infection , urinary tract infection.
Parenteral:
• DOC for serious infections (nosocomial infections (entero, kleb, serratia, etc)- resistant
to penicillin, ampicillin, aminoglycoside and 1st generation cephalosporins.
• Gonorrhoea- ceftriaxone or cefixime is the present day DOC (single adm).
• Meningitis
– Ceftriaxone and cefotaxime are DOC for meningitis due to pneumo, meningo, H.
influenzae and enteric gram –ve rods.
– Ceftazidime with aminoglycoside- used for pseudomonal meningitis.
– For penicillin resistant strains of pneumococci- may add rifampin or vancomycin.
• Empirical therapy of sepsis of unknown cause–use with aminoglycoside.
• Typhoid- cefoperazone, ceftriaxone.
• Lyme’s disease
• Ceftazidime alone for pseudomonas infection in neutropenic patients. 22
• CAP
4th generation cephalosporins
Cefepime
• More resistant to hydrolysis by beta lactamases (produced by
enterobacter, and also organisms which destroy 3rd
generation cephalosporins).
3. GIT disturbances.
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3. Carbapenem derivatives
Parenteral β lactam antibiotics, β lactamase resistant.
Have broadest spectrum of activity. Examples: imipenem, meropenem,
ertapenem
i. Imipenem with cilastatin
Marketed as primaxin containing equal amount of imipenem and cilastatin
(an inhibitor of renal dipeptidase (dehydropeptidase) which hydrolyses
imipenem to a nephrotoxic metabolite.
Mechanism of action:
It binds to penicillin binding proteins and disrupts bacterial cell wall synthesis and
causes death of susceptible microorganisms. It is very resistant to hydrolysis by
most beta lactamases.
Antimicrobial activity
• Broad spectrum of activity- effective against –ve and + aerobic and
anaerobic microorganisms, e.g., streptococci ( including penicillin resistant S
pneumoniae), enterococci , Enterobacteriaceae, Pseudomonas, Acinetobacter,
anaerobes including B. fragilis.
• It is not effective against Enterococcus faecium, MRSA and Clostridium.
difficile
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Carbapenem derivatives. Imipenem contd
ADME
Not absorbed orally, given IV, penetrates body tissues and fluids,
including CSF. T ½ of 1 hour. 70% excreted in urine – reduce dose in
renal insufficiency.
Therapeutic uses:
• Organisms resistant to other drugs: for UTI, lower RTI,
nosocomial pneumonia, intraabdominal and pelvic infection,
septicemia, skin, soft tissue, bone and joint infection
• Penicillin resistant pneumococci
• DOC for mixed infections caused by cephalosporin-resistant
nosocomial organisms such as Citrobacter and Enterobacter
spp.
iii. Ertapenem
Less active than other two.
Not degraded by dehydropeptidase.
Half life is longer -4 hours- given once or twice daily.
Can be given by IM route.
Uses: CAP, intraabdominal sepsis.
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4. Monobactam: aztreonam
Aztreonam
• Monocyclic beta lactam-active against –ve rods including pseudomonas and
serratia.
Mechanism of action: It interacts with PBP (PBP target 3 site is preferred) and induces
formation of long filamentous bacteria.
Antibacterial activity
• Resembles that of an aminoglycoside- highly effective against β lactamase
producing G-ve rods :enterobacteriacea, Kleb, pseudo, serratia. H. influenzae;
• G-ve cocci (N. meningitidis, N. gonorrhae)
• Gram-positive bacteria and anaerobic organisms are resistant.
ADME
Adm.IM or IV, exc.unchanged in urine, T ½ is inc. in renal failure.
Adverse reactions
• Patients allergic to beta lactam antibiotics don't show cross hypersensitivity.
• Nausea, diarrhea, urticaria, rash, hepatitis (increase in transaminases), and blood
disorders (thrombocytopenia, neutropenia) may occur.
Therapeutic uses 28
• Used as an alternative to aminoglycosides, in septicemia, or complicated UTI