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Beta lactam antibiotics

Dr. Suman Jain

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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

1. Structural differences in PBP due to mutation: e.g.


Strep. Pneumoniae for penicillin G (called penicillin
non-sensitive S. pneumoniae PNSP)
Methicillin resistance in Staph. aureus.

2. Changes in porin structure- inability to penetrate, e.g


E. coli, pseudomonas.

3. Production of beta lactamase (penicillinase) most


important mechanism for development of resistance.
e.g., Staph aureus, H. influenzae, bacteroids,
enteric G-ve organisms (E. Coli, Pseudomonas).

4. Presence of efflux pump: gram negative organisms-


salmonella. 5
Abs oral Resis.to Useful antimicrobial Comments
Name administrati Penicillinase spectrum
on
Benzyl penicillin G Variable No Streptococcus species, Neisseria High activity against gram positive bacteria, low activity against
meningitidis, many anaerobes, gram –ve bacteria, acid labile, destroyed by β lactamase.
Penicillin V Good No spirochetes, actinomyces…

Antistaphylococcal Staphylococci aureus


penicillins:

Isoxzolyl penicillins: Good Yes Highly protein bound >95%


Oxacillin
Cloxacillin
Dicloxacillin
Flucloxacillin

Nafcillin Variable Yes Similar to isoxazolyl penicillin; resistant to staph.β lactamase

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.

Penicillin V- more stable in acidic medium and better absorbed orally.

Benzylpenicillin G is administered IV.


Penicillin G procaine, and Penicillin G benzathine (repository preparations- slowly
release penicillin)- are adm.IM.

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.

i. Methicillin: may produce interstitial nephritis- no longer used.

ii. Isoxazolyl penicillins - Dicloxacillin is the most active of all these.


30-80% absorption from GIT.
Adverse reactions: with oxacillin- hepatitis.
iii. Nafcillin. CSF concentration is adequate to treat Staph. meningitis.
Adverse reactions: hepatitis, neutropenia
Uses:
Βeta-lactamase producing staph, also for penicillin susceptible strep

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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)

Sensitive organisms are:


• The Meningococci, Pneumococci, Gonococci and Listeria monocytogenes.
• Gram –ve bacilli- H. influenzae, enterobacteriaceae (E. coli, Proteus
mirabilis, salmonella and Shigella).
• Gram –ve cocci- Moraxella. catarrhalis
• Enterococci – synergism with aminoglycoside
• Concurrent administration of a β lactamase inhibitor such as clavulanate or
sulbactam markedly expands the spectrum of activity of these drugs.

Resistant organisms- Enterobacter species, less active against B. fragilis

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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.

2. Urinary tract infections: Most uncomplicated UTIs.

3. Meningitis: Acute bacterial meningitis in children caused by H.


influenzae, Strep. pneumoniae or Neisseria meningitides. Ampicillin-
excellent activity against L. monocytogenes- common in
immunocompromised patients. of suspected bacterial meningitis.

4. Salmonella infections:A fluoroquinolone or ceftriaxone - drug of choice, but


co-trimoxazole or high doses of ampicillin also effective.
For carrier without gall bladder disease - ampicillin, cotrimoxazole or
ciprofloxacin are effective.

5. Bacillary dysentery: Infection due to Shigella responds to ampicillin, but


quinolones are preferred.

6. Gonorrhea: If organisms are sensitive then use ampicillin or amoxicillin

7. Other infections: Ampicillin plus aminoglycoside or one of the newer


cephalosporins –to treat sepsis caused by gram-negative bacteria. Also for
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subacute bacterial endocarditis- ampicillin + gentamicin.
IV. Antipseudomonal penicillins
Carboxypenicillin: example: ticarcillin disodium
• Active against pseudomonas aeruginosa and certain indole
positive Proteus, enterobacter species resistant to ampicillin.
Bacteroides fragilis is susceptible in high concentration.

• Currently preferred drug for Pseudomonas but is inferior to


piperacillin for the treatment of serious pseudomonal infection.

• Has synergistic activity with aminoglycosides.

• Available in combination with clavulanic acid.

• Be careful in patients with cardiac and renal function


impairment- sodium load due to use of Na+ salts.

• Therapeutic indications: Serious infections caused by gram-


negative bacteria in patients with impaired immune system,
aminoglycoside is usually added.
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V. Extended spectrum penicillins
Ureidopenicillins: Example: piperacillin.
Active against Klebsiella in addition to the organisms inhibited by
ticarcillin.

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

• Injection: Pain, and sterile inflammatory reaction, phlebitis or


thrombophlebitis.
• Oral administration may cause nausea, vomiting and diarrhea- esp with
ampicillin.
• Intrathecal injection of penicillin G – arachnoiditis, encephalopathy.
• Large doses in patients with renal insufficiency – convulsions.
• Injection of large doses of procaine penicillin G procaine –may produce
procaine toxicity- dizziness, tinnitus, headache, hallucination and
sometimes seizures.
• Jarisch Herxheimer reaction- in syphilitic patients 15
Βeta-lactamase inhibitors
• Resemble β lactam molecules

• Themselves are weak antibacterial substances.

• They bind irreversibly to β lactamase and inhibit them (


suicide inhibitors)- are potent inhibitors of many but not
all β lactamase and can protect hydrolyzable penicillins
from inactivation by these enzymes.

• Are particularly effective against plasmid encoded


transferable element β lactamase such as staph, H.
influenzae, bacteroids, N. gonococci, salmonella,
shigella, E.coli, K.pneumoniae, pseudomoas.

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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.

– Ticarcillin + clavulanic acid = timentin (parenteral)- used for mixed


nosocomial infection along with an aminoglycoside.

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

These are 7 amino cephalosporanic acid derivatives. In cephamycin


there is methoxy group at 7th position in beta lactam ring. Cefoxitin
and Cefotetan are 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.

Mechanisms of bacterial resistance to cephalosporins


• Beta lactamase that can hydrolyze the beta lactam ring. Most
prevalent mechanism of resistance is destruction of cephaloporins
by beta lactamases.
• Decreased permeability
• Alteration in penicillin binding proteins (PBPs).

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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.

D Cefuroxime (2nd gen), cefotaxime, ceftriaxone and ceftizoxime


(3rd gene) penetrate into cerebrospinal fluid and are useful in
meningitis.
All cephalosporins cross placenta.
Cefoperazone is found in high concentration in bile.

ME Excreted through kidney, dosage should be adjusted in


patients with renal insufficiency, probenecid slows tubular
secretion of most.
Cefoperazone- exc. predominantly in bile.
Some are deacetylated, metabolites also possess antimicrobial
activity and are excreted in urine. 19
Classification: By generation is based on general
features of antimicrobial activity
1st generation
Oral: cephalexin
Injection: Cefazolin IV
Spectrum:
• Good for gram +ve cocci (strep, staph, pneum) not for enterococci, not for MRSA.
• Good for gram –ve organisms like E. coli, Kleb, proteus mirabilis but poor for others
(pseudo, proteus indole +ve, enterobacter,serratia, citrobacter and acinetobacter).
• Anaerobic cocci (peptococcus, peptostreptococcus) but not for B. fragilis.
Uses:
Oral
• UTI
• Minor staph. lesion
• Minor polymicrobial infections (strep, staph) e.g cellulites , skin and soft tissue abscess.
• Strep pharyngitis.
• Not for serious infections- not for empirical treatment of otitis media or sinusitis.
Parenteral
Cefazolin
• DOC for surgical prophylaxis- single injection just before surgery (procedure where skin
flora are likely pathogen. For colorectal surgery 2nd generation cefoxitin is preferred for
prophylaxis.
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2nd generation
(More for gram –ve and less for gram +)
Oral: Cefaclor, Cefuroxime axetil
Parenteral
• Cefuroxime- Crosses BBB.
• Cefoxitin, cefotetan (anaerobic organisms)

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).

• Active against pseudo, enterobacteriaceae, Staph. aureus,


Strep. pneumoniae, H. influenzae, Neisseria.

• Good for penicillin resistant Strep. and is useful for


enterobacter.

• Penetrates BBB, excreted in urine, half life is 2 hours.


Uses
• Nosocomial infection with organisms producing extended
spectrum beta lactamase, such as enterobacter, citrobacter,
serratia)- susceptible
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Adverse effects
1. Hypersensitivity reactions:
– Type I: less frequent, cross reactive with penicillin (5-10%). Patient with a
H/O anaphylaxis to penicillins should not receive cephalosporins
– Type II: thrombocytopenia, hemolytic anemia, neutropenia, interstitial nephritis
or abnormal liver functions- reversible.
– Type III: serum sickness- cefaclor.

2. Nephrotoxicity with cephalothin.

3. GIT disturbances.

4. Biliary pseudolithiasis (ceftriaxone)

5. Hypoprothombinemia, bleeding tendency (responds to vitamin K),


disulfiram like reaction with alcohol- cefoperazone, cefotetan.

6. Superinfection with 2nd and 3rd generation – fungi and staph.

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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.

Adverse reactions of carbapenems:


• Nausea, vomiting and diarrhea, skin rashes.
• Reaction at infusion sites
• Seizures with high concentration in patients with CNS disease or
renal insufficiency. Seizures are less with meropenem and ertapenem.
• Hypersensitivity reactions may occur- cross sensitivity with
penicillin exists.
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Carbapenem derivatives contd
ii. Meropenem
• Does not require co administration of cilastatin, as it is not
sensitive to renal dehydropeptidase.
• Effective against imipenem resistant Pseudomonas aeruginosa.
• It crosses BBB - used in meningitis. Uses similar to imipenem- IV
every 6 hrs.
• Incidence of seizures is less than that with imipenem.
• No nausea

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