Beta lactam antibiotics are four major bactericidal classes of drugs:
Penicillin
Cephalosporins
Monobactams
Carbapenems
These narrow spectrum antibiotics which are chemically altered to increase their spectrum, thus giving birth to extended spectrum antibiotics
They should be appropriately used with respect to their spectrum to ensure proper treatment. These antibiotics should be used cautiously to avoid growing concern of ‘antibiotic resistance’
5. HISTORY
Sir Alexander Fleming
• Discovered penicillin
accidentally while studying
properties of Staphylococcus
• Named it Penicillin coz the
mould belonged to the genus
Penicillium
• Florey , Chain and Abraham developed a systematic
therapeutic agent from penicillin extract
• Mass production of new drug in World War II;
saved many lives.
• Penicillin is the first antibiotic to be used clinically.
• Fleming won the Nobel Prize in 1945
WORLD WAR II
Penicillium notatum
Penicillium chrysogenum
SERENDIPITY !!
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6. STRUCTURE
Side chains can be split off by amidase
Other side chains can be attached
Beta Lactamase breakdown Beta lactam ring and render the penicillin ineffective
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7. MECHANISM OF ACTION
Courtesy : Goodman & Gilman’s The Pharmacological Basis of Therapeutics 13th Edition
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8. MECHANISM OF ACTION
Cell wall
Peptidoglycan
layer 50-100
molecules thick
Cell wall
Peptidoglycan
layer 1-2
molecules
thick
Only
peptidoglycan
layer
Alternate
lipoprotein
and
peptidoglycan
layer
Extensively
crosslinked
Little
crosslinking
GRAM POSITIVE GRAM NEGATIVE
Courtesy : Goodman & Gilman’s The Pharmacological Basis of Therapeutics 13th Edition
BETA
LACTAMASES
PORIN
CHANNELS
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9. Alterations in PBPs
Inability of the agent to penetrate to its site of action
Active efflux pumps - removing the antibiotic from its site of action
Producing β-lactamases
MECHANISM OF RESISTANCE
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10. Acid labile – orally inactive
Rapid and complete absorption – i.m.
Shorter t1/2 – 30 min
Rapid excretion by glomerular filtration and tubular secretion
Narrow spectrum
PHARMACOKINETIC PROPERTIES
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11. LIMITATIONS OF PENICILLIN G
Poor oral efficacy
Short duration of action
Susceptibility to penicillinase
Narrow spectrum
Hypersensitivity reactions
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12. Acid-resistant alternative to Penicillin G
Penicillin G (PnG) = Penicillin V similar spectrum
Penicillin V is Acid resistant Given orally
Plasma t1/2 : 30-60 min
Dose 250-500 mg 6 hrly
PHENOXYMETHYL PENICILLIN ( PENICILLIN V)
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13. LIMITATIONS OF PENICILLIN G
Poor oral efficacy
Short duration of action
Susceptibility to penicillinase
Narrow spectrum
Hypersensitivity reactions
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14. BENZATHINE PENICILLIN PROCAINE PENICILLIN
0.6 – 2.4 MU im
2-4 weeks
Prophylaxis upto 4 weeks
Dry powder in vial
0.5– 1 MU im
12 – 24 hrly
Fortified: 3 Lac U procaine penicillin
plus 1 Lac U sodium penicillin G for
rapid action
Dry powder in vial
BENZATHINE PENICILLIN PROCAINE PENICILLIN
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15. LIMITATIONS OF PENICILLIN G
Poor oral efficacy
Short duration of action
Susceptibility to penicillinase
Narrow spectrum
Hypersensitivity reactions
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16. INDICATION/MICRO
ORGANISM
DURATION REMARKS
Pneumococcal infection **
• Pneumococcal pneumonia
5days (2-3
days after
fever
subsides)
PnG
• Pneumococcal meningitis 10-14 days
Treat with vancomycin and third generation
cephalosporin until it is proved pneumococcus is
penicillin sensitive.
PnG 24 million units daily divided doses
Dexamethasone – improves treatment outcomes
USES
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17. INDICATION/MICRO
ORGANISM
DURATION
REMARKS
Beta Hemolytic Streptococci
infection **
• Streptococcal pyogenes –
pharyngitis , scarlet fever
10 days
Penicillin V 500mg twice daily
Reduces the risk of subsequent acute rheumatic
fever
Prophylaxis
• Toxic shock and necrotising
fascitis
-
PnG plus Clindamycin to decrease toxin
production
• Pneumonia, meningitis,
arthritis, endocarditis
2-4 weeks PnG 12-24 million units
Streptococci viridans** 4-6 weeks
Endocarditis : 20 million units iv PnG with
Gentamicin
Aminoglycoside sensitive
24 million units PnG with 12g ampicillin daily
with low dose Gentamicin
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18. INDICATION/MICRO
ORGANISM
DURATION REMARKS
Anaerobic infection
Pulmonary and periodontal
infections
7-10 days
Clindamycin preferred
Mild : Penicillin V 250 mg four times daily
Severe : PnG 20 million units iv
Meningococcal infection** -
PnG DOC
But it does not eliminate carrier state
Not given prophylactically
Neisseria gonorrhoea -
PnG i.m. 2 divided doses, 2 different sites,
after 1g of probenecid orally.
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19. INDICATION/MICRO
ORGANISM
DURATION REMARKS
Syphilis
Primary, Secondary and Latent 1-3 weeks
PnG 2.4 million units
Prophylaxis
Neurosyphilis or cardiovascular
syphilis
10-14 days
18-24 million units PnG
Safe in pregnant patients
Secondary syphilis: Jarisch Herxheimer
reaction
Actinomycosis 6 weeks PnG 18-24 million units iv per day
Anthrax** 2 weeks 24 million units per day
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20. INDICATION/MICRO
ORGANISM
DURATION REMARKS
Clostridial infections
Gas gangrene 1-3 weeks
PnG or Benzathine Penicillin
2.4 million units
Tetanus
10-14 days
18-24 million units PnG
Safe in pregnant patients
Secondary syphilis: Jarisch
Herxheimer reaction
Diphtheria 12 days
Specific antitoxin is the only
antidote
PnG eliminates the carrier
state
2.3 million units per day
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21. NARROW
SPECTRUM
GRAM POSITIVE GRAM NEGATIVE RESISTANT
Streptococci
Neisseria gonorrheae
Neisseria meningitis
Streptococci viridans ,
group D, Enterococci
S. aureus and S.
epidermidis
Bacillus anthracis Pneumococci
Corneybacterium
diphtheriae
Bacteroides fragilis
All Clostridia Amebae
Listeria Plasmodia
Spirochetes Rickettssiae
Actinomycetes israeli Fungi
Viruses
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24. Poor oral efficacy
Short duration of action
Susceptibility to penicillinase
Narrow spectrum
Hypersensitivity reactions
WHY SEMISYNTHETIC?
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25. Penicillinase resistant Penicillins
• Have side chains - protect Beta lactam ring from attack by staphylococcal penicillinase
• Non-penicillinase producing organisms are less sensitive to these drugs than PnG
METHICILLIN, CLOXACILLIN, DICLOXACILLIN
Not resistant to the beta – lactamases produced by gram negative organisms
ONLY INDICATION
Infections due to Penicillinase
producing Staphylococcal
which are not Methicillin
resistant
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26. Methicillin
Cloxacillin
/Dicloxacillin
Acid labile Penicillinase and acid
resistant - PO
Nafcillin Oxacillin/Flucloxacillin
Acid labile Penicillinase and acid
resistant - PO
MRSA(METHICILLIN-RESISTANT STAPH AUREUS
Insensitive to Penicillinase resistant penicillins and other Beta Lactam
antibiotics
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28. Beta Lactamase Inhibitors
Beta Lactamases -- family of enzymes -- many gram-positive
and gram-negative bacteria that inactivate beta-lactam antibiotics
by opening the beta-lactam ring.
CLAVULANIC ACID
Nil intrinsic
antimicrobial activity
‘Suicide’ inhibitor
Combined with
amoxicillin as an oral
preparation
Combined with
ticarcillin as a
parenteral preparation.
SULBACTAM
structure = Clavulanic
acid
intravenous or
intramuscular use
Ampicillin +
Intrinsic activity against
Acinetobacter ++
High doses -- treat
multidrug-resistant
Acinetobacter infections
TAZOBACTAM
activity against many of
the plasmid β-lactamases,
including some of the extended
spectrum class +++
Tazobactam+ piperacillin –
parenteral
AVIBACTAM
non–β-lactam β-lactamase
inhibitor that provides clinically
useful inhibition against narrow-
spectrum, ESBL-type,
chromosomal AmpC, and KPC-
type β-lactamases (although not
metallo-β-lactamases).
Avibactam + ceftazidime –
parenteral
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29. Poor oral efficacy
Short duration of action
Susceptibility to penicillinase
Narrow spectrum
Hypersensitivity reactions
WHY SEMISYNTHETIC?
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31. 1) AMINOPENICILLINS : AMPICILLIN, BACAMPICILLIN
AMOXICILLIN
PARAMETER AMPICILLIN AMOXICILLIN BACAMPACILLIN
Acid stable Yes
Yes
Not a prodrug
Yes
Ester prodrug of
ampicillin
Frequency of
administration
QID TID QID
Oral absorption ++ ++++ ++++
Diarrhoea
++++
Unabsorbed drug
irritates lower
intestine, causes
marked alteration in
bacterial flora
++ ++
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32. PARAMETER AMPICILLIN AMOXICILLIN BACAMPACILLIN
Spectrum PnG plus S. viridans, enterococci
and Listeria
Less active Shigella
and H. influenza
More active penicillin
resistant S. pneumoniae
S. viridans, enterococci
and Listeria
Excretion
Bile excreted &
Primary excretion through
kidney
DDI
Enterohepatic circulation
If affected by alternation
in colonic flora, failure of
OCP can occur
Clinically relevant DDI
- -
1) AMINOPENICILLINS : AMPICILLIN, BACAMPICILLIN
AMOXICILLIN
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33. PARAMETER AMPICILLIN AMOXICILLIN BACAMPACILLIN
Uses
UTI : FQs DOC
Not empirical therapy
RTI : Higher doses
Meningitis** :
combine with third
generation
Cephalosporin
Gonorrhea: 1st line
drug
Cholecystitis :
Ampicillin preferred
due to higher
concentration in bile
H pylori kit
ANUG :
Aminopenicillins
combined with
metronidazole
Preferred by
physicians in
UTI
Bronchitis
SABE
Gonorrhea
Seldom used now
1) AMINOPENICILLINS : AMPICILLIN, BACAMPICILLIN
AMOXICILLIN
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34. 2) CARBOXYPENICILLINS : CARBENECILLIN, TICARCILLIN
CARBENECILLIN TICARCILLIN
Pseudomonas aeruginosa ++++
Indole positive Proteus ++++
More active
Im 1-2 g
Iv 1-5 g every 4-6 hrs (Na salt)
Not a sodium salt
A/E –
Higher doses
• fluid retention and CHF in pts of borderline
cardiac functions ( Na salt)
• Bleeding by interfering with platelet function
Produces fewer side effects
Severe infections-
Pseudomonas , Proteus
Burns, UTI, septicimia
Combined with clavulanic acid – covers beta
lactamase producing organisms
Pseudomonas - used with gentamicin
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35. 3) UREIDOPENICILLIN : PIPERACILLIN
Anti-pseudomonal penicillin, Activity against Klebsiella ++++
Not active against MRSA
More active than carbenicillin
Piperacillin serious gram-negative infections in neutropenic /
immunocompromised or burn patients.
Piperacillin + tazobactam covers beta -lactamase producing strains
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36. • Poor oral efficacy
• Short duration of action
• Susceptibility to penicillinase
• Narrow spectrum
• Hypersensitivity reactions
WHY SEMISYNTHETIC?
SCRATCH
TEST
i.d.
PENICILLOY
POLYLYSINE
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38. INTRODUCTION
Prof Brotzu Cultures of sea water at sewage
outfall fungus Cephalosporium acremonium
antagonistic to intestinal pathogen Florey
1955 extracted and refined.
7-aminocephalosporanic acid
Beta lactam ring and dihydrothiazine ring
MOA Same as Penicillin alters cell wall
synthesis
MOR Same as Penicillin Cephalosporinase
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46. Single ring produced by bacteria beta lactam antibiotic acts by binding to
specific PBPs
Narrow spectrum Gram negative aerobic species , H. influenzae,
E.coli, Klebsiella, Proteus, Pseudomonas++++
Gram positive cocci or anaerobes ××××
Resembles aminoglycosides
Resistant to gram-negative beta lactamases
Indication :-
Hospital-acquired infections urinary, biliary, gastrointestinal and female genital
tracts
AZTREONAM
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47. Advantages
• Lack of cross sensitivity with other beta lactam antibiotics except ceftazidime
(which has chemical similarity to aztreonam)
• Used in patients allergic to penicillins or cephalosporins
A/E Rashes
Rise in serum aminotransferases
Dose: 1- 2 g i.m or i.v. 8-12 hourly
AZTREONAM
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49. • Derivative of thienamycin Imipenem first member
• Extremely potent and broad-spectrum beta lactam antibiotic
Gram positive cocci, Enterobacteriaceae, P. aeruginosa, Listeria
anaerobes - B. fragilis and C. difficile.
resistant to most beta lactamases; inhibits penicillinase producing staphylococci (not reliable for
MRSA infections)
• Limiting feature of imipenem rapid hydrolysis by the enzyme dehydropeptidase
innovative solution - combination with cilastatin (reversible
inhibitor of dehydropeptidase)
All carbapenems are eliminated by the kidney (dose reduction in renal failure)
IMEPENEM, MEROPENEM, FAROPENEM, DORIPENEM,
ERTAPENEM
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50. • Dose Imipenem-cilastatin 0.5 g i.v. 6 hourly (max 4 g/day)
• Indication
serious hospital-acquired respiratory,
urinary, abdominal, pelvic, infections
skin and soft tissue infections including those in neutropenic, cancer and AIDS
patients
P. aeruginosa infection imipenem + gentamicin
• A/E
propensity to induce seizures
Diarrhoea, vomiting, skin rashes
IMEPENEM, MEROPENEM, FAROPENEM, DORIPENEM,
ERTAPENEM
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51. PARAMETERS MEROPENEM FAROPENEM DORIPENEM ERTAPENEM
Dihydropeptidase ××× ++ ××× ++
Spectrum
Gram positive +
Gram negative
+++
Gram positive +
Gram negative
+++
Same as
Meropenem
Pseudomonas ++
Less broad
spectrum
Uses
Nosocomial
infections
septicaemia,
intraabdominal,
pelvic infections,
diabetic foot.
P. aeruginosa
infections
meropenem +
aminoglycoside
Strep. pneumoniae,
H. influenzae,
Moraxella
cafarrhalis +++
Hence,
Respiratory, ET
Genitourinary
infections.
Same as
Meropenem
E.coli,H.influenzae,
K.pneumoniae,
Moraxella, Proteus,
many anaerobes
++++
Pseudomonas,
Acinetbacter,
MRSA, PR S.
pneumoniae ----
IMEPENEM, MEROPENEM, FAROPENEM, DORIPENEM,
ERTAPENEM
IMEPENEM, MEROPENEM, FAROPENEM, DORIPENEM,
ERTAPENEM
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52. PARAMETERS MEROPENEM FAROPENEM DORIPENEM ERTAPENEM
Seizure
propensity
+ - ++ ++
Dose
0.5 - 2.0 g i. v.
8 hourly.
150-300 mg oral
TDS
500 mg iv TDS 500 mg iv OD
A/E
Abdominal pain,
diarrhoea , rashes
Nausea,
diarrhoea,
superinfections,
thrombophlebitis
Resistance Efflux pump
IMEPENEM, MEROPENEM, FAROPENEM, DORIPENEM,
ERTAPENEM
IMEPENEM, MEROPENEM, FAROPENEM, DORIPENEM,
ERTAPENEM
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53. SUMMARY
1. Beta lactam antibiotics are four major bactericidal classes of drugs:
Penicillin Cephalosporins Monobactams Carbapenems
2. These narrow spectrum antibiotics which are chemically altered to increase
their
spectrum, thus giving birth to extended spectrum antibiotics
3.They should be appropriately used with respect to their spectrum to ensure
proper treatment.
4. These antibiotics should be used cautiously to avoid growing concern of
‘antibiotic resistance’
Dr. Prerana Manik Kadam 53
Addition of side chains at position 7 in beta lactam ring Alters spectrum
Addition of side chain at position 3 of thiazolidene ring Alters PK properties
Chromobacterium violaceum
Status :
Alternative to aminoglycosides uti
Neonatal gram –ve infections with ampicillin
Pts allergic to penicillins and cephalosporins