Beta lactam antibiotics

Dr. Suman Jain

1
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 additionβ lactamase inhibitors (clavulanic
acid, sulbactam )also haveβ 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.
ADME of Penicllin G
Absorption
Benzylpenicillin G-Only 1/3rdabs.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.
7

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
8

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
produceinterstitial 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.
Carbapenemderivat
ives
Parenteralβ lactam antibiotics,β
lactamase resistant.
Have broadest spectrum of
activity.Examples: imipenem,
meropenem,
ertapenem
i. Imipenem with cilastatin
Marketed asprimaxin 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
25

Carbapenem
derivatives.Imipenem
contd
ADMENot 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,
nosocomialpneumonia,
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
•
Seizureswith 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.
26
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.
27

4.
Monobactam:
aztreonam
Aztreonam
• Monocyclic beta lactam-active
against –ve rodsincluding
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
againstβ 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), andblood
disorders(thrombocytopenia,
neutropenia) may occur.
Therapeutic uses
• Used as an alternative to
aminoglycosides, in septicemia, or
complicated UTI

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