Beta lactam antibiotics

1. BETA LACTAM ANTIBIOTICS:
THE PENICILLIN STORY
Dr. K. Manimekalai
(Professor and Head)
Dept. of Pharmacology

2. LEARNING OBJECTIVES
• What are beta lactam antibiotics?
• How was penicillin discovered?
• How does penicillin act and against which
organisms?
• What are the methods by which bacteria
became resistant to penicillins?
• What are the different classes of penicillins?
• How are they used and what are the safety
precautions during their use?
• What are beta lactamase inhibitors?

3. BETA LACTAMS
• Penicillins, Cephalosporins, Monobactams,
Carbapenems.
• Common structure (BETA LACTAM RING) fused
with a THIAZOLIDINE ring and a side chain
• Both rings constitute Penicillin nucleus = 6 -
AMINO PENICILLINIC ACID
• Nucleus + side chain ~ Antibacterial activity
• Side chain ~ Stability against degradation by
gastric juice and PENICILLINASE (BETA
LACTAMASE)

4. DISCOVERY OF PENICILLIN
• In 1928, Alexander Fleming observed that a
mould contaminating one of his cultures of
Staphylococcus caused the bacteria in its vicinity
to undergo lysis.
• Broth in which the fungus was grown was
inhibitory for many micro-organisms.
• Because the mould belonged to the genus
Penicillium, Fleming named the antibacterial
substance Penicillin.

5. DISCOVERY OF PENICILLIN
• A decade later, penicillin was developed as a
systemic therapeutic agent by Florey, Chain, and
Abraham
• By May 1940, a crude preparation produced
dramatic therapeutic effects in mice with
streptococcal infection.
• By 1941, therapeutic trials in several patients
with staphylococcal and streptococcal infections
refractory to all other therapy
• Effective procedure developed for mass
synthesis of penicillins by the late 40s

6. MOA
• Peptidoglycan cell wall
• Penicillin binding proteins (PBPs)
• CELL WALL SYNTHESIS
(Transpeptidation, Carboxypeptidation,
Endopeptidation)
• Activation of autolysins
• Bactericidal effect
• CWD bacteria bursts bcos interior is
hyperosmotic.

7. CLASSIFICATION
• NATURAL PENICILLINS
Penicillin G (Benzyl penicillin)
Procaine penicillin G
Benzathine penicillin G
Penicillins other than natural are semisynthetic
• ACID RESISTANT PENICILLINS
Penicillin V (Phenoxymethyl penicillin)
• PENICILLINASE RESISTANT PENICILLINS
Methicillin, Nafcillin, Cloxacillin, Flucloxacillin

8. CLASSIFICATION
• EXTENDED SPECTRUM PENICILLINS
Aminopenicillins – Ampicillin, Amoxicillin
Carboxypenicillins – Carbenicillin, Ticarcillin
Ureidopenicillins – Piperacillin, Mezlocillin
Amidinopenicillins - Mecillinam
• PENICILLINS WITH BETA LACTAMASE INHIBITORS
Amoxycillin – Clavulanic acid
Ampicillin – Sulbactam
Piperacillin - Tazobactam

9. ANTIMICROBIAL SPECTRUM
NATURAL PENICILLINS
• Narrow spectrum
• Cocci – Strep-, Pneumo- (G+), Nisseria- (G-)
• Bacilli – B.anthracis, Corynebacterium
diphtheriae, Clostridia, Listeria, Treponema
PENICILLINASE RESISTANT PENICILLINS
• Beta lactamase producing Staph
(Now >> MRSA infections)

10. RESISTANCE
• Natural resistance as target enzymes and PBPs
are deep seated (G-)
• Acquired resistance

11. RESISTANCE MECHANISMS
• MODIFICATION OF PBPs (MRSA, Streptococcus
pneumoniae, Enterococcus)
• ↓ PERMEABILITY TO REACH PBPs
(Pseudomonas)
• ACTIVATION OF EFFLUX MECHANISMS
(Salmonella, Pseudomonas)

12. PENICILLIN G
PK
• A - Acid labile (Poor oral absorption)
IM Sod. PnG absorption rapid and complete
• D – CSF, serous cavities poor, except when
inflamed, 60% plasma protein binding
• E – Renal
Caution in elderly, renal failure
Q. What happens when PROBENECID and
PENICILLIN are given concurrently?

13. PENICILLIN G
PREPARATIONS AND DOSE
• UNITAGE: 1U of Crystalline sodium Benzyl Penicillin
= 0.6µg of the standard preparation
or, 1g = 1.6 Million U (MU)
• Inj Sod PnG (Crystalline penicillin) 0.5-5 MU IM/IV
q6h – 12h
• Repository PnG inj to be administered deep IM
ONLY (NEVER IV)
Inj Procaine PnG 0.5-1 MU IM q12-24h
Inj Fortified Procaine PnG (Procaine PnG + Sod. PnG)
Inj Benzathine PnG – 0.6 – 2.4 MU IM/2-4 WKS
(sustained release for prophylaxis)

14. PENICILLIN G
USES
• Streptococcal infections – URTI, Otitis media,
Rheumatic fever, SABE (with Gentamicin)
• Pneumococcal infections – ONLY if organism is
sensitive
• Meningococcal infections – IV >> doses
• Gonorrhoea – Ophthalmia neonatorum due to
sensitive N. gonorrhoae

15. PENICILLIN G
• Syphilis – Benzathine PnG 2.4 MU IM /WK X 2-3
WKS or,
Procaine PnG 1.2 MU IM/DAY X 10 DAYS
• Diphtheria - Procaine PnG 1.2 MU IM/DAY X 10
DAYS (ADJUVANT)
• Tetanus and Gas gangrene (ADJUVANT)
• Anthrax, Trench mouth, Rat bite fever,
Actinomycosis (craniofacial/thoracic/abdominal
abscess)

16. PENICILLIN G
• PROPHYLACTIC USES –
Rheumatic fever
SABE (during dental extraction, endoscopy,
catheterisation, surgical procedures likely
to cause bacteremia)
Gonorrhoea
Syphilis
Surgical site infections

17. PENICILLIN G
ADRs
• Local irritation & Direct toxicity
- Inj site pain
- Thrombophlebitis of injected Vv
- CNS toxicity
- Platelet malfunction (Bleeding)
- Microembolism
• Hypersensitivity

18. PENICILLIN G
- Rash, itching, urticaria, fever, wheezing,
angioneurotic edema, serum sickness,
exfoliative dermatitis
- ANAPHYLAXIS
- Partial cross sensitivity
Q. How will you manage anaphylaxis caused by
penicillin?
• Superinfections
• Jarisch-Herxheimer reaction
Precautions – Elicit H/O penicillin allergy, scratch test or
intradermal test (2-10 U)

19. SEMISYNTHETIC PENICILLINS
The major drawbacks of benzyl penicillin are:
• Inactivation by the gastric acid.
• Short duration of action.
• Poor penetration into the CSF.
• Narrow spectrum of activity.
• Development of resistant organisms,
especially staphylococci; and
• Possibility of anaphylaxis.

20. • (Penicillin V)
• Spectrum is like that of benzyl penicillin.
• Penicillin V may be employed in less serious
infections due to pneumococci and
streptococci.

21. METHICILLIN
• As several strains of staphylococci have
developed resistance to methicillin, it is now
rarely used except for laboratory testing for
MRSA.
• The term methicillin resistant staphylococcus
aureus (MRSA) is used to refer to beta-lactam-
antibiotic-resistant (i.e., penicillinase
producing) staphylococci.

22. • CLOXACILLIN: Acid resistant.
• DICLOXACILLIN: Highly (95%) protein.
• AMPICILLIN: Ampicillin is water soluble and acid
resistant.
• It is highly effective against various Gram-
negative bacteria.
• The Gram-positive cocci are less sensitive to
ampicillin.
• ADVERSE REACTIONS:
• Skin rashes are more common.

23. THERAPEUTIC USES:
• Urinary tract infections.
• Respiratory tract infections
• Meningitis and subacute bacterial
endocarditis.
• Biliary tract and intestinal infections.

24. • Miscellaneous:
• Management of intestinal malabsorption and
is preferred in the treatment of whooping
cough.
• The other drugs useful in whooping cough are
azithromycin (the drug of choice),
erythromycin and co-trimoxazole.

25. • TALAMPICILLIN: is a prodrug.
• AMOXICILLIN:
• Advantages:
a) Almost completely absorbed
b) Absorption is not influenced by food.
c) Less protein bound and the urinary excretion is
higher than that of ampicillin.
d) The incidence of diarrhoea is less
However, much more expensive.
Preferred for preventing the carrier state in typhoid
fever.

26. EXTENDED SPECTRUM PENICILLINS
Carboxypenicillins and the ureido penicillins
They are acid labile and susceptible to beta
lactamase.
They are highly active against anaerobes.
They are most useful in infections caused by P.
aeruginosa and other Gram negative rods.
They are much less active than penicillin G
against Gram positive organisms and are not
reliable for treating staphylococcal infections.

27. • The CNS penetration of the carboxy and the
ureido-penicillins is about 10% of their serum
levels, and hence they are not recommended for
the treatment of meningeal infections.
• They act synergistically with aminoglycoside
antibiotics, particularly against P.aeruginosa and
the Enterobacteriaceae.
• They may inactivate the aminoglycoside
antibiotics in vitro when mixed together in the
same bottle.

28. CARBENICILLIN
• Its important advantage over ampicillin is that
it is effective against all strains of Proteus and
P. aeruginosa.
• The drug can cause CHF because of its large
sodium content, and bleeding due to
abnormal platelet aggregation.

29. TICARCILLIN
• Analogue of Carbenicillin is twice as active
against P. aeruginosa.
• Anaerobes Bacteroides fragilis.
• Usually combined with clavulanic acid to
increase effective blood levels.
• It can be combined with amino glycosides.
• Because of its high sodium content, it may
cause sodium overload in patients with cardiac
or renal damage.

30. PIPERACILLIN
• Gram negative bacilli, particularly P. aeruginosa
• Eliminated in the urine adjustment of its dose in
the presence of renal damage.
• Piperacillin crosses the BBB and may be useful in
neonatal meningitis.
• Less likely to cause sodium overload.
• Azlocillin and mezlocillin have similar indications
as piperacillin.

31. Amidinopenicillins
MECILLINAM
• Mecillinam has no therapeutic activity against
Gram positive organisms but is highly effective
against Gram negative organisms
• Poorly absorbed orally and is given IM.
• Used in UTI and in typhoid fever, but do not
appear to be superior to the other commonly
used drugs.

32. BETA LACTAMASE INHIBITORS
CLAVULANIC ACID:
• It is well absorbed on oral administration but
has only a weak antibacterial activity.
• It is a potent and irreversible inhibitor of many
beta lactamases and protects beta lactam
antibiotics from inactivation, when combined
with them.

33. • Combined with amoxicillin, it widens the
antibacterial spectrum of the latter to include
beta lactamase producing strains of staph.
aureus, H. influenzae, N. gonorrhoea, E. coli,
Proteus, Klebsiella, M. catarrhalis and
Bacterodies species.
• Used in combination with amoxicillin or
ticarcillin.

34. SULBACTAM
• It is combined with ampicillin.
• Tazobactam is a penicillanic-acid-sulfone
• It is combined with piperacillin.
• These combinations are expensive and are not
cost-effective for routine infections
• Should be reserved for infection due to beta
lactamase producing organisms.

35. • The beta lactamases produced by Ps.
Aeruginosa and by Enterobacter species are
resistant to clavulanic acid and sulbactam.
• Further, MRSA are not susceptible to
antimicrobials containing clavulanic acid or
sulbactam.

36. SUMMARY
• Penicillins - beta lactam antibiotics
• Discovered by Alexander Fleming
• MOA by inhibition of cell wall synthesis by
inhibiting PBPs and autolysin activation
• Classified into natural and semisynthetic
• Spectrum narrow, mainly G+ cocci, bactericidal,
but semisynthetic penicillins have broader
spectrum
• Natural penicillins injectible only and used in
coccal infections, syphilis, prophylaxis of
Rheumatic fever, SABE

37. THANK YOU