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BETA LACTAM ANTIBIOTICS:
THE PENICILLIN STORY
Dr. K. Manimekalai
(Professor and Head)
Dept. of Pharmacology
• What are beta lactam antibiotics?
• How was penicillin discovered?
• How does penicillin act and against which
• 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?
• Penicillins, Cephalosporins, Monobactams,
• 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
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
DISCOVERY OF PENICILLIN
• A decade later, penicillin was developed as a
systemic therapeutic agent by Florey, Chain, and
• By May 1940, a crude preparation produced
dramatic therapeutic effects in mice with
• 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
• Natural resistance as target enzymes and PBPs
are deep seated (G-)
• Acquired resistance
• MODIFICATION OF PBPs (MRSA, Streptococcus
• ↓ PERMEABILITY TO REACH PBPs
• ACTIVATION OF EFFLUX MECHANISMS
• 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?
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)
• Streptococcal infections – URTI, Otitis media,
Rheumatic fever, SABE (with Gentamicin)
• Pneumococcal infections – ONLY if organism is
• Meningococcal infections – IV >> doses
• Gonorrhoea – Ophthalmia neonatorum due to
sensitive N. gonorrhoae
• Syphilis – Benzathine PnG 2.4 MU IM /WK X 2-3
Procaine PnG 1.2 MU IM/DAY X 10 DAYS
• Diphtheria - Procaine PnG 1.2 MU IM/DAY X 10
• Tetanus and Gas gangrene (ADJUVANT)
• Anthrax, Trench mouth, Rat bite fever,
• PROPHYLACTIC USES –
SABE (during dental extraction, endoscopy,
catheterisation, surgical procedures likely
to cause bacteremia)
Surgical site infections
• Local irritation & Direct toxicity
- Inj site pain
- Thrombophlebitis of injected Vv
- CNS toxicity
- Platelet malfunction (Bleeding)
- Rash, itching, urticaria, fever, wheezing,
angioneurotic edema, serum sickness,
- Partial cross sensitivity
Q. How will you manage anaphylaxis caused by
• Jarisch-Herxheimer reaction
Precautions – Elicit H/O penicillin allergy, scratch test or
intradermal test (2-10 U)
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.
• (Penicillin V)
• Spectrum is like that of benzyl penicillin.
• Penicillin V may be employed in less serious
infections due to pneumococci and
• As several strains of staphylococci have
developed resistance to methicillin, it is now
rarely used except for laboratory testing for
• The term methicillin resistant staphylococcus
aureus (MRSA) is used to refer to beta-lactam-
antibiotic-resistant (i.e., penicillinase
• CLOXACILLIN: Acid resistant.
• DICLOXACILLIN: Highly (95%) protein.
• AMPICILLIN: Ampicillin is water soluble and acid
• It is highly effective against various Gram-
• The Gram-positive cocci are less sensitive to
• ADVERSE REACTIONS:
• Skin rashes are more common.
• Management of intestinal malabsorption and
is preferred in the treatment of whooping
• The other drugs useful in whooping cough are
azithromycin (the drug of choice),
erythromycin and co-trimoxazole.
• TALAMPICILLIN: is a prodrug.
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
EXTENDED SPECTRUM PENICILLINS
Carboxypenicillins and the ureido penicillins
They are acid labile and susceptible to beta
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.
• 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
• They may inactivate the aminoglycoside
antibiotics in vitro when mixed together in the
• Its important advantage over ampicillin is that
it is effective against all strains of Proteus and
• The drug can cause CHF because of its large
sodium content, and bleeding due to
abnormal platelet aggregation.
• 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.
• 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
• Less likely to cause sodium overload.
• Azlocillin and mezlocillin have similar indications
• 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
BETA LACTAMASE INHIBITORS
• 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
• 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
• Used in combination with amoxicillin or
• 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.
• 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
• 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
• Natural penicillins injectible only and used in
coccal infections, syphilis, prophylaxis of
Rheumatic fever, SABE