-lactam antibiotics

Dr. Tejas K. Patel

Asst. Professor,
Department of Pharmacology,
GMERS Medical Collge, Gotri,
Vadodara

-lactam antibiotics

-lactam antibiotics
-lactam

antibiotics include four

different groups

Penicillins
Cephalosporins
Monobactams
Carbapenems

All

-lactam shares

Common structure ( -lactam ring)

Mechanism of action
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-lactam antibiotics

Penicillins
Originally

obtained form fungus

Penicilllium notatum
At

presnet

Penicllium chrysogenum

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-lactam antibiotics

Mechanism of action

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Pharmacovigilance

Bacteria have no mechanism to

regulate osmolarity
Thick
Cell wall
Bacteria
PeptidoglycLow
an

High
osmolarity

osmolairity

Peptide+ glycan
(polysaccharide)
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Glycan

chain: consists of two

repeating subunits of
N-acetylmuramic acid (NAcM)
N-acetyl glucosamine (NACG)

Pentapeptide

side chain is linked

to NAcM
This cross bridging provides
strength to cell wall
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Process

of cross bridging is
known as transpeptidation
reaction
It is catalyzed by transmembrane
surface enzymes known as Penicllin
binding proteins (PBPs)

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-lactam

antibiotics acting
through inhibition of cell wall
synthesis and lysis of bacteria
(bactericidal drug)
Pencillins are lethal in multiplying
phase rather than dormant phase
of bacteria
Bactericidal activity of penicillin
is greater on Gram +ve than
Gram ve organisms
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Gm +ve bacteria

Gm -ve bacteria
Have

Thick

layer of
peptidoglycan and
teichoic acid
surrounds the cell wall
Peptidoglycan layer is
easily accessible to lactam antibiotics
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two membranes:
outer membrane and
cytoplasmic membrane
with a thin layer of
peptidoglycan
sandiwitched between
two
Outer membrane
consists of LPS with
narrow porin channels
Penicillin is not able to
cross LPS membrane
and have weaker
activity against Gm-ve
bacteria
Pharmacovigilance

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Penicillin G
Narrow

spectrum antibiotic
Activity mainly limited to Gm+ve
bacteria

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Spectrum
Gm+ve

cocci
Sterp. Pyogenes
Strep. Viridans
Strep. Faecalis
(enterococcus)
Strep. Pneumoniae
Gm-ve cocci
N. Gonorrhoea
N. Meningitidis

Gm+ve

bacilli
B. Anthracis
C. diphtheriae
Clostridia tetani
Cl. Perfringenes
Listeria
Spirochaetes: T.
pallidum, Leptospira

Not effective against Gm-ve bacilli (GNB), AFB,

rickettsia, chlamydia
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Pharmacovigilance

Penicillin resistance
Natural resistance

Acquired resistance

In Gm-ve organisms
PBPs are located
deeper under
lipoprotein barrier

Penicillin destroying
organisms
Penicillin tolerating
organisms

Penicillin destroying organisms

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Gm+ve organisms (Majority of

staphylococci) & N. Gonorrhoea

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 Gm-ve organisms:
Penicillinase is found in small quantities,
Located in-between lipoprotein and
peptidoglycan layer of cell wall

Penicillin tolerating organisms

Alteration of PBPs (low affinity for lactam antibiotics
Alteration of permeability of outer
layers of cell wall
Alteration of permeability of porin
channels

Pharmacokinetics
Absorption: acid labile, used
parenterally
Distribution: limited, good in the
presence of inflammation
Excretion
10 % by GFR
90% by tubular secretion
Half life increased by probenecid

Preparation and dose

Sodium Penicillin G (crystalline
penicillin) contains : 1600 units per
mg
1 Unit = 0.625 g
1 MU = 625 mg

Na PnG :
Inj 0.5-5 MU im/iv 6-12 hrly

Repository PnG innjections

Procaine PnG
Inj 0.5-5 MU im 12-24 hrly

Fortified procaine PnG

3 lac U procaine PnG + 1 lac unit Na PnG

Benzathine PnG
Inj 0.6-2.4 MU im every 2 to 4 wks
Used for prophylactic purpose only

Adverse effects
Hypersensitivity reaction
1-10% incidence
More in pts with allergic diathesis
Parenteral > oral route
Can occur with all forms of Pn, highest with
procaine Pn
Partial cross reactivity between all types of
penicillins
Pn should not be used in patient with H/o
immediate type of hypersensitivity reactions
H/o allergy must be elicited before using it
Should only be given after negative intradermal
test (sensitivity tests)

 Jarisch-Herxheimer reaction
Occurs with the use of Pn in syphilitic pt.
Due to sudden release of spirochaetal
lytic products and lasts for 12-72 hrs
Manifestations:
Shivering, fever
Arthralgia, Myalgia
Exacerbation of lesions
Vascular collapse

Therapeutic uses
Streptococcal infections
Pharyngitis, Otitis media
Rheumatic fever
Subacute bacterial endocarditis along with
gentamicin

Pneumococcal infections
Not reliable due to resistance

Gonococcal infections
Not reliable due to resistance

Meningococccal infections
Can be used, cephalosporins are preferred

 Syphilis
Drug of choice
Early and latent syphilis
Benzathine Pn for 1-3 wk

Late syphilis
Benzathine Pn for 4 wk

Cardiovascular and neurosyphilis

Sod Pn G 5 MU 6 hrly X 2 wks f/b above regime

Leptospirosis

 Diphtheria
Antidiphtheritic serum is drug of choice
Procaine Pn 1-2 MU daily X 10 days

Tetanus & Gas gangrene

Antitoxin is DoC
PnG 6-12 MU/ day

 Prophylactic uses
Rheumatic fevers
Benzathine Pn till 18 yrs of age or 5 yrs after
attack

Bacterial endocarditis inCan

ptscause
with
valvular defects
bacteremia in
Dental extraction
Endoscopies
Catheterization

Agranulocytosis

pts with
valvular defects

Semisynthetic penicillin
Acid resistant alternative to PnG
Phenoxymethyl Pn (Pn V)

Penicillinase resistant Pn
Methicillin, Cloxacillin

Extended spectrum Pn
Aminopenicillin: Ampicillin, Amoxicillin,
Bacampicillin
Carboxypenicillin: Carbenecillin, Ticarcillin
Uriedooenicillin: Piperacilllin, Mezlocillin

-lactamase inhibitors
Clavulinic acid, Sulbactam, Tazobactam

Acid resistant alternative to PnG

Phenoxymethyl Pn
Acid stable
Antibacterial spectrum same as PnG
Not reliable for serious infections

Penicillinase resistant Pn
These congeners have side chains
that protect the -lactam ring from
staphylococcal penicillinase
Not effective against gram ve -lactamase

Side chains also partially protects the

bacteria from -lactam ring
Non-penicillinase producing organisms
are less sensitive to these drugs
Used only for staphylococcal infections

Methicillin
Highly penicillinase resistance
Not acid resistance
Spectrum: Staph. aureus (penicillinase
producing)
Resistance to methicillin develops by
Alteration of PBPs
Resistance staph. aureus knowns as MRSA

ADR
Hematuria
Albuminura
Reversible interstitial nephritis

Cloxacillin
Highly penicillinase resistance
Acid resistance
Spectrum: Staph. Aureus
(penicillinase) producing
Not effective against MRSA
Dose: 250 mg-500 mg oral/im/iv 6 hrly
Uses
Skin & soft tissue infections

Extended spectrum Pn
Aminopencillins
None is resistance to
pencillinase or other lactamase

Ampicillin
Spectrum
Gm+ve cocci
Sterp. Pyogenes
Strep. Viridans
Strep. Faecalis
(enterococcus)
Strep. Pneumoniae
Gm-ve cocci
N. Gonorrhoea
N. Meningitidis
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Gm-ve bacilli
E. coli
Proteus mirabillis
Salmonella
Shigella
H.influenza

Resistance organisms
are

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Staph. aureus
Klebsiella
Proteus vulgaris
Pseudomonas
Bacteroides fragilis

Pharmacovigilance

Pharmacokinetics
Absorption
Not degraded by gastric acid
Oral absorption is incomplete
Food delays absorption

Enterohepatic circulation
Excretion: Tubular secretion
Half life: 1 hr

Adverse effects
Diarrhoea
Frequent with oral administration
Unabsorbed drug irritates lower
intestine and alters bacterial flora

Rashes
Frequent side effect
Common in pts with AIDS, EB virus
infection, Lymphatic leukemia

Uses
Dose: 500 mg- 2g oral/im/iv 6 hrly
Respiratory tract infections
Pharyngitis
Sinusitis
Otitis media
Bronchitis

500 mg 6hrly

SABE
2 g iv 6 hrly along with gentamicin for 46 wks

 Meningitis
Meningococci, pneumcocci, H. influenzae
Combined with third generation
cephalosporins for emperical therapy

Gonorrhoea
For nonpenicllinase producing gonococcal
infections only
Used along with probenecid

Urinary tract infection

Fluoroquinoloes are preferred

 Cholecystitis
Attains high concentration in bile

Septicemia
Along with 3rd generation cephalosporins /
amonoglycosides

Typhoid fever
Not reliable, fluoroquinolones are preferred

Bacillary dysentery
Not reliable, fluoroquinolones are preferred

 Drug interactions
Failure of contraception
Interfere with enterohepatic cycling of
estrogen

What is the rationality of FDC ampicillin (250 mg)

+cloxacillin combination (250 mg)?
Irrational combination

Bacampicillin
Prodrug of ampicillin
Completely abosorbed from GIT and
than
Hydrolyzed into ampicillin
Less diarrhoea

 ADR
Bleeding
Interferes with platelet function

Uses
Used along
Burns
with
Hospital acquired UTI
aminoglycosi
Septicemia
des
Piperacillin
Hospital acquired respiratory
tract is
preferred
infection

Ticarcillin
More potent
Same as carbenicillin

Ureidopenicillins

Piperacillin
8 times more active than carbenicillin
Spectrum
Pseudomonas aeruginosa
Proteus vaulgaris
Klebsiella

Preferred over carbenicillin

Not penicillinase resistant
Not acid resistant
Dose: 100-150 mg in 3 divided doses iv

Mezlocillin
Same as Piperacillin

-lactamase inhibitors
-lactamases:
Family of enzymes (Class I to V)
Produced by gram +ve and ve organisms
Inactivate the -lactam antibiotics by opening lactam ring

-lactamase inhibitors has no antibacterial

action by itself
Only enhance the activity of other -lactam
antibiotics

Clavulanic acid
Inhibits wide variety -lactamase
enzymes (Class II to V -lactamase)
But not class I cephalosporinase

Mechanism of action
Initially binds with -lactamase enzyme
reversibly

Later on covalent binding

(Progressive inhibitor)

It gets inactivated after biding to enzyme

(Suicidal inhibitor)
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Mechanism of action
In Gram ve bacteria
It permeates through outer layer of cell
wall
Inhibits periplasmically located lactamase enzyme

Pharmacokinetics
Absorption good oral absorption
Distribution and half life (1 hr) matches
with amoxicillin
Excretion: Amoxicillin
tubular
secretion
Clavulanic acid Glomerular
filtration

Spectrum of amoxcillin because of addition of

clavulanic acid

Gm+ve cocci
Staph. aureus
Gm-ve cocci
N. Gonorrhoea
Amoxicillin
sensitive
strain is not affected by
clavulanic acid
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Gm-ve bacilli
E. coli
Klebsiella
Proteus
Salmonella
Shigella
H.influenza
Gm+ve bacili
Bact. Fragilis
Brahnmella catarrhalis

Uses
Dose: Amoxicillin 500 mg+ Clavulanic
acid 125 mg
Skin and soft tissue infections
Intra-abdominal and gyanecological
infections
UTI
Biliary tract infection
Respiratory tract infection
Gonorrhoea (PPNG)

ADR

Same as amoxicllin alone

Poor GI intolerance esp. in children
Hepatic injury
Candida stomatitis / vaginitis

Sulbactam
Chemically related to clavulanic acid
Less potent
Mechanism of action same as
clavulanic acid
P/K matches with ampicillin
Used parenterally

 Dose: Ampicillin 1g+ Sulbactam 0.5 g per

vial,
1-2 vial iv 6-8 hrly
Uses
Mixed aerobic and anaerobic infections
Intrabdominal infections
Surgical & skin/soft tissue infections

ADR
Pain at the site of injection, thrombophlebitis
Rash
Diarrhoea

Tazobactam
Similar to sulbactam & clavulanic
acid
P/K matches with piperacillin
Used for severe infections like
Peritonitis
Pelvic
Urinary
Respiratory tract infection

 Pipreacilllin+tazobactam is not active

against piperacillin resistant
pseudomonas
As tazobactam
Does not affect resistance due to altered
permeability
Does not inhibit inducible chromosomal lactamse