Transcript BETA LACTAM ANTIBIOTICS AND OTHER INHIBITORS OF CELL

BETA LACTAM ANTIBIOTICS AND OTHER
INHIBITORS OF CELL WALL SYNTHESIS
Penicillins
Cephalosporins
Monobactams
Carbapenems
INHIBITORS OF CELL WALL SYNTHESIS
Beta lactam antibiotcs
Penicillins
Penicillin G
Penicillin V
Methicillin
Oxacillin
Nafcillin
Cloxacillin
Dicloxacillin
Ampicillin
Piperacillin
Ticarcillin
Carbenicillin
Amoxycillin
Mezlocillin
Azlocillin
Cephalosporins
1st generation
Cefazolin
Cefadroxil
Cephalexin
Cephalothin
Cephradine
Cephapirin
3rd generation
Cefdinir
Cefixime
Cefoperazone
Cefotaxime
Ceftazidime
Moxalactam
Ceftriaxone
Ceftibuten
Ceftizoxime
2nd generation
Cefaclor
Cefamandole
Cefonicid
Cefametazole
Cefotetan
Cefoxitin
Cefuroxime
4th generation
Cefepime
Carbepenams
Imipenams/Cilastatin
Other antibiotics
Monobactams
Aztreonam
Vancomycin
Bacitracin
Penicillins
• First antibiotic to be used clinically.
• Alexander Fleming – 1929.
• First penicillins from cultures of Penicillium
notatum( fungus ) in 1941-Chain & Florey.
• Presently from cultures of Penicillium
chrysogenum.
• Basic structure of Penicillin
consists of a
Thiazolidine ring (A) fused to a
Beta lactam ring (B) to which
side chains (R) are attached
through an amide linkage.
• In Natural penicillin, Pn G, R- side chain
is a benzyl side chain
• But in semisynthetic penicillins R is
anything other than benzyl moiety.
Penicillin Structural Features &
Requirements for Antibacterial Activity
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• Moieties A and B together constitute the 6aminopennicillanic acid nucleus.
• The penicillin nucleus is the chief structural
requirement for antibacterial activity.
• Side chain determines many of the antibacterial
and pharmacological characteristics of a
particular type of penicillin.
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• Several types of natural penicillins
– F, G , X , & K.
– PnG (benzyl penicillin)
• Greatest antimicrobial activity
• Only natural penicillin used clinically.
• Na & K salts more stable.
UNITAGE OF PENICILLIN
• Activity of natural penicillins (Pn G) is
described in units
– Crystalline sod Pn G contains 1600 units /mg.
– 1 unit of PnG =o.6 Ug
– Or, 600 mg of Pn G = 1 million units
• Semi synthetic penicillins are prescribed by weight
– Amox 500 mg 8 hrly orally
• 1 mg = 1600 units
• 1600 units = 1 mg
• 1 unit = 0.6 Ug
•
•
•
•
•
0.6 Ug = 1 unit
6 Ug = 10 unit
6000 Ug = 10,000 units
6 mg = 10,000 units
600 mg = 10,000,00 units
Mechanism of action
• All β lactam antibiotics interfere
with the synthesis of bacterial Cell
wall
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• Bacteria are surrounded by a thick cell wall
that confers stability & rigidity to their cell
structure
• Cell wall is composed of peptide chains &
glycan chains
• Extensively cross linked
• Peptidoglycan layer envelops the cell &
does not allow bacteria to swell & prevent
death due to lysis
Bacterial Cell Wall Synthesis
• Glycan chains consist of two aminosugars
– N acetyl muramic acid (NAM) &
– N acetyly glucosamine (NAG)
• Pentapeptide side chain is linked to NAM sugar
• Forms the peptidoglycan molecule
• Peptidoglycan residues are linked together and
UDP is split off
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• Final step is cleavage of terminal D alanine of the
peptide chains by transpeptidases
• Catalyzed by PBPs, transmembrane surface
enzymes present in bacteria
• Energy is released which is utilized for
establishing cross linkages between peptide
chains of the neighbouring strands.
• This cross linking Provides stability and rigidity
to the cell wall
Mechanism of action
• Penicillins inhibit bacterial cell
wall synthesis
• Inhibit the PBPs catalysed process of
transpeptidation
– cross linking (maintains close knit structure of
bacterial cell wall) does not occur
• Last step in peptidoglycan synthesis
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• When susceptible bacteria divide in the presence
of β lactam antibiotic cell wall deficient forms
are produced.
• Interior of bacterium is hyperosmotic
• Osmotic drive occurs
• CWD form swell and bursts
• Lysis of bacteria- BACTERICIDAL
• Lytic effect may also be due to derepression
of some bacterial autolysins.
• Rapid cell wall synthesis occur when
organisms are actively multiplying.
– Beta lactam antibiotics are more lethal in this phase.
– Peptidoglycan cell wall is unique to bacteria.
– No such substance is synthesized by higher
animals.
Penicillins are practically non toxic to man.
• G +ve bacteria
– Cell wall is entirely made of peptidoglycan.
– Cell wall is 50-100 layers thick
– Extensively cross linked and
– May be considered as a single giant peptide molecule,
– The peptidoglycan layer is easily accessible to β lactam antibiotics
– Inhibition of transpeptidation reaction becomes easier
• G -ve bacteria
– Have two membranes
– Outer membrane
– Inner membrane
– Peptidoglycan sandwiched b/w the two
– Outer membrane consists of lipopolysaccharides with
narrow porin channels ;
• barrier to β-lactam antibiotics
• Hence weaker activity
Reason for higher susceptibility of g +ve
bacteria to Pn G
Gram-positive Bacterial Membrane
Structure
The lipid bilayer cell
membrane of
most of the
Gram-positive
bacteria is
covered by a
porous
peptidoglycan
layer
Peptidoglyc
d an cell wall
d Cytoplasmic
Membrane
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Gram-negative Bacterial Membrane
Structure
• Gram-negative
bacteria are
surrounded by two
membranes.
• The outer membrane
functions as an
efficient permeability
barrier containing
lipopolysaccharides
(LPS) and porins.
d
Outer
membrane
d
Peptidoglycan
cell wall
d
Cytoplasmic
membrane
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• Penicillins with hydrophillic character ,
Ampicillin & amoxycillin can diffuse
through these porin channels ;
• show activity against some gramnegative bacteria also
• but not against psuedomonas
aeruginosa because these bacteria lack
in such classical permeable porin
channels.
Resistance
Inherent
Acquired:
Gram -ve bacteria are
inherently insensitive
Production of
penicillinase.
Deeper localisation
of target enzymes &
penicillin binding
protein.
loss or alteration of
porin channels ;
Pn G is unable to
penetrate.
PENICILLINASE
opens the β lactam ring and
inactivates Pn G
Staphylococcus, Gonococcus,
B subtilis, E coli, H influenzae
produce penicillinase.
Penicillinase
Gram +ve organisms
produce large
quantity of
penicillinase
which diffuse in
the surroundings
and protect the
bacteria.
In Gram -ve bacteria
constitutive enzyme
small quantity
strategically located
between the lipoprotein and
peptidoglycan layers of the cell wall.
PBP’s :
Penicillin
Binding
Proteins
Gram –ve bacteria
Gram +ve bacteria
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• Efflux pump in some G -ve bacteria.
Penicillin G
• Natural Penicillin
• Narrow spectrum
• Primarily active against G +ve
bacteria
–Few gram negative & anaerobes
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Antibacterial spectrum :
• G +ve Cocci : streptococci are highly sensitive
• So are pneumococci
• S. aureus- >90% have acquired resistance.
• Gram +ve Bacilli : B. anthrasis, C. diphtheria, all
Clostridia, Listeria are highly sensitive.
• Gram -ve cocci:
• N. gonorrhoe (Highly resistant),
• N. meningitides are susceptible to Pn G.
• G –ve bacilli , Myco TB rickettsia, chlamydia,
protozoa, fungi & viruses are totally
unresponsive.
• Most anaerobic microorganisms including
clostridium species are highly sensitive.
• So are spirochaetes (T. pallidum, Leptospira
and others)
•
•
•
•
•
Strepto
Pneumo
Meningo
Anaerobes
Spirochaetes
Pharmacokinetics:
• Acid labile -destroyed by gastric acid.
• Absorption from IM site is rapid, reaches
most body fluids
• Plasma half life is 30 minutes.
• To prolong the duration of action:
excreted by rapid renal excretion.
–10 % by GF; 90 % TS.
–TS is blocked by Probenecid, higher
and long lasting plasma
concentrations are achieved.
–Rarely used for this purpose
–Repository preparations are used
»Pencillin G procaine
»Pencillin G benzathine
• Release penicillin slowly from the
area in which they are injected &
produce relatively low but persistent
concentrations of antibiotics in the
blood.
Preparations:
• Penicillin G(Sodium penicillin G (crystalline)/
benzyl penicillin).
• Procaine penicillin G.
• Bezathaine penicillin G.
• Fortified Procaine penicillin G.
Therapeutic Uses :
• Streptococcal infections.
–DOC for sensitive strains
• Pneumococcal.
–Used for senstive strains
–Replaced by third generation cephalosporins.
• Meningococcal.
• Gonorrhoea- not reliable,
• Syphylis- drug of choice,
• Diphtheria- for carrier state.
• Tetanus and gas gangrene.
Infections with Anaerobes
• Periodontal infections usually respond well to
penicillin G.
– Mild-to-moderate infections at these sites may be
treated with oral medication
(either penicillin G or penicillin V 400,000
units four times daily).
– More severe infections should be treated with 12
million to 20 million units of penicillin G intravenously..
• Necrotising gigivitis
• Vincents angina
Prophylactic use :
• Rheumatic fever
– 1.2 million units , im, once a month, lifelong
in high risk people.
• Bacterial endocarditis - caused by dental
extractions, endoscopies, catheterization,
etc. cause bacteremia which in patients
with valvular defects can cause
endocarditis.
INFECTIVE ENDOCARDITIS
• Some cases of endocarditis occur after
dental procedures.
• Prophylactic antibiotics are given to
patients with predisposing congenital
or valvular anomalies.
Endocarditis prophylaxis recommended
• Prosthetic cardiac valves
• Previous BE
• Congenital heart diseases.
– unrepaired cyanotic CHD
– Completely repaired CHD with prosthetic
material / device.
• Cardiac transplantatiom recipients in whom
cardiac valvulopathy developes.
AHA - 2007
Dental procedures for which:
Endocarditis prophylaxis
recommended
Endocarditis prophylaxis not
recommended
All dental procedures thast involve
manipulation if gingival tissue or
the periapical region of the teeth or
perforation of the oral mucosa.
• Dental extractions.
• Periodontal procedures.
• Dental implant replacement or
reimplantation.
• Initial placement of orthodontic
bands but not brackets.
• Prophylactic cleaning of teeth or
implants where bleeding is
anticipated.
• Restorative dentistry (filling
cavities, operative &
prosthodontics) with or without
retraction cord.
• LA injections
• Postoperative suture removal.
• Taking of oral impressions.
• Fluoride treatment.
• Orthodontic appliance adjustment.
ROUTE
DOC
ORAL
AMOXICILLIN
DOSE
ENDOCARDITIS PROPHYLAXIS
2 g; 1 hr before procedure
CLINDAMYCIN, OR
600 mg; 1 hr before procedure
CEPHALEXIN OR
2 g; 1 hr before procedure
AZITHROMYCIN /
CLARITHROMYCIN
500 mg; 1 hr before procedure
AMPICILLIN
2 g IM or IV; 30 minutes before
procedure
Penicillin
allergy
PAREN
TERAL
Penicillin CLINDAMYCIN
allergy
600 mg IV; 1 hr before
procedure
OR
CEFAZOLIN
1 g IM or IV; 30 minute before
procedure
Semisynthetic penicillins:
Chemically
combining
specific side
chain in place
of benzyl side
chain.
Aim is to overcome the short
comings of Penicillin G.
Narrow
spectrum
Poor oral
efficacy
Susceptibility
to
penicillinase
Hypersensitivity
(has not been
overcome in any
preparation).
• Acid resistant alternative to Pn G:
• Phenoxymethyl penicillin (Penicillin V)
• Penicillinase resistant penicillin:
• Cloxacillin
• Methicillin
• Extended spectrum penicillins:
• Aminopenicillins
– Ampicillin
– Bacampicillin
– Amoxycillin
• Carboxypenicillins
– Carbenicillin,
– Ticarcillin.
• Ureidopenicillins
– Mezlocillin,
– Piperacillin.
Phenoxymethyl penicillins: (Pn V)
• It differs from Pn G only in that it is acid stable
• Oral absorption is better
• Antibacterial spectrum is identical to penicillin G. Less
active against Neisseria & other gram -ve bacteria &
anaerobes.
• Not dependable in serious conditions.
• Primarily for streptococcal infections like pharyngitis,
sinusitis, otitis media, prophylaxis of rheumatic fever.
Dose: 250-500 mg 6 hrly. 250 mg= 4 lac unit.
Penicillinase resistant penicillins:
• Have side chains that protect the beta lactam ring
from attack by staphylococcal penicillinase.
• Their only indication is infection caused by
penicillinase producing staphylococci infection for
which they are drug of choice.
Cloxacillin:
–Highly penicillinase & Acid resistant.
–Can be given orally.
–Effective against penicillinase producing
bacteria.
–Dose: 250-500 mg 6 hrly.
Oxacillin
dicloxacillin
flucloxacillin are similar (not available in
India).
Methicillin:
–Highly penicillinase but not Acid resistant.
–Must be injected i.v
–MRSA have emerged in many areas
–These are insensitive to penicillinase
resistant penicillins / other B lactams &
erythromycin/ aminoglycosides/
tetracyclines etc.
–Have altered PBPs ; do not bind penicillins
–DOC Vancomycin/ linezolid/ ciprofloxacin
can also be used.
–Nephrotoxicity
Extended spectrum penicillins:
• Active against wide variety of gram –ve
bacteria as well. X Psuedomonas,
kleibseilla, proteus (lack porin channels)
Aminopenicillins :
• Amino substitution in the side chain
Ampicillin
• Active against all organisms as penicillin G + many gram
–ve bacteria(Hydrophillic; penetrate porin chanels).
– H.influenzae, E.coli, Proteus, Salmonella,
and Shigella.
– Many have developed resistance.
• Pharmacokinetics:
–oral absorption-incomplete but
adequate.
– Food interferes with absorption,
I hour before meals.(X
amoxycillin)
–primary channel kidney.
• Dose: 0.5-2gm oral/IM/IV 6 hrly.
Adverse effects :
Diarrhoea
• Unabsorbed drug irritates the lower
intestines.
• Alteration of normal bacterial flora.
Rashes
Bacampicillin
• Prodrug of ampicillin
• Completely absorbed.
– Does not disturb intestinal ecology.
– Incidence of diarrhoea is less
• Higher plasma levels are obtained.
• Better tissue penetration
Talampicillin
Pivampicillin
Hetacillin
• Are other prodrugs of ampicillin.
Amoxycillin :
Congener of ampicillin
Similar in all respects except:
»Oral absorption is better.
»Food does not interfere.
»Higher & more sustained blood levels.
»Incidence of diarrhoea is less.
»Less active against shigella & H.influenzae.
• Dose : 0.25-1 gm TDS oral/IM.
Aminopenicillins
Therapeutic Uses:
• In dentistry: Ampicillin/ Amoxicillin is used alone or with
metranidazole in
– acute necrotising ulcerative gingivitis
– or peridontitis
– pulpitis,
– dentoalveolar abcess,
– ludwig’s Angina,
– osteomyelitis of mandible etc
• UTI/RTI/Meningitis/Gonorrhoea/Typhoid fever/Bacillary dystentry/
• Cholecystitis/SABE/Septicemia & mixed infections.
Carboxypenicillins:
• Carbenicillin
• Ticarcillin
Carbenicillin
 Comparable activity against many gram
positive & -ve organisms.
 Special feature of this penicillin congener is
its activity against Pseudomonas auerginosa
and indole positive Proteus which are not
inhibited by Pn G or aminopenicillins.
 Neither penicillinase nor acid resistant
 Inactive orally ; P/E administration.
 Used as : 1-5 gm IV 4-6 hrly.
 and excreted in urine.
 C/I : in renal patients.
Indications:
Serious infections caused by Pseudomonas or
Proteus eg.
 Burns,
 UTI,
 Septicemia.
Piperacillin is now preferred.
Ticarcillin
• More potent than carbenicillin.
• Other properties are similar to carbenicillin.
Ureidopenicillins :
Piperacillin
• This Antipseudomonal penicillin is 8 times
more active than carbenicillin.
• Good activity against Klebsiella.
• Dose: 3-4 gm 6-8 hrly.
• It is available in combination with Tazobactam.
Piperacillin in combination with beta lactamase
inhibitor (zosyn)
• has the broadest antibacterial spectrum amongst
the penicillins.
• High billiary concentrations are achieved.
• Important agent for the treatment of patients with
serious infections caused by psuedomonas,
proteus & klebseilla
– Bacteremias
– pneummonias
– and infections following burns and UTIs
– Pseudomonas infection in neutropenic/
immunocompromised patients .
Adverse reactions to penicillins
• Pain & sterile inflammatory reactions at
the sites of i.m injection.
• Phlebitis & thrombophlebitis on i.v
injection.
• Nausea with / without vomiting.
• Mild to severe diarrhoea.
• mental confusion, muscular twitchings,
convulsions, coma.
• Procaine penicillin: hallucinations,
convulsions.
•Hypersensitivity reactions:
incidence 1-10%., rash, itching,
urticaria & fever acute
anaphylactic reactions.
–History
–Senstivity test
–Inj adrenaline & hydrocortisone
handy
•Jarisch Herxheimer Reaction.
β - Lactamase inhibitors
β lactamases
• Family of enzymes produced by g-ve
& g+ve organisms
• Inactivate β lactam antibiotics by
opening the β lactam ring
β -lactamase inhibitors
• Potent inhibitors of β -lactamases
• Resemble β -lactam antibiotic
• Do not possess antimicrobial action
• Bind irreversibly to the catalytic site of
susceptible β -lactamases particularly
penicillinase to prevent hydrolysis of
penicillins
• Suicide inhibitors
Currently 3 ß-lactamase
inhibitors are available
Beta lactamase Inhibitors
Clavulanic acid
Sulbactam
Tazobactam
–Clavulanic acid, ORAL/PARENTRAL
derived S. clavuligerus
–Sulbactam I.M/I.V semisynthetic,
–and tazobactam I.M/I.V str. analogue of
sulbactam
• These agents are given together with
hydrolyzable penicillins to protect them from
inactivation.
• Extends the use of penicillin against β - lactamase
producing bacteria.
• ACCORDING TO THEIR COMMON pK features
– Clavulanic acid + amoxacillin
– Sulbactam + ampicillin
– Tazobactam + piperacillin & are available as fixed dose
combinations
–Clavulanic acid 125 mg + amoxacillin
250mg
–Sulbactam 0.5g + ampicillin 1g
–Tazobactam 0.25g +piperacillin 2g
available as fixed dose combinations
Most effective against β-lactamases produced
by:
• Staphylococci
• H. influenzae
• N. gonorrhoeae
• Salmonella
• Shigella
• E. coli
• K. pneumoniae
• The β -lactamase inhibitors are effective
against ß-lactamase producing organisms.
– e.g. ampicillin in combination with sulbactam is
effective against ß-lactamase producing S.
aureus and H. influenzae.
• Non β - lactamase producing microorganisms : no advantage
• Ineffective against Methicilin resistant staph
aureus.
THERAPEUTIC USES
• Sulbactam is used in Odontogenic infections
caused by β-lactamase producing strains of Staph.
Aureus, H. influenzae E. coli, N. gonorrhoeae,
Salmonella, Shigella.
• Mixed nosocomial infections.
• Skin & Soft tissue infection,
• Urinary, biliary and respiratory tract infection,
• Mixed intra-abdominal and pelvic infections,
• Hospital acquired infection.
THANK YOU
Mechanism of action
• Cell wall of bacteria essential for normal growth
&development
• Peptidoglycan
• Highly cross linked latticework structure
• Glycan chains (linear strands of two aminosugars;
NAG NAM) cross linked by peptide chains
• Provides rigid mechanical stability
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Endocarditis prophylaxis not recommended
• Surgical repair of
– ASD, VSD
– PDA
• Previous CABG
• MVP without valvular regurgitation.
• Physiologic, functional or innocent heart murmurs.
• Previous rheumatic fever without valvular dysfunction.
• Cardiac pacemakers (intravascular & epicardial) & implanted
defibrillators.