BETA LACTAM ANTIBIOTICS AND OTHER
INHIBITORS OF CELL WALL SYNTHESIS
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INHIBITORS OF CELL WALL SYNTHESIS
Beta lactam antibiotcs
Penicillins Cephalosporins
2nd generation
Penicillin G
Penicillin V
Methicillin
Oxacillin
Nafcillin
Cloxacillin
Dicloxacillin
Ampicillin
Piperacillin
Ticarcillin
Carbenicillin
Amoxycillin
Mezlocillin
Azlocillin
1st generation
Cefazolin
Cefadroxil
Cephalexin
Cephalothin
Cephradine
Cephapirin
3rd generation
Cefdinir
Cefixime
Cefoperazone
Cefotaxime
Ceftazidime
Moxalactam
Ceftriaxone
Ceftibuten
Ceftizoxime
Cefaclor
Cefamandole
Cefonicid
Cefametazole
Cefotetan
Cefoxitin
Cefuroxime
4th generation
Cefepime
Carbepenams
Imipenams/Cilastatin
Monobactams
Aztreonam
Other antibiotics
Vancomycin
Bacitracin

• 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 .

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• 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.
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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.

• 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

•
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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

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Glycan chains consist of two aminosugars
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N acetyl muramic acid (NAM) &
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N acetyly glucosamine (NAG)
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Pentapeptide side chain is linked to NAM sugar
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Forms the peptidoglycan molecule
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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
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Catalyzed by PBPs , transmembrane surface enzymes present in bacteria
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Energy is released which is utilized for establishing cross linkages between peptide chains of the neighbouring strands.
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This cross linking Provides stability and rigidity to the cell wall

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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
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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.
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Interior of bacterium is hyperosmotic
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Osmotic drive occurs
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CWD form swell and bursts
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Lysis of bacteriaBACTERICIDAL

• 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 d
Peptidoglyc an cell wall d
Cytoplasmic
Membrane
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Gram-negative Bacterial Membrane
Structure
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Gram-negative bacteria are surrounded by two membranes.
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The outer membrane functions as an efficient permeability barrier containing lipopolysaccharides
(LPS) and porins. d d d
Outer membrane
Peptidoglycan cell wall
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.

Inherent
Deeper localisation of target enzymes & penicillin binding protein.
loss or alteration of porin channels ;
Pn G is unable to penetrate.
Acquired
:
Production of penicillinase.

opens the β lactam ring and inactivates Pn G
Staphylococcus, Gonococcus,
B subtilis, E coli, H influenzae produce penicillinase.

Penicillinase
Gram +ve organisms In Gram -ve bacteria produce large quantity of penicillinase which diffuse in the surroundings and protect the bacteria.
constitutive enzyme small quantity strategically located between the lipoprotein and peptidoglycan layers of the cell wall.

Gram –ve bacteria
PBP’s :
Penicillin
Binding
Proteins
Gram +ve bacteria
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• Efflux pump in some G -ve bacteria .

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Natural Penicillin
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Narrow spectrum
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Primarily active against G +ve bacteria
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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.

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Some cases of endocarditis occur after dental procedures .
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Prophylactic antibiotics are given to patients with predisposing congenital or valvular anomalies.

Endocarditis prophylaxis recommended
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Prosthetic cardiac valves
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Previous BE
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Congenital heart diseases.
– unrepaired cyanotic CHD
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Completely repaired CHD with prosthetic material / device.
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Cardiac transplantatiom recipients in whom cardiac valvulopathy developes.
AHA - 2007

Dental procedures for which:
Endocarditis prophylaxis recommended
All dental procedures thast involve manipulation if gingival tissue or the periapical region of the teeth or perforation of the oral mucosa.
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Dental extractions.
• Periodontal procedures.
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Dental implant replacement or reimplantation.
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Initial placement of orthodontic bands but not brackets.
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Prophylactic cleaning of teeth or implants where bleeding is anticipated.
Endocarditis prophylaxis not recommended
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Restorative dentistry (filling cavities, operative & prosthodontics) with or without retraction cord.
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LA injections
• Postoperative suture removal.
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Taking of oral impressions.
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Fluoride treatment.
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Orthodontic appliance adjustment.

ROUTE DOC DOSE
ENDOCARDITIS PROPHYLAXIS
2 g; 1 hr before procedure
AMOXICILLIN
ORAL
CLINDAMYCIN, OR 600 mg; 1 hr before procedure
Penicillin allergy
CEPHALEXIN OR
2 g; 1 hr before procedure
AZITHROMYCIN /
CLARITHROMYCIN
500 mg; 1 hr before procedure
PAREN
TERAL AMPICILLIN
Penicillin allergy
CLINDAMYCIN
OR
CEFAZOLIN
2 g IM or IV; 30 minutes before procedure
600 mg IV; 1 hr before procedure
1 g IM or IV; 30 minute before procedure

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.

• 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.

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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 .

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.

• Carbenicillin
• Ticarcillin

 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.

– History
– Senstivity test
– Inj adrenaline & hydrocortisone handy
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• 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

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Clavulanic acid, ORAL/PARENTRAL derived S. clavuligerus
–
Sulbactam I.M/I.V semisynthetic ,
– and tazobactam I.M/I.V str. analogue of sulbactam

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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:
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Staphylococci
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H. influenzae
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N. gonorrhoeae
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Salmonella
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Shigella
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E. coli
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K. pneumoniae

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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.

• 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.

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Cell wall of bacteria essential for normal growth
&development
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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
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Surgical repair of
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ASD, VSD
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PDA
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Previous CABG
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MVP without valvular regurgitation.
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Physiologic, functional or innocent heart murmurs.
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Previous rheumatic fever without valvular dysfunction.
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Cardiac pacemakers (intravascular & epicardial) & implanted defibrillators.