inhibitor of bacterial cell wall synthesis.ppt

Dr. NDAYISABA CORNEILLE
CEO of CHG
MBChB,DCM,BCSIT,CCNA
Supported BY
INHIBITORS OF
BACTERIAL CELL
WALL SYNTHESIS

Inhibitors of bacterial cell wall synthesis
1. Beta lactam antibacterial drugs
a. Penicillins *
b. Cephalosporins*
c. Carbapenems *
d. Monobactams*
e. Beta-lactamase inhibitors *
2. Non-beta lactam antibacterial drugs
a. Vancomycin*
b. Teicoplanin*
c. Daptomycin*
d.Cycloserine D*
e.Bacitracin*
f.Fosfomycin*

PENICILLINS
Dr Ndayisaba Corneille

Introduction
 Penicillins;
— Are examples of beta lactam antibacterials bcoz
they contain a beta lactam ring in their structure
— Are either natural & semi synthetic antibacterial
drugs
— Have the same basic structure
— Are usually used in tx of gram +ve bacterial
infections Dr Ndayisaba Corneille

— Were the first antibiotic drugs to be effective
against many previously serious diseases
like;
 Syphilis
 Staphylococcus infections
— Are still widely used today but many types
bacteria are currently resistant
— Can be inactivated by bacterial penicillase
enzymes (beta-lactamase enzymes)

Mechanism of action of penicillins
— Inhibit bacterial growth by interfering with the
bacterial cell wall synthesis
— This eventually leads to bacterial cell death
— This is by inhibiting transpeptidation reaction
involved in formation of bacterial cell wall
-Penicillins kill bacterial cells only when they are
actively growing & synthesizing cell wall

Classification of
Penicillins

a) Natural penicillins
b) Repository forms of penicillin G
c) Semi synthetic penicillins
d) Beta-lactamase resistant penicillins
e) Broad spectrum penicillins
f) Antipseudomonal penicillins
g) Penicillins combined with beta-lactamase
inhibitors

a) Natural penicillins
 Penicillins obtained from a fungus known as
penicillin notatum
 Are highly active against gram +ve bacteria
 Less active against gram –ve bacteria
 Are inactivated by bacterial beta-lactamase
Example
 Benzyl penicillin (penicillin G)

b) Repository forms of penicillin G:
 Penicillin G procaine
 Penicillin G Benzathine
 Procaine penicillin Fortified (PPF)
 Penicillin Aluminium Methysylate - PAM oil

c) Semi synthetic penicillins:
 Penicillins produced by modification of
natural penicillins
Examples
 Phenoxymethyl penicillin

d) Beta-lactamase resistant penicillins:
 Are penicillins which are resistant to
beta-lactamase enzymes produced by some
bacteria like S.aeurus , E.coli etc
Examples
— Methicillin or Meticillin
— Temocillin
— Nafcillin

— Isoxazolyl penicillins like:
 Cloxacillin
 Flucloxacillin
 Dicloxacillin
 Oxacillin

e) Broad spectrum penicillins
— Can kill both gram +ve & gram -ve bacteria
Examples
1. Aminopenicillins: contain an amino group
 Ampicillin
 Amoxicillin
 Pavampicillin
 Bacampicillin

f) Anti-pseudomonal penicillins
 Penicillins that are usually indicated to tx
pseudomonas aeruginosa infections
 They can also be used to tx other bacteria
infections
Examples
1. Carboxypenicillins:
 Carbenicillin
 Ticarcillin Dr Ndayisaba Corneille

2. Ureidopenicillins:
 Piperacillin
 Azlocillin
 Mezlocillin

g) Penicillins combined with beta-lactamase
inhibitors:
 Beta-lactamase inhibitors are agents which
inhibit beta-lactamase enzymes produced by
some bacteria like s.aeurus
 Examples of beta-lactamase inhibitors
 Clavulanic acid
 Sulbactam
 Tozabactam Dr Ndayisaba Corneille

 Penicillin + beta-lactamase inhibitors include;
 Clavulanic Acid + Amoxicillin
 Sulbactam + Ampicillin
 Tozabactam + piperacillin

Pharmacokinetics of penicillins
 They can be given by;
 Oral route in mild infections
 IM
 Intravenously in severe infections
 Intrathecal x-pen cozes convulsions thus this
route is not recommended

 Absorption of oral penicillins is ↓ when taken with
foods like;
 Caffeine -Citrus fruit
 Cola beverages -Fruit juices
 Tomato juice

 Penicillins are widely distributed to most body
fluids & parts like;
 Joints
 Pleural cavity
 Pericardial cavity
 Gall bladder
 Saliva & milk
 Across the placenta

 Bcoz penicillins are lipid insoluble this means
they;
 They do not enter mammalian cells
 Do not cross the BBB to get to brain unless
the meninges are inflamed like in meningitis
 Elimination of most penicillins is mainly by renal
tubular secretion Dr Ndayisaba Corneille

Clinical uses of the penicillins
 Genitourinary infections like cystitis ,pyelonephritis :Amoxiclav
 Severe dental infections like dental abscesses:Amoxiclav
 Cellulitis,Intra-abdominal infections :Amoxiclav
 Ampicillin Combined with flucloxacillin for empirical tx of cellulitis
(co-fluampicil)
 Ampicillin Combined with cloxacillin during tx of pyomyositis &
myositis (ampiclox)
 Ampicillin :Tx of chorioamnionitis in combination with gentamicin
 Ampicillin :Tx of exacerbations of bronchitis
 Ampicillin :Tx of bacterial peritonitis in combination with gentamicin
+ metronidazole
 Ampicillin:Tx of septicaemia in combination with gentamicin
 Ampicillin :Meningitis due to Listeria monocytogenes
 Ampicillin :Invasive salmonellosis

 Bacterial meningitis due to Neisseria meningitidis,
Streptococcus pneumoniae: IV benzylpenicillin
 Bone & joint infections due to S. aureus: flucloxacillin
 Skin & soft tissue infections due to Strep pyogenes or S.
aureus ;IV benzylpenicillin or flucloxacillin
 Serious infections due to pseudomonas aeruginosa:
piperacillin.
 Syphilis:procaine benzylpenicillin or benzathine
penicillin
 TX of animal bites: co-amoxiclav
 Pharyngitis due to S. pyogenes: phenoxymethylpenicillin

 UTIs due to Escherichia coli: amoxicillin
 Oral infections like dental abscess: amoxicillin
 Used in triple therapy in eradication of helicobacter pylori during tx
of peptic ulcer disease : amoxicillin
 Endocarditis due to S. viridans or Enterococcus faecalis:Amoxillin in
combination with other antibiotics
 Gonorrhea: amoxicillin + probenecid
 Tx of LRTIs like Pneumonia, Bronchitis: amoxicillin,Amoxiclav
 Tx ENT Bacterial Infection such as sinusitis, Otitis media: amoxicillin
 Otitis media due to S. pyogenes, haemophilus influenzae:
amoxicillin
 Tx meningitis due to Listeria monocytogenes:IV amoxicillin

Indications of CLOXACILLIN
 Mild to moderate infections due to penicillase producing staph. Aureus
like;
1. Otitis externa
2. Staphylococcal pneumonia when cloxacillin is combined with
gentamicin
3. Impetigo
4. Cellulitis
5. Staphylococcal endocarditis
6. Localized soft tissue/skin infections like boils
7. Septicaemia when its combined with gentamicin
8. Pyogenic arthritis
9. Osteomyelitis
10. Pyomyositis
11. Myositis

Indications OF Benzylpenicillin
1. Bacterial meningitis
2. Aspiration pneumonia in combination with fragyl
3. Lung abscess
4. Community-acquired pneumonia
5. Syphilis
6. Gonorrhea
7. Bacterial endocarditis
8. Septicemia in children & adults
9. Septic Arthritis
10. Cellulitis
11. Septic wounds
12. Gangrenous wounds like diabetic foot
13. Bacterial otitis media
14. Given as a prophylactic antibiotic after limb amputation & after major
surgeries
15. Treatment of anthrax
16. Throat infections like tonsillitis ,Pharyngitis

S/Es
— Penicillins are remarkably nontoxic
1.Hypersensitivity reactions like
— Anaphylactic shock
— Urticaria
— Fever
— Joint swelling
— Intense pruritus

— DIB
— Skin rashes
— Oral ulcerations
— Interstitial nephritis
— Hemolytic anemia
— Vasculitis
— Eosinophilia
— Angioneurotic edema

2. Others less common S/Es
 Seizures esp in pts with RF
 Supra-bacterial infections like vaginal
candidiasis
 N +V & diarrhea with oral penicillins
 Pseudomembranous colitis with ampicillin
 Neutropenia with nafcillin

 Hepatitis with Oxacillin
 Non allergic skin rashes with ampicillin &
amoxicillin
Contraindications to penicillins
 Hx of hypersensitivity to penicillins

Introduction
 Cephalosporins:
— Are broad spectrum antibiotics which are similar to
penicillins
— Are semi-synthetic broad spectrum antibiotics
— They are resistant to many bacterial beta-
lactamase enzymes which destroy penicillins

Mechanism of action
 As for penicillins
Antibacterial activity of cephalosporins
— They are active against gram-ve & gram+ve
bacteria
— Some strains of E.coli &Klebsiella spp produce
beta-lactamase enzymes that break down most
cephalosporins

— They are not active against;
 Enterococci
 Listeria monocytogenes

Classification of cephalosporins
 They are classified into 4 major generations
depending on;
 Spectrum of antimicrobial activity
 When they were discovered
1. First generation cephalosporins
2. Second generation
3. Third generation
4. Fourth generation Dr Ndayisaba Corneille

First generation cephalosporins
Examples
 Cefadroxil
 Cefazolin
 Cephalexin
 Cephalothin
 Cephapirin
 Cephradine Dr Ndayisaba Corneille

2nd generation
 Cefaclor
 Cefonicid
 Cefprozil
 ceforanide
 Cefamandole
 Cefmetazole
 Cefoxitin
 Cefotetan
 Cefuroxime
 Loracarbef
 Ceforanide

3rd generation
Examples
 Cefixime
 Ceftizoxime
 Cefpodoxime
 Ceftriaxone
 Cefoperazone
 Ceftazidime
 Cefotaxime
 Moxalactam
 Proxetil
 Cefdinir
 Cefditoren pivoxil
 Ceftibuten

4th generation
1. Cefepime
 Its resistant against beta-lactamase
enzymes

Indications of cephalosporins
Used for tx of;
— Bacterial Bacteremia/septicaemia (cefotaxime/
ceftriaxone)
— Bacterial meningitis
— Biliary tract infections like acute Cholecystitis,
cholangitis
— Peritonitis in combination with metronidazole

— UTIs like urethritis ,PID,cystitis, pyelonephritis ,Gonorrhea
— UTIs in pregnancy & those resistant to other drugs
— ENT condition –Sinusitis:cefadroxil. OTM: Cephalexin
-Arrhythmias after MI.for example: use of cefotaxime
— Septic wound in combination with fragyl
— Bacterial otitis media
— Given prophylactically before surgery
— Obstetric infections like post operative wound sepsis
— Respiratory tract infections.eg: pneumonia

-Skin infections like boils & carbuncles.eg
cephalexin, ceftriaxone ,etc.
-Soft tissue abscess due to staph / strep.eg:
cephalexin, ceftriaxone,etc.
-Tx of oral infections like dental abscesses
eg:Cephalexin in combination with metronidazole
-Bone & joint infections.eg: Cephalexin,ceftriaxone
-Prophylaxis against meningococcal meningitis.for
example:ceftriaxone Dr Ndayisaba Corneille

Pharmacokinetics
 Cephalosporins are available inform of;
 Tablets, capsules, syrups & injectable form
 Routes of administration
 Orally as tablets, capsules & oral solution
 Parenterally by IM injection or IV
 Cephalosporins are widely distributed in the body

 The following cephalosporins cross the blood brain
barrier;
 Cefoperazone
 Cefotaxime
 Cefuroxime
 Ceftriaxone
 Excretion of cephalosporins is by;
 Kidney tubular secretion (mostly)
 Via bile excretion

Adverse effects
1. Hypersensitivity reactions similar to those of
penicillins penicillins like;
 Anaphylaxis
 Fever
 Skin rashes
 Nephritis
 Granulocytopenia
 Hemolytic anemia

2. Other S/Es
— Local irritation with severe pain after IM injection
— Thrombophlebitis after IV injection
— N+V
— Diarrhoea
— Hypoprothrombinemia
— Bleeding disorders

— Renal damage with;
 Interstitial nephritis
 Acute tubular necrosis
Contraindications
 Pts with h/o hypersensitivity to cephalosporins
 Pts with h/o anaphylaxis to penicillins
 Neonates with jaundice/hyperbilirubinaemia
 Hypoalbuminaemia ,Patients with acidosis
 Children receiving calcium supplements due risk of
urine stone formation

Carbapenems
 Are structurally similar to beta-lactam antibiotics
 -lactams : fused -lactam ring & a 5-membered
ring system that differs from PCNs in being
saturated and containing a carbon atom instead of
a sulfur atom
 Broader spectrum of activity
Examples
1. Ertapenem
2. Imipenem/Cilastatin

Imipenem/Cilastatin
 Imipenem:
Binds to PBPs, disrupts bacterial cell wall
synthesis = death of microorganisms
 Cilastatin:
Inhibits the enzyme dehydrogenase in
renal proximal convoluted tubules =
inhibits cleavage of Imipenem (has
nephrotoxic metabolite)

Imipenem/Cilastatin
 Good tissue and CNS penetration
 Resistant to -lactamases
 Given IM or IV; Not absorbed orally
 Clearance :
Kidneys = 70% unmetabolized
* adjust dose in renal insufficiency

Imipenem/Cilastatin
SPECTRUM:
Broadest spectrum -lactam antimicrobial
Excellent activity against:
Aerobic & anaerobic G ( + ) & G ( - )
organisms
Good activity against:
P.aeruginosa & B. fragilis
Poor activity:
Methicillin-resistant S. aureus

Imipenem/Cilastatin
SIDE-EFFECTS:
 Nausea & vomiting – most common
 Seizures (1.5%) :
In high doses (pxs with CNS lesions) and
those with renal insufficiency
 Cross-sensitivity allergic reactions
 Contraindicated in epilepsy :
decreased seizure threshold

MONOBACTAMS

Monobactams
 These also contain a beta-lactam ring
Examples
1. Aztreonam
 Its given IV
 Dosage;1–2g tds

Aztreonam
 Monobactam :
Interacts with PBPs = induces formation
of long, filamentous bacterial structures
 Extremely resistant to -lactamases
 Given IM or IV
SPECTRUM:
G ( - ) Aerobic rods
P. aeruginosa & Serratia

Aztreonam
 Administered intravenously
 Renal clearance half-life: 1.5 hrs.
 Dosing: q 8 hours
 Clinical application:
Treatment of infections caused by G (-)
aerobic bacteria with immediate
hypersensitivity to Penicillins

Aztreonam
SIDE-EFFECTS:
 No Cross-reactivity with Penicillin &
Cephalosporin
 Streptococcus & Enterococci superinfections
 Elevation of transaminases

BETA-LACTAMASE
INHIBITORS

Beta-lactamase inhibitors
 Are substances which resemble beta-lactam
antibiotics
 They have very weak antibacterial action
Mechanism of action
 Inhibit many bacterial beta-lactamase enzymes
which destroy penicillins & cephalosporins

Examples
1. Clavulanic acid
2. Sulbactam
3. Tazobactam

 Beta-Lactamase inhibitors are most active against
beta-lactamases produced by;
 Staphylococci
 H influenzae
 N gonorrhoeae
 Salmonella spp
 Shigella
 E. coli
 K pneumoniae Dr Ndayisaba Corneille

 Beta-lactam inhibitors are not good inhibitors of
beta-lactamases produced by;
 Enterobacter
 Citrobacter
 Serratia
 pseudomonas
 Bacteroides
 Branhamella

NON-BETA LACTAM
ANTIBACTERIAL
DRUGS

Vancomycin
 Streptococcus orientalis
 Active only against G(+) bacteria :
staphylococci
MOA: binds firmly to D-Ala-D-Ala terminus of
nascent peptidoglycan pentapeptide = inhibits
transglyosylase = prevents elongation
of peptidoglycan and cross-linking
= inhibition of cell wall synthesis

Resistance to Vancomycin
 Modification of D-Ala-D-Ala binding site of the
peptidoglycan building block = terminal D-Ala
is replaced by D-lactate
 Results in loss of a critical hydrogen bond
that facilitates high-affinity binding of
Vancomycin to its target -> loss of activity

Antibacterial Activity
 Bactericidal for G (+) pathogens
 Most Staphylococci (including nafcillin &
methicillin-resistant strains) are killed by
4ug/ml or less
 Kills slowly & only if cells are actively dividing

Pharmacokinetics
 Poorly absorbed in GIT (if given p.o.=>
treatment of antibiotic –induced
enterocolitis due to Clostridium dificile
 Must be administered IV
 Widely distributed = CNS penetration is 7 -
30 % if with meningeal inflammation
 90 % - glomerular filtration
 Clearance –proportionate to creatinine
clearance

Clinical Uses
 Sepsis
 Endocarditis due to Methecillin-resistant
staphylococci
 Combined with gentamicin = for enterococcal
endocarditis in penicillin-allergic patients
 Combined with cefotaxime, ceftriaxone,
rifampin = for meningitis caused by highly
penicillin-resistant pneumococci

Adverse Reactions
 10% - Minor
 Phlebitis at injection site – chills & fever
 Ototoxicity & nephrotoxicity – rare, BUT if
combined with drugs having these toxicities =
Increased risk
 “Red man” or “Red neck syndrome” –
infusion-related flushing (histamine-induced) :
prolong infusion or increase dose-intervals

FOSFOMYCIN TROMETAMOL
 Stable salt of Fosfomycin
 Inhibits the cytoplasmic enzyme
enolpyruvate transferase – covalently
binds to cysteine residue of the active site
= blocks the addition of
phosphoenolpyruvate to UDP N-
acetylglucosamine = blocks formation
of N-acetylmuramic acid (found
only in bacterial cell walls)

 Against both G (+) & G (-) organisms at
concentrations ≤ 125 ug/ml
 In vitro synergism with -lactams,
aminoglycosides, fluoroquinolones
 Oral or parenteral
 Oral bioavailability = 40 %
 Half-life – 4 hours
 Excretion – kidneys

Daptomycin
 Cyclic lipopeptide
 Spectrum:
Similar to Vancomycin = > bactericidal in vitro
Vancomycin resistant strains of enterococci and S.
aureus

Daptomycin
 MOA: Binds to cell-membrane via calcium-dependent
insertion of its lipid tail:
=> Depolarization of cell-membrane
=> K+ efflux = rapid cell death

Bacitracin
 Cyclic peptide mixture from Tracy strain of
Bacillus subtilis
 Active against G (+) pathogens
 MOA : interferes with dephosphorylation in
cycling of the lipid carrier that transfers
peptidoglycan subunits to the growing cell
wall

Bacitracin
 Markedly nephrotoxic – if given systemically :
proteinuria, hematuria, nitrogen retention
 Allergies – rare
 Limited to TOPICAL use = local antibacterial
activity
 Excretion – glomerular filtration

Bacitracin
 500 units/g in ointment form (mixed with
polymyxin or neomycin)
 Treatment of mixed bacterial flora infections
in surface wounds, skin or mucous
membranes
 Solutions (100-200 units/ml) : in saline – for
irrigation of joints , wounds or pleural cavity

Clinical use
 Uncomplicated lower urinary tract
infections in women
 Single dose : 3 grams
 Safe for pregnant women

END
BY
DR NDAYISABA CORNEILLE
MBChB,DCM,BCSIT,CCNA,Cyber Security
contact: amentalhealths@gmail.com ,
ndayicoll@gmail.com
whatsaps :+256772497591 /+250788958241
THANKS FOR LISTENING

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