Transcript Antimicrobial drugs

Antimicrobial drugs
Farah Morad
IUG
Faculty Of Medicine
220061056
Selective toxicity
The ability to kill an invading microorganism without harming
the cells of the host ..
Why ?
differences between microorganisms and human beings
Relative, rather than absolute
Concentration ..carefully controlled
More antibacterial than antiviral …Why ?
Broad & narrow spectrum :
1- Broad spectrum
both gram-positive and gram-negative
the critically ill patient delay ..example ??
tetracycline ,chloramphenicol
Superinfection
2- Narrow spectrum:
more specific..
Isoniazid for Mycobacteria ..Name? , Penicillin
3- Extended spectrum:
effective against gram-positive & significant Number of
gram-negative bacteria
Ampicillin
Bacteriostatic & Bactericidal
** Bacteriostatic
(1) the bacteria can grow again
(2) host defense mechanisms
** Bactericidal
1- Immediately life-threatening infection
2-leukocyte count is below 500/IuL
3-Endocarditis, phagocytosis is limited
III.Inhibition
Mechanisms
of Antimicrobial
of bacterial
Cell WallDrugs
Synthesis:
B-Iactam drugs: Penicillins and cephalosporins.
Non B-Iactam drugs: Vancomycin ,Cycloserine & Bacitracin
Inhibition of bacterial Cell Wall Synthesis:
Penicillin
1-Transpeptidases (pbps)
No cross-linking peptidoglycan
2- Autolytic enzymes : murein hydrolases
Staphylococcus aureus, : Tolerant
Penicillins kill bacteria when they are growing
which phase of bacterial Growth ?
Log Phase
Gram +ve or –ve ? Why ?
Gram +ve because they have a cell wall
Gram –ve have a cell membrane
Penicillin Mechanism of Action - Animation
Shift +F5 to see the animation
penicillin Kills Bacteria in log phase
Disadvantages:
1-limited effectiveness against many gram-negative rods.. Why ?
Extended-spectrum penicillins
ampicillin & amoxicillin.. modified R
Ampicillin 4 /daily
Amoxicillin 3/ daily.. Compliance
Pseudomorms aeruginosa,,No effect Because it Lacks porins
2-hydrolysis by gastric acids ..oral effectiveness ??
oxygen : penicillin V
amino group: ampicillin
(3) inactivation by B-lactamases.
A -methicillin, oxacillin, nafcillin,
large aromatic rings contain- bulky methyl or ethyl
B-inhibitors such clavulanic acid and and supbactam.
-(Augmentin) Combinations, amoxicillin and clavulanic acid ..
Expensive !!
(4) disadvantage hypersensitiv- anaphylaxis,
in 0.5% of patients..fatal
skin rashes, hemolytic anemia, nephritis, fever.
No solution till now !
•
Bacterial Resistance to penicillin
Beta lactamases
Alteration of PBP (Pseudomonas)
Shift +F5 To see the animation
•
Penicilinase-resistant penicillins
Augmentin ,Naficillin, sublactam ,Methacillin,Floxacillin
•
Extended-spectrum penicillins
ampicillin & amoxicillin
B- lactamases- Animation
Shift +F5 to see the animation
Forms of penicillin G
1-Aqueous
2-Procaine..IM
3-Benzathine..depot
Cephalosporins
- against gram-positive cocci primarly..1st Generation
- From 1- 4 generations : increased sensitivity to gram –ve
-4 th against a broad range of organisms,
-Same Action of penicilllin
- fewer hypersensitivity reactions than do the penicillin
Carbapenems: (Imipenem)
- B-lactam drugs
- not inactivated by most B-Lactamases.
- structurally different from penicillins and cephalosporins
- widest spectrum of activity of the B-Lactam
- many gram-positive, gram-negative, and anaerobic bacteria
- In combination with cilastatin an inhibitor of dehydropeptidase
a kidney enzyme that inactivates imipenem.
Monobactams (Aztreonam)
- B-lactam
- resistant to most B-lactamases…Good !!
- they are monocyclic
- Aztreonam, has excellent activity against many gram -ve rods
- no cross-reactivity.. Patients hypersensitive to penicillin
Vancomycin:
not B-lactam
Transpeptidase compititive inhibition
binds directly to the D-alanyl-D-alanine of peptidoglycan
bactericidal against gram-positive bacteria
Uses:
1-S. aureus strains resistant to the penicillinase-resistant
penicillins (MRSA)
VMRSA?!!!
2- Antimicrobial induced Cholitis …Oral
Vancomycin Action –Animation
Shift +F5 to see the animation
Cycloserine
1- analogue of D-alanine inhibits dipeptide D-alanyl-Dalanine
2- It is used as a second line drug in the treatment TB
Remember : What first line ??
Great !!
Rifampin & isoniazide
Bacitracin
1- prevents dephosphorylation of the phospholipid carrier of
the
peptidoglycan
2- Treatment of superficial skin infections (Topical)
too toxic for systemic use.
2. Inhibition of Fungal Cell Wall Synthesis
Caspofungin
- lipopeptide
-Inhibition of B-glucan synthase
-Aspergillus and Candida but not Cryptococcus or Mucor.
-Disseminated candidiasis and Invasive aspergillosis
3- INHIBITION OF PROTEIN SYNTHESIS
Principle:
- differences between bacterial and human ribosomal proteins,
RNAs
- Bacteria 70S ..50S and 30S subunits,
- human cells have 80S ..60S and 40S subunits
I. Drugs That Act on the 30S Subunit
Aminoglycosides
Are bactericidal drugs.. Broad spectrum
Streptomycin, neomycin, gentamycin ,tobramycin ,Kanamycin.
No Initiation complex .. and misreading (mRNA)
Aminoglycosides Animation-1
Shift +F5 to see the animation
Aminoglycosides Animation 2
Shift +F5 to see the animation
Aminoglycosides cont.
1- Toxicicity the kidneys
How to Avoid ?? Urea & Creatinine tests
2- eighth cranial nerveToxicicity
3- Cannot be given orally.
4- Must be given intrathecally meningitis.
5- Ineffective against anaerobes ..Needs O2 to enter cells
Tetracyclines
Bacteriostatic
Gram +ve & -ve bacteria, mycoplasmas, chlamydiae, and rickettsiae.
The 30S ribosomal & (tRNA)
Selectivity : greatly increased uptake into susceptible bacteria
compared with human cells.
Doxacycline…(Cholera)
Side Effects :
1- Diarrhea & superinfection .
2- Brown staining of the teeth of fetuses and young children
3- Tetracydines are avid calcium chelators
4- Contraindicated for use in pregnant women and in children<8
* Advantages of drug combinations
• show synergism
- B-Iactams and aminoglycosides,.
- B-lactams + calvulanic acid
• Disadvantages of drug combinations
bacteriostasis & bactericidal.
Needs To modify drugs :
1- Change route of administration ..Compliance
2- Overcome resistance
3- Minimize side effects
4-Wideninig Spectrum of activity
Thank you !