Antimicrobial drugs

Farah MoradIUG

Faculty Of Medicine220061056

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 ?

Selective toxicity

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 ofgram-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

Inhibition of bacterial Cell Wall Synthesis: III. Mechanisms of Antimicrobial Drugs

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 /dailyAmoxicillin 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)

• Penicilinase-resistant penicillins

Augmentin ,Naficillin, sublactam ,Methacillin,Floxacillin    

• Extended-spectrum penicillins ampicillin & amoxicillin

Shift +F5 To see the animation

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-D- alanine

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

Principle:

- differences between bacterial and human ribosomal proteins, RNAs

- Bacteria 70S ..50S and 30S subunits,

- human cells have 80S ..60S and 40S subunits

3- INHIBITION OF PROTEIN SYNTHESIS

I. Drugs That Act on the 30S Subunit Aminoglycosides

No Initiation complex .. and misreading (mRNA)

Are bactericidal drugs.. Broad spectrum

Streptomycin, neomycin, gentamycin ,tobramycin ,Kanamycin.

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 !