Antimicrobial drugs Farah Morad IUG Faculty Of Medicine

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 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

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 /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) 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..1 st 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 !