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Drug
ANTI-MICROBIAL AGENTS
Side Effects Low toxicity may cause diarrhoea due to disturbance in normal gut flora. Seizures if injected intrathecally. Allergic reaction in 2%
BETA-LACTAMS
1. 2. 3. 4.
Penicillin is a mimetic of Ala-Ala natural substrate for transpeptidase enzyme Irreversibly inhibits transpeptidase preventing cell wall cross linking cell lys Build-up of peptidoglycan precursors triggers the activation of autolysins, which further digest the existing peptidoglycan. -
1) Penicillins
Standard Penicillin - Penicillin G IV only - Penicillin V Oral Anti-staphylococcal penicillin - Methicillin IV - Oxacillin & Doxacillin Aminopenicillins - Ampicillin IV - Amoxicillin Anti-pseudomonal penicillins Carboxy penicilins - Carbenicillin, ticarcillin Ureidopenicillins - Piperacillin Beta lactamase Inhibitors
Clavulanate Sulbactam Tazobactam They covalently bind Beta-lactamase and inhibit their function. Thus Beta-lactam activity is restored and the anti-biotic is active again. Used in combination therapy with Beta-Lactam anti-biotics. Amoxicillin + Clavulanate Ampicillin + Sulbactam Ticarcillin + Clavulanate Piperacillin + Tazobactam
Treating streptococci, meningococci and syphilis These are resistant to degredation. Used to treat staphylococcal infections. A drug of choice for resistant infections.
Ineffective against staphylococci. Enhanced activity against gram ve infection. Used for treatment of H. influenza, E. coli, Salmonella. Not active against staphylococci. Similar to aminopenicillin however enhanced activity against Pseudomonas aeruginosa.
Methicillin Resistance - Due to gene mecA - Codes variant penicillin binding protein (PBP 2a) low affinity for beta-lactams. - PBP 2a takes over cell wall synthesis in presence of methicillin unreactive to it.
2) Cephalosporins
1st generation - Cefadroxil po 2nd generation - Cefaclor 3rd generation - Cefotaxime 4th generation - Cefixime Active against staphylococci, streptococci and E. coli
Active against H. influenzae, B. fragilis Increased activity against gram ve bacteria Less activity against gram ve bacteria
Drug GLYCOPEPTIDES
Vancomycin Teicoplanin
Side Effects
Glycopeptide resistance - VanR and VanS detects vancomycin - Activates VanH, VanA/B and Van X - VanH converts pyruvate to lactate - VanA/B produces D-ala-lactate - [instead of D-ala-D-alanine] - VanX hydrolyses D-ala-D-alanine
Side Effect/ Comments Nephrotoxicity (frequent, however mild and reversible) Ototoxicity (may be permanent) Toxicity limits the use of aminoglycosides to serious infections.
Aminoglycosides
Gentamin Streptomycin Amikacin Neomycin
Work againsg aerobic gram ve organisms IV They enter cell using an oxygen dependant transporter system. Thus anaerobes are resistant to aminoglycosides Bind to 30S ribosome and prevent 50S ribosome from binding. Binding to 30S ribosome may also cause misreading of code.
Aminoglycoside resistance - Resistance due to reduced permeability - Xenobiotic pump - Aminoglycoside modifying enzymes which can acetylate and adenylate the antibiotic enzymes specific for individual antibiotic.
Macrolides
- Erythromycin - Azithromycin
Orally active Bacteriostatic bacteriosidal in some species Used in respiratory infections Binds 50S sub-unit.
Azythromycin - Broad spectrum orally active (once a day). - Short treatment course
Lincosamides
-Clindamycin Lincomycin Similar mechanism of action as macrolides (50S bind) Oral Active against gram +ve cocci and anaerobes.
Streptogranins
-Quinupristin -Dalfopristin Binds distinct sites on 50S subunit Synergistic effect as each is bacteristatic but combination is bactericidal. IV infusions daily
Drug
Mechanism of action/ Clinical Linezolid works on the initiation of protein synthesis. (This is in contrast to most other protein synthesis inhibitors, which inhibit elongation). It does this by stopping the 30S and 50S subunits of the ribosome from binding together. Linezolid binds to 50S subunit [inhibited by chloramphenicol and lincomycin]. This then stops the interaction with the 30S subunit. Po and IV preparations Activity against MRSA
Oxazolidonone
- Linezolid
Oxazolidinone resistance - Oxazolidinone act by binding to V- domain of 23S rRNA inhibits formation of ribosomal initiation complex. - Resistance due to mutations in domain V of 23S rRNA thus the initiation can happen.
Daptomycin - Cyclic lipopeptide binds to bacterial membranes causing depolarization resulting in an inability to synthesize proteins. - Bacteriocidal against anaerobic gram +ve bacteria. - Works by disrupting multiple aspects of bacterial cell membrane function. It appears to bind to the membrane and cause rapid
depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death. Daptomycin RESISTANCE Mechanism of action: - Increased fluidity increased positive surface charge resulting in reduced drug binding reduced permeabilization capacities reduced depolarization.
Tetracyclines
Tetracycline Doxycycline
Binds to ribosomes selective for bacteria due to transport mechanism It works by inhibiting action of the prokaryotic 30s ribosome, by binding the 16S rRNA thereby blocking the aminoacyl-tRNA.
Resistance due to pump that reduces intraceullar levels. Skin photosensitivity; Drug-induced lupus, and hepatitis Tinnitus Should be avoided during pregnancy as it may affect bone growth of fetus.
Quinolones
C1st generation -nalixidic acid 2nd generation -Ciprofloxacin 3rd generation - Levofloxacin 4th generation -Trovafloxacin