antimicrobials
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CLASSIFICATION OF ANTIMICROBIALSand
PROBLEMS ARISING FROM ANTIMICROBIALS
Dr. Anupam Das
ANTI-MICROBIALS?
HOW CAN WE CLASSIFY ANTIMICROBIAL AGENTS?
StructureMechanism of ActionType of organism it acts againstSpectrum of ActivityType of ActionSources
CHEMICAL STRUCTURE• 1.SULFONAMIDES and related drugs• 2.DIAMINOPYRIMIDINES• 3.QUINOLONES• 4.Beta- LACTAM ANTIBIOTICS• 5.NITROBENZENE derivatives• 6.MACROLIDES• 7.AMINOGLYCOSIDES• 8.LINCOSAMIDES
CHEMICAL STRUCTURE…• 9.TETRACYCLINES• 10.GLYCOPEPTIDES• 11.OXAZOLIDINONE• 12.POLYPEPTIDES• 13.NITROFURAN derivatives• 14.NITROIMIDAZOLES• 15.NICOTINIC ACID derivatives• 16.POLYENE antibiotics• 17.AZOLE derivatives• 18. Others
MECHANISM OF ACTION• Drugs inhibiting cell wall synthesis.
DRUG STEP INHIBITED IN CELL WALL SYNTHESIS
Firmly FOSFOMYCIN Enolpyruvate transferase
Bind to Beta-LACTAMS Transpeptidase
Bacterial BACITRACIN Dephosphorylation of bactoprenol
Cell CYCLOSERINE Alanine racemase, Alanine ligase
Wall VANCOMYCIN Transglycosylase
DRUGS INHIBITING TRANSLATION(PROTEIN SYNTHESIS)
DRUG BINDS TO MOA
AMINOGLYCOSIDES 30S mainly FREEZING OF INITIATIONMISREADING OF mRNA code
TETRACYCLINES 30S Inhibit aminoacyl tRNA attachment to A site.
CHLORAMPHENICOL 50S Inhibits peptidyl transferase that results in the inhibition of peptide bond formation and transfer of peptide chain from P to A site.
MACROLIDESLINCOSAMIDESTETRACYCLINES
50S Inhibit translocation of peptide chain from A to P site
LINEZOLID 50S Inhibit initiation
• Buy AT 30 and SELL at 50. • AT : Aminoglycosides and Tetracyclines-
30S• SELL:
Streptogramins,Erythromycin,Lincosamide,Linezolid.-50S
DRUGS AFFECTING CELL MEMBRANE
• These drugs act by causing disruption of cell membrane and leakage of ions and molecules from the cell. These drugs include:
• POLYPEPTIDE ANTIBIOTICS: Polymyxin B, Colistin,
• POLYENE ANTIBIOTICS: Amphotericin B, nystatin, Natamycin.
• AZOLES: Ketoconazole, fluconazole, Itraconazole.
DRUGS AFFECTING NUCLEIC ACIDS (DNA and RNA)
• DNA GYRASE INHIBITORS• RNA POLYMERASE INHIBITORS• DRUGS DESTROYING DNA• NUCLEOTIDE/NUCLEOSIDE
ANALOUGES
DRUGS ACTING BY INTERMEDIARY METABOLISM
• DRUGS INHIBITING FOLIC ACID SYNTHESIS
• Dihydrofolate reductase inhibitors• Arabinogalactan synthesis inhibitors
TYPES OF ORGANISMS AGAINST WHICH PRIMARILY
ACTIVE• ANTIBACTERIAL• ANTIFUNGAL• ANTIVIRAL• ANTIPROTOZOAL• ANTIHELMINTIC
SPECTRUM OF ACTIVITY
• NARROW SPECTRUM:
Penicillin G, Streptomycin, Erythromycin• BROAD SPECTRUM:
Tetracyclines, Chloramphenicol
TYPES OF ACTION
• BACTERIOSTATIC:
Sulfonamides, Erythromycin, Tetracyclines,
Linezolid, Ethambutol.• BACTERICIDAL:
Penicillins, Aminoglycosides, Cephalosporins, Vancomycin, Isoniazid, Ciprofloxacin
SOURCES
• Fungi: Penicillin, Cephalosporin, Griseofulvin
• Bacteria: Polymyxin B, Colistin, Bacitracin• Actinomycetes: Polyenes,
Chloramphenicol, Aminoglycosides, Macrolides
PROBLEMS FROM AMAs.
TOXICITY : Local / Systemic.HYPERSENSITIVITY REACTIONS.DRUG RESISTANCESUPERINFECTIONNUTRITIONAL DEFICIENCIESMASKING OF AN INFECTION
DRUG RESISTANCE
• Refers to unresponsiveness of a microorganism to an AMA, similar to the phenomenon of tolerance seen in higher organisms.
NATURALAQUIRED
NATURAL RESISTANCE
Lack of metabolic process or target site which is affected by the particular drug.
This is characteristic of the group or species.
Gm-ve bacilli unaffected by penicillin G.Aerobic organisms unaffected by
metronidazole.
ACQUIRED RESISTANCE
Development of resistance due to the use of an AMA over a period of time.
This is a major clinical problem.Rapid acquisition of resistance:
Staphylococci,Tubercle Bacilli, Coliforms.This type of resistance develops either by:
MUTATION
GENE TRANSFER
MUTATION
aka : VERTICAL RESISTANCE.Relatively slow and of low grade.
MUTATION
MUTATION
.
GENE TRANSFER
• The resistance causing gene is passed from one organism to the other.
• aka HORIZONTAL TRANSFER.• Rapid and can cause multidrug resistance.• Occurs via:
# CONJUGATION
# TRANSDUCTION
#TRANSFORMATION
THREE TYPES OF RESISTANT ORGANISMS
DRUG TOLERANT : loss of affinity of the target biomolecule of the microorganism for a particular AMA.
DRUG DESTROYING: The resistant microbe elaborates an enzyme which inactivates the drug.
DRUG IMPERMEABLE: Loss of certain specific channels / porins via which AMA enters into the microorganism.
CROSS RESISTANCE
• Aquistion of resistance to one AMA conferring resistance to another AMA, to which the organism has not been exposed.
• Usually occurs between chemically related drugs.
How do we prevent resistance?
Avoid unnecessary use and prolongation of AMAs.
Prefer rapidly acting and selective (narrow spectrum ) drugs whenever possible.
Use combined therapy whenever there is need of prolonged therapy. Eg. TB, SABE.
Intensive treatment of infections which develop resistance rapidly.
SUPERINFECTION
• Refers to the appearance of a new infection as a result of AMA therapy.
• Mainly due to supression of normal flora of the body.
• Frequently involved organisms: Candida AlbicansResistant staphylococciClostridium difficleProteus Pseudomonas
Conditions predisposing to superinfection…
Corticosteroid therapy. Leukemias and other malignancies.AIDS.Agranulocytosis.Diabetes.Disseminated lupus erythomatosus(DLE)
Choosing an AMA
• PATIENT FACTORS• ORGANISM RELATED CONSIDERATIONS• DRUG FACTORS
PATIENT FACTORS
AgeRenal and Hepatic functionLocal factors like the presence of pus
decreases efficacy;the presence of necrotic matter or foreign body decreases penetration of drug.
Drug allergyPregnancy Genetic factors
Organism related factors
Clinical diagnosis itself directs choice of AMA.
Choice based on bacteriological examinations
Drug factors
Spectrum of activity.Type of activity.Sensitivity to organism.Relative toxicity.Pharmacokinetics of the drug.Route of administration.Cost.
Combined use of AMA
To achieve synergismTo reduce severity or incidence of adverse
effects.To prevent emergence of resistance.To broaden the spectrum of antimicrobial
action Treat mixed infection.Initial treatment of severe infections.Topical application.
PROPHYLACTIC USE OF AMAs.
• Refers to the use of AMAs for preventing the setting in of an infection, or supressing contacted infection before it manifests clinically.
• Difference b/w treating and preventing infections?
treatment is directed against a specific organism infecting an individual.
Prophylaxis is against all organisms capable of causing infection.
Prophylaxis against specific organisms.Prevention of infection in high risk
situationsPrevention of infection in general
Rheumatic fever- penicillinG TB – given to children & HIV +ve : INH+Rmp MAC – in HIV+ve : azithro/clarithro. HIV – zidovudine+ lamivudine +/- indinavir Meningococcal Meningitis : Rmp/
Ceftriaxone/ Suphazidine. Malaria : travel prophylaxis : chloroquine Cholera : tetracycline.
• Influenza A : amantadine• Plague : doxycycline
High risk situations
• Dental extraction, tonsillectomy : there is
ed risk of endocarditis – amoxy / clinda• Catheterization / instrumentation of urinary
tract : cotrimox / norflox ; In patients with valvular heart dz: ampi / genta.
• COPD/ Chr. Bronchitis : ampi / doxy/ cipro• Immunocompromised : penicillin/ cephalo
Prevention in general
• Neonates• Viral URTI : to prevent 2nd ry bacterial
infection.• Prevent respiratory infections in patients
on ventilators.
Surgical prophylaxis
• Oral: AmoxyCephalexinCephadroxilClindaAzithroClarithro
Surgical prophylaxis
• Parenteral : AmpicillinCefazolinVancoClinda
• DOC for MRSA : vancomycin• DOC for VRSA : linezolid
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