Antimicrobials

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