ANTIMICROBIALS MAJID MOHIUDDIN

Drugs designed to inhibit/kill the infecting organism and to have no/minimal effect on the recipient. T – Chemotherapy Treatment of systemic infections with specific drugs . Both synthetic and microbiologically . Antimicrobial agent (AMA) to designate synthetic as well as natural.

Drugs designed to inhibit/kill the infecting organism and to have no/minimal effect on the recipient. T – Chemotherapy

Treatment of systemic infections with specific drugs .

Both synthetic and microbiologically .

Antimicrobial agent (AMA) to designate synthetic as well as natural.

CLASSIFICATION OF ANTIMICROBIALS Chemical structure Mechanism of action Type of organisms against which primarily active. Spectrum of activity Type of action Antibiotics are obtained from.

Chemical structure

Mechanism of action

Type of organisms against which primarily active.

Spectrum of activity

Type of action

Antibiotics are obtained from.

Chemical structure Sulfonamides and related drugs: Sulfadiazine and other, Sulfones – Dapsone(DDS), Paraaminaosalicyclic (PAS) Diaminopyrimidines: Trimethoprim, Pyrimethamine. Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin etc. β -lactam antibiotics: Penicillins, Cephalosporins, Monobactams, Carbapenems. Tetracyclines: Oxytetracycline, Doxycycline etc. Nitrobenzene derivative: Chloramphenicol Aminoglycosides: Streptomycin, Gentamicin, Neomycin etc. Macrolide antibiotics: Erythromycin, Roxithromycin, Azithromycin etc. Polypepetide antibiotics: Polymyxin-B, Colistin, Bacitracin, Tyrothricin. Nitrofuran derivatives: Nitrofurantoin, Furazolidone. Nitroimidazoles: Metronidazole, Tinidazole. Nicotinic acid derivatives: Isoniazid, Pyrazinamide, Ethionamide. Polyene antibiotics: Nystatin, Amphotericin-B, Hamycin. Imidazole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole. Others: Rifampin, Lincomycin, Clindamycin, Spectinomycin, Vancomycin, Sod. Fusidate, Cycloserine, Viomycin, Ethambutol, Thiacetazone, Clofazimine, Griseofulvin.

Sulfonamides and related drugs: Sulfadiazine and other, Sulfones – Dapsone(DDS), Paraaminaosalicyclic (PAS)

Diaminopyrimidines: Trimethoprim, Pyrimethamine.

Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin etc.

β -lactam antibiotics: Penicillins, Cephalosporins, Monobactams, Carbapenems.

Tetracyclines: Oxytetracycline, Doxycycline etc.

Nitrobenzene derivative: Chloramphenicol

Aminoglycosides: Streptomycin, Gentamicin, Neomycin etc.

Macrolide antibiotics: Erythromycin, Roxithromycin, Azithromycin etc.

Polypepetide antibiotics: Polymyxin-B, Colistin, Bacitracin, Tyrothricin.

Nitrofuran derivatives: Nitrofurantoin, Furazolidone.

Nitroimidazoles: Metronidazole, Tinidazole.

Nicotinic acid derivatives: Isoniazid, Pyrazinamide, Ethionamide.

Polyene antibiotics: Nystatin, Amphotericin-B, Hamycin.

Imidazole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole.

Others: Rifampin, Lincomycin, Clindamycin, Spectinomycin, Vancomycin, Sod. Fusidate, Cycloserine, Viomycin, Ethambutol, Thiacetazone, Clofazimine, Griseofulvin.

MECHANISM OF ACTION Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin. Cause leakage from cell membranes: Polypeptides : Polymyxins, Colistin, Bacitracin Polyenes – Amphotericin B, Nystatin, Hamycin. Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin. Cause misreading of m-RNA code and affect permeability: Aminoglycosides – Streptomycin, Gentamicin etc. Inhibit DNA gyrase: Fluoroquinolones – Ciprofloxacin. Interfere with DNA function: Rifampin, Metronidazole. Interfere with DNA synthesis: Idoxuridine, Acyclovir, Zidovudine. Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Ethambutol.

Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin.

Cause leakage from cell membranes:

Polypeptides : Polymyxins, Colistin, Bacitracin

Polyenes – Amphotericin B, Nystatin, Hamycin.

Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin.

Cause misreading of m-RNA code and affect permeability: Aminoglycosides – Streptomycin, Gentamicin etc.

Inhibit DNA gyrase: Fluoroquinolones – Ciprofloxacin.

Interfere with DNA function: Rifampin, Metronidazole.

Interfere with DNA synthesis: Idoxuridine, Acyclovir, Zidovudine.

Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Ethambutol.

TYPE OF ORGANISMS AGAINST WHICH PRIMARILY ACTIVE Antibacterial: Penicillins, Aminoglycosides, Eruthromycin etc. Antifungal: Griseofulvin, AmphotericinB, Ketoconazole etc. Antiviral: Idoxuridine, Acyclovir, Amantadine, Zidovudine etc. Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole, Diloxanide etc. Anthelmintic: Mebendazole, Pyrantel, Niclosamide, Diethyl carbamazine etc.

Antibacterial: Penicillins, Aminoglycosides, Eruthromycin etc.

Antifungal: Griseofulvin, AmphotericinB, Ketoconazole etc.

Antiviral: Idoxuridine, Acyclovir, Amantadine, Zidovudine etc.

Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole, Diloxanide etc.

Anthelmintic: Mebendazole, Pyrantel, Niclosamide, Diethyl carbamazine etc.

SPECTRUM OF ACTIVITY NARROW SPECTRUM: Penicillin G, Streptomycin Erthromycin BROAD SPECTRUM: Tetracyclines, Chloramphenicol.

NARROW SPECTRUM: Penicillin G, Streptomycin Erthromycin

BROAD SPECTRUM: Tetracyclines, Chloramphenicol.

TYPE OF ACTION PRIMARILY BACTERIOSTATIC: Sulfonamides, Tetracyclines, Chloramphenicol, Erythromycin, Ethambutol PRIMARILY BACTERICIDAL: Penicillins, Aminoglycosides, Polypeptides, Rifampin, Cotrimoxazole, Cephalosporins, Vancomycin, Nalidixic acid, Ciprofloxacin, Isoniazid.

PRIMARILY BACTERIOSTATIC:

Sulfonamides, Tetracyclines, Chloramphenicol, Erythromycin, Ethambutol

PRIMARILY BACTERICIDAL: Penicillins, Aminoglycosides, Polypeptides, Rifampin, Cotrimoxazole, Cephalosporins, Vancomycin, Nalidixic acid, Ciprofloxacin, Isoniazid.

ANTIBIOTICS ARE OBTAINED FROM FUNGI: Penicillin, Cepholosporin,Griseofulvin. BACTERIA: Polymyxin B, Colistin, Bacitracin, Tyrothricin, Aztreonam. ACTINOMYCETES: Aminoglycosides, Tetracyclines, Chloramphenicol, Macrolides, Polyenes.

FUNGI: Penicillin, Cepholosporin,Griseofulvin.

BACTERIA: Polymyxin B, Colistin, Bacitracin, Tyrothricin, Aztreonam.

ACTINOMYCETES: Aminoglycosides, Tetracyclines, Chloramphenicol, Macrolides, Polyenes.

PROBLEMS THAT ARISE WITH THE USE OF AMAs. TOXICITY: HYPERSENSITIVITY REACTIONS: DRUG RESISTANCE Mutation Gene Transfer Cross resistance Prevention of drug resistance. SUPERINFECTION (SUPRAINFECTION)

TOXICITY:

HYPERSENSITIVITY REACTIONS:

DRUG RESISTANCE

Mutation

Gene Transfer

Cross resistance

Prevention of drug resistance.

SUPERINFECTION (SUPRAINFECTION)

TOXICITY: A) LOCAL IRRITANCY: Erythromycin, Tetracyclines, certain cephalosporins and chloramphenicol. B) SYSTEMIC TOXICITY: Dose related and predictable organ toxicities - High therapeutic index – Penicillins, some cephalosporins and erythromycin. - Lower Therapeutic index – individualized and toxicity watched Aminoglycosides: 8 th cranial nerve and kidney toxicity. Tetracyclines : Liver and kidney damage, antianabolic effect. Chloramphenicol: Bone marrow depression. - Very low Therapeutic index - Use is highly restricted Polymyxin B : neurological and renal toxicty. Vancomycin : hearing loss, kidney damage. Amphotericin B : kidney, bone marrow and neurological toxicity.

TOXICITY:

A) LOCAL IRRITANCY: Erythromycin, Tetracyclines, certain cephalosporins and chloramphenicol.

B) SYSTEMIC TOXICITY: Dose related and predictable organ toxicities

- High therapeutic index – Penicillins, some cephalosporins and erythromycin.

- Lower Therapeutic index – individualized and toxicity watched

Aminoglycosides: 8 th cranial nerve and kidney toxicity.

Tetracyclines : Liver and kidney damage, antianabolic effect.

Chloramphenicol: Bone marrow depression.

- Very low Therapeutic index - Use is highly restricted

Polymyxin B : neurological and renal toxicty.

Vancomycin : hearing loss, kidney damage.

Amphotericin B : kidney, bone marrow and neurological toxicity.

2. HYPERSENSITIVITY REACTIONS: Practically All AMAs. Unpredictable and unrelated to dose. Reactions from rashes to anaphylactic shock. Penicillins, cephalosporins, sulfonamides.

2. HYPERSENSITIVITY REACTIONS:

Practically All AMAs.

Unpredictable and unrelated to dose.

Reactions from rashes to anaphylactic shock.

Penicillins, cephalosporins, sulfonamides.

3. DRUG RESISTANCE: Natural resistance: always resistance. Pencillin G – Gram –ve bacilli. Tetracyclines – M.tuberculosis Acquired resistance: develop resistance rapid acquisition – staphylococci, coliforms, tubercle bacilli. Strep.pyogenes & spirochetes – penicillin when >40 years. Gonococci – quick to sulfonamides but low to penicillin. Resistance may be developed by mutation or gene transfer

3. DRUG RESISTANCE:

Natural resistance: always resistance.

Pencillin G – Gram –ve bacilli.

Tetracyclines – M.tuberculosis

Acquired resistance: develop resistance

rapid acquisition – staphylococci, coliforms, tubercle bacilli.

Strep.pyogenes & spirochetes – penicillin when >40 years.

Gonococci – quick to sulfonamides but low to penicillin.

Resistance may be developed by mutation or gene transfer

MUTATION: 1. Single Step: high degree of resistance, emerges rapidly – e.g. Enterococci to streptomycin E.Coli and Staphylococci to Rigampin 2. Multistep: Resistance to erythromycin, tetracyclines and chloramphenicol Low grade penicillin resistant gonococci have decreased virulence. Staphylococci to rifampin.

MUTATION:

1. Single Step: high degree of resistance, emerges rapidly – e.g. Enterococci to streptomycin

E.Coli and Staphylococci to Rigampin

2. Multistep: Resistance to erythromycin, tetracyclines and chloramphenicol

Low grade penicillin resistant gonococci have decreased virulence. Staphylococci to rifampin.

Gene transfer (infectious resistance) from one organism to another can occur by: Conjugation: R – factor (Resistance transfer factor (RTF)). Chloramphenicol resistance of typhoid bacilli, streptomycin resistance of E.coli, Penicillin resistance of Haemophilus and gonococci. Transduction: Penicillin, erythromycin and Chloramphenicol – phage mediated. Tranformation: Pneumococcal resistance to penicillin G due to altered penicillin binding protein.

Gene transfer (infectious resistance) from one organism to another can occur by:

Conjugation: R – factor (Resistance transfer factor (RTF)). Chloramphenicol resistance of typhoid bacilli, streptomycin resistance of E.coli, Penicillin resistance of Haemophilus and gonococci.

Transduction: Penicillin, erythromycin and Chloramphenicol – phage mediated.

Tranformation: Pneumococcal resistance to penicillin G due to altered penicillin binding protein.

Resistant Organisms can be: Drug tolerant: loss of affinity of the target biomolecule of the microorganism for a particular AMA. E.g., resistant Staph.aureus and E.coli developa RNA polymerase that does not bind rifampin. Drug destroying: β - lactamase by Staphylococci, Haemophilus, Gonococci etc., which inactivate penicillin G. Chloramphenicol acetyl transferase is acquired by resistant E.coli, H.influenzae and S.typhi. Aminoglycoside resistant coliforms – produce enzymes which adenulate/acetylate/phosphorylate specific aminoglycoside antibitotics. c) Drug impermeable: Many hydrophilic antibiotics access though porins, or need specific transport mechanisms. Glycosides and tetracyclines in the resistant gram negative bacterial strains.

Resistant Organisms can be:

Drug tolerant: loss of affinity of the target biomolecule of the microorganism for a particular AMA. E.g., resistant Staph.aureus and E.coli developa RNA polymerase that does not bind rifampin.

Drug destroying: β - lactamase by Staphylococci, Haemophilus, Gonococci etc., which inactivate penicillin G. Chloramphenicol acetyl transferase is acquired by resistant E.coli, H.influenzae and S.typhi.

Aminoglycoside resistant coliforms – produce enzymes which adenulate/acetylate/phosphorylate specific aminoglycoside antibitotics.

c) Drug impermeable: Many hydrophilic antibiotics access though porins, or need specific transport mechanisms. Glycosides and tetracyclines in the resistant gram negative bacterial strains.

Cross resistance: Acquisition of resistance to one AMA conferring resistance to another AMA, to which the organism has not been exposed, is called cross resistance. Sulfonamide – to all others. Tetracycline – insensitivity to all others. Aminoglycoside – not extend to another Gentamicin - amikacin also Cross resistance e.g., between tetracyclines and chloramphenicol, between erythromycin and lincomycin. Newmycin resistance by enterobacteriaceae – insensitive to streptomycin.

Cross resistance: Acquisition of resistance to one AMA conferring resistance to another AMA, to which the organism has not been exposed, is called cross resistance.

Sulfonamide – to all others.

Tetracycline – insensitivity to all others.

Aminoglycoside – not extend to another

Gentamicin - amikacin also

Cross resistance e.g., between tetracyclines and chloramphenicol, between erythromycin and lincomycin.

Newmycin resistance by enterobacteriaceae – insensitive to streptomycin.

4. Superinfection ( Suprainfection) Appearance of a new infection as a result of antimicrobial therapy. The normal flora contributes to host defence by elaborating substances called bacteriocins which inhibit pathogenic organisms. Superinfections are more common when host defence is compromised, as in: Corticosteriod therapy Leukemias and other malignancies (WBC count) Acquired immunodeficiency syndrome (AIDS) Agranulocysis Diabetes, disseminated Lupus Erythematosus.

4. Superinfection ( Suprainfection)

Appearance of a new infection as a result of antimicrobial therapy.

The normal flora contributes to host defence by elaborating substances called bacteriocins which inhibit pathogenic organisms.

Superinfections are more common when host defence is compromised, as in:

Corticosteriod therapy

Leukemias and other malignancies (WBC count)

Acquired immunodeficiency syndrome (AIDS)

Agranulocysis

Diabetes, disseminated Lupus Erythematosus.

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