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ANTIMICROBIAL AGENT & MECHANISM OF

RESISTANCE

Julia Hartati, dr

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Antimicrobials Agents

Definition Antibiotic is :

A chemical substance produce by microorganism (natural products) which has the capacity to inhibit the growth of bacteria, fungi, viruses or protozoa. It has a high chemotherapeutical index to reduce the active process in organism in a diluted solution.

Antibiotics = anti microorganisms = anti microbes

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Classification of antibiotics

1. Based on chemical structures

2. Based on the sources

3. Based on mechanism of action

4. Based on spectrum of action / activity

5. Based on modes of action

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1. Based on chemical structures1. Groups of sulfonamides Sulfamethoxazole,

sulfadiazine

2. Groups of Penicillin Penicillin G (Benzylpenicillin), Penicillin V, Ampicillin, amoxicillin, nafcillin

3. Groups of cephalosporins cefalotin, cefazolin, cefamandole, cefuroxime, cefotaxime, ceftriaxone.

4. Groups of aminoglycosides streptomycin, neomycin, kanamycin, gentamycin, tobramycin

5. Groups of chloramphenicol chloramphenicol, tiamphenicol

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1. Based on chemical structures6. Groups of tetracyclines chlortetracycline,

oxytetracycline, doxycycline, minocycline HCl

7. Groups of macrolides erythromycin, roxithromycin, spiramycin, azithromycin

8. Groups of polyenes amphotericin B, nystatin

9. Groups of Lincomycins lincomycin, clindamycin

10. Groups of polymixins Polymyxin B, Polymyxin E

11. Groups of sulfon dafsone

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1. Based on chemical structures

12. Other groups vancomycin, cycloxerine, bacitracin, metronidazole

13. Groups of quinolones nalidixic acid, norfloxacin, ciprofloxacin, offloxacin

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II. Based on the sourcesa. Antibiotic from microbes

1. A.B. from fungi Penicillin from P. notatum

2. A.B. from bacteria

• A.B. from eubacteria polymyxin from bacillus polymyxa

• A.B. from micromonosporaceae gentamyicin from micromonospora purpurea

b. Antibiotics from algae Usnat Acid

c. Antibiotics from higher plants Garlisina from Allium sativum

d. Antibiotics from animals Eritrina from hemoglobin of cow

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III. Based on mechanism of action

A. Inhibition of cell wall synthesis leads to the death of the bacteria lysis (bactericidal effect) penicillin, cycloserine, vancomycin, bacitracin, cefottaxime, ceftriaxone.

B. Disruption of cell membrane function polymyxin (polymyxin B, polymyxin E), polyenes, nystatin

C. Inhibition of protein synthesis:

This antibiotics inhibit one of the reactions in the process of transcription

1. Inhibition of translation process of microbes

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III. Based on mechanism of action

a. Inhibit ribosome on the 30 S subunit streptomycin, tetracylines, netilmicin, kanamycin

b. Inhibit ribosom on the 50 S subunit chloramphenicol, clyndamycin, lincomycin

2. Inhibits the transcription process of microbes Rifampin, actinomycin

D. Inhibits spesific metabolic reaction

Inhibits the enzymatic reactions sulfonamides, INH, PAS, trimethoprim

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IV. Based on spectrum of action1. Broad spectrum: Effective to Gram +, Gram -

bacteria, mycoplasmas, chlamydiae, rickettsiae, sometimes protozoa chloramphenicol, tetracyclines

2. Narrow spectrum: Effective to Gram + / Gram - bacteria only penicillins, cephalosporins, erythromycins, polymyxins

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V. Based on modes of action 1938 : N. gonorrhoeae are sensitive to sulfa

1948 : N. gonorrhoeae became resistant, sulfa was no longer used

N. gonorrhoeae that resistant to penicillin ----- penicillinase producer - strains.

Staphylococcus that resistant to penicillin beta-lactamase enzymes.

Paul Ehrlich (1902 – 1909) mice infected with Paul Ehrlich (1902 – 1909) mice infected with trypanosoma and treated with azo dyes, organic arsenyl trypanosoma and treated with azo dyes, organic arsenyl and triphenyl methone trypanosoma became resistant and triphenyl methone trypanosoma became resistant after contactedafter contacted with the drugs.with the drugs.

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Mechanisms of resistanceMechanisms of resistance Bacteria produce enzymes that destroy the active drugs

such as beta-lactamases which will destroy beta-lactams antibiotics.

Natural resistance :

genetic chromosomal resistance and extrachromosomal resistance

non genetic

Genetic resistance happen because of genetic changes

Non genetic resistance happen because of antibiotics come into contact with bacteria which have active metabolism.

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Mechanisms of resistanceMechanisms of resistance Example : M. tbc can persist in the tissues for a

long time. The bacteria persist for years after infection without replication, due to the good immune system of the patient.

In this condition M .tuberculosis can not be killed by antibiotics

Acquired resistance Acquired resistance Sensitive bacteria will get Sensitive bacteria will get this resistance properties through plasmid which this resistance properties through plasmid which contains resistance factors (R factors) from contains resistance factors (R factors) from resistance bacteria.resistance bacteria.

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Mechanisms of resistance (Weinstein, 1984)Mechanisms of resistance (Weinstein, 1984)

1. 1. Alteration of cell membrane permeability, such alteration inhibit penetration of antibiotics to bacterial cell Staphylococcus against tetracyclines

2. Alteration in bacterial cell, so that a big ammount of antibiotic destroy enzymes are produced

-lactamase against penicillins and cephalosporins

Acetyltransferase against chloramfenicol

Phosphorilase, acetylase and adenylase against aminoglycosides

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Mechanisms of resistance (Weinstein, 1984)Mechanisms of resistance (Weinstein, 1984)

3. 3. Alteration of receptors usually affects bacterial Alteration of receptors usually affects bacterial ribosomes. The mutation alters the DNA that ribosomes. The mutation alters the DNA that produces a ribosomal protein receptor so the a produces a ribosomal protein receptor so the a antibiotics cannot bind to it antibiotics cannot bind to it erythromycin erythromycin receptor in staphylococcusreceptor in staphylococcus

4. Alteration of a metabolic pathway in bacterial cell, to bypass a reaction inhibited by an antimicrobial agent dehidrofolate by trimethoprim, sulfanomide, INH and PAS

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Some approaches to solve resistance problems

1. Administration of antibiotics prescription only if the clinical signs and tests indicated that certain bacteria are the most probable caused of infection

2. Bacteriologic diagnosis must be sought and susceptibility tests must be determined

3. Avoid the usage of antibiotics which have been known resistance in one population

4. Reduce the usage of topical antibiotics, use antiseptics instead.

5. Limit the period of consuming antibiotics

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Some approaches to solve resistance problems

6. Reduce the usage of prophylactic antibiotics

7. Use narrow spectrum antibiotics

8. Always follow directions for use of antibiotics

9. Prescrible antibiotics based on clinical situation and not on patient’s will or pharmaceutical advertisements.

Rational drug: drugs given after accurate diagnosis. It will be effective with minimal side effects.

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Factors involve in the usage of AB rationally, effectively and safely.

1. Accurate diagnosis

2. Accurate choices of antibiotics

3. Deliver accurate dose

4. Accurate dosing interval

5. Accurate examinations of patophysiologic conditions of the patient

Factors involve in choosing antibiotics Disease factors

Drug factors

Recipient factors FK UNISBA

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Factors involve in choosing antibiotics

1. Disease factors

Selective for etiologic bacteria susceptibility test

Types and doses depend on location of infection

Enough penetrating potentials to cross :

• blood-brain barrier in

• abscess walls

2. Drugs factors Ideal antibiotics :

Have a narrow spectrum, affect only to etiologic bacteria

Have a bactericidal effect, unless none is sensitive, bacteriostatic drugs can be delivered

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Ideal antibiotics : Effective even in the presence of body fluids

exudate, protein or enzymes.

Ability to reach the infected tissue, enough drug concentration during the span of a dosing interval in blood / infected area.

Do not caused resistance

Have a minimal toxic effects for the patient

Safe for pregnancy and pediatric patients

Low costs

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Factors involve in choosing antibiotics

3. Patient factors : Age Genetics Pregnancy Accompanying diseases

Antibiotic prophylaxis: An antibiotic is used to anticipate infection from certain bacteria which are sensitive to the drug.

Goal: To minimize the surgical wound infection, by treating with antibiotic in lethal concentration for microorganisms at the beginning of surgery until it finished (done).

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Sensitivity tests / resistance tests

1. Qualitative :

1. Stokes method

2. Ericcson method

3. Kirby-Bauer method

4. Comparison method

2. Quantitative :

1. MIC

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Qualitative

The Kirby-Bauer Method: Commonly in microbiology use the Kirby-Bauer Method . It use medium of Mueller-Hinton Agar on the susceptibility test

Mueller-Hinton Agar

Sensitive : clear area (zones of inhibition) Resistance : No zones of inhibition

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Side effects of antibiotics1. Allergic reaction : Is a respond in sensitive

individual due to the abnormality in his immune system Penicillin, Sulfonamides, Streptomycin

Mild symptoms are skin rashes and itching.

Severe symptoms are anaphylactic shock.

2. Toxic reaction : Can happen in individual depend on the doses of drugs in the body Hearing disorder because of gentamycin

Manifestation can occur :

Temporary and permanently

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Antiviral Agents1. Inhibit viruses coverage

2. Inhibit DNA and RNA synthesis in the viruses

3. Inhibit protein synthesis in the viruses

4. Inhibit specific enzymes activities in the viruses

5. Inhibit the growth of viruses

6. Promote immunity system of the body

7. Prevent virus infection to the body

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The Drugs that use :• To inhibit viruses coverage: Amantadine, Rimantidine

• To inhibit DNA and RNA synthesis: Acyclovir, Ganciclovir, Foscarnet, Ribavirin, Valacyclovir, vidarabine, cidofovir

• To inhibit return transcription from nucleocid: Zidovudine, Didanosine, Zalcitabine

• Inhibit protease enzyme Other antiviral drugs: Idoxuridine, Trifluridine, Fluorouracil, Interferons, Immunoglobulins

Notes : Antiviral drugs only inhibit the early stage of replication

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Antifungal Agents Fungal infection occur less frequently than bacterial or

viral infections.

Three major groups of antifungal agents :

1. Groups of polyenes :

• Amphotericin B

• Nystatin

2. Groups of Azole Imidazoles :

• Ketoconazole

• Miconazole

• Clotrimazole

• Fluconazole

• Itraconazole FK UNISBA

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Antifungal Agents

3. Groups of Alilamin:

• Terbinafin

• Naftitin

Other antifungal agents :

Griseofulvin

Flucytosine

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