Antimicrobial agent

ANTIMICROBIAL AGENT & MECHANISM OF RESISTANCE Julia Hartati, dr

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 FK UNISBA

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 FK UNISBA

1. Based on chemical structures 1. 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 FK UNISBA

1. Based on chemical structures 6. 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 FK UNISBA

1. Based on chemical structures 12. Other groups  vancomycin, cycloxerine, bacitracin, metronidazole 13. Groups of quinolones  nalidixic acid, norfloxacin, ciprofloxacin, offloxa cin FK UNISBA

II. Based on the sources Antibiotic from microbes A.B. from fungi  Penicillin from P. notatum 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 FK UNISBA

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 Inhibition of translation process of microbes FK UNISBA

III. Based on mechanism of action Inhibit ribosome on the 30 S subunit  streptomycin, tetracylines, netilmicin, kanamycin Inhibit ribosom on the 50 S subunit  chloramphenicol, clyndamycin, lincomycin Inhibits the transcription process of microbes  Rifampin, actinomycin D. Inhibits spesific metabolic reaction Inhibits the enzymatic reactions  sulfonamides, INH, PAS, trimethoprim FK UNISBA

IV. Based on spectrum of action Broad spectrum: Effective to Gram +, Gram - bacteria, mycoplasmas, chlamydiae, rickettsiae, sometimes protozoa  chloramphenicol, tetracyclines Narrow spectrum: Effective to Gram + / Gram - bacteria only  penicillins, cephalosporins, erythromycins, polymyxins FK UNISBA

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 trypanosoma and treated with azo dyes, organic arsenyl and triphenyl methone trypanosoma became resistant after contacted with the drugs. FK UNISBA

Mechanisms 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. FK UNISBA

Mechanisms 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  Sensitive bacteria will get this resistance properties through plasmid which contains resistance factors (R factors) from resistance bacteria. FK UNISBA

Mechanisms of resistance (Weinstein, 1984) 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 FK UNISBA

Mechanisms of resistance (Weinstein, 1984) 3. Alteration of receptors usually affects bacterial ribosomes. The mutation alters the DNA that produces a ribosomal protein receptor so the a antibiotics cannot bind to it  erythromycin receptor 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 FK UNISBA

Some approaches to solve resistance problems Administration of antibiotics prescription only if the clinical signs and tests indicated that certain bacteria are the most probable caused of infection Bacteriologic diagnosis must be sought and susceptibility tests must be determined Avoid the usage of antibiotics which have been known resistance in one population Reduce the usage of topical antibiotics, use antiseptics instead. Limit the period of consuming antibiotics FK UNISBA

Some approaches to solve resistance problems Reduce the usage of prophylactic antibiotics Use narrow spectrum antibiotics Always follow directions for use of antibiotics 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. FK UNISBA

Factors involve in the usage of AB rationally, effectively and safely. Accurate diagnosis Accurate choices of antibiotics Deliver accurate dose Accurate dosing interval Accurate examinations of patophysiologic conditions of the patient Factors involve in choosing antibiotics Disease factors Drug factors Recipient factors FK UNISBA

Factors involve in choosing antibiotics 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 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 FK UNISBA

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 FK UNISBA

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). FK UNISBA

Sensitivity tests / resistance tests Qualitative : Stokes method Ericcson method Kirby-Bauer method Comparison method Quantitative : MIC MIC plate FK UNISBA

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 FK UNISBA

Side effects of antibiotics 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. 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 After a prolonged used / acute respond FK UNISBA

Antiviral Agents Inhibit viruses coverage Inhibit DNA and RNA synthesis in the viruses Inhibit protein synthesis in the viruses Inhibit specific enzymes activities in the viruses Inhibit the growth of viruses Promote immunity system of the body Prevent virus infection to the body FK UNISBA

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 FK UNISBA

Antifungal Agents Fungal infection occur less frequently than bacterial or viral infections. Three major groups of antifungal agents : Groups of polyenes : Amphotericin B Nystatin Groups of Azole Imidazoles : Ketoconazole Miconazole Clotrimazole Fluconazole Itraconazole FK UNISBA

Antifungal Agents Groups of Alilamin: Terbinafin Naftitin Other antifungal agents : Griseofulvin Flucytosine FK UNISBA

Antimicrobial agent

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Antimicrobial agent