Antimicrobial Medications

1. Antimicrobial Medications Kathy Huschle Northland Community and Technical College

2. History • Paul Ehrlich 1910 Upon making the observation that some dyes stained bacterial cells, but not animal cells, Ehrlich determined that there was a fundamental difference between the 2 types of cells. He began the search for the “magic bullet”- a drug that would kill a microbial pathogen without harming the human host.

3. History After 605 tests to find a cure for syphilis, Ehrlich was successful in 1910. He proved that arsphenamine, a compound of arsenic, was effective in treating lab animals. The ability of the new drug, named Salvarson, to cure syphilis, proved that chemicals could be used to selectively kill microorganisms without harming the human host permanently. Paul Ehrlich

4. History • Gerhard Domagk 1932 • accidentally discovered the first sulfa drug, sulfanilamide, while testing a red dye called Prontosil on streptococci Gerhard Domagk

5. History • Fleming 1928 • noticed that colonies of Staphylococcus were inhibited by mold • Fleming identified the mold as a species of Penicillium • with further testing, it was shown that Penicillium was a bacteria-killing substance Alexander Fleming

6. History • Ernst Chain & Howard Florey • successfully purified penicillin • 1941 - 1st test on an ill human • the patient improved dramatically, but died when the penicillin ran out • mass development of penicillin was spurred on by WW2 • first antibiotic developed for the general public Sir Howard Florey Dr. Ernst Chain

7. Terms • chemotherapeutic agent • any drug used for any medical condition • antimicrobial drug • a chemical that destroys pathogens, includes antibiotics and chemically synthesized drugs • antibiotic • an antimicrobial agent produced naturally by a bacterium or fungus • bactericidal • capable of killing a microorganism • bacteriostatic • inhibits the growth of microorganisms

8. Features of Antimicrobial Drugs • the pharmacological properties of a potential antimicrobial agent needs to be considered to determine if the agent is the best for the particular infection • properties that are considered include • selective toxicity • spectrum of activity • distribution, metabolism, excretion • interaction between drugs • adverse effect • resistance

9. Selective Toxicity • antimicrobials • cause greater harm to microorganism than to human host • are able to attack biological structures or functions unique to the microorganism • non-toxic to humans is ideal, but realistically all antimicrobial drugs can be harmful in high concentrations

10. Selective Toxicity • measurement of the toxicity of a drug is called the therapeutic index • the therapeutic index of a medication is a comparison of the amount that causes the therapeutic effect to the amount that causes toxic effects • a high therapeutic index is LESS toxic to the patient • Penicillin G: high index • a low therapeutic index requires monitoring of the patient to be certain that it does not reach a toxic level • if a drug is too toxic for the systemic (internal) system, it may be used as a topical application

11. Spectrum of Activity • refers to the range of microorganisms that a antimicrobial agent can kill or inhibit • broad spectrum • affect a wide range • can disrupt the normal flora of the body • used particularly in the cases of rapid onset life-threatening infections, when there is no time to culture the causative agent • narrow spectrum • limited range • requires the identification of the pathogen

12. Distribution, Metabolism, Excretion • antimicrobials have to get where they are needed • a drug that is destroyed by acid cannot be taken orally • the rate of elimination is expressed as the half-life of the drug • the half-life is the time it takes the body to eliminate 1/2 of original dose • knowing the half-life of a drug will determine how frequently the doses have to be administered • this is why some medications are prescribed every four hours, others 2X per day

13. Interaction Between Drugs • combined drug therapy • sometimes necessary to use two antimicrobial agents for successful treatment of an infection • it is possible that one antimicrobial agent could influence the action of the other • synergism • action of one antimicrobial agent enhancing the other’s activity • antagonistic action • action of one interferes with the other • additive • neither synergistic or antagonistic

14. Adverse Effects • most all antimicrobial agents have concerns and dangers • allergic reactions • toxic effects to the body such as kidney damage • suppression of normal flora • normal flora is an important key to our immune system • if it is altered too greatly, it can create an imbalance of those “friendly” microorganisms

15. Resistance • resistance to antimicrobial agents is of mounting concern in the medical field • innate or intrinsic resistance can be found in antimicrobial agents naturally • this natural resistance, leads to survival of the fittest, or survival of those antimicrobial agents that are resistant • this resistance is then inherited by the offspring

16. Resistance

17. Resistance • 3 major mechanisms that lead to antimicrobial agents resistance • inactivation of the antimicrobial agent by an enzyme • prevention of the antimicrobial agent from reaching its target cell structure • alteration of the target cell structure so that it is no longer affected by the antimicrobial agent

18. Mechanisms of Action of Antimicrobials • different cell structures or microbial processes are the targets of antimicrobial agents • structures that are different or absent from eukaryotic cells • cell wall synthesis • protein synthesis • nucleic acid synthesis • metabolic pathways • plasma membrane integrity

19. Cell Wall Inhibitors • target peptidoglycan • peptidoglycan only occurs in bacteria, which makes it an excellent target • penicillin, cephalosporin, vancomycin, bacitracin (topical)

20. Protein Synthesis Inhibitors • all living organisms depend on protein synthesis • inhibitors act at different stages of protein synthesis • there is enough difference in the ribosomal structure (where proteins are synthesized) between prokaryotic and eukaryotic cells • aminoglycosides • streptomycin, gentamicin, neomycin

21. Protein Synthesis Inhibitors • chloramphenicol • last resort because of its rare, but life-threatening side effects • the inability to form red or white blood cells Proteins being tested with chloramphicol

22. DNA Replication Inhibitors • target is the enzymes necessary for DNA replication • block bacterial DNA replication • fluoroquinolones • one of the enzymes inhibited is gyrase, which prevents the unwinding of the DNA double helix • ciprofloxacin • rifamycins • blocks the initiation of transcription • rifampin

23. Metabolic Pathway Inhibitors • very few of these agents are available • sulfonamides (sulfa drugs) • Trimethoprim • the above 2 drugs inhibit the metabolism of folic acid at different steps in the process • animal cells lack these enzymes • makes folic acid a dietaryrequirement

24. Membrane Transport Inhibitors • damage to the plasma membrane leads to leakage of the cell contents and ultimately death of the cell • polymyxins • cause changes in structure of membrane • can bind to eukaryotic cells • limits the use of polymyxins to topical use

25. Antimicrobial Susceptibility Testing • determines effectiveness of an antimicrobial agent to a specific microorganism • Minimum Inhibitory Concentration (MIC) • determines the lowest concentration of an antimicrobial agent needed to prevent growth of the microorganism in the lab Tests for finding Minimum inhibitory concentration

26. Antimicrobial Susceptibility Testing • Kirby-Bauer • qualitative determination of effectiveness • automated liquid diffusion • commercial modification that speeds up the process of determining the effectiveness of a drug • able to know in 4 hours Kirby-Bauer

27. Resistance to Antimicrobial Drugs • overuse and misuse of antimicrobial drugs • resistance is generally a result of • inactivation by microbial enzyme • prevention of reaching target • alteration of target

28. Mechanisms of Resistance • some resistance is innate, some is acquired • most common methods of acquiring drug resistance include 1. drug-inactivating enzymes (produced by the organism) • the organism chemically modifies an antimicrobial drug to render it ineffective

29. Mechanisms of Resistance 2, alteration in target molecule • structural changes from mutation of the organism prevents the drug from recognizing and binding to the target 3. decreased uptake of drug • alterations in porin proteins found in the plasma membrane can alter permeability of the membrane • may prevent some drugs from crossing the barrier and entering the cell Multi-resistant S. aureus

30. Mechanisms of Resistance • increased elimination • efflux pumps are the mechanisms that bacterial cells use to eliminate harmful compounds from the cell • an alteration that increases the expression of the efflux pumps , can increase the ability of a cell to eliminate an antimicrobial drug

31. Emerging Antimicrobial Resistance • some examples of increasing resistance include • vancomyvin- resistant enterococci • vancomycin is a last resort drug for enterococci infections • the resistance to vancomycin is coded in the plasmid, so the potential for spreading to other organisms is possible • methicillin-resistant Staphylococcus arueus (MRSA) • concern in hospitals

32. Slowing Antimicrobial Resistance • can be minimized by • discriminating use of drugs in appropriate concentrations and dosages • compliance of patients to follow the instructions completely

33. Antiviral Drugs • not much progress in the development of antiviral drugs • targets for selective toxicity are difficult to find • viruses are only nucleic acid and protein • lack the structures that are successful targets for bacteria cells such as cell wall, plasma membrane • role of mammalian host cell gets in the way • virus is only active while inside a host cell

34. Antiviral Drugs • no broad spectrum drugs are available • best “treatment” for viral diseases is vaccination • recovery from a viral infection is almost totally dependent on your immune system

35. Antiviral Drugs • several antiviral drugs that are being used include • amantadine and rimantadine • block uncoating of the protein coat from the nucleic acid • acyclovir • antiherpes drug • nucleioside analog • terminates growing nucleotide chain

36. Antiviral Drugs • azidothymidine (AZT) • AIDS treatment • blocks ability of reverse transcriptase to synthesize DNA from the RNA template • mutational resistance is rapidly developed

37. Antifungal Drugs • pathogens such as fungi, more closely resemble their eukaryotic cousin, the human cell • very few drugs have been developed that can be used systemically (orally) for fungal infections • polyene antibiotics • alter permeability of plasma membrane of the fungus • most antifungal drugs are administered topically, because of their low therapeutic index

38. Antiprotozoan Agents • protozoa and helminths have complex life cycles • often interact with mammalian cells • antiprotozoan agents attack at certain stages of their life cycle