Antimicrobial Medications

Antimicrobial Medications
Chapter 21

History and Development of Antimicrobial Drugs
Discovery of antimicrobial drugs Paul Erlich (1909)found the first pharmaceutical effective for treatment of syphilis: Salvarsan Arsphenamine highly toxic Sulfonamide was the first sulfa drug In vitro derivative of Prontosil dye effective against streptococcal infections Bayer Labs, 1939 Nobel prize in Medicine

Discovery of antibiotics Penicillin discovered by Alexander Fleming Identified mold Penicillium that produced a bactericidal substance that was effective against a wide range of gram + microbes Inhibits cell wall synthesis Mass production of penicillin during WWII Streptomycin (1943) isolated from soil bacterium Streptomyces griseus by Selman Waksman Bacteriostatic Inhibits protein synthesis by binding to ribosome

Development of new generation of drugs In 1960s scientists alteration of drug structure gave them new properties Penicillin G altered to create ampicillin Broadened spectrum of antimicrobial killing

Features of Antimicrobial Drugs
Most modern antibiotics come from organisms living in the soil Includes bacterial species Streptomyces and Bacillus as well as fungi Penicillium and Cephalosporium To commercially produce antibiotics Strain is grown until maximum antibiotic concentration is reached Drug is extracted from broth medium Extensively purified May be chemically altered Termed semi-synthetic

Selective toxicity Antibiotics cause greater harm to microorganisms than to human host Toxicity of drug is expressed as therapeutic index Lowest dose toxic to patient divided by dose typically used for treatment High therapeutic index = less toxic to patient Narrow therapeutic index = more toxic, monitor closely

Antimicrobial action Bacteriostatic drugs Inhibit bacterial growth rely on host immunity Bacteriocidal drugs Kill bacteria Most useful in situations when host defenses cannot control pathogen

Spectrum of activity Antimicrobials vary with respect to range of organisms controlled Narrow spectrum Work on narrow range of organisms Gram-positive only OR Gram-negative only Advantage: effects pathogen only Disadvantage: requires identification of pathogen Broad spectrum Advantage: Work on broad range of organisms Disadvantage : disruption of normal flora

Effects of combinations of antimicrobial drugs Combination sometimes used to treat infections Synergistic: whole is > sum Antagonistic: whole is < sum Additive: whole is the sum

Tissue distribution, metabolism and excretion Drugs differ in how they are distributed, metabolized and excreted Half-life: Rate of elimination of drug from body Time it takes for the body to eliminate one half the original dose in serum Half-life dictates frequency of dosage Patients with liver or kidney damage tend to excrete drugs more slowly

Adverse effects Allergic reactions Toxic effects Suppression of normal flora Antimicrobial resistance

Mechanisms of Action of Antibacterial Drugs
Mechanism of action include: Inhibition of cell wall synthesis Penicillins, Cephalosporins, Vancomycin, Bacitracin Inhibition of protein synthesis Aminoglycosides, tetracyclines, macrolides, chloramphenicol, lincosamides Inhibition of nucleic acid synthesis Fluoroquinolones, rifamycins Inhibition of metabolic pathways Sulfonamides, trimethoprim Interference with cell membrane integrity Polymyxin

Mechanisms of Action: Cell Wall Synthesis
Inhibition of cell wall synthesis Antimicrobials that interfere with the synthesis of peptidoglycan These drugs have very high therapeutic index Antimicrobials of this class include β lactam drugs (penicillin, cephalosporin) Vancomycin Bacitracin

Drugs vary in spectrum Some more active against Gram (+) Some more active against Gram (-) Resistance through production of β-lactamase enzyme Penicillins + β lactamase inhibitor Augmentin = amoxicillin + clavulanic acid

Vancomycin Inhibits formation of glycan chains Does not cross lipid membrane of Gram (-) Important in treating infections caused by penicillin resistant Gram (+) organisms Given intravenously due to poor GI absorption Acquired resistance most often due to alterations in side chain of NAM molecule Prevents binding of vancomycin to NAM component of glycan

Bacitracin Interferes with transport of PTG precursors across cytoplasmic membrane Toxicity limits use to topical applications Common ingredient in non-prescription first-aid ointments

Mechanisms of Action: Protein Synthesis
Inhibition of protein synthesis Structure of prokaryotic ribosome acts as target for many antimicrobials of this class Drugs of this class include Aminoglycosides Tetracyclins Macrolids Chloramphenicol Lincosamides Oxazolidinones Streptogramins

Aminoglycosides Irreversibly binds to 30S ribosomal subunit Blocks initiation translation Causes misreading of mRNA Not effective against anaerobes, enterococci and streptococci Often used in synergistic combination with β-lactam drugs Examples include Gentamicin, streptomycin and tobramycin Side effects with extended use include Nephrotoxicity Otto toxicity

Tetracyclins Reversibly bind 30S ribosomal subunit Blocks attachment of tRNA to ribosome Prevents continuation of protein synthesis Narrow range: Effective against certain Gram (+) and Gram (-)

Macrolids Reversibly binds to 50S ribosome Prevents continuation of protein synthesis Effective against variety of Gram (+) organisms Often drug of choice for patients allergic to penicillin Macrolids include Erythromycin, clarithromycin and azithromycin Resistance can occur via modification of RNA target

Chloramphenicol Binds to 50S ribosomal subunit Prevents peptide bond formation Wide spectrum Drug of last resort Rare but lethal side effect is aplastic anemia

Lincosamides: clindamycin Binds to 50S ribosomal subunit Prevents continuation of protein synthesis Inhibits variety of Gram (+) and Gram (-) organisms Useful in treating infections from intestinal perforation Especially effective against Bacterioides fragilis and Clostridium difficile

New class effective against β-lactams and vancomycin resistant Gram (+) forms Oxazolidinones Binds 50S ribosomal subunit Interferes with initiation Streptogramins Bonds to two different sites on 50S ribosomal subunit

Mechanisms of Action: DNA Replication
Fluoroquinolones Inhibit action of topoisomerase DNA gyrase Topoisomerase maintains supercoiling of DNA Broad-Spectrum: Effective against Gram (+) and Gram (-) Examples include Ciprofloxacin and ofloxacin Resistance due to alteration of DNA gyrase

Mechanisms of Action: RNA Synthesis
Rifamycins Block prokaryotic RNA polymerase initiation of transcription Rifampin most widely used rifamycins Broad-spectrum: Effective against many Gram (+) and some Gram (-) as well as Mycobacterium Treatment of Tuberculosis Hansen’s disease N. meningitidis meningitis Resistance develops rapidly

Mechanisms of Action: Inhibition of Metabolic Pathways
Folate inhibitors Mode of actions to inhibit the production of folic acid Mimic PABA Antimicrobials in this class include Sulfonamides Trimethoprim Human cells lack specific enzyme in folic acid pathway Resistance due to plasmid

Mechanisms of Action: Cell Wall Integrity
Polymixn B most common Common ingredient in first-aid skin ointments Binds membrane of Gram (-) cells Alters permeability Also binds eukaryotic cells Limits use to topical application

Susceptibility of Bacteria to Antimicrobial Drug
Susceptibility of organism to specific antimicrobials is unpredictable Often drug after drug tried until favorable response was observed Better approach Determine susceptibility Prescribe drug that acts against offending organism Best to choose one that affects as few others as possible

Determining Susceptibility of Bacterial to Antimicrobial Drug
MIC = Minimum Inhibitory Concentration Quantitative test to determine lowest concentration of specific antimicrobial drug needed to prevent growth of specific organism

Kirby-Bauer disc diffusion method qualitative determination of susceptibility Discs impregnated with specific concentration of antibiotic placed on plate and incubated Clear zone of inhibition around disc reflects susceptibility size of clearing zone indicates if susceptible or resistant

E-test Uses strips impregnated with gradient concentration of antibiotic Test organism will grow and form zone of inhibition Zone is tear-drop shaped Zone will intersect strip at inhibitory concentration

Resistance to Antimicrobial Drugs
Mechanisms of resistance Drug inactivating enzymes Penicillinase breaks β-lactam ring of penicillin antibiotics Alteration of target molecule Minor structural changes in antibiotic target can prevent binding Changes in ribosomal RNA prevent macrolids from binding to ribosomal subunits

Mechanisms of resistance Decreased uptake of the drug Alterations in porin proteins decrease permeability of cells Increased elimination of the drug Some organisms produce efflux pumps Tetracycline resistance

Acquisition of resistance Can be due to spontaneous mutation vertical evolution Or acquisition of new genes horizontal transfer Plasmid mediated

Spontaneous mutation Example of spontaneous mutation Resistance to streptomycin is result a change in single base pair encoding protein to which antibiotic binds When antimicrobial has several different targets it is more difficult for organism to achieve resistance through spontaneous mutation

Acquisition of new genes through gene transfer Most common mechanism of transfer is through conjugation Transfer of R plasmid Plasmid often carries several different resistance genes Organism acquires resistance to several different drugs simultaneously

Examples of emerging antimicrobial resistance Enterococci Intrinsically resistant to many common antimicrobials Some strains resistant to vancomycin VRE: Vancomycin resistant enterococcus Many strains achieve resistance via transfer of plasmid

Staphylococcus aureus Common cause of nosocomial infections Becoming increasingly resistant Most strains acquired resistance to penicillin Until recently most infections could be treated with methicillin MRSA  methicillin resistant Staphylococcus aureus many of these strains still susceptible to vancomycin VISA vancomycin intermediate Staphylococcus aureus

Streptococcus pneumoniae Has remained sensitive to penicillin Some strains have now gained resistance Resistance due to modification in genes coding for penicillin-binding proteins Acquisition via DNA mediated transformation

Slowing emergence and spread of resistance Responsibilities of physicians and healthcare workers Prescribe antibiotics for specific organisms Educate patients on proper use of antibiotics Responsibilities of patients Follow instructions carefully Complete prescribed course of treatment Misuse leads to resistance

Slowing emergence and spread of resistance Importance of an educated public Greater effort made to educate public about appropriateness and limitations of antibiotics Antibiotics have no effect on viral infections Misuse selects antibiotic resistance in normal flora Global impacts of the use of antimicrobial drugs Organisms which develop resistance in one country can be transported globally Many antimicrobials are available as non-prescription basis Use of antimicrobial drugs added to animal feed Produce larger more economically productive animals Also selects for antimicrobial resistant organisms

Mechanisms of Action of Antiviral Drugs
Available antiviral drugs effective specific type of virus None eliminate latent virus Targets include Viral uncoating Nucleoside analogs Non-nucleoside polymerase inhibitors Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Neuraminidase inhibitors

Viral uncoating Drugs include amantadine and rimantadine Mode of action is blocking uncoating of influenza virus after it enters cell Prevents severity and duration of disease Resistance develops frequently and may limit effectiveness of drug

Nucleoside analogs Incorporation of analog results in termination of growing nucleotide chain Examples of nucleoside analogs Zidovudine (AZT) Didanosine (ddI) Lamivudine (3TC)

Non-nucleoside polymerase inhibitor Inhibit activation of viral polymerases by binding to site other than nucleotide binding site Example = foscarnet and acyclovir Non-nucleoside reverse transcriptase inhibitor Inhibits activity of reverse transcriptase by binding to site other than nucleotide binding site Example = nevirapine, delavirdine, efavirenz Used in combination to treat HIV

Protease inhibitor Inhibit HIV encoded enzyme protease Enzyme essential for production of viral particles Examples = indinavir and ritonavir Neuraminidase inhibitor Inhibit neuraminidase enzyme of influenza Enzyme essential for release of virus Examples = zanamivir and oseltamivir

Mechanisms of Action of Antifungal Drugs
Target for most antifungal medications is plasma membrane Ergosterol Include Polyenes Azoles Allylamines Other targets Cell wall synthesis Cell division Nucleic acid synthesis

Mechanisms of Action of Antifungal Drugs
Cell wall synthesis Echinocandins interfere with synthesis of fungal cell wall Cell division Griseofulvin Exact mechanism unknown Appears to interfere with action of tubulin Selective toxicity may be due to increased uptake by fungal cells Used to treat skin and nail infections Nucleic acid synthesis Flucytosine Inhibits enzymes required for nucleic acid synthesis Flucytosine converted to 5-fluorouricil

Mechanisms of Action of Antiprotozoans and Antihelminthics
Many antiparasitic drugs most likely interfere with biosynthetic pathways of protozoan parasites or neuromuscular function of worms Example of parasitic drugs includes Malarone Synergistic combination of atovaquone and proguanil HCl Interferes with mitochondrial electron transport and disruption of folate synthesis

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