Antimicrobial Medications

Antimicrobial Medications
Chapter 21

History and Development of Antimicrobial Drugs
Discovery of antimicrobial drugs Salvarsan first documented example of chemical successfully used as antimicrobial Discovered by Paul Erlich in for treatment of syphilis Prontosil dye effective against streptococcal infections No effect on Streptococcus growing in vitro Enzymes in blood split prontosil into small sulfonamide molecules Sulfonamide was the first sulfa drug Acts as a competitive inhibitor to para-aminobenzoic acid

Discovery of antibiotics Alexander Fleming Discovered penicillin while working with Staphylococcus Noticed there were no Staphylococcus colonies growing near a mold contaminant The colonies appeared to be melting Identified mold as Penicillium which was producing a bactericidal substance that was effective against a wide range of microbes Fleming unable to purify compound Eventually abandoned his study

Discovery of antibiotics Ernst Chain and Howard Florey successfully purified penicillin In 1941tested on human subject with life threatening Staphylococcus aureus infection Treatment effective initially Supply of penicillin ran out before disease under control Patient dies of infection Drug tested again with adequate supply Patients recovered fully Mass production of penicillin during WWII Treatment of wounded soldiers and war workers Selman Waksman isolated streptomycin from soil bacterium Streptomyces griseus

Development of new generation of drugs In 1960s scientists alteration of drug structure gave them new properties Penicillin G altered to created 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 inoculated into broth medium Incubated until maximum antibiotic concentration is reached Drugs is extracted from broth medium Antibiotic extensively purified In some cases drugs are chemically altered to impart new characteristics Termed semi-synthetic

Selective toxicity Antibiotics cause greater harm to microorganisms than to human host Generally by interfering with biological structures or biochemical processes common to bacteria but not to humans 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

Antimicrobial action Drugs may kill or inhibit bacterial growth Inhibit = bacteriostatic Kill = bacteriocidal Bacteriostatic drugs rely on host immunity to eliminate pathogen Bacteriocidal drugs are useful in situations when host defenses cannot be relied upon to 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 Broad spectrum Work on broad range of organisms Gram-positive AND Gram-negative Disadvantage of broad spectrum is disruption of normal flora

Tissue distribution, metabolism and excretion Drugs differ in how they are distributed, metabolized and excreted Important factor for consideration when prescribing Rate of elimination of drug from body expressed in half-life 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

Effects of combinations of antimicrobial drugs Combination some times used to treat infections When action of one drug enhances another effect is synergistic When action of one drug interferes with another effect is antagonistic When effect of combination is neither synergistic or antagonistic effect said to additive

Adverse effects Allergic reactions Allergies to penicillin Allergies often life threatening Toxic effects Aplastic anemia Body cannot make RBC or WBC Suppression of normal flora Antibiotic associated colitis Toxic organisms given opportunity to establish themselves Antimicrobial resistance Microorganisms have innate or adaptive resistance to antibiotics

Mechanisms of Action of Antibacterial Drugs
Mechanism of action include: Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acid synthesis Inhibition of metabolic pathways Interference with cell membrane integrity Interference with essential processes of M. tuberculosis

Inhibition of cell wall synthesis Bacteria cell wall unique in construction Contains PTG Antimicrobials interfere with the synthesis of cell walls, and do not interfere with eukaryotic cell Due to the lack of cell wall in animal cells and differences in cell wall in plant cells These drugs have very high therapeutic index Low toxicity with high effectiveness Antimicrobials of this class include β lactam drugs Vancomycin Bacitracin

Penicillins and cephalosporins Part of group of drugs called β–lactams Have shared chemical structure called β-lactam ring Competitively inhibits function of penicillin-binding proteins Inhibits peptide bridge formation between glycan molecules Drugs vary in spectrum Some more active against Gram + Due to access of PTG Some more active against Gram - Some organisms resist effects through production of β-lactamase enzyme Enzyme breaks β-lactam ring

The penicillins Each member has common structure Modified side chains create derivatives Penicillin drugs include Natural penicillins Penicillinase-resistant penicillin Broad-spectrum penicillins Extended spectrum penicillins Penicillins + β lactamase inhibitor

Natural penicillins Narrow spectrum Effective against Gram + and some Gram - cocci Penicillinase-resistant penicillin Developed in laboratory Side chains prevent inactivation from penicillinase enzymes Broad-spectrum penicillins Modified side chains give them a more broad spectrum Effective against Gram + and Gram - Extended spectrum penicillins Greater effectiveness against Pseudomonas species Less effective against Gram + organisms Penicillins + β lactamase inhibitor Combination of penicillin drug and enzyme inhibitor Augmentin = amoxicillin + clavulanic acid

The cephalosporins Chemical structures make them resistant to inactivation by certain β-lactamases Tend to have low affinity to penicillin-binding proteins of Gram + bacteria Chemically modified to produce family of related compounds First, second, third and fourth generation cephalosporins

Other β-lactam antibiotics Two groups Carbapenems and monobactams Very resistant to β-lactamases Carbapenems effective against wide range of Gram + and Gram - organisms Monobactams primarily effective against members of family Enterobacteriaceae Can be given to patients with penicillin allergies

Vancomycin Inhibits formation of glycan chains Inhibits formation of PTG and cell wall construction Does not cross lipid membrane of Gram - Gram - organisms innately resistant Important in treating infections caused by penicillin resistant Gram + organisms Must be given intravenously due to poor absorption from intestinal tract Acquired resistant 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

Inhibition of protein synthesis Structure of prokaryotic ribosome acts as target for many antimicrobials of this class Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity Drugs of this class include Aminoglycosides Tetracyclins Macrolids Chloramphenicol Lincosamides Oxazolidinones Streptogramins

Aminoglycosides Irreversibly binds to 30S ribosomal subunit Causes distortion and malfunction of ribosome Blocks initiation translation Causes misreading of mRNA Not effect against anaerobes, enterococci and streptococci Often used in synergistic combination with β-lactam drugs Allows aminoglycosides to enter cells that are often resistant Examples of aminoglycosides 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 Effective against certain Gram + and Gram - Newer tetracyclines such as doxycycline have longer half-life Allows for less frequent dosing Resistance due to decreased accumulation by bacterial cells Can cause discoloration of teeth if taken as young child

Macrolides Reversibly binds to 50S ribosome Prevents continuation of protein synthesis Effective against variety of Gram + organisms and those responsible for atypical pneumonia Often drug of choice for patients allergic to penicillin Macrolids include Erythromycin, clarithromycin and azithromycin Resistance can occur via modification of RNA target Other mechanisms of resistance include production of enzyme that chemically modifies drug as well as alterations that result in decreased uptake of drug

Chloramphenicol Binds to 50S ribosomal subunit Prevents peptide bonds from forming and blocking proteins synthesis Effective against a wide variety of organisms Generally used as drug of last resort for life-threatening infections Rare but lethal side effect is aplastic anemia

Lincosamides 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 Most commonly used lincosamide is clindamycin

Oxazolidinones New class of antimicrobials Binds 50S ribosomal subunit Interferes with initiation of proteins synthesis Effective against variety of Gram + bacteria Especially those resistant to β-lactams and vancomycin

Streptogramins Bonds to two different sites on 50S ribosomal subunit Acts synergistically through the combination of quinupristin and dalfopristin Medication called Synercid Effective against variety of Gram + bacteria Especially those resistant to β-lactams and vancomycin

Inhibition of nucleic acid synthesis These include Fluoroquinolones Rifamycins

Fluoroquinolones Inhibit action of topoisomerase DNA gyrase Topoisomerase cuts DNA to allow swiveling during DNA replication. Effective against Gram + and Gram - Examples include Ciprofloxacin and ofloxacin Resistance due to alteration of DNA gyrase

Rifamycins Block prokaryotic RNA polymerase Block initiation of transcription Rifampin most widely used rifamycins Effective against many Gram + and some Gram - as well as members of genus Mycobacterium Primarily used to treat tuberculosis and Hansen’s disease as well as preventing meningitis after exposure to N. meningitidis Resistance due to mutation coding RNA polymerase Resistance develops rapidly

Inhibition of metabolic pathways Relatively few Most useful are folate inhibitors Mode of actions to inhibit the production of folic acid Antimicrobials in this class include Sulfonamides Trimethoprim

Sulfonamides Group of related compounds Collectively called sulfa drugs Inhibit growth of Gram + and Gram - organisms Through competitive inhibition of enzyme that aids in production of folic acid Structurally similar to para-aminobenzoic acid Substrate in folic acid pathway Human cells lack specific enzyme in folic acid pathway Basis for selective toxicity Resistance due to plasmid Plasmid codes for enzyme that has lower affinity to drug

Trimethoprim Inhibits folic acid production Interferes with activity of enzyme following enzyme inhibited by sulfonamides Often used synergistically with sulfonamide Most common mechanism of resistance is plasmid encoded alternative enzyme Genes encoding resistant to sulfonamide and trimethoprim are often carried on same plasmid

Interference with cell membrane integrity Few damage cell membrane Polymyxin B most common Common ingredient in first-aid skin ointments Binds membrane of Gram - cells Alters permeability Leads to leakage of cell and cell death Also bind eukaryotic cells but to lesser extent Limits use to topical application

Inference with processes essential to Mycobacterium tuberculosis Limited range of antimicrobials used in treatment of infections caused by M. tuberculosis Due to numerous factors including chronic nature of disease, slow growth and waxy lipid in cell wall Waxy cell wall due to mycolic acid is impervious to many drugs Five medications termed first-line drugs preferentially because of effectiveness with low toxicity First-line drugs include rifampin, streptomycin and Isoniazid  inhibits synthesis of mycolic acid Ethambutol  inhibits enzymes for cell wall synthesis Pyrazinamide  mechanism of action unknown

Determining Susceptibility of Bacterial to Antimicrobial Drug
Susceptibility of organism to specific antimicrobials is unpredictable Often drug after drug tried until favorable response was observed If serious infection, several drugs were prescribed at one time with hope that one was effective Better approach Determine susceptibility Prescribe drug that acts against offending organism Best to choose one that effects as few others as possible

Determining MIC MIC = Minimum Inhibitory Concentration Quantitative test to determine lowest concentration of specific antimicrobial drug needed to prevent growth of specific organism Determined by examining strain’s ability to growth in broth containing different concentrations of test drug

MIC is determined by producing serial dilutions with decreasing concentrations of test drug Known concentrations of organism is added to each test tube Tubes are incubated and examined for growth Growth determined by turbidity of growth medium Lowest concentration to prevent growth is MIC

Conventional disc diffusion method Kirby-Bauer disc diffusion routinely used to qualitatively determine susceptibility Standard concentration of strain uniformly spread of standard media Discs impregnated with specific concentration of antibiotic placed on plate and incubated Clear zone of inhibition around disc reflects susceptibility Based on size of zone organism can be described as susceptible or resistant

E-test Modification of disc diffusion test Uses strips impregnated with gradient concentration of antibiotic From highest concentration to lowest 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 Some organisms produce enzymes that chemically modify drug 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 mecrolides from binding to ribosomal subunits

Mechanisms of resistance Decreased uptake of the drug Alterations in porin proteins decrease permeability of cells Prevents certain drugs from entering Increased elimination of the drug Some organisms produce efflux pumps Increases overall capacity of organism to eliminate drug Enables organism to resist higher concentrations of drug Tetracycline resistance

Acquisition of resistance Can be due to spontaneous mutation Alteration of existing genes Spontaneous mutation called vertical evolution Or acquisition of new genes Resistance acquired by transfer of new genes called horizontal transfer

Spontaneous mutation Occurs at relatively low rate Such mutations have profound effect of resistance of bacterial population 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 Each gene mediating resistance to a specific antibiotic Organism acquires resistance to several different drugs simultaneously

Examples of emerging antimicrobial resistance Enterococci Part of normal intestinal flora Common cause of nosocomial infections Intrinsically resistant to many common antimicrobials Some strains resistant to vancomycin Termed VRE Vancomycin resistant enterococcus Many strains achieve resistance via transfer of plasmid

Staphylococcus aureus Common cause of nosocomial infections Becoming increasingly resistant In past 50 years most strains acquired resistance to penicillin Due to acquisition of penicillinase genes Until recently most infections could be treated with methicillin (penicillinase resistant penicillin) Many strains have become resistant MRSA  methicillin resistant Staphylococcus aureus MRSA many of these strains still susceptible to vancomycin Some hospitals identified VISA 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 Changes due to acquisition of chromosomal DNA from other strains of Streptococcus Generally via DNA mediated transformation

Mycobacterium tuberculosis First-line drugs incur spontaneous mutations readily Organisms in active infection often resistant to one of the multiple drugs used to treat Reason for multiple drug therapy required When organisms become resistant to rifampin and isoniazid organisms termed multi-drug-resistant

Slowing emergence and spread of resistance Responsibilities of physicians and healthcare workers Increase efforts to 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 develop resistance in one country can be transported globally Many antimicrobials are available as non-prescription basis Use of antimicrobials 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 Similar in chemical structure and mechanism of action 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 Similar in structure to nucleoside Analogs phosphorylated and become nucleotide 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 Used to treat CMV and HSV Non-nucleoside reverse transcriptase inhibitor Inhibits activity of reverse transcriptase by binding to site other than nucleotide binding site Example: nevirapine, delavirdine, efavirenz Used to in combination to treat HIV

Protease inhibitor Inhibit HIV encoded enzyme protease Enzyme essential for production of viral particles Examples: indinavir and ritonavir Used in treatment of HIV Neuraminidase inhibitor Inhibit neuraminidase enzyme of influenza Enzyme essential for release of virus Examples: zanamivir and oseltamivir Zanamivir administered via inhalation Oseltamivir administered orally

Mechanisms of Action of Antifungal Drugs
Target for most antifungal medications is ergosterol In plasma membrane Drugs targeting ergosterol include Polyenes Azoles Allylamines Other targets Cell wall synthesis Cell division Nucleic acid synthesis Ergosterol is to fungi what cholesterol is to humans: the major membrane sterol.

Polyenes Produced by Streptomyces Disrupts fungal membrane Causes leakage of cytoplasmic contents leading to cell death Polyenes very toxic to humans Limited to use in life-threatening disease Amphotericin B effective against systemic infection Causes severe side effects Nystatin used topically due to toxicity

Azoles Chemically synthesized drugs Includes two classes Imidazoles and triazoles Both inhibit synthesis of ergosterol Triazoles including fluconazole and itraconazole increased in use for systemic infections Imidazoles like miconazole used in topical creams and ointments Allylamines Inhibit pathway of ergosterol synthesis Administered topically Used for treatment of dermatophyte infections

Cell wall synthesis Echinocandins Family of agents that interfere with synthesis component 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 Synthetic derivative of cytosine Flucytosine converted to 5-fluorouracil Inhibits enzymes required for nucleic acid synthesis Often combined with amphotericin

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 Used to treat malaria Interferes with mitochondrial electron transport and disruption of folate synthesis

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