Transcript Chapter 21
Antimicrobial Medications Chapter 21 Preview • History of antimicrobials • Wars between human and pathogens – How antimicrobials kill--features and mechanism of antimicrobials – Fighting back of pathogens-mechanism of resistance to antimicrobial drugs –Human returns History and Development of Antimicrobial Drugs • Discovery of antimicrobial drugs – Salvarsan • Discovered by Paul Erlich for treatment of syphilis (1910) • Basis for modern pharmaceutical research – Prontosil dye • effective against streptococcal infections by Dr. Domagk (1930’s) • 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 Antimicrobial drugs naturally produced by microorganisms Alexander Fleming discovered penicillin 1929 staphylococcus Penicillium (mold) History and Development of Antimicrobial Drugs • Discovery of antibiotics – Ernst Chain and Howard Florey successfully purified penicillin • Successfully treated patients with infection – Mass production of penicillin during WWII • Treatment of wounded soldiers and war workers – Selman Waksman isolated streptomycin from soil bacterium Streptomyces griseus Features of Antimicrobial Drugs • Most modern antibiotics come from organisms living in the soil – bacterial species Streptomyces and Bacillus – Fungus sepcies Penicillium and Cephalosporium • To commercially produce antibiotics – Antibiotic extensively purified from culture medium – In some cases drugs are chemically altered to impart new characteristics • Termed semi-synthetic History and Development of Antimicrobial Drugs • Development of new generation of drugs – alteration of drug structure gave them new properties • Penicillin G altered to created ampicillin – Broadened spectrum of antimicrobial killing Features of Antimicrobial Drugs • 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 Features of Antimicrobial Drugs • Antimicrobial action – Drugs may kill or inhibit bacterial growth • Inhibit = bacteriostatic • Kill = bacteriocidal – Bacteriostatic drugs rely on host immunity to eliminate pathogen • UTI drugs – Bacteriocidal drugs are useful in situations when host defenses cannot be relies upon to control pathogen Features of Antimicrobial Drugs • 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 Features of Antimicrobial Drugs • 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 Features of Antimicrobial Drugs • Effects of combinations of antimicrobial drugs – enhances each other’s effect--- synergistic – interferes with each other’s effect --antagonistic – neither synergistic nor antagonistic effect -additive Features of Antimicrobial Drugs • 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 – Clostridium difficile given opportunity to establish themselves – Antimicrobial resistance • Microorganisms have innate or adaptive resistance to antibiotics Mechanism of Antimicrobial Drugs Action target Inhibition of cell wall synthesis - lactam drugs Penicillin G Target - peptidoglycan synthesis Transpeptidases aka penicillin-binding proteins (PBPs) •High therapeutic index (note: allergies) •Not effective against most Gram-negatives •Cell wall •PBP Fig. 3.34 Inhibition of cell wall synthesis - lactam drugs Penicillin G Target - peptidoglycan synthesis; Transpeptidases Side chain aka penicillin-binding proteins (PBPs) •High therapeutic index (note: allergies) •Not effective against most Gram-negatives •Acid-sensitive •Destroyed by penicillinase (a -lactamase) Family of penicillins •Natural penicillins •Penicillinaseresistant penicillins •Broad-spectrum penicillins •Penicillins + lactamase inhibitor Mechanisms of Action of Antibacterial Drugs • Vancomycin – Inhibits formation of glycan chains • 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 Mechanisms of Action of Antibacterial Drugs • 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 Antibiotics protein synthesis Mechanisms of Action of Antibacterial Drugs • Tetracyclins – Reversibly bind 30S ribosomal subunit • Blocks attachment of tRNA to ribosome – 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 Mechanisms of Action of Antibacterial Drugs • Inhibition of nucleic acid synthesis – These include • Fluoroquinolones • Rifamycins Mechanisms of Action of Antibacterial Drugs • 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 Mechanisms of Action of Antibacterial Drugs • 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 Enzymes Enzyme inhibition Competitive inhibition - Inhibitor/substrate act at the same site Ex.: PABA folic acid coenzyme Sulfa Antiviral Drugs Nucleic Acid synthesis • Virally-encoded enzymes as target for antiviral drugs • Reverse transcriptase, Error-prone ( mutations) ex. AZT - nucleotide analog. • Herpes simplex virus (HSV) has an enzyme convert acyclovir to a nucleotide analog. Viral uncoating--block influenza A viruses. Assembly and Release of viral particlesprotease inhibitors Determining Susceptibility of Bacteria to Antimicrobial Drug • 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 Determining the susceptibility of a bacterial strain to an antimicrobial drug - Minimum Inhibitory Concen. (MIC) Determining the susceptibility of a bacterial strain to an antimicrobial drug - Minimum Inhibitory Concen. (MIC) Resistant vs intermediate vs susceptible Determining the susceptibility of a bacterial strain to an antimicrobial drug - Disk diffusion (Kirby-Bauer) test Determining the susceptibility of a bacterial strain to an antimicrobial drug - Disk diffusion (Kirby-Bauer) test Resistance to antimicrobial drugs Mechanisms of resistance Acquisition of resistance Spontaneous mutation Single-step S R Multi-step SS S S R Gene transfer Acquisition of Resistance • Spontaneous mutation – Occurs at low rate – 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 – Better drug development: target multiple proteins. Acquisition of resistance Gene transfer Resistance plasmids (R plasmids) Can encode resistance to multiple medications Don’t use antimicrobial medications except when necessary!!!!! Examples of drug resistant bugs • Staphylococcus aureus (Superbug) – Common cause of nosocomial infections – Becoming increasingly resistant • most strains acquired resistance to penicillin in past 50yrs. – Due to acquisition of penicillinase genes • treated with methicillin (penicillinase resistant penicillin) – MRSA methicillin resistant Staphylococcus aureus • MRSA many of these strains still susceptible to vancomycin – Some hospitals identified VISA » VISA vancomycin intermediate Staphylococcus aureus Examples of drug resistant bugs • Streptococcus pneumoniae – Has remained sensitive to penicillin • Some strains have now gained resistance – Gain of gene coding for penicillin-binding proteins » Generally via DNA mediated transformation Examples of drug resistant bugs • Mycobacterium tuberculosis – First-line drugs incur spontaneous mutations readily • often develop resistant to one of the multiple drugs used to treat – Reason for multiple drug therapy required • multi-drug-resistant: resistant to rifampin and isoniazid. Solutions • 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 Solutions • Slowing emergence and spread of resistance – Importance of an educated public • 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