Title: Antimicrobial%20Medications
1Antimicrobial Medications
2(No Transcript)
3History and Development ofAntimicrobial 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
4History and Development ofAntimicrobial Drugs
- 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
5History and Development ofAntimicrobial Drugs
- 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
6Features 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
7Features of Antimicrobial Drugs
- 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
8Features of Antimicrobial Drugs
- 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
9Features 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
- Advantage effects pathogen only
- Disadvantage requires identification of pathogen
- Broad spectrum
- Advantage Work on broad range of organisms
- Disadvantage disruption of normal flora
10Features of Antimicrobial Drugs
- Effects of combinations of antimicrobial drugs
- Combination sometimes used to treat infections
- Synergistic whole is gt sum
- Antagonistic whole is lt sum
- Additive whole is the sum
11Features of Antimicrobial Drugs
- 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
12Features of Antimicrobial Drugs
- Adverse effects
- Allergic reactions
- Toxic effects
- Suppression of normal flora
- Antimicrobial resistance
13Mechanisms 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
14Mechanisms 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
- ß lactam drugs (penicillin, cephalosporin)
- Vancomycin
- Bacitracin
15Mechanisms of Action Cell Wall Synthesis
- Drugs vary in spectrum
- Some more active against Gram ()
- Some more active against Gram (-)
- Resistance through production of ß-lactamase
enzyme - Penicillins ß lactamase inhibitor
- Augmentin amoxicillin clavulanic acid
16Mechanisms of Action Cell Wall Synthesis
- 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
17Mechanisms of Action Cell Wall Synthesis
- Bacitracin
- Interferes with transport of PTG precursors
across cytoplasmic membrane - Toxicity limits use to topical applications
- Common ingredient in non-prescription first-aid
ointments
18Mechanisms 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
19Mechanisms of Action Protein Synthesis
- 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
ß-lactam drugs - Examples include
- Gentamicin, streptomycin and tobramycin
- Side effects with extended use include
- Nephrotoxicity
- Otto toxicity
20Mechanisms of Action Protein Synthesis
- 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 (-)
21Mechanisms of Action Protein Synthesis
- 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
22Mechanisms of Action Protein Synthesis
- Chloramphenicol
- Binds to 50S ribosomal subunit
- Prevents peptide bond formation
- Wide spectrum
- Drug of last resort
- Rare but lethal side effect is aplastic anemia
23Mechanisms of Action Protein Synthesis
- 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
24Mechanisms of Action Protein Synthesis
- New class effective against ß-lactams and
vancomycin resistant Gram () forms - Oxazolidinones
- Binds 50S ribosomal subunit
- Interferes with initiation
- Streptogramins
- Bonds to two different sites on 50S ribosomal
subunit
25Mechanisms 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
26Mechanisms 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
- Hansens disease
- N. meningitidis meningitis
- Resistance develops rapidly
27Mechanisms 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
28Mechanisms 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
29Susceptibility 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
30Determining 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
31Determining Susceptibility of Bacterial to
Antimicrobial Drug
- 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
32Determining Susceptibility of Bacterial to
Antimicrobial Drug
- 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
33Resistance to Antimicrobial Drugs
- Mechanisms of resistance
- Drug inactivating enzymes
- Penicillinase breaks ß-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
34Determining Susceptibility of Bacterial to
Antimicrobial Drug
- 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
35Resistance to Antimicrobial Drugs
- Acquisition of resistance
- Can be due to spontaneous mutation
- vertical evolution
- Or acquisition of new genes
- horizontal transfer
- Plasmid mediated
36Resistance to Antimicrobial Drugs
- 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
37Resistance to Antimicrobial Drugs
- 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
38Resistance to Antimicrobial Drugs
- 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
39Resistance to Antimicrobial Drugs
- 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
40Resistance to Antimicrobial Drugs
- 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
41Resistance to Antimicrobial Drugs
- 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
42Resistance to Antimicrobial Drugs
- 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
43Mechanisms 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
44Mechanisms of Action of Antiviral Drugs
- 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
45Mechanisms of Action of Antiviral Drugs
- Nucleoside analogs
- Incorporation of analog results in termination of
growing nucleotide chain - Examples of nucleoside analogs
- Zidovudine (AZT)
- Didanosine (ddI)
- Lamivudine (3TC)
46Mechanisms of Action of Antiviral Drugs
- 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
47Mechanisms of Action of Antiviral Drugs
- 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
48Mechanisms 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
49Mechanisms 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
50Mechanisms 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