Download Chapter 10 Antimicrobial Drugs

MICROBIOLOGY
WITH DISEASES BY TAXONOMY, THIRD EDITION
Chapter 10
Controlling Microbial Growth in the Body: Antimicrobial Drugs
Lecture prepared by Mindy Miller-Kittrell, University of Tennessee, Knoxville
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Antimicrobial Drugs
“One day we could not save lives, or hardly any
lives; on the very next day we could do so
across a wide spectrum of diseases.
This was an awesome acquisition of power…”
Walsh McDermott, M.D.
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Antimicrobial Drugs
• Chemotherapeutic drugs
– Drugs that act against diseases
• Antimicrobial drugs
– Drugs that treat infectious diseases
• Antibiotic
– Chemical produced naturally by a microbe that inhibits or kills another
microbe
• Semi-synthetic antibiotics
– Modified antibiotics to enhance effectiveness
• Synthetic drugs – Antimicrobial drugs that are completely manmade
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Table 10.1
List of Antibiotics
• Generic Name/Brand Names
• Common Uses/ Possible side Effects
• Mechanisms of Action
List of antibiotics - Wikipedia, the free encyclopedia
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Principle of Selective Toxicity
• Antimicrobial agent must be more toxic to
pathogen than to host
– Based on differences in structure & metabolism
between pathogen & host
– Many differences = many options
– i.e. bacteria vs. eukaryotic hosts
– Fewer differences = fewer options,
– i.e. fungi, protozoa & helminths vs eukaryotic hosts
– Fewest options = Viruses inside host cell
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Principle of Selective Toxicity
• Ideal antimicrobial drug
– A drug that kills harmful microbes without damaging the host
• Reality
– A drug that is more toxic to microbes than the host; try to limit
“side effects” of drug
• Therapeutic Index
– Measurement of drug toxicity
– Ratio of toxic dose to the therapeutic dose
– Toxic dose
= Therapeutic Index
Therapeutic dose
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Spectrum of Activity
• Range of activity of a drug against microbes
• Narrow spectrum
– Effective against EITHER gram positive OR gram negative
microbes
• Extended spectrum
– Beyond original spectrum
• Broad spectrum
– Effective against a variety of microbes
– Long term use may cause “superinfections”
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Spectrum of Activity
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Mechanisms of Action of Antimicrobial Agents
1.
2.
3.
4.
5.
Inhibition of Cell Wall Synthesis
Inhibition of Protein Synthesis
Injury to Cell Membrane
Inhibition of Nucleic Acid Synthesis
Inhibition of Metabolic Pathways
Pearson Animation – Chemotherapeutic Agents Modes of Action
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Mechanisms of Action of Antimicrobial Agents
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1. Inhibition of Cell Wall Synthesis
•Antimicrobial drugs block formation of peptidoglycan
causing cell lysis
•Has no effect on existing peptidoglycan –only works on
actively reproducing cells
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1. Inhibition of Cell Wall Synthesis
Beta-lactams (penicillin & cephalosporin)
• irreversibly bind to enzymes that cross-link NAG-NAM subunits
Vancomycin & cycloserine –
– interfere with alanine-alanine bridges that link NAM subunits
Bacitracin
– Block secretion of NAG & NAM subunits
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1. Inhibition of Cell Wall Synthesis
• “Beta Lactam” antimicrobial drugs have a beta lactam ring in
the structure
• Penicillins and Cephalosporin are the most common beta
lactam antimicrobial drugs
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1. Inhibition of Cell Wall Synthesis
• Semisynthetic beta lactam drugs
– use beta-lactam ring and added side chains
– provide a broader spectrum of activity and greater resistance to betalactamase
– Oxacillin, Methicillin (MRSA)
– Ampicillin, Amoxacillin, Carbenicillin, Ticarcillin
– Augmentin, Timentin
– Primaxin (imipenem + cilastin)
– Aztreonam
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Beta Lactam Antibiotic: Penicillins
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Figure 20.6
1. Inhibition of Cell Wall Synthesis
Bacitracin– Topical application (triple antibiotic ointment)
– Narrow spectrum - gram-positive bacteria
Vancomycin– Narrow spectrum – gram positive bacteria
– Important "last line" against antibiotic resistant S. aureus (MRSA)
– Toxicity – auditory nerve, kidneys
– Streptogramins - effective against VRE and VRSA
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1. Inhibition of Cell Wall Synthesis
Isoniazid (INH) –
• blocks gene for enzyme in mycolic acid synthesis
• effective against Mycobacterium tuberculosis
• toxic to liver
Ethambutol –
• prevents formation of mycolic acid
• effective against Mycobacterium tuberculosis
• used in combination with other antimycobacterial drugs
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2. Inhibition of Protein Synthesis
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2. Inhibition of Protein Synthesis
Aminoglycosides Streptomycin, Neomycin, Gentamicin, Tobramycin
– broad spectrum – G+ & G– toxic to kidneys, auditory nerves (deafness)
– targets 30S subunit; change shape so cannot read codon correctly
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2. Inhibition of Protein Synthesis
Tetracycline & Doxycycline –
– Broad spectrum–
– G+, G-, mycoplasmas, chlamydia, rickettsias
– Adverse Effects –
– binds to Ca+, teeth, bones, light sensitivity
– Target – tRNA docking site
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Tetracycline & Doxycycline
Tetracycline causes brown band in developing teeth
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2. Inhibition of Protein Synthesis
Chlorampenicol –
– Broad spectrum but rarely used except for typhoid fever
– Adverse Effects – aplastic anemia in 1/24,000; neurological
damage
– Targets 50S subunit; blocks enzymatic activity
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2. Inhibition of Protein Synthesis
Macrolides –
Erythromycin
–
–
–
–
–
Alternative to penicillin- if penicillin allergy
Broad spectrum–G+ & a few G-; Mycoplasma
Zpak – azithromycin
Prevent newborn eye infections
Target – 50S subunit; block movement of mRNA
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2. Inhibition of Protein Synthesis
Streptogramins
– Synercid
– Effective against Gram-positives
– Answer to VRE and VRSA
• Oxazolidinones
– Linezolid
– Effective against Gram-positives
– Treatment for MRSA and VRE
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3. Injury to the Plasma Membrane
Polymyxin B
– Effective against Gram negatives, especially Pseudomonas
– Toxic to human kidneys
– Topical – Combined with bacitracin and neomycin in over-thecounter preparation
Antifungal drugs:
– Amphotericin B (polyene) attaches to ergosterol found in fungal
membranes
– Azoles inhibit ergosterol synthesis
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3. Injury to the Plasma Membrane
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4. Inhibition of Nucleic Acid Synthesis
• Antimicrobial drugs often affect prokaryotic and eukaryotic
DNA due to similar DNA
• Antimicrobial drugs (nucleotide analogs) interfere with
function of nucleic acids
• Most often used against viruses
– Viral DNA polymerases more likely to incorporate and synthesize
viral nucleic acid more rapidly than host cells
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4. Inhibition of Nucleic Acid Synthesis
Nucleotide analogs
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Figure 10.7
4. Inhibition of Nucleic Acid Synthesis
Rifampin
– Inhibits mRNA synthesis
– Effective against Mycobacterium tuberculosis
– Causes orange-red body fluids
Quinolones and fluoroquinolones
– Ciprofloxacin, Nalidixic acid
– Inhibits prokaryotic DNA gyrase
– Urinary tract infections, Anthrax (bioterrorism)
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5. Inhibition of Metabolic Pathways
• Use differences between metabolic processes of pathogen and
host
Quinines
• interfere with the metabolism of malaria parasites
Heavy metals
• inactivate enzymes
• Zinc: (Zicam) block attachment of viruses
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5. Inhibition of Metabolic Pathways
Sulfonamides (Sulfa drugs)
– Broad spectrum
– G+, G-, protozoa, fungi; lots of resistance
– Rare allergic reactions, anemia, jaundice, mental
retardation of fetus if given in last trimester
– Urinary tract infections
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5. Inhibition of Metabolic Pathways
Sulfonamides (Sulfa drugs)
– Competitive enzyme inhibitor
– Inhibit production of folic acid
– Similar structure to PABA - required for nucleotide
synthesis
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PABA and Sulfonamides
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Figure 10.6a
Sulfa + Trimethoprim = SXT, Bactrim
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Figure 20.13
Effects of Combinations of Drugs
• Synergism occurs when the effect of two drugs together is greater
than the effect of either alone. (sulfa + trimethoprim)
• Antagonism occurs when the effect of two drugs together is less
than the effect of either alone. (penicillin + tetracycline)
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Safety and side effects of antibiotics
1. Toxicity
– Kidneys, liver or nerves (polymyxin & aminoglycosides
– Fetus (tetracycline)
2. Allergies – mild to severe
– anaphylactic shock by penicillin ingestion
3. Disruption of Normal Microbiota
– GI tract – causes diarrhea
– Superinfections – by opportunistic pathogens like Candida
albicans and Clostridium difficile
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http://www.cdc.gov/drugresistance/about.html
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Antibiotic Resistance in Bacteria
http://www.knowabouthealth.com/extremely-resistant-superbug-triggers-globalconcern/5338/
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Bacterial Resistance to Antibiotics
• Some bacteria are Naturally resistant
– Do not have the target site of the antibiotic
• Bacteria can Acquire resistance
1. New mutations of chromosomal genes
2. Acquire R-plasmids through recombination
Pearson Animation: Antimicrobial Resistance- Origins
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Figure 10.15 - Overview
Bacterial Resistance to Antibiotics
• MDR (multiple drug-resistance) – Staphylococcus,
Streptococcus, Enterococcus, Pseudomonas, Mycobacterium,
Plasmodium
– Called superbugs
– Usually resistant to 2-3 drugs
– Common when R-plasmids are exchanged
• Cross resistance –
– resistance to one drug may confer resistance to another
– usually when antimicrobial drug is similar in structure
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Bacterial Resistance to Antibiotics
• Bacteria acquire mechanisms of drug resistance in
several ways:
1.
2.
3.
4.
5.
Produce enzymes that destroy drug
Decrease entry of drug in to cell
Pump drug out of cell before it can act
Alter target site of drug
Change metabolic pathway
Pearson Animation: Antimicrobial Resistance: Forms
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Mechanism of Bacterial Resistance:
1. Produce Enzymes that Destroy Drugs
A. Beta lactamase - Penicillinase –
– Produced by bacteria which deactivates penicillin
B. Extended-Spectrum beta-lactamase (ESBL)
– ESBLs are capable of hydrolyzing:
Semisynthetic penicillins and cephalosporins
–
Beta-lactamase inhibitors (e.g. clavulanic acid) generally inhibit
ESBL producing strains.
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Mechanism of Bacterial Resistance:
1. Produce Enzymes that Destroy Drugs
Penicillinase – Inhibits Beta lactam antibiotics
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Figure 20.8
Mechanism of Bacterial Resistance:
2. Decrease entry of
drug in to cell
3. Pump drug out of
cell before it can act by
efflux pumps
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Mechanism of Bacterial Resistance:
4. Alteration of metabolic pathway
• Some sulfonamide-resistant bacteria do not require PABA
– an important precursor for the synthesis of folic acids and
nucleic acids in bacteria inhibited by sulfonamides.
– Instead, like mammalian cells, sulfonamide-resistant
bacteria utilize preformed folic acid.
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Mechanism of Bacterial Resistance:
4. Alteration of target site
• Alteration of PBP (Penicillin Binding Protein)—the binding target
site of penicillins
• Mechanisms of quinolone resistance:
1. Produce proteins that can Bind to DNA gyrase
2. Mutations in DNA gyrase –
– decrease their binding affinity to quinolones (decrease the
drug's effectiveness)
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Common Misconceptions about antibiotics
1. People are (or become) resistant to antibiotics
2. Antibiotics cause mutations to make the bacteria resistant
3. Bacteria that are resistant to antibiotics are stronger than
sensitive bacteria
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Drug Resistance
Poor Countries
• Can’t afford full
course of medicines
• Drugs don’t require
prescriptions
• Counterfeit drugs
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Drug Resistance
Wealthy Countries
• Overuse – in many products like lotion, shampoo, soap, toys,
socks, etc.
• Over-prescribed
• Patients demand when not needed
• Prescriptions taken incorrectly
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Drug Resistance
• 50% of antibiotics used in
U.S. are for food animals –
90% used to prevent
disease before it occurs
• Thousands of pounds
sprayed on fruit trees
• Fed probiotics of bacteria
with R-plasmids
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http://www.cdc.gov/drugresistance/about.html
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Slow the Rate of Resistance
1. Limit use of antimicrobials
– Only prescribe to necessary cases
– Complete the prescribed regimen
– Toss outdated antibiotics; Do not use others’ drugs
2. High concentrations of drug
– Maintain in patient for long enough time to kill all sensitive cells and
inhibit others long enough for immune system to destroy
3. Use antimicrobial agents in combination
– Synergism vs. antagonism
4. Development of new variations of drugs
– Second-generation & Third-generation drugs
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New Antibiotics
• Most antibiotics are developed by pharmaceutical companies.
• 8-10 years & $800 million to $1.7 billion to develop a new
antibiotic, only to lose it to resistance.
• More profitable to make antidepressants and drugs for chronic
diseases.
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According to WHO
• Patients with infections caused by drug-resistant bacteria
– at increased risk of worse clinical outcomes and death
– consume more health-care resources than patients infected with the
same bacteria that are not resistant
• Treatment failures due to resistance to treatments of last resort for
gonorrhoea (third-generation cephalosporins) have been reported from
10 countries.
– Gonorrhoea may soon become untreatable as no vaccines or new
drugs are in development.
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According to WHO
• In 2012, gradual increase in resistance to HIV drugs
-further increases in resistance to first-line treatment drugs were
reported, which might require using more expensive drugs in the
near future
• In 2013, there were about 480 000 new cases of multidrug-resistant
tuberculosis (MDR-TB)
– . Extensively drug-resistant tuberculosis (XDR-TB) has been
identified in 100 countries.
– MDR-TB requires treatment courses that are much longer and less
effective than those for non-resistant TB.
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Antibiotic Resistance
“It’s a very real possibility that today’s antibiotics will be rendered
useless in 10 to 15 years. We must face the reality of a
worldwide problem of ineffective antibiotics.”
Nils Daulaire
President of the Global Health Council
June 13. 2000
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