Chapter 3 Concepts in Antimicrobial Therapy

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Chapter 3 - Concepts in Antimicrobial Therapy

• MLAB 2434 Clinical Microbiology
• Cecile Sanders Keri Brophy-Martinez

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Definitions

• Antimicrobial Therapy broad term for use of
  chemical compounds to treat diseases caused by
  microorganisms
• Antibiotic most commonly used term
  technically, antibiotics are naturally occurring
  substances produced by a microorganism (ex.
  Penicillin produced by penicillium, a fungus)

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Definitions (Contd)

• Antimicrobial agents can also be either synthetic
  (totally manufactured or artificial) or
  semi-synthetic compounds (naturally occurring
  substances that have been chemically altered)
• Bacteriocidal kills the bacteria
• Bacteriostatic inhibit microbial growth

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Definitions (Contd)

• Additive Effects combining two antimicrobials
  causes twice the effect of the two drugs by
  themselves
• Indifference no effect of combining
  antimicrobial therapies
• Synergy combined effect is great than the two
  individual effects added together

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Definitions (Contd)

• Antagonism one drug counteracts the other

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Antimicrobial Factors

• Antimicrobials are designed to target a specific
  biological characteristic of microbes
• Factors to consider
• What is the targeted bacteria?
• Where is it located? Can the antimicrobial reach
  that site in sufficient concentration?

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Antimicrobial Factors (contd)

• Factors to consider (contd)
• Can the antimicrobial be retained in the body
  long enough to be effective?
• What are the side effects? How is it excreted?
• What is the cost?

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Antimicrobial Categories Based on Action on
Bacteria

• Effects on Cell Wall Integrity
• Interruption of Cell Membrane Structure and
  Function
• Inhibition of Protein Synthesis
• Inhibition of Essential Metabolites
• Interference with Nucleic Acid Metabolism

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Effects on Cell Wall Integrity

• Cell wall protects the bacteria cytoplasmic
  membrance
• Cell wall primarily composed of a peptidoglycan
  layer
• Inactivating or interfering with enzymes that
  synthesize the cell wall can destroy the bacteria

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Effects on Cell Wall Integrity (contd)

• ß-Lactam Antibacterial Agents
• Sizable portion of antibacterial agents used
  today
• Includes penicillins, cephalosporins,
  carbapenems, and monobactams
• All these have a ß-lactam chemical ring (see
  Figure 3-2, page 55 in text)

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Effects on Cell Wall Integrity (contd)

• ß-Lactam Antibacterial Agents (contd)
• ß-lactams interrupt specific enzymes known as
  transpeptidases, which cause cross-linking of the
  peptidoglycan layer
• Simple penicillins are effective against many
  streps, Neisseria, Pasteurella, and a number of
  anaerobes
• Ampicillin has same spectrum as penicillins, plus
  enterococci, Listeria, Haemophilus, and some
  enterics

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Effects on Cell Wall Integrity (contd)

• ß-Lactam Antibacterial Agents (contd)
• Cephalosporins are classified by their spectrum
  of activity and are spoken of in terms of
  generations
• First-generation cephalosporins have good G but
  modest G- activity
• Second-generation have better G- activity

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Effects on Cell Wall Integrity (contd)

• ß-Lactam Antibacterial Agents (contd)
• Third-generation cephalosporins are better with
  Enterobacteriaceae and some Pseudomonas, but less
  activity against G organisms
• Monobactam limited to aerobic G- bacilli
• Carbapenems broadest antimicrobial spectrum

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Effects on Cell Wall Integrity (contd)

• ß-Lactamase Inhibitors
• Certain bacteria produce beta-lactamase that
  hydrolyzes the ß-lactam ring, inactivating the
  antimicrobial
• ß-lactams can be administered with a ß-lactamase
  inhibitor, such as clavulanic acid

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Effects on Cell Wall Integrity (contd)

• Other Cell Wall Agents
• Affect the second stage of cell wall synthesis,
  inhibiting enzymes vital to continued formation
  of peptidoglycan
• Vancomycin is the most clinically important ONLY
  for G organisms
• Bacitracin and cycloserine are limited because of
  their toxic effects and limited bacterial activity

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Interruption of Cell Membrane Structure and
Function

• Polymyxins and Bacitracin
• Primarily effective against G- bacilli
• Because of toxicity, these are limited to topical
  medications (ex. Neosporin, etc.)

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Inhibition of Protein Synthesis

• These antimicrobials bind to ribosomal subunits
• This binding is either irreversible, resulting in
  cell death, or reversible, resulting in
  bacteriostatic effects
• Aminoglyosides bind irreversibly and are used
  primarily against Enterobacteriaceae

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Inhibition of Protein Synthesis (contd)

• Tetracyclines bind reversibly, so are
  bacteriostatic broad spectrum against G and G-
  organisms, including mycoplasmas
• Tetracycline is NOT used in children, as it
  affects tooth development

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Inhibition of Protein Synthesis (contd)

• Macrolides
• Binding is reversible
• Erythromycin is relatively broad-spectrum,
  including G cocci, mycoplasmas, chlamydiae,
  rickettsiae, and treponemes
• Newer macrolides, azithromycin and
  clarithromycin, also effective against some G-
  organisms and have fewer side effects

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Inhibition of Protein Synthesis (contd)

• Macrolides (contd)
• Clindamycin has excellent activity against
  aerobic G organisms and is extremely potent
  against anaerobes
• Chloramphenicol has broad activity but is
  extremely toxic to the bone marrow

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Inhibition of Essential Metabolites

• Inhibition of folinic acid synthesis
• Sulfonamides
• Trimethoprim
• Active against broad spectrum, including G and
  G- organisms, except for P. aeruginosa

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Interference with Nucleic Acid Metabolism

• Antimicrobials in this category interfere with
  either DNA or RNA metabolism
• Rifampin interferes with RNA production mainly
  used for M. tuberculosis, but has a broad
  spectrum of activity

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Interference with Nucleic Acid Metabolism (contd)

• DNA Synthesis Interference
• Nalidixic acid and fluorinated quinolones
  (norfloxacin, ciprofloxacin, ofloxacin) interfere
  with DNA synthesis most activity against G-
  aerobes
• Metronidzole makes DNA unstable only effective
  against anaerobes and protozoa

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Common Bacterial Resistance Mechanisms

• Prevent access to target
• Aminoglycosides
• ß-lactams
• Tetracyclines
• Modify target
• Macrolides
• Quinolones
• Rifampin
• Sulfonamides
• ß-lactams

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Common Bacterial Resistance Mechanisms (contd)

• Produce inactivating enzymes
• ß-lactams
• Chloramphenicol
• Aminoglycosides

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Reasons and Indications for Performing
Antimicrobial Susceptibility Tests

• Performed on bacteria isolated from clinical
  specimens if the bacterias susceptibility to
  particular antimicrobial agents is uncertain
• Susceptibilities NOT performed on bacteria that
  are predictably susceptible to antimicrobials
  commonly used to treat infections with those
  bacteria. (ex. Group A Strep)

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Factors to Consider When Determining Whether
Testing is Warranted

• Body site of infection
• Susceptibility not performed on bacteria isolated
  from body site where they are normal flora
• Ex. Susceptibility for E. coli is NOT performed
  when isolated from stool, but IS performed when
  isolated from blood

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Factors to Consider When Determining Whether
Testing is Warranted (contd)

• Presence of other bacteria and quality of
  specimen
• Ex. Three or more organisms grown in a urine
  specimen
• Host status
• Immunocompromised patients
• Allergies to usual antimicrobials

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Selecting Antimicrobial Agents for Testing and
Reporting

• There are approximately 50 generic antimicrobial
  agents
• Each laboratory should have a battery of
  antibiotics ordinarily used for testing decided
  by medical staff, pharmacists, and medical
  technologists (Drug Formulary)
• Clinical Laboratory Standards Institute
  (formerly NCCLS) recommendations

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Selection of Test Batteries

• Generally, labs choose 10-15 antibiotics to test
  susceptibility for G organisms and another 10-15
  for G- organisms
• 12 fit comfortably on 150 mm Mueller-Hinton plate
• Too many choices can confuse physicians and be
  too expensive

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Selection of Test Batteries (contd)

• Primary objective should be to use the least
  toxic, most cost-effective, and most clinically
  appropriate agents and refrain from more costly,
  broader-spectrum agents

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Traditional Antimicrobial Susceptibility Test
Methods

• Standardization of inoculum (using 0.5 McFarland
  standard)
• Dilution Methods
• MIC Minimum Inhibitory Concentration
• Tube Dilution Tests (too expensive and time
  consuming)
• Microdilution Tests (plastic trays with dilutions
  of antimicrobials)

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Traditional Antimicrobial Susceptibility Test
Methods (contd)

• Disk Diffusion Testing Kirby Bauer test
• Automated Antimicrobial Susceptibility Test
  Methods
• Microscan uses microdilution trays with
  automated reader
• Vitek (page 87)
• E Test

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Quality Control in Susceptibility Testing

• Quality control is recommended each day that
  patient tests are performed
• The frequency of QC can be reduced to weekly if
  lab can demonstrate acceptable proficiency

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Quality Control in Susceptibility Testing (contd)

• Routine QC organisms include
• E. coli ATCC 25922
• S. aureus ATCC 25923
• P. aeruginosa ATCC 27853
• - American Type Culture Collection