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Micro Exam 2: Antibiotics
Antibiotic Lecture
80
Microbiology
Undergraduate 2
10/20/2012

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Cards

Term
differential toxicity
Definition
based on the concept that the drug is more toxic to the infecting organism than the host
Term
minimal inibitory concentration (MIC)
Definition
minimum concentration of antibiotic required to inhibit growth of test organism
Term
Minimum Bactericidal Concentration
Definition
minimal concentration of antibiotic needed to kill the test organism
Term
prophylaxis
Definition
antimicrobial agents are administered to prevent infection
Term
treatment
Definition
antimicrobial agents are administered to cure existing or suspected infection
Term
therapeutic index; which drugs have a low one?
Definition

= toxic dose (TD)/effective dose (ED)

drugs with low may require therapeutic drug monitoring (TDM) 

 

-- aminoglycosides and vancomycin

Term
Ideal antibioitic?
Definition
low toxicity, low development of resistance, no hyper-sensitivity to host, rapid and extensive distribution, long half-life, free of drug interations, convenient and cheap
Term
synergy
Definition

1+1=10

more than added

Term
antagonism
Definition

1+1 = 0.5

does not add; less

Term
only bacteria that emergence of resistance can be prevented by combination therapy?
Definition

1. mycobacterium tuberculosis

2. S. aureus (fluroquinonlone, rifampin)

Term
Empiric Therapy
Definition

immediate treatment  prior to identification

- prior to growth, identification, or susceptibility reports

- based on epidemiology (most probable etiologies)

- severity of disease and local rates of disease

Can narrow the original broad therapy once we know.
Term
Define Resistance
Definition

inability to kill or inhibit organism with clinically achievable drug concentrations

 

- may be innate (mutation) or acquired (acquisition of foreign DNA)

Term
What are the mechanisms of resistance gene transfer?
Definition
Transformation - take up naked DNA
Conjugation - 2 cells sharing DNA
Transduction - introduction of new DNA via bacteriophage.
Term
Penicillin Binding Proteins (PBP)
Definition

 - transglycosylases: transver of nascent peptidoglycan to growing backbone

carboxypeptidases/transpeptidases: similar function as above, cleave the terminal D-ala from pentapeptide; ratio determines extent of cross-linking (influences cell shape)

Term
glycopeptides
Definition

-vancomycin/teicoplanim

-gram positive agents

 

bind to terminal D-ala of nascent cell wall peptides and prevents cross-linking of these peptides to form mature peptidoglycan

Term
mechanisms of vancomycin action
Definition
inhibits peptidoglycan synthesis in bacterial cell wall by complexing with D-alanyl-D-alanyl portion of cell wall precursor
Term
B-lactam resistance
Definition

1. production of B-lactamase (most common)

2. altered penicillin binding proteins (s. pneumoniae)

3. novel penicillin binding proteins (MRSA)

4. altered permeability

Term
glycopeptide resistance
Definition

- primary concern = enterococcus/S. aureus

- altered target, bacteria substitutes D-lac for D-ala; vancomycin can no longer bind

Term
Beta-lactamase inhibitors
Definition

- clavulanate (w/ amoxicillin or ticarcillin)

- tazobactam (w/ piperacillin)

 

  • S aureus
  • H influenza
  • Neisseria sp
  • Bacteriodes fragilis
  • E coli and Klebsiella
  • not better for psudomonas or enterobacter
Term
Inhibitors of protein synthesis (drugs)
Definition

-macrolids, lincosamides, streptogramins (MLS), tetracyclines, aminoglycosides, linezolid

-binding may be reversable or irreversable

Term
Macrolids (4)
Definition

1. erythromycin

2. clarithromycin

3. azithromycin

4. telithromycin (ketolide)

Term
Macrolides
Definition

exert antibacterial effect by inhibiting protein synthsis

- bind to 50s subunit of bacteria ribosomes

 

1. block growth of nascent peptide chain by stimulating dissociation of peptidyl-tRNA from ribosome

2. inhibit assembly of new large ribosomal subunits (depletion of functional ribosomal subunits in cell)

Term
Macrolide-Resistance
Definition

1. Efflux pump mef(A)

2. Target Site Modification erm(B)

 

S. pneumoniae

Term

Where should you use macrolides? (1st and 2nd choice)

 

Definition

First Choice: 

    - community acquired pneumonia

    - pertussis

    - chlamydia trachomatis infections

    - mycoplasma infections

 

Second Choice:

    - pyogenic streptococcal infections

    - C. jejuni gastroenteritis

 

Term
Fluroquinolones - static or cidal? Time or concentration dependent?
Definition

concentration-dependent and highly bactericidal

 

Term
Evolution of Fluoroquinolones
Definition

1st: nalidixic acid

2nd: ciprofloxacin - broader spectrum, anti-pseudomonal

3rd: moxifloxacin - enhanced gram (+), +/- anaerobic activity

Term
Fluoroquinolones mechanism of action
Definition

Inhibit DNA Gyrase (gyrA)

Topoisomerase IV (parC)

Term
Development of Fluoroquinolone resistance
Definition

 

   - spontaneous mutation in gyrA and parC 

   - efflux pumps (pump it out)

   - down regulation of porin channels (don't let it in)

   

 

Term
Aminoglycosides
Definition

- natural/semi-synthetic antibiotics (streptomycin - 1944)

- excellent gram (-) activity (pseudomonas)

- good gram (+) activity

- bactericidal/concentration dependent

 

ex. Gentamicin, Tobramicin, Amikacin

Term
Aminoglycosides mechanism of action
Definition

gain entry through inner membrane via energy dependent transport (dependent on electron transport)

-- this step is rate limiting and blocked by divalent cations and anaerobiosis

 

CANNOT work in anaerobic environments (abscess)

 

they irreversibly bind to 30S ribosomal subunit through energy dependent process; perturbs elongation of nascent polypeptides by impairing proofreading process; aberrant/truncated proteins

--can interfere with mammalian protein synthesis at high concentrations

Term
Aminoglycosides - mechanisms of resistance
Definition

1. altered ribosome binding sites (streptomycin only!)

2. reduced uptake or decreased cell permeability

3. enzymatic modification - most common form (>70 ezymes); different substrate specificities and plasmid mediated

Term
Inhibitors of Metabolic Pathways
Definition
  • Trimethoprim/sulfamethoxazole (Septra, TMP/SMX)   ----- good gram (-), some gram (+)
  • block folic acid synthesis at 2 points (TMP and SMX act synergistically)
Term
Mechanisms of action of TMP-SMX
Definition

PABA --> Dihydofolic Acid (by sulfonamides)

Dihydofolic Acid --> Tetrahydrofolic Acid (Trimethoprim)

Term
TMP/SMX
Definition

- commonly used as 1st line antibioitc in uncomplicated UTIs

- gastro-intestinal infections

- management of penicillin resistant protein pneumonia

- very active anti-Staphylococcal agent (CA-MRSA)

 

Term
Metronidazole (mechanism of action and side effects)
Definition
  • mechanism of action: short lived toxic intermediates or free radicals; damage to DNA (or other macromolecules)
  • >90% bioavailablility
  • long half life (BID dosing)
  • Side effects: GI intolerance, antabuse effect, peripheral neuropathy
  • cheap
  • resistance is slow to develop

 

Term
Uses of Metronidazole 
Definition
  • anaerobic infections
  • C. difficile colitis
  • giardiasis
  • Trichmonas vaginitis and BC
  • H. pylori (in combination)
  • Perianal disease in IBD
Term
Bacteriostatic vs. bacteriocidal
Definition
Stalls growth vs. Kills
Term
Time Dependent
Definition
Once you reach a concentration, no further increase in concentration will make a difference. Time exposure is key factor. Multiple doses per day.
Term
Concentration Dependent
Definition
Higher the concentration, the more bactericidal. Give once a day
Term
Targets of Antibiotics
Definition
Folic Acid metabolism, Cell wall synthesis, DNA gyrase, topoisomerase IV, protein synthesis (50s 30s)
Term
Do ATBX cause resistance?
Definition
NO, they select for pre-existing mutations. Darwinian
Term
What are the general mechanisms of resistance?
Definition
Altered permeability, Inactivation/destruction of ATBX, altered binding site (PBP), new binding sites, efflux pumps
Term
What are the types of Beta- Lactam drugs?
Definition
Penicillins, Cephalosporins, Carbapenems
Term
Mechanism of action of Beta-Lactam drugs?
Definition
Inhibition of transpeptidases, disinhibition of autolysins. Cell swells and ruptures due to high osmotic pressure inside the cell. Transpeptidase creates the cross links between peptidoglycan polymer strands. BIND TO PBP (transpep, and autolysins)
Term
Piperacillin
Definition
Effective against pseduomonas
Term
Cloxacillin
Definition
effective against staphylococcus(produce beta lactamases), with the exception of MRSA.
Term
Penicillins are normall active against which type of organisms?
Definition
Gram Positive, Outer membrane of gram negative organisms is difficult to penetrate.
Term
Carbapenems
Definition
Reserved for hospital use. Very broad spectrum. Kills everything
Term
Ampicillin affective against?
Definition
E. Coli, H. Influenzae, Salmonella, Shigella. Broad spectrum penicillin.
Term
What is often combined with beta lactam drugs to boost effectiveness?
Definition
Clavulanic acid - beta lactamase inhibitors.
Term
Broad spectrum penicillins(amoxicillin ampicillin) are more effective because?
Definition
ability to penetrate gram-negative cell envelope. Ineffective against staph aureus because of beta lactamase.
Term
Staph Aureus difficult to treat because?
Definition
Produces beta lactamase.
Term
If a history of a rash exists with penicillin use, which other class can be used?
Definition
Cephalosporins.
Term
Ticarcillin and Piperacillin - special because?
Definition
Antipseudomonals
Term
How does vancomycin/teicoplanin work?
Definition
Against gram positive, binds to D-ala, D-ala ending on premature glycopeptides so they can't be cross-linked.
Term
Bugs that produce Beta Lactams?
Definition
S. Aureus, H. Influenzae, Neisseria, Bacteroides Fragilis, E. coli, Klebsiella.
Term
Protein Synthesis Inhibitors target what?
Definition
Ribosomes, may be reversible or irreversible.
Term
Protein Synthesis inhibitors include which ATBX?
Definition
Macrolides, aminoglycosides, tetracyclines etc.
Term
Protein Synthesis inhibitors include which ATBX?
Definition
Macrolides, aminoglycosides, tetracyclines etc.
Term
What are the primary drugs in the macrolide class?
Definition
Erythromycin, clarithromycin, azithromycin, ketolide.
Term
How do macrolides exert antibacterial effects?
Definition
Bind to 50s ribosomal subunit.
Term
Mechanism of macrolide resistance?
Definition
Efflux pump - Mef gene. Low level of resistance.
Target site modification - erm gene. High level of resistance
These are acquired genes, not normally present.
Term
Where should you use macrolides?
Definition
1st choice - community acquired pneumonia, chlamydia, mycoplasma(no cell wall, penicillin won't work), pertussis.

Lower Respiratory tract infections.
Term
Mechanism of action of fluoroquinolones - concentration dependent.
Definition
Action against gram negative. Interfere with DNA replication. Target Gyrase(enzyme responsible for supercoiling, without which replication can't take place) and topoisomerase (separates daughter strands during cell division).
Term
Ciprofloxacin is important because ________?
Definition
antipsuedomonal activity.
Term
Uses of aminoglycosides?
Definition
Gram negative activity, including antipseudomonals. Good gram positive activity.
Term
Examples of Aminoglycosides and uses?
Definition
Gentamicin - most commonly prescribed.
Tobramicin - anti-pseudomonal.
Term
Pseudomonas?
Definition
bacteria, gram negative, found in hospitals, multidrug resistance, causes life threatening infections.
Term
Aminoglycosides and abscesses
Definition
Amino's need energy to be transported into the cell, require oxygen. Do not work in anaerobic environments such as abscess.
Term
Aminoglycosides inhibit protein synthesis how?
Definition
Bind to the 30s ribosome.
Term
Aminoglycoside mechanisms of resistance?
Definition
1. Altered ribosome binding site.
2. Reduced uptake or decreased cell permeability.
3. Enzymatic modification. * most common.
Term
Inhibitors of metabolic pathways (Trimethoprim and sulfonamides) - mechanism of action?
Definition
Inhibit folic acid production, which is required by cells to synthesize DNA RNA and proteins. Humans take up folic acid from food and don't synthesize it. Block at two different points.
Usually used to treat UTI, GI, treats STAPH!. Gram negative drug.
Term
Metronidazole - mechanism of action?
Definition
taken up into cell and converted into active form (free radicals) that damage DNA and other macromolecules.
Term
Metronidazole other points?
Definition
Available PO, long half life. CAN"T DRINK ALCOHOL. Best for anaerobic organisms (and CLINDAMYCIN). Resistance is slow to develop. CHEAP.
Term
Best drugs for anaerobes?
Definition
Clindamycin and metronidazole.
Term
Ciprofloxacin (fluoroquinolone) action against?
Definition
Antipsuedomonals. 
Term
Excellent use for anaerobics?
Definition
Metronidazole
Term
Protein synthsis inhibitors - 50s?
Definition
Macrolides, clindamycin
Term
Protein synthesis inhibitors - 30s?
Definition
Aminoglycosides, tetracyclines
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