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Pharmacology > Antibacterials 4 > Flashcards

Antibacterials 4 Flashcards

1
Q

List Protein Synthesis Inhibitors antibiotics?

A
  • Tetracyclines
  • Glycylcyclines
  • Aminoglycosides
  • Macrolides
  • Chloramphenicol
  • Clindamycin
  • Streptogramins
  • Linezolid
  • Mupirocin
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2
Q

General Idea of protein synthesis inhibitors?

A

• Bind to and interfere with ribosomes
• Bacterial ribosome (70S) differs from mammalian
(80S) but closely resembles mammalian mitochondrial
ribosome
• Bacterial ribosome made of 30S and 50S subunits
• Mostly bacteriostatic

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3
Q

3 types of tetracyclines and decribe?

A 
Doxycycline, Minocycline, Tetracycline 
• Broad-spectrum
• Bacteriostatic
• Activity against many aerobic and anaerobic Grampositive
& Gram-negative organisms
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4
Q

Tetracycline MOA?

A

• Entry via passive diffusion & energy-dependent
transport unique to bacterial inner cytoplasmic
membrane
• Susceptible cells concentrate drug intracellularly
• Bind reversibly to 30S subunit of ribosome, preventing
attachment of aminoacyl tRNA

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5
Q

Describe tetracycline resistance and 3 main mechanisms?

A

• Widespread resistance (usually plasmid mediated)
• 3 main mechanisms:
• Impaired influx or increased efflux by active
(plasmid-encoded) protein pump
• Production of proteins that interfere with binding to
ribosome
• Enzymatic inactivation

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6
Q

Tetracycline Clinical applications?

A

• Most common use = severe acne & rosacea
• Used in empiric therapy of community-acquired
pneumonia (outpatients)
• Can be used for infections of respiratory tract,
sinuses, middle ear, urinary tract, & intestines
• Useful at treating atypical pneumonias (Mycoplasma,
Chlamydia, Legionella)
• Syphilis (patients allergic to penicillin)

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7
Q

Describe Tetracycline PK?

A

• Variable oral absorption (decreased by divalent &
trivalent cations)
• Doxycycline (lipid soluble) = preferred for parenteral
admin. and good choice for STD’s and prostatitis
• Concentrate in liver, kidney, spleen & skin
• Excreted primarily in urine except doxycycline (primarily
via bile)
• TERATOGENIC – all cross placenta & are excreted into
breast milk (FDA category D)

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8
Q

Tetracyclines AE?

A

• Gastric effects / superinfections (nausea, vomiting, diarrhea)
• Discoloration & hypoplasia of teeth, stunting of
growth (generally avoided in pregnancy & not given in
children under 8y)
• Fatal hepatotoxicity (in pregnancy, with high doses,
patients with hepatic insufficiency)
• Exacerbation of existing renal dysfunction
• Photosensitization
• Dizziness, vertigo (esp. doxycycline & minocycline)

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9
Q

Describe Glycylcyclines and antibacterial spectrum?

A

Tigecycline
Antibacterial spectrum
Broad-spectrum against multidrug-resistant Grampositive,
some Gram-negative & anaerobic organisms

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10
Q

Describe Glycylcyclines resistance?

A

• Little resistance
• Not subject to same resistant mechanisms as
tetracyclines (exceptions = efflux pumps of Proteus &
Pseudomonas species)

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11
Q

Glycyclines Clinical applications and black box warning?

A

• Treatment of complicated skin, soft tissue and intraabdominal
infections
• Increased risk of mortality has been observed with
tigecycline compared with other antibiotics when
used to treat serious infections
• FDA recommends considering the use of alternative
antimicrobials when treating patients with serious
infections

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12
Q

Glycylcyclines PK, AE, and Contraindications?

A 
• IV only
• Excellent tissue & intracellular penetration
• Primarily biliary/fecal elimination
Adverse effects
• Well tolerated
• AE similar to tetracyclines
Contraindications
• Pregnancy &amp; children <8y
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13
Q

List the 5 Aminoglycosides?

A

Amikacin, Gentamicin, Tobramycin, Streptomycin,

Neomycin

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14
Q

Describe Aminoglycosides? Relevant Pharmacodynamic effect?

A 
• Bactericidal
• Associated with serious toxicities
• Largely replaced by safer antibiotics
Postantibiotic effect
\+Concentration-dependent killing= Once-daily dosing
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15
Q

What are concentration dependent vs time dependent antibiotic examples?

A
  • Concentration-dependent (aminoglycosides)

* Time-dependent (penicillins, cephalosporins)

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16
Q

Aminoglycoside MOA?

A

• Passively diffuse across membranes of Gram negative organisms
• Actively transported (O
2-dependent) across cytoplasmic membrane
• Covalently bind to 30S ribosomal subunit prior to
ribosome formation leading to irreversible inhibition of
initiation complex :
• misreading of mRNA, &
• blockade of translocation

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17
Q

Antibacterial spectrum of Aminoglycosides?

A
  • Most active against aerobic Gram-negative bacteria

* Anaerobes lack O2-dependent transport

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18
Q

What are the 3 principle mechanisms of aminoglycoside resistance?

A

3 principal mechanisms:
• Plasmid-associated synthesis of enzymes that
modify and inactivate drug by acetylation,
phosphorylation and adenylation
• Decreased accumulation of drug
• Receptor protein on 30S ribosomal subunit may be
deleted or altered due to mutation

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19
Q

Aminoglycoside Clinical Applications?

A

• Used mostly in combination
• Once organism is identified aminoglycosides are normally discontinued in favor of less toxic drugs
• Empiric therapy of serious infections eg, septicemia,
nocosomial respiratory tract infections, complicated
UTI’s, endocarditis etc
• Neomycin for bowel surgery and hepatic
encephalopathy, as well as topically
Drugs of choice for:
• Empiric therapy of infective endocarditis in
combination with vancomycin

20
Q

Aminoglycoside PK?

A
  • Parenteral admin. only (except neomycin - topical)
  • Once-daily admin.
  • Well distributed (excluding CSF, bronchial secretions)
  • High levels in renal cortex & inner ear
  • 99% excreted in urine (reduce dose in renal insufficiency)
21
Q

AE of Aminoglycosides?

A

Both time- and concentration-dependent
• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade (myasthenia gravis =
contraindicated)
• Pregnancy (contraindicated unless benefits outweigh risks
– FDA Category D)

22
Q

Describe oral Neomycin?

A 
• Used as adjunct in treatment for hepatic
encephalopathy
Alternative treatment options for hepatic
encephalopathy:
• Lactulose
• Oral vancomycin
• Oral metronidazole
• Rifaximin
23
Q

Lactulose MOA

A 
• Nonabsorbable disaccharide
MOA
• Degraded by intestinal bacteria ->lactic acid + other
organic acids
-> acidification of gut lumen
-> favors formation of NH
4+ from NH3
-> NH4
\+ is trapped in colon effectively reducing
plasma ammonia concentrations
24
Q

Other effects and adverse effects of lactulose?

A 
Other Effects
• Prebiotic (suppression of urase producing
organisms)
• Osmotically active laxative
Adverse Effects
• Osmotic diarrhea
• Flatulence
• Abdominal cramping
25
Q

Name 4 Macrolides

A

Erythromycin, Clarithromycin, Azithromycin, Telithromycin

26
Q

Describe Macrolides?

A
  • Mainly used to treat Gram-positive infections

* Bacteriostatic (bactericidal at high conc.)

27
Q

Macrolides MOA?

A

• Reversibly bind to the 23S rRNA of the 50S subunit
blocking translocation
• Binding site is identical or close to that for clindamycin & chloramphenicol

28
Q

Macrolides Resistance(last 2 most important?

A

3 main mechanisms (usually plasmid encoded):
• Reduced membrane permeability or active efflux
• Production of esterase that hydrolyze drugs (by
enterobacteriaceae)
• Modification of ribosomal binding site (by
chromosomal mutation or by methylation)

• Complete cross-resistance between erythromycin,
azithromycin, & clarithromycin
• Partial cross-resistance with clindamycin & streptogramins

29
Q

Describe Macrolide antibacterial spectrum?

A

• Most active against Gram-positive bacteria (some activity against Gram-negatives)
• Spectrum is slightly wider than that of penicillins
• Azithromycin, clarithromycin & telithromycin have broader
spectrum than erythromycin

30
Q

Macrolides Clinical Applications?

A

• Used in empiric therapy of community-acquired
pneumonia (outpatient & in combination with beta-lactam for inpatients)
• Useful at treating atypical pneumonias (Mycoplasma,
Chlamydia, Legionella)
• Treatment of upper respiratory tract & soft-tissue
infections
• Erythromycin = DOC for whooping cough (B.pertussis)
• Common substitute for patients with penicillin allergy

31
Q

Macrolides PK?

A

• Clarithromycin, azithromycin, telithromycin = improved
oral absorption, longer t1/2, increased bioavailability
compared to erythromycin
• Erythromycin, clarithromycin & telithromycin = CYP P450
inhibition (NOT azithromycin)

32
Q

Macrolides AE?

A
  • GI irritation
  • Hepatic abnormalities (erythromycin & azithromycin)
  • QT prolongation
  • Severe reactions are rare (anaphylaxis, colitis)
33
Q

Macrolide Contraindications?

A

• Statins (due to macrolides inhibiting CYP P450)
• Telithromycin – fatal hepatotoxicity, exacerbations of
myasthenia gravis, & visual disturbances
-> don’t use for
minor illnesses

34
Q

Describe Chloramphenicol?

A

• Potent inhibitor of protein synthesis
• Broad-spectrum (aerobic & anaerobic Gram-positive & -
negative organisms)
• Bacteriostatic (usually)
• Toxicity limits use to life-threatening infections with
no alternatives

35
Q

Chloramphenicol MOA?

A

• Enters cells via active transport process
• Binds reversibly to 50S ribosomal subunit (site adjacent
to site of action of macrolides & clindamycin), inhibiting
peptidyltransferase
• Can inhibit protein synthesis in mitochondrial ribosomes
-> bone marrow toxicity

36
Q

Chloramphenicol Resistance?

A

• Presence of factor that codes for chloramphenicol
acetyltransferase (inactivates drug)
• Changes in membrane permeability

37
Q

Chloramphenicol antibacterial spectrum?

A

• Very broad spectrum
• Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes
• N.meningitidis, H.influenzae, Salmonella & bacteroides =
highly susceptible
• Never given systemically for minor infections (due to
adverse effects)

38
Q

Chloramphenicol Clinical Applications?

A

• Serious infections resistant to less toxic drugs
• When chloramphenicol’s penetrability to site of
infection is clinically superior to other drugs
• Active against many VRE
• Topical treatment of eye infections (mainly outside
US)

39
Q

Chloramphenicol PK?

A
  • Oral, IV or topical
  • Wide distribution (readily enters CSF)
  • Inhibits hepatic oxidases (3A4 & 2C9)
40
Q

Chloramphenicol AE?

A 
• GI distress
• Bone marrow depression
• dose-related reversible depression
• severe irreversible aplastic anemia
• Gray baby syndrome (cyanosis), due to drug
accumulation
41
Q

Clindamycin MOA and uses?

A

• MOA = same as macrolides (binds to 50S subunit and
blocks transolcation)
• Mainly bacteriostatic
• Primarily used against Gram-positive anaerobic
bacteria.
• Also active against bacteroides and Gram-positive
aerobes

42
Q

Clindamycin Resistance?

A 
Due to:
• mutation of ribosomal receptor site
• modification of the receptor
• enzymatic inactivation of drug
• Most Gram-negative aerobes &amp; enterococci are
intrinsically resistant
• Cross-resistant with macrolides
43
Q

Clindamycin clinical applications?

A

• Anaerobic infections (eg, bacteroides infections,
abscesses, abdominal infections)
• Skin and soft tissue infections (streptococci and
staphylococci, and some MRSA)
• In combination with primaquine as an alternative in PCP
• In combination with pyrimethamine as an alternative
treatment for toxoplasmosis of brain
• As an alternative for prophylaxis in penicillin-allergic patients

44
Q

Clindamycin PK?

A
  • Oral or IV

* Good penetration (including abscesses and bones)

45
Q

Clindamycin AE?

A

• Potentially fatal pseudomembranous colitis
(superinfection of C.difficile)
• GI irritation (~ 20% people experience diarrhea)
• Skin rashes (~10 %)
• Neutropenia & impaired liver function

Pharmacology (49 decks)

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