Antimicrobial Agents (Aminoglycosides, tetracyclines, macrolides and other assorted drugs)

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Antimicrobial Agents(Aminoglycosides,
tetracyclines, macrolides and other assorted
drugs)

• Dr. Jeff Hobden
• MIP

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The Aminoglycosides

• Two or more amino sugars attached to a hexose
  nucleus
• Narrow spectrum of coverage (G- aerobes)
• Bactericidal protein synthesis inhibitor
• Resistance
• Enzymatic modification
• Impaired uptake
• Mutation in ribosome

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The Aminoglycosides

• Given parenterally only
• Poor penetration
• Inside cells (no effect on intracellular bugs)
• CSF
• Eye
• Accumulates in perilymph and endolymph of the
  inner ear
• Excreted mostly through kidneys, a little through
  the liver

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Streptomycin

• An anti-TB drug
• Also useful for
• Bacterial endocarditis when combined with a
  beta-lactam
• Tularemia
• Plague

Tuberculosis
Plague
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Gentamicin, Tobramycin, Amikacin, Netilmicin

• Gentamicin and tobramycin are good against P.
  aeruginosa
• amikacin and netilmicin are effective against
  gentamicin-resistant bugs

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Therapeutic Uses( a beta-lactam)

• UTI
• Community acquired pneumonia
• Meningitis
• Dialysis associated peritonitis
• Bacterial endocarditis
• Sepsis
• Topical infections (keratitis)

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Toxicity/Contraindications of the Aminoglycosides

• Ototoxic (common)
• Auditory dysfunction
• Vestibular dysfunction
• Nephrotoxic (common)
• Rare side effects
• Neuromuscular blockade
• hypersensitivity

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The Tetracyclines

• Natural products of Streptomyces or
  semi-synthetic derivatives
• Broad spectrum but work better against G than G-
• Work against anaerobes, intracellular bacteria,
  and atypical bacteria
• Bacteristatic
• Resistance due to decreased influx or active
  efflux, production of protection protein,
  enzymatic inactivation

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Pharmacology of the Tetracyclines

• Absorbance is incomplete
• Oral or parenteral
• Dairy products, antacids, etc interfere with
  absorption
• Wide distribution in tissues and fluids
  (including CSF)

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Pharmacology of the Tetracyclines

• Crosses placenta and enters fetal circulation
• Found in breast milk
• Most are excreted by kidneys, others are
  concentrated into bile and pooped out

Tetracyclines are secreted here
and excreted here!
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Pharmacology of Select Tetracyclines

• Tetracycline, oxytetracycline, democycline
• Incompletely absorbed from stomach (60-80)
• Primarily excreted through the kidneys
• Minocycline, doxycycline
• Completely absorbed from stomach (95-100)
• Excreted through liver

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Tigecycline

• A glycylcycline antibiotic, a derivative of
  minocycline
• Truly broad spectrum
• Complicated intra-abdominal infections, soft
  tissue infections
• Toxicities and side effects similar to the
  tetracyclines

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Therapeutic Uses of Tetracyclines

• Rickettsial infections
• RMSF
• All forms of typhus
• Q fever
• Mycoplasma infections
• Chlamydia infections
• Lymphogranuloma venereum
• Trachoma
• Non-specific urethritis

RMSF
LGV
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Therapeutic Uses of Tetracyclines

• Syphilis
• Anthrax
• Bacillary infections
• Brucellosis
• Tularemia
• Cholera
• Infections with spirochetes
• Yaws
• Lyme disease
• Relapsing fever

Vibrio cholerae
Lyme Disease
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Toxicity/Contraindications of Tetracyclines

• Gastrointestinal
• Nausea, vomiting, etc.
• Food helps (not dairy)
• Photosensitivity
• Hepatic toxicity
• Large doses
• Worse when pregnant
• Renal toxicity
• Fanconi syndrome
• Degraded drug
• Nausea, vomiting, etc.

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Toxicity/Contraindications of Tetracyclines

• Because drug is deposited in tooth dentine and
  enamel, brown bands form
• Do not give to children or pregnant/nursing women
• Misc. side effects
• Thrombophlebitis
• Various WBC dystrophies
• Increased intracranial pressure in neonates
• Hypersensitivity reactions

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Chloramphenicol

• A natural product (contains a nitrobenzene
  moiety)
• Broad spectrum
• Bacteristatic
• Resistance
• Acetylation
• Efflux
• Mutations in ribosome

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Chloramphenicol

• Given orally or parenterally
• Wide distribution, including CSF
• Present in bile, milk, and placental fluid
• Rapidly excreted by kidneys
• Used to treat typhoid fever, bacterial
  meningitis, anaerobic infections, rickettsial
  disease (second choice drug)

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Toxicity/Contraindications of Chloramphenicol

• Hypersensitivity
• Hematological toxicity anemia
• Gastrointestinal nausea, vomiting, nasty taste,
  diarrhea
• Gray baby syndrome (2-9 days after dose)
• Within 24 hours, baby starts to vomit, stops
  eating, rapid and irregular respiration,
  abdominal distension, periods of cyanosis, and
  pooping loose green stool
• Baby then turns ashen gray and becomes flaccid
  and hypothermic
• Also can occur in adults who OD
• Death in 40 of cases
• Prolongs half lives of warfarin, dicumerol, and
  anti-retroviral protease inhibitors

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The Macrolides

• Erythromycin is natural product, clarithromycin
  and azithromycin are semi-synthetic derivatives
• 14 to 15 member lactone ring attached to one or
  more deoxy sugars
• Effective against G
• Effective against atypical mycobacteria and some
  intracellular bugs
• Bacteristatic, binds ribosomes much like
  chloramphenicol
• Resistance efflux, ribosomal protection,
  esterases, mutate ribosome

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Pharmacology of the Macrolides

• Administered orally
• Adsorbed in upper small intestine
• Gastric acid inactivates drug so pills are coated
  
• Food delays adsorption of erythromycin and
  azithromycin
• Readilly diffuses in all intracellular fluids
  except CSF and brain
• Crosses placenta and enters fetal circulation
• Secreted in breast milk
• Excreted by kidney and liver (through bile)

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Pharmacology of Select Macrolides

• Clarithromycin
• More effective against staph and strep than
  erythromycin
• Can be given with food
• Azithromycin
• Slightly less effective against G but works
  better than other 2 against Haemophilus
  influenzae
• good against atypical mycobacteria

Azithromycin
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Therapeutic Uses of Macrolides

• Mycoplasma infections
• Legionairres Disease
• Chlamydia infections
• Diphtheria/pertussis
• Staph/strep
• GI infections
• Tetanus
• AIDs related infections

pseudomembrane of diphtheria
H. pylori
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Toxicity/Contraindications of the Macrolides

• Epigastric distress with large doses
• Cholestatic hepatitis (rare)
• Potentiate the effects of
• Carbamazepine
• Corticosteroids
• Cyclosporine
• Digoxin
• Ergot alkaloids
• Theophylline
• Triazolam
• Valproate
• warfarin

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The Streptogramins

• Two agents combined (Synercid)
• Derived from pristinamycin
• Covers G cocci
• Effect on bugs similar to macrolides
• Only given IV in 5 dextrose in water
• Wide distribution
• Mostly hepatic excretion

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The Streptogramins

• Treatment of vancomycin-resistant enterococci,
  MSSA, and strep infections
• Toxicity
• Infusion related pain and phlebitis
• Potentiates same drugs as macrolides

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Clindamycin

• similar to macrolides in many ways
• Good against anaeobes
• Given orally, parenterally, or topically
• Food does not interfere with absorption
• Wide distribution excluding CSF
• Crosses placenta
• Accumulates in PMN, alveolar macrophages, and pus
• Excreted by liver and kidneys

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Clindamycin

• Good for anaerobic infections (except brain
  abscesses)
• Staph infections (including MRSA)
• Diarrhea is common side effect
• Pseudomembranous colitis to toxic megacolon
• Skin rash
• Rare side effects SJS, anaphylaxis

toxic megacolon
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Linezolid

• Synthetic agent (an oxazolidinone)
• G coverage only, no anaerobes
• Prevents assembly of ribosome
• Oral or IV 100 absorption
• Food does not interfere with absorbtion
• Distributed widely to well perfused tissues
• Excreted mostly by kidney
• Treat VR enterococci, MSSA, MRSA
• Well tolerated, minor gastrointestional
  complaints

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Vancomycin

• Tricyclic Glycopeptide
• G coverage only
• Inhibits polymerization of peptidoglycan subunits
• given IV over an hour or orally for
  pseudomembranous colitis
• Wide distribution
• Secreted by kidneys
• Treatment of MRSA
• Red-man syndrome a complication of too rapid an
  infusion

MRSA
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The End? Almost