Transcript Antimicrobial Agents

Antimicrobial Agents
(Aminoglycosides, tetracyclines,
macrolides and other assorted drugs)
Dr. Jeff Hobden
MIP
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
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
Streptomycin
• An anti-TB drug
• Also useful for:
Tuberculosis
Plague
• Bacterial
endocarditis when
combined with a
beta-lactam
• Tularemia
• Plague
Gentamicin, Tobramycin,
Amikacin, Netilmicin
• Gentamicin and
tobramycin are
good against P.
aeruginosa
• amikacin and
netilmicin are
effective against
gentamicinresistant bugs
Therapeutic Uses
(+ a beta-lactam)
• UTI
• Community acquired
pneumonia
• Meningitis
• Dialysis associated
peritonitis
• Bacterial endocarditis
• Sepsis
• Topical infections
(keratitis)
Toxicity/Contraindications of
the Aminoglycosides
• Ototoxic (common)
• Auditory
dysfunction
• Vestibular
dysfunction
• Nephrotoxic (common)
• Rare side effects
• Neuromuscular
blockade
• hypersensitivity
The Tetracyclines
• Natural products of
Streptomyces or semisynthetic 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
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)
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!
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
Tigecycline
• A glycylcycline
antibiotic, a derivative
of minocycline
• Truly broad spectrum
• Complicated intraabdominal infections,
soft tissue infections
• Toxicities and side
effects similar to the
tetracyclines
Therapeutic Uses
of Tetracyclines
• Rickettsial infections
• RMSF
• All forms of typhus
• Q fever
RMSF
• Mycoplasma infections
• Chlamydia infections
• Lymphogranuloma
venereum
• Trachoma
• Non-specific urethritis
LGV
Therapeutic Uses
of Tetracyclines
• Syphilis
• Anthrax
• Bacillary infections
• Brucellosis
• Tularemia
• Cholera
Vibrio cholerae
• Infections with
spirochetes
• Yaws
• Lyme disease
• Relapsing fever
Lyme Disease
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.
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
Chloramphenicol
• A natural product
(contains a
nitrobenzene moiety)
• Broad spectrum
• Bacteristatic
• Resistance
• Acetylation
• Efflux
• Mutations in ribosome
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)
Toxicity/Contraindications
of Chloramphenicol
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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
The Macrolides
• Erythromycin is natural
product, clarithromycin and
azithromycin are semisynthetic 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
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)
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
Therapeutic Uses
of Macrolides
pseudomembrane
of diphtheria
H. pylori
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Mycoplasma infections
Legionairre’s Disease
Chlamydia infections
Diphtheria/pertussis
Staph/strep
GI infections
Tetanus
AIDs related infections
Toxicity/Contraindications
of the Macrolides
• Epigastric distress with large doses
• Cholestatic hepatitis (rare)
• Potentiate the effects of
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Carbamazepine
Corticosteroids
Cyclosporine
Digoxin
Ergot alkaloids
Theophylline
Triazolam
Valproate
warfarin
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
The Streptogramins
• Treatment of vancomycin-resistant
enterococci, MSSA, and strep
infections
• Toxicity
• Infusion related pain and phlebitis
• Potentiates same drugs as macrolides
Clindamycin
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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
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
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
Vancomycin
MRSA
• 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
The End?
Almost…