Aminoglycosides

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Aminoglycosides
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Aminoglycosides

• Streptomycin Gentamicin
• Spectinomycin Tobramycin
• Neomycin Amikacin
• Paramomycin Netilmicin
• Kanamycin Sisomicin
• Not available in U.S.

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Description

• Natural and semisynthetic compounds derived from
  Streptomyces spp. (-mycins) and Micromonospora
  spp. (-micins).
• Six membered amino-group-containing ring,
  aminocyclitol, that is linked to one or two
  sugars.

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Antimicrobial Activity

• Many aerobic gram negative bacteria including
  most Enterobacteriaceae, Pseudomonas sp.,
  Yersinia sp., Brucella sp.
• Staphylococcus aureus, Enterococcus sp.
• Many mycobacteria , including M. tuberculosis
• Highly variable activity between different
  hospitals and geographic locations
• Generally inactive vs. anaerobic bacteria

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Mechanism of Action

• Inhibition of protein synthesis through
  irreversible binding to 30s ribosome leading to
  synthesis of mistranslated proteins.
• Direct damage to the outer cell membrane.
• Exact mechanism of action not fully elucidated.

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Pharmacokinetics

• Given i.v. or i.m., through i.v. preferred
• Poorly absorbed p.o.
• Weakly protein bound, freely distributes into
  interstitial and extra cellular fluid
• Tissue/body fluid levels are less than serum
  levels except for kidneys, per lymph of the inner
  ear, and urine
• Poor CNS penetration in normal circumstances
• Eliminated unchanged through urine
• Removed by hemodialysis peritoneal dialysis

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Pharmacodynamics

• Concentration-dependant bacteriocidal activity
• Post-antibiotic effect
• Immunomodulation
• AUC/MIC
• Peak MIC

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Mechanisms of Resistance

• Decreased uptake (intrinsic vs. acquired)
• Ribosomal target modification
• Aminoglycoside-modifying enzymes
• acetyltransferases
• adenyltransferases
• phosphotransferases

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Toxicity

• Neuromuscular brockade (reversible)
• - rapid infusion
• - increase risk with neuromuscular blockers
• - myasthesia gravis
• - reversible with calcium gluconate
• Ototoxicity (irreversible)
• - vestibular
• - auditory (high frequency)
• Nephrotoxicity (usually reversible)
• - proximal tubular cell necrosis

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Risk Factors for Nephrotoxicity

• Multiple dose regimen
• Advanced age
• Pre-existing renal function
• Hypovolemia
• Shock
• Liver dysfunction
• Obesity
• Length of therapy
• Nephrotoxic agents (e.g. cyclosporine,
  amphotericin B, furosemide)

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Dosing Regimens for Aminoglycosides

• Multiple daily dosing
• Single daily dose
• Dosing according to renal function

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Clinical Uses of Specific Aminoglycosides

• Gentamicin, Tobramicin, Amikacin
• - Serious gram negative bacillary infections
• Streptomycin
• - Antituberculous therapy
• Neomycin
• - Topical (cutaneous) therapy
• - Bowel decontamination
• Paromomycin
• - Oral therapy for Cryptosporidium and
• E. histolytica intestinal infections

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Clinical Indications

• Severe Gram negative bacterial infections due to
  susceptible organisms
• Febrile neutropenia
• Serious S. aureus infections
• Enterococcal endocarditis
• Viridans streptococcal endocarditis
• Prosthetic valve endocarditis
• Mycobacterial infections

In combination with a B-lactam or vancomycin
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Fluoroquinolones
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Mechanisms of Action

• DNA gyrase inhibition
• Rapidly bacteriocidal
• Significant post-antibiotic effect

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Mechanisms of Resistance

• Alternations in DNA gyrase leading to decreased
  drug binding
• Alternations in other membrane protein
• leading to decreased intracellular drug
  accumulation

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Adverse Events

• Gastrointestinal 3-13
• CNS 1-7
• Skin 1-11
• Allergic 1-2
• Hepatic 1-3
• Hematologic lt1
• Overall 5-20

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Drug Interactions
Decreased absorption - Aluminum and
magnesium containing compounds (including
sucralfate) - Ferrous sulfate Delayed
absorption - H2blockers - Food Other -
Theophylline levels (enox, cipro) -
Cyclosporine?
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Antimicrobial Activity of Fluoroquinolones

• Enterobacterialeae (all)
• Legionella sp.
• Fastidious GNRs (all)
• P. aeruginosa (Cipro)
• Methicillin-sensitive S. aureus
• Streptococci (Cipro, Oflox, Levo, Spar)
• PRSP (Spar, Levo)
• Anaerobes (Levo, Spar)
• Chlamydia sp. (Oflox, Levo)
• Mycobacteria sp. (Oflox, Levo, Cipro)

All lack significant activity vs. Enterococcus
sp., Listeria, Nocardia sp.
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Clinical Uses

• Uncomplicated UTIs
• Complicated UTIs
• Prostatitis
• STDs
• Bacterial gastroenteritis
• LRTI
• Sinusitis
• Skin and soft tissue
• Bone and joint
• Bacteremia
• Complicated nosocomial infections