ICU Meeting Once-daily Aminoglycoside

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ICU MeetingOnce-daily Aminoglycoside

• 2004/08/23
• By Ri ???

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Contents

• Introduction
• Mechanism of action and antimicrobial activity
• Pharmacokinetics and pharmacodynamics
• Toxicity
• Clinical use (an OD model)
• Recent studies
• Summary

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Introduction
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Mechanism of action and antimicrobial activity

• Impairing bacterial protein synthesis
• Irreversibly binding to 30S subunit of bacterial
  ribosome
• For serious gram-negative bacillary infections
  broaden coverage against GNB such as P
  aeruginosa, Enterobacter spp
• In combination with other antimicrobial agents
  (ß-lactam antibiotics) against serious
  gram-positive coccal infections such as
  staphylococcal , enterococcal and streptococcl
  endocarditis
• Infectious Disease Clinics of North
  America Vol.18 No.3.Sep,2004 Donald Kaye MD etl

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Mechanism of action and antimicrobial activity

• Two phase mechanism
• 1st phase fast bactericidal activity depends on
  peak drug concentration
• 2nd phase slower and independent of drug
  concentration (postantibiotic effect)?Basis for
  the once-daily dosage recommendation
• Pharmacokinetic dosing of Aminoglycosides
  Acontrolled trial Carmi Baral. MD Am J
  Med.2003114194-198

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Pharmacokinetics and pharmacodynamics

• Poorly absorbed orally
• Half-life 23 hours low protein binding(lt10)
• IV 1.7 mg/kg gentamicin q8h
• Cmax4-10µg/mL ,T1-2 µg/mL
• IV 5mg/kg (once-daily)
• Cmax20 µg/mL, Tlt1 µg/mL
• Excretion by glomerular filtration
• Infectious Disease Clinics of North America
  Vol.18 No.3.Sep,2004 Donald Kaye MD etl

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Pharmacokinetics and pharmacodynamics

• Concentration-dependent activity
• In vivo higher dose
• ? rate of bacterial reduction
• ?length of time of drug exposure to
  bactericidal concentrations (in AUC)
• Up to 1012 times above MIC( MIC of P aeruginosa
  2 µg/mL)
• 24-hour AUC/MIC 80100 or Cmax/MIC 810
• Infectious Disease Clinics of North America
  Vol.18 No.3.Sep,2004 Donald Kaye MD etl

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Pharmacokinetics and pharmacodynamics

• Postantibiotic effect for Staphylococci and
  gram-negative bacilli-- suppresion of bacterial
  growth persists despite concentrations of
  antibiotics below MIC
• Postantibiotic leukocyte enhancement
• Adaptive resistance
• Infectious Disease Clinics of North America
  Vol.18 No.3.Sep,2004 Donald Kaye MD etl

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Toxicity

• Nephrotoxicity (15-17 in MDD)
• Cochlear (8)and vestibular bodies of the ear(3)
• Renal proximal convoluted tubules a saturable
  process
• Once-daily will not cause greater toxicity, even
  lower than multiple dose in rodents
• Infectious Disease Clinics of North America
  Vol.18 No.3.Sep,2004 Donald Kaye MD etl

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Toxicity

• Dosing frequency rather than peak serum
  concentration correlates with renal cortical
  accumulation
• Some studies reported once-daily dosing decreased
  nephrotoxicity
• Most studies reported no significant decrease
• Infectious Disease Clinics of North America
  Vol.18 No.3.Sep,2004 Donald Kaye MD etl

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Clinical use

• IBM
• Female 45.5 kg2.3kg per inch(2.54cm) over 5
  feet(1.524m)
• Male50kg2.3kg per inch over 5 feet
• Estimated Ccr (140-age)(IBW in kg)/(72)(serum
  creatinine)

The Sanford Guide to antimicrobial therapy 34th
edition 2004
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Clinical use Normal renal function
The Sanford Guide to antimicrobial therapy 34th
edition 2004
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Clinical use In renal insufficiency
The Sanford Guide to antimicrobial therapy 34th
edition 2004
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OD Model of Hartford Hospital , Hartford,
Connecticut

• Computer simulation of gentamicin (7mg/kl)and
  tobramycin (5mg/kg)concentrations versus time
  profile for OD
• Peak serum to MIC gt10
• Serum concentration falls below 0.5 µg/mL within
  12 hrs and then remain undetectable
• Less nephrotoxicity and ototoxicity
• CohenPowderly Infectious Diseases, 2nd
  edition,2004

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OD Model of Hartford Hospital , Hartford,
Connecticut

• Monitor check serum creatinine 2 to 3 day
  intervals
• For OD longer than 5 days , random serum
  aminoglycoside concentration obtained on 5th days
  and weekly thereafter
• CohenPowderly Infectious Diseases, 2nd
  edition,2004

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OD Model of Hartford Hospital , Hartford,
Connecticut

• OD is not recommended for
• On chronic peritoneal dialysis or H/D
• Pregnant women
• Major burns(gt20), ascites or enterococcal
  endocarditis
• Dosing interval24,36,48 hr for Ccr gt60,40-60
  and 20-40 ml/min

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Recent Studies

• High peak concentrations and long dosing
  intervals improve efficacy and reduce toxicity
• Many studies demonstrated small improved clinical
  efficacy
• Barza M, Ioannidis JP, Cappelleri JC, et al.
  Single or multiple daily doses of
  aminoglycosides a meta-analysis. BMJ
  1996312338-45

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Barza M, Ioannidis JP, Cappelleri JC, et al.
Single or multiple daily doses of
aminoglycosides a meta-analysis. BMJ
1996312338-45

• Meta-analysis of 21 randomised trials
• Total 3091 patients with bacterial infection,
  most without pre-existing renal disease
• MDD or OD
• OD produced a non-significant decrease in
  antibiotics failures
• Benefit of once daily dosing was greater when the
  percentage of pseudomonas isolates in a trial was
  larger.

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Barza M, Ioannidis JP, Cappelleri JC, et al.
Single or multiple daily doses of
aminoglycosides a meta-analysis. BMJ
1996312338-45

• Once daily administration reduced risk of
  nephrotoxicity (fixed effects risk ratio 0.74
  (0.54 to 1.00)).
• There was no significant difference in
  ototoxicity between the two dosing regimens, but
  the power of the pooled trials to detect a
  meaningful difference was low.
• There was no significant difference in mortality

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Barza M, Ioannidis JP, Cappelleri JC, et al.
Single or multiple daily doses of
aminoglycosides a meta-analysis. BMJ
1996312338-45

• OD in patients without pre-existing renal
  impairment is as effective as multiple daily
  dosing, has a lower risk of nephrotoxicity, and
  no greater risk of ototoxicity.
• Given the additional convenience and reduced
  cost, once daily dosing should be the preferred
  mode of administration

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Endotoxin-like Reactions to Gentamicin JAMA
1999282932

• Since start of 1998, FDA and CDC received
  130reports (IV GM two brands )
• 70 of these OD of one products
• Fever, rigors, and/or hypertension
• 1.7 endotoxin units per milligram
• 40-60 OD in GM use
• Under investigations

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Summary

• Once-daily aminoglycoside has small improvement
  in efficacy
• Less nephrotoxicity / no greater nephrotoxicity
• Recently reported endotoxin-like reaction in use
  of GM