Acid Base

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Acid Base

• David Shure

September 2008
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Overview

• Mitochondria Krebs Cycle/ ETC energy
  production
• Linezolid induced lactic acidosis.
• - How does it happen?
• NRTI induced lactic acidosis?
• Mechanism
• Is it bad for you?

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Linezolids Mechanism of Action
Inhibits bacterial protein synthesis
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Linezolid-Induced Lactic Acidosis - 1st report

• Apodaca and Rakita NEJM 2003 (Virginia Mason
  Medical Ctr, WA)
• 52 F f/c/ 2wk cough, CT chest RML infiltrate,
  mediastinal adenopathy
• BAL/mediastinal biopsy Nocardia
  ottidis-caviarum
• CT brain, kidney, adrenal, ie disseminated
• Had 11 weeks linezolid and 5 wks gatifloxacin

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Cont.

• Low bicarbonate levels
• Lactate level 9.9 mmol/L, both abx stopped ?
  lactate 1.4 after 10 days
• Both abx restarted, lactate level measured 7 days
  later was 4.8, nausea returned, gatiflx DCd,
  lactate now 6.5, DC linezolid ?normalization
  lactate level after 2 weeks.
• Pt switched to avalox, lactate levels remained
  normal, disseminated nocardiosis resolved.

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Mitochondrial Toxicity Assoc w/LinezolidSoriano,
et al Spain 2005 NEJM

• 3 pts developed weakness and lactic acidosis
  during prolonged course oral linezolid
• 25 M, E. faecium of knee prostehsis (LA 40,59,41
  mg/d NLlt20)
• 75 M, Waldenstroms macroglob and nocardia
  cerebral abscess (LA 28 after 2 mths rx)
• 55 M, MRSA knee prosthesis (peak LA 44 after 1.5
  mths)

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• Mt studies in PBMC to determinate enzyme activity
  for Mt resp-chain complex II ( synthesized by
  cytoplasmic ribosomes)
• Complex IV (cytochrome c oxidase, partially
  synthesized by mt ribosomes).
• Measurement of spontaneous intracellular oxidation

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• CII NL for all pts
• Complex IV activity below NL in all 3 pts
• Suggests linezolid interferes w/ mitochonidral
  protein synthesis, owing to similarities bet bact
  and mt ribosomes

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Linezolid-Induced Inhibition of Mt Protein
Synthesis De Vriese, et al, 2006 CID

• Methods studied mt respiratory chain activity,
  mt DNA, mt ultrastructure in muscle, liver,
  kidney samples from pt w/optic neuropathy,
  encephalopathy, skeletal myopathy, LA, and RF
  after 4 mth linezolid.
• Studied mtDNA, respiratory chain enzyme activity,
  and protein amt in muscle, liver samples from
  rats on linezolid vs placebo.

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Muscle125mg/kg/d x 2wks
Muscle250 mg/kg/d x 4wk
Liver125mg/kg/d x 2 wks
Liver250mg/kg/d x 4 wks
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Length Of Rx

• FDA approved rx length 28d
• Increasingly used for prolonged outpt rx for pts
  with OM or slow growing organisms requiring
  longer rx length
• Toxicities to be aware of incl LA,
  myelosuppression, optic and peripheral neuropathy

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Falco, et al. 2002University of Barcelona, CID

• Severe Nucleoside-Associated Lactic Acidosis
  (NALA) Report of 12 Cases and Review of
  Literature (60 published cases)
• 21 of NRTI-Rx pts have low-level hyperlactatemia
  and are asymptomatic
• Mortality 33, severe NALA
• Propose that treatment with cofactors may improve
  outcome

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Mechanism of Injury

• NRTI assoc Mt toxicity from inhibition of Mt DNA
  polymerase
• Impairs synthesis of Mt enzymes that generate ATP

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Specific Therapy

• Defined as admin of gt/ 1 thiamine, riboflavin,
  L-carnitine, coenzyme Q, prostaglandin E
• Out of 12 cases 1 zidovudine, 11 pts stavudine
  alone or in assoc w/other NRTI
• Clinical Sxs GI sxs, cough, dyspnea, wt loss,
  numbness, painful dyesthesias
• All pts had evid of metab acidosis low pH, and
  low bicarbonate levels

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Mortality Statistics

• Univariate lactate level, pH, use of zidovudine
  assoc w/ higher mortality
• Stavudine, lamivudine, admin of therapy with
  cofactors against LA assoc w/lower mortality rates

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Findings

• 4/12 pts died
• Therapy w/cofactors ie thiamine and /or
  riboflavin given to 7 pts, 6/7 survived
• Autopsy on one pt hepatic steatosis
• HAART stopped on all pts
• After recovery, 7 pts given NRTI sparing regimen,
  2 pts w/new NRTI regimen

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Multivariate Analysis only lactate level gt10 mM
assoc w/higher mortality
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Take Home

• All NRTIs assoc w/LA, most casesStavudine
• More potent NRTIs w/respect to inhibitory effect
  on MT DNA, greater chance of LA
  zalcitabinegtdidanosinegtstavudinegtlamivudinegtAZTgtab
  acavir
• ? Only minority of pts on NRTIs develop Mt
  toxicity?
• ?Deficiencies in riboflavin and thiamine,
  cofactors required for ox-phos, predisposing pts
  to development of LA?

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NALA

• Can develop at any stage of HIV
• 6/12 pts in this study developed NALA at CD4
  gt200, and 6 with undetectable VL
• Treatment supportive, fluids and bicarbonate
  administration
• Essential to discontinue all HAART
• NNRTIs lack affinity for mt DNA polymerases,
  suggests rx with NNRTI and PI might be optimal in
  these pts

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Letter to EditorOxazolidinones and HIV

• Maradiaga and Swindells, HIV Clinic, Univ of
  Nebraska Med Ctr.
• Suggest caution w/ concurrent use of OZD and
  NRTIs, particularly if the former are planned for
  long courses of therapy.May lead to greater
  susceptibility of LA.

Antimicrobial Agents and Chemotherapy, March 2007