acid base david shure september 2008. overview mitochondria: krebs cycle/ etc & energy...
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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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Linezolid’s 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 DC‘d, 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/Linezolid
Soriano, et al; Spain 2005 NEJM• 3 pts developed weakness and lactic acidosis
during prolonged course oral linezolid
1. 25 M, E. faecium of knee prostehsis (LA 40,59,41 mg/d: NL<20)
2. 75 M, Waldenstrom’s macroglob and nocardia cerebral abscess (LA 28 after 2 mths rx)
3. 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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Muscle:125mg/kg/d x 2wks
Muscle:250 mg/kg/d x 4wk
Liver:125mg/kg/d x 2 wks
Liver:250mg/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 >/= 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 >10 mM assoc w/higher mortality
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Take Home
• All NRTIs assoc w/LA, most cases=Stavudine• More potent NRTIs w/respect to inhibitory
effect on MT DNA, greater chance of LA: zalcitabine>didanosine>stavudine>lamivudine>AZT>abacavir
• ? 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
>200, 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