David Shure
September 2008

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

Inhibits bacterial protein synthesis

• 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 ottidiscaviarum
• CT = brain, kidney, adrenal, ie disseminated
• Had 11 weeks linezolid and 5 wks gatifloxacin

• 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.

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)

• 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

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/k g/d x 2 wks
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Liver:250 mg/kg/d x
4 wks

• 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

• 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

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

• 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

• 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

• 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

• 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>lamivudin e>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?

• 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

• 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