Acid Base

David Shure

September 2008

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?

Linezolid’s Mechanism of Action

Inhibits bacterial protein synthesis

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

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.

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)

• 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

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

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

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

Mechanism of Injury

• NRTI assoc Mt toxicity from inhibition of Mt DNA polymerase

• Impairs synthesis of Mt enzymes that generate ATP

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

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

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

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?

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

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