Linezolid, the first clinically available oxazolidinone antibiotic, causes potentially severe toxicities (myelosuppression, lactic acidosis, and neuropathies) ascribed to impairment of mitochondrial protein synthesis and consecutive mitochondrial dysfunction. Tedizolid, a newly approved oxazolidinone, shows an enhanced activity compared to linezolid but is also a more potent inhibitor of mitochondrial protein synthesis. We compared linezolid and tedizolid for (i) inhibition of the expression of subunit I of cytochrome -oxidase (CYTox I; Western blot analysis), (ii) cytochrome-oxidase activity (biochemical assay), (iii) mitochondrial oxidative metabolism (Seahorse technology), and (iv) alteration of mitochondrial ultrastructure (electron microscopy) using HL-60 promyelocytes and THP-1 monocytes exposed to microbiologically (multiples of modal MIC against ) and therapeutically ( - ) pertinent concentrations. Both drugs caused a rapid and complete (48 to 72 h) inhibition of CYTox I expression, cytochrome-oxidase activity, and spare respiratory capacity, with conspicuous swelling of the mitochondrial matrix and loss of their cristae. Globally, tedizolid was a more potent inhibitor than linezolid. For both drugs, all effects were quickly (48 to 72 h) and fully reversible upon drug withdrawal. Using an alternation of exposure to and withdrawal from drug mimicking their approved schedule of administration (twice daily and once daily [qD] for linezolid and tedizolid, respectively), only partial inhibition of CYTox I expression was noted for up to 96 h. Thus, rapid reversal of toxic effects upon discontinuous administration may mitigate oxazolidinone toxicity. Since tedizolid is given qD, this may help to explain its reported lower preclinical and clinical toxicity.

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Thrombocytopenia is commonly seen in patients receiving linezolid for > 14 days. Linezolid is a reversible inhibitor of mitochondrial function in various cell types. This study investigated the inhibitory effects of linezolid and tedizolid, and their potential recovery on (i) CYTox I expression (subunit I of cytochrome coxidase; encoded by the mitochondrial genome), (ii) cytochrome c-oxidase activity and (iii) mitochondrial respiration (Seahorse bioanalysis) in two megakaryocytic cell lines [UT-7 WT (human acute megakaryoblastic leukaemia cells) and UT-7 MPL (transduced to express the thrombopoietin receptor)]. Cells were exposed to linezolid (0.5-25 mg/L) or tedizolid (0.1-5 mg/L) for up to 5 days and recovery followed after drug removal. Both oxazolidinones caused concentration-and time-dependent inhibition of CYTox I expression, cytochrome c-oxidase activity and mitochondrial spare capacity. On electron microscopy, mitochondria appeared dilated with a loss of cristae. Globally, tedizolid exerted stronger effects than linezolid. While CYTox I expression recovered completely after 6 days of drug washout, only partial (linezolid) or no (tedizolid) recovery of cytochrome c-oxidase activity, and no rescue of mitochondrial spare capacity (after 3 days) was observed. Thus, and in contrast to previous studies using a variety of cell lines unrelated to megakaryocytic lineages, the inhibitory effects exerted by oxazolidinones on the mitochondrial function of megakaryoblastic cells appear to be particularly protracted. Given the dynamics of platelet production and destruction, these results may explain why oxazolidinone-induced thrombocytopenia is one of the most common side effects in patients exposed to these antibiotics.

Apstrakt: Orijentacija dece u prostoru je značajna za celokupan razvoj, kao i razvoj specifičnih veština koje su važne, kako za snalaženje u svakodnevnom životu, tako i za uspeh u nekim školskim predmetima (naročito za čitanje, pisanje, računanje, likovno i fizičko vaspitanje). Dolazak dece u vrtić, kao svakodnevna životna situacija, može da obezbedi dragocena iskustva za razvoj orijentacije u prostoru. Cilj istraživanja je da se utvrdi kako deca opažaju, shvataju i grafički predstavljaju prostor kroz koji se svakodnevno kreću. Uzorak istraživanja čini 156 ispitanika (dece), po 52 od 4,5 i 6 godina, uz podjednaku zastupljenost devojčica i dečaka. Sva deca pohađaju neki od vrtića u Novom Sadu. Korišćena je metoda intervjua i crtanja mape puta od kuće do vrtića. Rezultati istraživanja -dobijeni analizom odgovora na pitanja i analizom crteža dece -pokazali su da deca iz uzorka relativno dobro opažaju, razumeju i predstavljaju prostor, ali ova situacija nije u dovoljnoj meri iskorišćena za unapređivanje dečjeg razumevanja pravca kretanja i korišćenja simbola u predstavljanju prostora. Odrasli bi trebalo da poklanjaju veću pažnju dečjem neposrednom iskustvu, više razgovaraju sa decom o njihovim doživljajima prostora i prostornih odnosa, kao i da podstiču decu da češće crtaju mape i više se služe različitim simbolima.

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