Hypersegmented Megakaryocytes and Megakaryocytes with Multiple Separate Nuclei in Dogs Treated with PNU-100592, an Oxazolidinone Antibiotic

Lund, John E.; Brown, Patricia K.

doi:10.1177/019262339702500401

Cited by 23 publications

(5 citation statements)

References 16 publications

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“…Notably, no myelosuppressive effect on platelet was observed in these animal studies with CZA. The absence of the adverse platelet decreases in animals differentiates CZA from earlier oxazolidinones, where significantly decreased platelets have been noted (Lund & Brown, 1997;Merck Sharp & Dohme, 2023;Wang et al, 2014). Linezolid was reported to induce hematocytopenia in rat in a time-and dose-dependent manner, and the myelosuppressive effect on platelet counts was observed at 100 mg/kg/dose BID as early as on Day 5 of the dosing (Wang et al, 2014).…”

Section: Discussionmentioning

confidence: 97%

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Wang,

Li,

Gordeev

et al. 2024

J of Applied Toxicology

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Contezolid acefosamil (CZA) is an intravenous prodrug of oxazolidinone antibiotic contezolid (CZD). It is being developed to treat infections due to Gram‐positive bacteria including multidrug‐resistant pathogens, while addressing myelosuppression and neurotoxicity limitations associated with long‐term use of this class of antibiotics. In vivo, CZA is rapidly deacylated into its first metabolite MRX‐1352, which is then dephosphorylated to release active drug CZD. Four‐week repeat‐dose toxicity studies of intravenous CZA were conducted in Sprague–Dawley rats (40, 80, and 160/120 mg/kg/dose twice a day [BID]) and beagle dogs (25, 50, and 100/75 mg/kg/dose BID). The high doses administered to both rats and dogs were adjusted due to adverse effects including decreased body weight and food consumption. Additionally, a dose‐dependent transient reduction in erythrocyte levels was recorded at the end of dosing phase. Importantly, no myelosuppressive reduction in platelet counts was observed, in contrast to the myelosuppression documented for standard‐of‐care oxazolidinone linezolid. The no‐observed‐adverse‐effect level (NOAEL) of CZA was 80 and 25 mg/kg/dose BID in rats and dogs, respectively. Separately, 3‐month neuropathological evaluation in Long–Evans rats (25, 37.5, and 50 mg/kg/dose, oral CZA, BID) demonstrated no neurotoxicity in the central, peripheral, and optical neurological systems. Toxicokinetic data from these studies revealed that CZD exposures at NOAELs were higher than or comparable with that for the intended clinical dose. These results confirm the favorable safety profile for CZA and support its clinical evaluation for long‐term therapy of persistent Gram‐positive infections, beyond the application for earlier oxazolidinones.

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Section: Discussionmentioning

confidence: 97%

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Wang,

Li,

Gordeev

et al. 2024

J of Applied Toxicology

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“…16 This toxicity was first seen in preclinical animal studies in which linezolid dosed to achieve AUC 24~1 0 times that observed in humans produced significant reductions in peripheral platelet counts over 1 month of administration. 17 Reversible myelosuppression develops typically after 14 days of treatment and is more often associated with patients who have underlying hematologic abnormalities or renal insufficiency. 18 In preclinical studies, there was a potential for myelosuppression in tedizolidtreated rats and dogs with increasing drug exposures, similar to linezolid.…”

Section: Safety Profilementioning

confidence: 99%

“…Hematologic toxicity is another well‐known and treatment duration–mediated toxicity linked to linezolid use . This toxicity was first seen in preclinical animal studies in which linezolid dosed to achieve AUC 24 ~10 times that observed in humans produced significant reductions in peripheral platelet counts over 1 month of administration . Reversible myelosuppression develops typically after 14 days of treatment and is more often associated with patients who have underlying hematologic abnormalities or renal insufficiency .…”

Section: Early Clinical Experiencementioning

confidence: 99%

Early Experience with Tedizolid: Clinical Efficacy, Pharmacodynamics, and Resistance

2014

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Antimicrobial resistance among gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) continues to limit therapeutic options. The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of serious MRSA and VRE infections. With increasing utilization of linezolid, resistant pathogens have once again begun to emerge. Tedizolid, a next-generation oxazolidinone, possesses a spectrum of activity including MRSA and VRE, with significantly enhanced potency also against linezolid-resistant strains. Preclinical and early clinical studies have reported positive results, demonstrating a favorable pharmacokinetic profile in combination with key potential safety advantages. In two phase III clinical trials, tedizolid was found noninferior to linezolid in the treatment of acute bacterial skin and skin structure infections. Investigations for treatment of ventilator-acquired and health care-associated pneumonia are currently underway. Tedizolid has been subjected to pharmacodynamics studies throughout its development that have highlighted properties unique to this agent. Considerable accumulations in epithelial lining fluid and antimicrobial activity greatly augmented by the presence of granulocytes suggest that slow but bactericidal activity may be possible in some clinical scenarios. Structural distinctions between tedizolid and linezolid suggest that tedizolid has decreased vulnerability to oxazolidinone resistance mechanisms. Tedizolid minimum inhibitory concentrations are essentially unchanged in organisms possessing the chloramphenicol-florfenicol resistance gene, a horizontally transferable linezolid resistance mechanism. Although the clinical experience with tedizolid remains limited, early data suggest a potential role in the treatment of serious infections due to multidrug-resistant gram-positive pathogens.

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“…On review of literature, using PubMed with keywords “sideroblastic anemia” and “linezolid” four case reports [3, 9–11] were identified. Also, a study in dogs treated with PNU‐100592, an Oxazolidinone analog, induced SA in dogs treated with high dose [13].…”

Section: Commentarymentioning

confidence: 99%

The perils of not digging deep enough—uncovering a rare cause of acquired anemia

et al. 2011

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Hypersegmented Megakaryocytes and Megakaryocytes with Multiple Separate Nuclei in Dogs Treated with PNU-100592, an Oxazolidinone Antibiotic

Cited by 23 publications

References 16 publications

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Early Experience with Tedizolid: Clinical Efficacy, Pharmacodynamics, and Resistance

The perils of not digging deep enough—uncovering a rare cause of acquired anemia

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