Study of Macrophage Functions in Murine J774 Cells and Human Activated THP-1 Cells Exposed to Oritavancin, a Lipoglycopeptide with High Cellular Accumulation

Lemaire, Sandrine; Mingeot‐Leclercq, Marie‐Paule; Tulkens, Paul M.; Bambeke, Françoise Van

doi:10.1128/aac.02475-13

Cited by 22 publications

(17 citation statements)

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“…For extracellular infections, homogenization of the tissue dilutes drugs that are mainly located in the extracellular compartment, which may lead to an underestimation of the active concentration of drug (17). Oritavancin is known to accumulate intracellularly within macrophages (18,19). In this case, total oritavancin concentrations in tissue may be overestimated if the infection is extracellular and underestimated if it is intracellular.…”

Section: Discussionmentioning

confidence: 92%

Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

Lehoux¹,

Ostiguy²,

Cadieux³

et al. 2015

Antimicrob Agents Chemother

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The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. (2) and rapid concentration-dependent bactericidal activity in vitro against a variety of Gram-positive species, including drug-resistant enterococci, staphylococci, and streptococci (3). Oritavancin is characterized by a long half-life (4), which allows for the treatment of ABSSSI with a single dose of the drug (Orbactiv package insert [1]).S. aureus is the most common pathogen responsible for bone and joint infections (5-8); these infections often require long treatment durations with frequent dosing. The high level of activity of oritavancin against S. aureus (including MRSA) and its long half-life are characteristics that warrant further investigations for the treatment of infections caused by Gram-positive infection requiring long-term antibiotic therapy, such as bone and joint infections. This study was conducted to determine the systemic exposure of oritavancin in rabbits relative to human exposure and to evaluate the bone penetration of oritavancin after a humanized dose in rabbits. MATERIALS AND METHODSAntimicrobial agent. Oritavancin was manufactured and provided by The Medicines Company. Oritavancin powder was dissolved in 5% dextrose in water, mixed by vortexing for 1 min, filtered through a sterile 0.22-m filter, and stored at room temperature until administration. Oritavancin was administered as a 5-min intravenous infusion via the marginal ear vein using an indwelling catheter.Animals. Ten-to 12-week-old male New Zealand White rabbits (Charles River Laboratories, Saint-Constant, Canada) weighing 2.1 to 2.5 kg were used. The animal care and use practices in this study were in accordance with the guidelines and policies of the American Association of Laboratory Animal Care and the Canadian Council on Animal Care. All experimental protocols were approved by an institutional animal care and use committee.Pharmacokinetic study in serum. Twelve rabbits (n ϭ 3/dose) were administered 10, 15, 20, or 40 mg/kg of body weight of oritavancin. Blood samples were collected at 0.5, 3, 6, 12, and 24 h after dosing from each rabbit via the central ear artery. It is to be noted that blood collection at 12 h from animals receiving 40 mg/kg was inadvertently not performed.Pharmacokinetic study in bone. Twenty-one rabbits (n ϭ 3/time point) were administered a 20-mg/kg dose of oritavancin. This dose was selected subsequently to the pharmacokinetic study in serum, as it provided an exposure close to the 1,200-mg single dose in humans. Blood samples were collected at 0. 08,3,6,14,24, 48, and 168 h after dosing via the central ear artery. Late blood sampling at 168 h was sele...

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Section: Discussionmentioning

confidence: 92%

Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

Lehoux¹,

Ostiguy²,

Cadieux³

et al. 2015

Antimicrob Agents Chemother

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“…Moreover, this effect was reversible upon drug removal [76]. When the exposure [173] of cells was limited to drug amounts for which cellular concentrations were of the same order of magnitude as those measured in patients, no specific sign of intoxication of macrophages was evidenced, including with respect to phagocytic or killing capacities or oxidant species production [77,78]. Telavancin also caused cellular lipidosis, but to a much lower extent than oritavancin, related to its lower cellular accumulation [79].…”

Section: In Vitro Models Of Persistent Infectionsmentioning

confidence: 95%

“…In vitro studies have indeed demonstrated the deposition of undigested lipidic material within lysosomes of cells exposed to the drug continuously for 1-3 days [76], but only in conditions generating intracellular concentrations well above those measured in macrophages from patients treated with the drug [77]. Moreover, this effect was reversible upon drug removal [76].…”

Section: In Vitro Models Of Persistent Infectionsmentioning

confidence: 96%

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

Bambeke

2015

Drugs

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Oritavancin, telavancin, and dalbavancin are recently marketed lipoglycopeptides that exhibit remarkable differences to conventional molecules. While dalbavancin inhibits the late stages of peptidoglycan synthesis by mainly impairing transglycosylase activity, oritavancin and telavancin anchor in the bacterial membrane by the lipophilic side chain linked to their disaccharidic moiety, disrupting membrane integrity and causing bacteriolysis. Oritavancin keeps activity against vancomycin-resistant enterocococci, being a stronger inhibitor of transpeptidase than of transglycosylase activity. These molecules have potent activity against Grampositive organisms, most notably staphylococci (including methicillin-resistant Staphylococcus aureus and to some extent vancomycin-intermediate S. aureus), streptococci (including multidrug-resistant pneumococci), and Clostridia. All agents are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin, for hospitalacquired and ventilator-associated bacterial pneumonia. While telavancin is administered daily at 10 mg/kg, the remarkably long half-lives of oritavancin and dalbavancin allow for infrequent dosing (single dose of 1200 mg for oritavancin and 1000 mg at day 1 followed by 500 mg at day 8 for dalbavancin), which could be exploited in the future for outpatient therapy. Among possible safety issues evidenced during clinical development were an increased risk of developing osteomyelitis with oritavancin; taste disturbance, nephrotoxicity, and risk of corrected QT interval prolongation (especially in the presence of at-risk co-medications) with telavancin; and elevation of hepatic enzymes with dalbavancin. Interference with coagulation tests has been reported with oritavancin and telavancin. These drugs proved non-inferior to conventional treatments in clinical trials but their advantages may be better evidenced upon future evaluation in more severe infections. Key PointsNew lipoglycopeptides (telavancin, oritavancin, dalbavancin) differ from vancomycin by the presence of a lipophilic side chain, which profoundly modifies their pharmacokinetic and/or pharmacodynamic profile.Among these agents, telavancin and oritavancin have multiple modes of action and are highly bactericidal.Oritavancin and dalbavancin have prolonged halflives, allowing for their use a single-dose or twodose (once-a-week) regimen, respectively. These three drugs are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin is indicated for hospital-acquired and ventilator-associated bacterial pneumonia.

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“…We believe that this can be over the best solution here is using advanced technology and a multidisciplinary approach. Recently, great advances have been made in the field of abiotic membrane-active polymers that can coat cell membranes whilst maintaining cell viability 98 . These polymers can be "decorated" with an opsonin to enhance encapsulation; the polymer can be deconstructed by e.g.…”

Section: Additional Factors To Considermentioning

confidence: 99%

Development of a transendothelial shuttle by macrophage modification

Visser

Smith

2017

J Tissue Eng Regen Med

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i Declaration By submitting this thesis electronically, I declare that the entirety of the work contained therein is my own, original work, that I am the sole author thereof (save to the extent explicitly otherwise stated), that reproduction and publication thereof by Stellenbosch University will not infringe any third party rights and that I have not previously in its entirety or in part submitted it for obtaining any qualification. Copyright © 2016 Stellenbosch UniversityAll rights reserved Stellenbosch University https://scholar.sun.ac.za ii Abstract Background: Targeted stem cell delivery via macrophage modification is a novel and

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Study of Macrophage Functions in Murine J774 Cells and Human Activated THP-1 Cells Exposed to Oritavancin, a Lipoglycopeptide with High Cellular Accumulation

Cited by 22 publications

References 53 publications

Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

Development of a transendothelial shuttle by macrophage modification

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