Glycopeptide Bone Penetration in Patients with Septic Pseudoarthrosis of the Tibia

Garazzino, Silvia; Aprato, Alessandro; Baietto, Lorena; D’Avolio, Antonio; Maiello, A.; Rosa, Francesco Giuseppe De; Aloj, Domenico; Siccardi, Marco; Biasibetti, A.; Massè, Alessandro; Perri, Giovanni Di

doi:10.2165/0003088-200847120-00004

Cited by 38 publications

(21 citation statements)

References 25 publications

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“…96-102 Similar variability and point estimates have been found for vancomycin in infected patients, with an average bone:serum ratio of ~0.20. 100,103 Higher doses would thus be necessary if mirroring drug exposures in the blood is desired. Fluoroquinolones, maintaining high volumes of distribution secondary to their lipophilicity, achieve higher bone:serum ratios than beta-lactams or vancomycin, ranging from ~0.35 (ciprofloxacin) to ~0.75 for levofloxacin.…”

Section: Antimicrobial Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

Onufrak

Forrest

González

2016

Clinical Therapeutics

124

104

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Purpose An understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine response to antimicrobial therapy can provide the clinician with better-informed dosing regimens. Factors influential on antibiotic disposition and clinical outcome are presented, with a focus on the primary site of infection. Techniques to better understand antibiotic PK and optimize PD are acknowledged. Methods PubMed (inception – April 2016) was reviewed for relevant publications assessing antimicrobial exposures within different anatomical locations and clinical outcomes for various infection sites. Findings A limited literature base indicates variable penetration of antibiotics to different target sites of infection, with drug solubility and extent of protein binding providing significant PK influences in addition to the major clearing pathway of the agent. PD indices derived from in vitro and animal models determine the optimal magnitude and frequency of dosing regimens for patients. PK/PD modeling and simulation has been shown an efficient means of assessing these PD endpoints against a variety of PK determinants, clarifying the unique effects of infection site and patient characteristics to inform the adequacy of a given antibiotic regimen. Implications Appreciation of the PK properties of an antibiotic and its PD measure of efficacy can maximize the utility of these life-saving drugs. Unfortunately, clinical data remains limited for a number of infection site-antibiotic exposure relationships. Modeling and simulation can bridge preclinical and patient data for the prescription of optimal antibiotic dosing regimens, consistent with the tenets of personalized medicine.

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Section: Antimicrobial Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

Onufrak

Forrest

González

2016

Clinical Therapeutics

124

104

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show abstract

“…Given the problematic penetration of antibiotics into infected tissues, e.g. joints and bones [61,62], it appears plausible to assume that indeed, during therapy S. epidermidis is exposed against only sub-inhibitory antibiotic concentrations, driving the development of biofilm formation. Thus, a phenotype is promoted which itself is associated with an inherently increased resistance to antimicrobials, and effectors of the host immune system.…”

Section: Augmentation Of S Epidermidis Biofilm Formation By Sub-inhimentioning

confidence: 99%

Sub-inhibitory tigecycline concentrations induce extracellular matrix binding protein Embp dependent Staphylococcus epidermidis biofilm formation and immune evasion

Weiser

Henke

Hector

et al. 2016

International Journal of Medical Microbiology

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“…Vancomycin has been demonstrated to be active in animal models of osteomyelitis (5). Concentrations in bone from 2.7 to 9.3 g/ml have been documented (6,7), exceeding the vancomycin MIC 90 for S. aureus of 1 g/ml (8). Because of the wide variety of underlying etiologies and comorbidities associated with osteomyelitis, it is difficult to generalize the rates of clinical success from clinical trials, but one study documented a clinical response in 10/15 patients after continuous intravenous (i.v.)…”

mentioning

confidence: 99%

Extended-Duration Dosing and Distribution of Dalbavancin into Bone and Articular Tissue

Dunne¹,

Puttagunta²,

Sprenger³

et al. 2015

Antimicrob Agents Chemother

162

137

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Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC 90 for Staphylococcus aureus of 0.06 g/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 g/g and 2 weeks later were 4.1 g/g. A twodose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed. Osteomyelitis is an infection of the bone associated with either hematogenous dissemination or direct inoculation as a consequence of trauma or infection from contiguous tissues. Its presentation may be either acute or chronic. The most common pathogen responsible for acute infection in adults is Staphylococcus aureus, with Pseudomonas aeruginosa, Serratia marcescens, and Escherichia coli also involved in traumatic infections and chronic presentations. Infection in children occurs less frequently and is predominantly a result of bacteremia with S. aureus and infection in the growth plate (1). Treatment regimens extend for 4 to 6 weeks, with durations as long as 8 weeks recommended for treatment of infection due to methicillin-resistant S. aureus (MRSA) (2). Commonly used therapies include cefazolin, oxacillin, or vancomycin for coverage of Gram-positive pathogens and cephalosporins, carbapenems, and the ␤-lactamase inhibitor agents for treatment of Gram-negative pathogens (2,3). No other therapies in recent times have received FDA approval.Because the incidence of MRSA in the community in the United States is as high as 40% (4), empirical treatment of osteomyelitis now requires consideration of antimicrobial coverage of this organism, typically with vancomycin. Vancomycin has been demonstrated to be active in animal models of osteomyelitis (5). Concentrations in bone from 2.7 to 9.3 g/ml have been documented (6, 7), exceeding the vancomycin MIC 90 for S. aureus of 1 g/ml (8). Because of the wide variety of underlying etiologies and comorbidities associated with osteomyelitis, it is difficult to generalize the rates of clinical success from clinical trials, but one study documented a clinical response in 10/15 patients after continuous intravenous (i.v.) infusion of vancomycin (9). Long-term d...

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Glycopeptide Bone Penetration in Patients with Septic Pseudoarthrosis of the Tibia

Cited by 38 publications

References 25 publications

Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

Sub-inhibitory tigecycline concentrations induce extracellular matrix binding protein Embp dependent Staphylococcus epidermidis biofilm formation and immune evasion

Extended-Duration Dosing and Distribution of Dalbavancin into Bone and Articular Tissue

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