Dalbavancin Population Pharmacokinetic Modeling and Target Attainment Analysis

Carrothers, Timothy J.; Chittenden, Jason; Critchley, Ian A.

doi:10.1002/cpdd.695

Cited by 25 publications

(24 citation statements)

References 30 publications

(72 reference statements)

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“…The major refractoriness of RIF-R/hVISA and DNS strains is also corroborated by other expression studies conducted on VISA and hVISA, in which the drastic change in the cell transcriptional profile was demonstrated to be mainly associated to rpoB mutations [21]. Nonetheless, it is to be mentioned that the dalbavancin MICs of these strains were only one/two dilutions above the EUCAST breakpoint, and that many in vitro and in vivo preclinical studies predicted that the pharmacokinetic/pharmacodynamic (PK/PD) profiles usually persist above the MIC level [22]. Our observations suggest that dalbavancin will be considered an excellent therapeutic alternative for the management of severe S. aureus infections sustained by MDR strains sharing diverse and increasing behaviors of antibiotic resistance, also belonging to most refractory MRSA phenotypes.…”

Section: Discussionsupporting

confidence: 66%

In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

et al. 2020

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The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections, always treated with vancomycin and daptomycin, has led to the emergence of vancomycin-intermediate (VISA), heteroresistant vancomycin-intermediate (hVISA) and daptomycin non-susceptible (DNS) S. aureus. Even if glycopeptides and daptomycin remain the keystone for treatment of resistant S. aureus, the need for alternative therapies that target MRSA has now become imperative. The in vitro antibacterial and bactericidal activity of dalbavancin was evaluated against clinically relevant S. aureus showing raised antibiotic resistance levels, from methicillin-susceptible to Multidrug-Resistant (MDR) MRSA, including hVISA, DNS and rifampicin-resistant (RIF-R) strains. A total of 124 S. aureus strains were tested for dalbavancin susceptibility, by the broth microdilution method. Two VISA and 2 hVISA reference strains, as well as a vancomycin-resistant (VRSA) reference strain and a methicillin-susceptible Staphylococcus aureus (MSSA) reference strain, were included as controls. Time–kill curves were assayed to assess bactericidal activity. Dalbavancin demonstrated excellent in vitro antibacterial and bactericidal activity against all S. aureus resistance classes, including hVISA and DNS isolates. The RIF-R strains showed the highest percentage of isolates with non-susceptibility, reflecting the correlation between rpoB mutations and VISA/hVISA emergence. Our observations suggest that dalbavancin can be considered as an effective alternative for the management of severe MRSA infections also sustained by refractory phenotypes.

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Section: Discussionsupporting

confidence: 66%

In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

et al. 2020

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“…Dalbavancin exhibits peculiar PK/PD properties, consisting in a long terminal half-life (approximately 14.4 days), high binding protein (93%), a predominant non-renal clearance, good tissue penetration, and high susceptibility rate (respectively 99.6% and 100.0%) against methicillinresistant Staphylococcus aureus (MRSA) and methicillinsusceptible Staphylococcus aureus (MSSA) isolates according to EUCAST clinical breakpoint (namely 0.125 mg/l). [12][13][14][15] The clearance of dalbavancin was not affected by the presence of cytochrome P450 substrates, cytochrome P450 inhibitors, cytochrome P450 inducers, or selected concomitant medications. Furthermore, age, gender and race had no impact on the pharmacokinetic profile of dalbavancin.…”

Section: Pk/pd Propertiesmentioning

confidence: 96%

Real-World Use of Dalbavancin in the Era of Empowerment of Outpatient Antimicrobial Treatment: A Careful Appraisal Beyond Approved Indications Focusing on Unmet Clinical Needs

Gatti

Andreoni

Pea

et al. 2021

DDDT

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Dalbavancin is a novel, long-acting lipoglycopeptide characterized by a long elimination half-life coupled with excellent in vitro activity against multidrug-resistant Gram-positives. Although it is currently approved only for the treatment of acute bacterial skin and skin structure infections, an ever-growing amount of evidence supports the efficacy of dalbavancin as a long-term therapy in osteomyelitis, prosthetic joint infections, endocarditis, and bloodstream infections. This article provides a critical reappraisal of real-world use of dalbavancin for off-label indications. A search strategy using specific keywords (dalbavancin, osteomyelitis, endocarditis, long-term suppressive therapy, bloodstream infection, pharmacokinetic/pharmacodynamic profile) until April 2021 was performed on the PubMed-MEDLINE database. As for other novel antibiotics, a conundrum between approved indications and potential innovative therapeutic uses has emerged for dalbavancin as well. The promising efficacy in challenging scenarios (i.e., osteomyelitis, endocarditis, prosthetic joint infections), coupled with the unique pharmacokinetic/pharmacodynamic properties, makes dalbavancin a valuable alternative to daily in-hospital intravenous or outpatient antimicrobial regimens in the treatment of long-term Gram-positive infections. This makes dalbavancin valuable in the current COVID-19 scenario, in which hospitalization and territorial medicine empowerment are unavoidable.

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“…Additionally, the MIC 50 and MIC 90 are 0.03 g/ml and 0.03 g/ml, respectively, for Staphylococcus aureus and 0.03 g/ml and 0.06 g/ml, respectively, for Streptococcus spp. Recent pharmacodynamic evaluations have suggested a free drug AUC/MIC ratio of Ն27.1, using a population protein binding estimate of 93% bound and 7% free dalbavancin plasma concentrations (18,19). Using pharmacodynamic attainment estimates combined with the AUC 0 -day 14 data generated from this study, the pharmacodynamic targets are far exceeded for both Staphylococcus aureus and Streptococcus spp., regardless of our current use of more conservative pharmacodynamic targets or the more recent pharmacodynamic target recommendation determined using population-based protein binding estimates.…”

Section: Discussionmentioning

confidence: 92%

Intravenous and Intraperitoneal Pharmacokinetics of Dalbavancin in Peritoneal Dialysis Patients

Matre

Teitelbaum

Kiser

2020

Antimicrob Agents Chemother

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Dalbavancin offers a possible treatment option for infectious peritonitis associated with peritoneal dialysis (PD) due to its coverage of Gram-positive bacteria and pharmacokinetic properties. We aimed to evaluate the clinical pharmacokinetics (PK) and pharmacodynamics of dalbavancin in a prospective, randomized, open-label, crossover PK study of adult patients with end-stage renal disease ESRD who were receiving PD. Sampling occurred prior to a single 30-min infusion of dalbavancin at 1,500 mg and at 1, 2, 3, 4, and 6 h and 7 and 14 days postadministration. Concentration-time data were analyzed via noncompartmental analysis. Pharmacodynamic parameters against common infectious peritonitis-causing pathogens were evaluated. Ten patients were enrolled. Patients were a median of 55 years old and had a median weight of 78.2 kg, 50% were female, and 70% were Caucasian. The terminal plasma half-life of dalbavancin was 181.4 ± 35.5 h. The day 0 to day 14 dalbavancin mean area under the curve (AUC) was 40,573.2 ± 9,800.3 mg·h/liter. The terminal-phase half-life of dalbavancin within the peritoneal fluid was 4.309 × 108 ± 1.140 × 109 h. The day 0 to day 14 dalbavancin mean peritoneal fluid AUC was 2,125.0 ± 1,794.3 mg·h/liter. The target plasma AUC/MIC was attained with the intravenous dose in all 10 patients for all Staphylococcus and Streptococcus species at the recommended MIC breakpoints. The intraperitoneal arm of the study was stopped early, because the first 3 patients experienced moderate to severe pain and bloating within 1 h following the administration of dalbavancin. Dalbavancin at 1,500 mg administered intravenously can be utilized without dose adjustment in peritoneal dialysis patients and will likely achieve the necessary peritoneal fluid concentrations to treat peritonitis caused by typical Gram-positive pathogens.

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Dalbavancin Population Pharmacokinetic Modeling and Target Attainment Analysis

Cited by 25 publications

References 30 publications

In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

Real-World Use of Dalbavancin in the Era of Empowerment of Outpatient Antimicrobial Treatment: A Careful Appraisal Beyond Approved Indications Focusing on Unmet Clinical Needs

Intravenous and Intraperitoneal Pharmacokinetics of Dalbavancin in Peritoneal Dialysis Patients

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