Pharmacokinetics and Pharmacodynamics of Linezolid in Obese Patients with Cellulitis

Stein, Gary E.; Schooley, Sharon; Peloquin, Charles A.; Kak, Vivek; Havlichek, Daniel H.; Citron, Diane M.; Tyrrell, Kerin L.; Goldstein, Ellie J. C.

doi:10.1345/aph.1e484

Cited by 80 publications

(50 citation statements)

References 34 publications

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“…Previously published data have reported lower linezolid concentrations in obese patients (7)(8)(9)(10). One study with seven obese patients receiving 600 mg oral linezolid every 12 h for cellulitis (9) compared a 1-h linezolid concentration of 12.3 g/ml in their patients with previously reported peak concentrations of 16.3 to 24 g/ml in nonobese patients (20,21).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

Bhalodi

Papasavas

Tishler

et al. 2013

Antimicrob Agents Chemother

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The pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m 2 receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (؎standard deviation) age, height, and weight were 42.2 ؎ 12.2 years, 64.8 ؎ 3.5 in, and 109.5 ؎ 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ؎ 1.9 liters/h), which could be inhibited to 85.5% ؎ 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ؎ 9.6 liters), and the intercompartment transfer constants (K 12 and K 21 ) of 8.04 ؎ 6.22 and 7.99 ؎ 5.46 h ؊1 , respectively. The areas under the curve for the 12-h dosing interval (AUC) were similar between moderately obese and morbidly obese groups: 130.3 ؎ 60.1 versus 109.2 ؎ 25.5 g · h/ml (P ‫؍‬ 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r 2 ‫؍‬ 0.524), adjusted body weight (r 2 ‫؍‬ 0.587), lean body weight (r 2 ‫؍‬ 0.495), and ideal body weight (r 2 ‫؍‬ 0.398), but not with BMI (r 2 ‫؍‬ 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUC values similar to those seen in nonobese participants.

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Section: Discussionmentioning

confidence: 99%

“…There are no weight-based recommendations or guidelines for dosing linezolid in obese patients. However, there is some evidence from case reports and small studies with sparse blood sampling that concentrations may be lower in obese patients, thus requiring dosage increases (7)(8)(9)(10).…”

mentioning

confidence: 99%

Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

Bhalodi

Papasavas

Tishler

et al. 2013

Antimicrob Agents Chemother

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“…Plates were incubated for 18 to 24 h at 37°C, after which time the zone sizes were measured using a protocol reader (Protocol; Microbiology International, Frederick, MD). Linezolid samples were evaluated using a validated high-performance liquid chromatography (HPLC) assay with standards ranging from 0.5 mg/liter to 30 mg/liter (12,24,35). This assay has a CV of 1.1 to 4.4%.…”

Section: Methodsmentioning

confidence: 99%

Novel Daptomycin Combinations against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations

Steed

Vidaillac

Rybak

2010

Antimicrob Agents Chemother

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Reduced susceptibility to daptomycin has been reported in patients with infections due to methicillinresistant Staphylococcus aureus (MRSA). Although infections with daptomycin-nonsusceptible (DNS) MRSA are infrequent, optimal therapy of these strains has not been determined. We investigated the killing effects of novel antibiotic combinations with daptomycin (DAP) against two clinical DNS MRSA isolates (SA-684 and R6003) in a 72-h in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (SEV). Simulated regimens included DAP at 6 mg/kg every 24 h (q24h) alone or in combination with trimethoprim-sulfamethoxazole (TMP/SMX) at 160/800 mg q12h, linezolid (LIN) at 600 mg q12h, cefepime (CEF) at 2 g q12h, and nafcillin (NAF) at 4 g q4h. Bactericidal activity was defined as a >3-log 10 CFU/g kill. Differences in CFU/g were evaluated between 4 and 72 h by analysis of variance with the Bonferroni post hoc test. DAP MICs were 4 and 2 mg/liter for SA-684 and R6003, respectively. In the PK/PD model, DAP alone was slowly bactericidal, achieving a 3-log 10 kill at 24 and 50 h for SA-684 and R6003, respectively. Against SA-684, DAP plus TMP/SMX, CEF, LIN, or NAF was bactericidal at 4, 4, 8, and 8 h, respectively, and maintained this activity for the 72-h study duration. DAP plus TMP/SMX or CEF exhibited superior killing than DAP alone against SA-684 between 4 and 72 h, and overall this was significant (P < 0.05). Against R6003, DAP plus TMP/SMX was bactericidal (8 h) and superior to DAP alone between 8 and 72 h (P < 0.001). The unique combination of DAP plus TMP/SMX was the most effective and rapidly bactericidal regimen against the two isolates tested and may provide a clinical option to treat DNS S. aureus infections.

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“…The study concluded standard dosing in patients weighing up to 150 kg should provide equivalent drug exposure. In contrast, two independent pharmacokinetics studies by Hamilton et al and Stein et al found significant differences in linezolid concentration in obese patients compared to nonobese patients [12,13] . Hamilton et al concluded that the average linezolid concentration was more than 50% lower in the pre-surgery period compared to the post-surgery period in patients with gastric bypass surgery [12] .…”

mentioning

confidence: 82%

Linezolid for Methicillin-Resistant Staphylococcus aureus Pneumonia: The Impact of Obesity on Clinical Outcomes

Lee¹

2016

JPP

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Pharmacokinetics and Pharmacodynamics of Linezolid in Obese Patients with Cellulitis

Cited by 80 publications

References 34 publications

Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

Novel Daptomycin Combinations against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations

Linezolid for Methicillin-Resistant Staphylococcus aureus Pneumonia: The Impact of Obesity on Clinical Outcomes

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