Nebulization of Vancomycin Provides Higher Lung Tissue Concentrations than Intravenous Administration in Ventilated Female Piglets with Healthy Lungs

Abstract

Background Intravenous vancomycin is used to treat ventilator-associated pneumonia caused by methicillin-resistant Staphylococcus aureus, but achieves high rates of failure. Vancomycin nebulization may be efficient to provide high vancomycin lung tissue concentrations. The aim of this study was to compare lung tissue and serum concentrations of vancomycin administered intravenously and by aerosol in mechanically ventilated and anesthetized healthy piglets. Methods Twelve female piglets received a single intravenous dose of vancomycin (15 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of administration. Twelve piglets received a single nebulized dose of vancomycin (37.5 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of the aerosol administration. In each group, vancomycin lung tissue concentrations were assessed on postmortem lung specimens using high-performance liquid chromatography. Blood samples were collected for serum vancomycin concentration measurement 30 min and 1, 2, 4, 6, 8, and 12 h after the end of vancomycin administration. Pharmacokinetics was analyzed by nonlinear mixed effect modeling. Results One hour after vancomycin administration, lung tissue concentrations in the aerosol group were 13 times the concentrations in the intravenous group (median and interquartile range: 161 [71, 301] μg/g versus 12 [4, 42] μg/g; P < 0.0001). Twelve hours after vancomycin administration, lung tissue concentrations in the aerosol group were 63 (23, 119) μg/g and 0 (0, 19) μg/g in the intravenous group (P < 0.0001). A two-compartment weight-scaled allometric model with first-order absorption and elimination best fit serum pharmacokinetics after both routes of administration. Area under the time-concentration curve from 0 to 12 h was lower in the aerosol group in comparison to the intravenous group (56 [8, 70] mg · h · l−1vs. 121 [103, 149] mg · h · l−1, P = 0.002). Using a population model, vancomycin bioavailability was 13% (95% CI, 6 to 69; coefficient of variation = 85%) and absorption rate was slow (absorption half life = 0.3 h). Conclusions Administration of vancomycin by nebulization resulted in higher lung tissue concentrations than the intravenous route. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Nebulized Antibiotics for Healthcare- and Ventilator-Associated Pneumonia

“…Twelve hours after vancomycin administration, lung tissue concentrations in the nebulization group were 63 μg/g vs. 0 [0-19] μg/g in the IV group (p < 0.0001). 59 To summarize, PK studies have shown that nebulized CMS achieves high colistin concentrations in infected lung tissue and very low concentrations in plasma; thus, it may be an attractive alternative to the IV route. The optimal dosing regimen is not clearly established; nevertheless, given the overestimation of concentrations in the ELF compared with the interstitial fluid and low plasma concentrations, high doses should be preferred especially for concentration-dependent antibiotics.…”

“…Twelve hours after vancomycin administration, lung tissue concentrations in the nebulization group were 63 [23–119] μg/g vs. 0 [0–19] μg/g in the IV group ( p < 0.0001). 59…”

Inhaled antibiotics during mechanical ventilation—why it will work

“…It is easy to imagine concentration-dependent antibiotic like Colistin or aminoglycosides to be administered by nebulization; it is way more difficult for time-dependent antibiotic like glycopeptides or ß-lactams, as continuous inhalation leads to specific constraints. However, Morais et al (38) observed in piglets that a single nebulization of Vancomycin induced higher lung concentration than a single injection. In a (39).…”

In vitro and in vivo local tolerability of a synergistic anti‐tuberculosis drug combination intended for pulmonary delivery

“…Pulmonary administration could enhance therapeutic effects, as drugs directly delivered to the lungs will act at higher drug concentration at the site of infection, with lower systemic side effects (Hickey et al, 2016; Tan et al, 2020). To date, VAN delivered by pulmonary route has proven its safety in humans (de Jesús Valle et al, 2007; Morais et al, 2020; Sullivan et al, 2015; Waterer et al, 2020), but no safety data have been reported on THL delivered to the lungs until now.…”