Aerosolized delivery of antibiotics is hindered by poor penetration within distal and plugged airways. Antibacterial perfluorocarbon ventilation (APV) is a proposed solution in which the lungs are partially or totally filled with perfluorocarbon (PFC) containing emulsified antibiotics. The purpose of this study was to evaluate emulsion stability and rheological, antibacterial, and pharmacokinetic characteristics.
Methods:
This study examined emulsion aqueous droplet diameter and number density over 24 hr and emulsion and neat PFC viscosity and surface tension. Additionally, Pseudomonas aeruginosa biofilm growth was measured after 2-hr exposure to emulsion with variable aqueous volume percentages (0.25, 1, and 2.5%) and aqueous tobramycin concentrations (Ca=0.4, 4, and 40 mg/mL). Lastly, the time course of serum and pulmonary tobramycin concentrations was evaluated following APV and conventional aerosolized delivery of tobramycin in rats.
Results:
The initial aqueous droplet diameter averaged 1.9±0.2 μm with little change over time. Initial aqueous droplet number density averaged 3.5±1.7×109 droplets/mL with a significant (p<0.01) decrease over time. Emulsion and PFC viscosity were not significantly different, averaging 1.22±0.03×10–3 Pa·sec. The surface tensions of PFC and emulsion were 15.0±0.1×10–3 and 14.6±0.6×10–3 N/m, respectively, and the aqueous interfacial tensions were 46.7±0.3×10–3 and 26.9±11.0×10–3 N/m (p<0.01), respectively. Biofilm growth decreased markedly with increasing Ca and, to a lesser extent, aqueous volume percentage. Tobramycin delivered via APV yielded 2.5 and 10 times larger pulmonary concentrations at 1 and 4 hr post delivery, respectively, and significantly (p<0.05) lower serum concentrations compared with aerosolized delivery.
Conclusions:
The emulsion is bactericidal, retains the rheology necessary for pulmonary delivery, is sufficiently stable for this application, and results in increased pulmonary retention of the antibiotic.
Get full access to this article
View all access options for this article.
References
1.
DaviesJC, and BiltonD: Bugs, biofilms, and resistance in cystic fibrosis. Respir Care., 2009; 54:628–640.
2.
HeadNE, and YuH: Cross-sectional analysis of clinical and environmental isolates of Pseudomonas aeruginosa: biofilm formation, virulence, and genome diversity. Infect Immun., 2004; 72:133–144.
3.
HoibyN, CiofuO, JohansenHK, SongZJ, MoserC, JensenPO, MolinS, GivskovM, Tolker-NielsenT, and BjarnsholtT: The clinical impact of bacterial biofilms. Int J Oral Sci., 2011; 3:55–65.
4.
GellerDE, PitlickWH, NardellaPA, TracewellWG, and RamseyBW: Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis. Chest., 2002; 122:219–226.
5.
ColePJ: The role of nebulized antibiotics in treating serious respiratory infections. J Chemother., 2001; 13:354–362.
6.
MarierJF, BrazierJL, LavigneJ, and DucharmeMP: Liposomal tobramycin against pulmonary infections of Pseudomonas aeruginosa: a pharmacokinetic and efficacy study following single and multiple intratracheal administrations in rats. J Antimicrob Chemother., 2003; 52:247–252.
7.
LabirisNR, and DolovichMB: Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. J Clin Pharmacol., 2003; 56:588–599.
8.
KuhnRJ: Pharmaceutical considerations in aerosol drug delivery. Pharmacotherapy., 2002; 22:80S–85S.
9.
RubinBK: Aerosolized antibiotics for non-cystic fibrosis bronchiectasis. J Aerosol Med Pulm Drug Deliv., 2008; 21:71–76.
10.
Van't VeenA, GommersD, VerbruggeSJC, WollmerP, MoutonJW, KoojiPPM, and LachmannB: Lung clearance of intratracheally instilled 99mTc-tobramycin using pulmonary surfactant as vehicle. Br J Pharmacol., 1999; 126:1091–1096.
11.
BabaA, KimYK, ZhangH, LiuM, and SlutskyAS: Perfluorocarbon blocks tumor necrosis factor-α-induced interleukin-8 release from alveolar epithelial cells in vitro. Crit Care Med., 2000; 28:1113–1118.
12.
BurkhardtW, KoehneP, WisselH, GrafS, ProquitteH, WauerRR, and RudigerM: Intratracheal perfluorocarbons diminish LPS-induced increase in systemic TNF-alpha. Am J Physiol Lung Cell Mol Physiol., 2008; 294:1043–1048.
13.
KochT, RagallerM, HaufeD, HoferA, GrosserM, AlbrechtDM, KotzschM, and LutherT: Perfluorohexane attenuates proinflammatory and procoagulatory response of activated monocytes and alveolar macrophages. Anesthesiology., 2001; 94:101–109.
14.
ThomassenMJ, BuhrowLT, and WiedemannHP: Perflubron decreases inflammatory cytokine production by human alveolar macrophages. Crit Care Med., 1997; 25:2045–2047.
15.
VaraniJ, HirschlRB, DameM, and JohnsonK: Perfluorocarbon protects lung epithelial cells from neutrophil-mediated injury in an in vitro model of liquid ventilation therapy. Shock., 1996; 6:339–344.
16.
CroceMA, FabianTC, PattonJHJr, MeltonSM, MooreM, and TrenthemLL: Partial liquid ventilation decreases the inflammatory response in the alveolar environment of trauma patients. J Trauma., 1998; 45:273–280; discussion 280–282.
17.
HirschlRB, PranikoffT, WiseC, OverbeckMC, GaugerP, SchreinerRJ, DechertR, and BartlettRH: Initial experience with partial liquid ventilation in adult patients with the acute respiratory distress syndrome. JAMA., 1996; 275:383–389.
18.
van EedenSF, KlutME, LealMA, AlexanderJ, ZonisZ, and SkippenP: Partial liquid ventilation with perfluorocarbon in acute lung injury: light and transmission electron microscopy studies. Am J Respir Cell Mol Biol., 2000; 22:441–450.
19.
DicksonEW, DoernGV, TrevinoL, MazzoniM, and HeardSO: Prevention of descending pneumonia in rats with perflubron-delivered tobramycin. Acad Emerg Med., 2003; 10:1019–1023.
20.
MatsudaK, SawadaS, BartlettRH, and HirschlRB: Effect of ventilatory variables on gas exchange and hemodynamics during total liquid ventilation in a rat model. Crit Care Med., 2003; 31:2034–2040.
21.
PohlmannJR, BrantDO, DaulMA, ReomaJL, KimAC, OsterholzerKR, JohnsonKJ, BartlettRH, CookKE, and HirschlRB: Total liquid ventilation provides superior respiratory support to conventional mechanical ventilation in a large animal model of severe respiratory failure. ASAIO J., 2011; 57:1–8.
22.
RicardJD, IserinF, DreyfussD, and SaumonG: Perflubron dosing affects ventilator-induced lung injury in rats with previous lung injury. Crit Care Med., 2007; 35:561–567.
23.
HirschlRB, CroceM, GoreD, WiedemannH, DavisK, ZwischenbergerJ, and BartlettRH: Prospective, randomized, controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome. Am J Respir Crit Care Med., 2002; 165:781–787.
24.
KacmarekRM, WiedemannHP, LavinPT, WedelMK, TutuncuAS, and SlutskyAS: Partial liquid ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med., 2006; 173:882–889.
25.
LeachCL, GreenspanJS, RubensteinSD, ShafferTH, WolfsonMR, JacksonJC, DeLemosR, and FuhrmanBP: Partial liquid ventilation with perflubron in premature infants with severe respiratory distress syndrome. The LiquiVent Study Group. N Engl J Med., 1996; 335:761–767.
26.
CoxCA, CullenAB, WolfsonMR, and ShafferTH: Intratracheal administration of perfluorochemical-gentamicin suspension: a comparison to intravenous administration in normal and injured lungs. Pediatr Pulmonol., 2001; 32:142–151.
27.
DicksonEW, HeardSO, TararaTE, WeersJG, BrueggemannAB, and DoernGV: Liquid ventilation with perflubron in the treatment of rats with pneumococcal pneumonia. Crit Care Med., 2002; 30:393–395.
28.
SmithDJ, GamboneLM, TararaT, MeaysDR, DellamaryLA, WoodsCM, and WeersJ: Liquid dose pulmonary instillation of gentamicin pulmospheres formulations: tissue distribution and pharmacokinetics in rabbits. Pharm Res., 2001; 18:1556–1561.
29.
AlbersGM, TomkiewiczRP, MayMK, RamirezOE, and RubinBK: Ring distraction technique for measuring surface tension of sputum: relationship to sputum clearability. J Appl Physiol., 1996; 81:2690–2695.
30.
TrediciS, TrediciF, BrantDO, HirschlRB, and BullJL: Effect of viscosity on instilled perfluorocarbon distribution in rabbit lungs. J Biomech Eng., 2006; 128:857–861.
31.
FabiilliML, LeeJA, KripfgansOD, CarsonPL, and FowlkesJB: Delivery of water-soluble drugs using acoustically triggered perfluorocarbon double emulsions. Pharm Res., 2010; 27:2753–2765.
32.
HirayamaY, HirasawaH, OdaS, ShigaH, MatsudaK, UenoH, and NakamuraM: Partial liquid ventilation with FC-77 suppresses the release of lipid mediators in rat acute lung injury model. Crit Care Med., 2004; 32:2085–2089.
33.
JengMJ, KouYR, SheuCC, and HwangB: Effects of partial liquid ventilation with FC-77 on acute lung injury in newborn piglets. Pediatr Pulmonol., 2002; 33:12–21.
34.
MerzU, KlosterhalfenB, HauslerM, KellinghausM, PeschgensT, and HornchenH: Partial liquid ventilation reduces release of leukotriene B4 and interleukin-6 in bronchoalveolar lavage in surfactant-depleted newborn pigs. Pediatr Res., 2002; 51:183–189.
35.
KripfgansOD, FowlkesJB, MillerDL, EldevikOP, and CarsonPL: Acoustic droplet vaporization for therapeutic and diagnostic applications. Ultrasound Med Biol., 2000; 26:1177–1189.
36.
MoskowitzSM, FosterJM, EmersonJ, and BurnsJL: Clinically feasible biofilm susceptibility assay for isolates of Pseudomonas aeruginosa from patients with cystic fibrosis. J Clin Microbiol., 2004; 42:1915–1922.
37.
OmriA, BeaulacC, BouhajibM, MontplaisirS, SharkawiM, and LagaceJ: Pulmonary retention of free and liposome-encapsulated tobramycin after intratracheal administration in uninfected rats and rats infected with Pseudomonas aeruginosa. Antimicrob Agents Chemother., 1994; 38:1090–1095.
38.
HinoT, KawashimaY, and ShimabayashiS: Basic study for stabilization of w/o/w emulsion and its application to transcatheter arterial embolization therapy. Adv Drug Deliv Rev., 2000; 45:27–45.
39.
MoriartyJA, and GrotbergJB: Flow-induced instabilities of a mucus-serous bilayer. J Fluid Mech., 1999; 397:1–22.
40.
RubinBK: Mucolytics, expectorants, and mucokinetic medications. Respir Care., 2007; 52:859–865.
41.
TreggiariMM, RosenfeldM, Mayer-HamblettN, Retsch-BogartG, GibsonRL, WilliamsJ, EmersonJ, KronmalRA, and RamseyBW: Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study. Contemp Clin Trials., 2009; 30:256–268.
42.
Clausell-TormosJ, LieberD, BaretJC, El-HarrakA, MillerOJ, FrenzL, BlouwolffJ, HumphryKJ, KosterS, DuanH, HoltzeC, WeitzDA, GriffithsAD, and MertenCA: Droplet-based microfluidic platforms for the encapsulation and screening of mammalian cells and multicellular organisms. Chem Biol., 2008; 15:427–437.
