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Pneumonia acquired during treatment of respiratory failure,
especially in patients with acute lung injury, remains a vexing problem, because of the frequent difficulty in diagnosing infection and the high rate of treatment failure, commonly up to
40% (1). Two factors contribute to therapeutic problems:
the severity of the underlying lung disease, and the high prevalence of organisms that are difficult to treat and resistant to
multiple antibiotics
especially aerobic gram-negative bacilli
(Pseudomonas and Acinetobacter spp.) and staphylococci
resulting in both inadequate empiric therapy and the emergence of further resistance during therapy (2). The best current option is to optimize the pharmacokinetics of available
antibiotics. Use of loading doses and avoiding underdosing, with appropriate dosing intervals, especially for aminoglycosides and fluoroquinolones, will result in greater antimicrobial
activity and fewer treatment failures, as shown by several studies from Schentag's group (4, 5). Some commonly used drugs,
however, such as aminoglycosides and vancomycin, both mainstays in treating nosocomial pneumonia, penetrate poorly in
respiratory secretions and epithelial lining fluid (6), and often
achieve antibiotic levels hardly above the minimum inhibitory
concentration (MIC) of offending organisms. Delivering antibiotics by aerosol is one possible answer to this problem, an
approach that has been successfully used in cystic fibrosis. Unfortunately, aerosols distribute poorly in the lower respiratory
tract of mechanically ventilated patients, resulting in erratic
distribution of drugs.
To achieve the target of delivering antibiotics in adequate amounts where they are required, Franz and coworkers (pp. 1595-1600) (7) have developed a new approach: they used a perfluorocarbon (perfluorodecaline) emulsion of gentamicin and vancomycin during partial liquid ventilation (PLV). In rabbits with and without acute lung injury induced by surfactant depletion, the authors compared intravenous with intrapulmonary administration of antibiotics, and found that perfluorocarbon emulsions achieved lung tissue levels of antibiotics that were 15 to 20 times higher in animals with normal lungs and 4 to 6 times higher in surfactant-depleted animals. In animals with normal lungs, the serum pharmacokinetics of both drugs were similar to the pattern seen after intrapulmonary administration, that is, a lower and delayed peak concentration, and a longer elimination half-life. In animals with acute lung injury, however, the two drugs behaved differently, probably because of their different molecular weights. With gentamicin, the serum pharmacokinetics were similar with both intravenous and intrapulmonary administration, suggesting that the alveolar- epithelial barrier was permeable to the drug. The serum pharmacokinetic profile with vancomycin was similar to that recorded in animals with normal lung, suggesting the high molecular weight of this compound impedes diffusion across the alveolar- epithelial barrier, even in animals with acute lung injury.
Intrapulmonary and intravenous administration achieved, at 5 h, median levels of gentamicin in lung tissue of 14 and 0.6 µg/g, respectively, in animals without lung disease, and 6.5 and 0.9 µg/g, respectively, in surfactant-depleted animals. Intrapulmonary administration achieved lung tissue levels of antibiotics well above the MIC of offending organisms and these levels were maintained for several hours. However, obtaining an optimal bactericidal effect from aminoglycosides is more dependent on a high peak concentration than on sustained levels. In the presence of lung injury, where diffusion of intravenously administered drugs is enhanced, it is not clear that intrapulmonary administration of aminoglycosides would result in higher bactericidal activity in lung tissue. Further studies are needed, in a model of pneumonia in animals with lung injury, to document the superior efficacy of intrapulmonary administration of perfluorocarbon-aminoglycoside emulsions.
Glycopeptides such as vancomycin (as well as 
-lactams)
have essentially a time-dependent effect, and sustaining high
levels at the site of infection is important. This goal was
achieved much better with intrapulmonary than with intravenous administration. Tissue and serum pharmacokinetics of
vancomycin were little influenced by the presence of lung injury. Although lung tissue levels at 5 h after administration
were about three times lower in surfactant-depleted than in
normal animals, a median level of 30.5 µg/g remains well above the MIC of target organisms. Conversely, a level of 6.9 µg/g, as achieved after intravenous administration, is in the range of MICs of emerging Staphylococcus aureus strains
demonstrating intermediate susceptibility to glycopeptides, a
situation prone to development of further resistance (8).
Franz and coworkers (7) have explored an innovative approach for delivering antibiotics to the injured lung. This approach may be especially useful for some drugs with high molecular weight and time-dependent efficacy such as glycopeptides. On the basis of histology findings, the perfluorocarbon-antibiotic emulsions produced no major side effects (7). This was, however, a brief experiment (5 h) involving a single administration; repeated administration of perfluorocarbon- antibiotic emulsions needs to be investigated to determine whether toxic levels are achieved through accumulation of drugs. The next step is to study the effect of perfluorocarbon- antibiotic emulsions in an experimental lung model of superinfection during acute lung injury.
A unique feature of perfluorocarbon is the predominance of its distribution to dependent areas of the lung and its even distribution (including in collapsed areas), because of its density and surface tension properties. This is of major potential relevance for treating pulmonary infection during mechanical ventilation, because lung infection and lung injury, although of heterogeneous and patchy distribution, predominate in the dependent areas. At the dose used by Franz and coworkers (7) (12 ml of perflubrodecaline per kg), concentrations in lung tissue were similar in dependent and nondependent lung areas (7). With relatively high doses of perfluorocarbon emulsions, as used by Franz and coworkers, adequate antibiotic levels should indeed be achieved both in areas of consolidation and relatively preserved areas throughout the lung. Experiments looking at antibiotic distribution in infected and noninfected lung, using various doses of perfluorocarbon, should be pursued.
There is, however, much work to be done before perfluorocarbon-antibiotic emulsions can be used clinically. Because this is a cointervention of partial liquid ventilation, safety of the latter must first be established. Preliminary data from a large, randomized multicenter trial in patients cast doubt on the safety of partial liquid ventilation at the dose tested, partly because of a higher incidence of barotrauma (Tütünaï AS and Lemaire F, personal communication). It is possible that lower doses of partial liquid ventilation could achieve satisfactory gas exchange, without increased hazards (9). Whether low doses of perfluorocarbon emulsions can achieve high concentrations of antibiotics throughout lung tissue remains to be investigated. An alternative and novel approach, described in the Journal by Kandler and coworkers (10), would be to use aerosolization of perfluorocarbon emulsions, which may allow the target to be reached safely and in a simpler way.
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  M. J. TOBIN Critical Care Medicine in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 565 - 583. [Full Text] [PDF]
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