Linezolid might be preferred in patients at risk of or with renal insufficiency in whom
vancomycin is often associated with a risk of nephrotoxicity and thus underdosed. In
particular, it is preferred in hospitals in which a substantial proportion of MRSA isolates show
a vancomycin MIC 1 mg/mL.
Further agents presently under investigation include tigecycline, a new glycylcycline
antimicrobial derived from tetracyclines. Tigecycline has an extremely broad spectrum of
action against gram-positive, gram-negative, and anaerobic pathogens, with the exception of
Pseudomonas(277). Its role in VAP is currently being re-evaluated in a new phase III clinical
trial. Still, the need for mechanical ventilation has been associated with lower microbiologic
clearance (278), and cancer patients with refractory pneumonia seem to show a relatively low
clinical response rate when treated with this drug (51%) (279).
Daptomycin cannot be used to treat pneumonia because it gets inactivated by lung
surfactant in the respiratory tract. Investigational glycopeptides, such as telavancin and
oritavancin, may eventually play a role in the treatment of nosocomial pneumonia, but a
definite date cannot be stated at present.
An anti-MRSA cephalosporin, ceftobiprole, is being evaluated for effectiveness against
nosocomial pneumonia in a phase III clinical trial. Pneumonia due toP. aeruginosain ventilated
patients is frequently a recurrent disease, caused most of the time by several relapsing
infections (280). Frequently, the pathogens are MDR, such that no single antibiotic is active
against all isolates. Empirical therapy includes the combination of two drugs active against
P. aeruginosato improve the chances of successful early treatment. Once the susceptibility
pattern is known, many physicians prefer combination therapy with a beta-lactam agent plus
either an aminoglycoside or an anti-Pseudomonasfluoroquinolone, based on early findings in
patients with bloodstream infections (281).
Despite combination therapy targeted at gram-negative microorganisms being common
clinical practice, there is presently no evidence to suggest that combination therapy has any benefit
over monotherapy in patients with VAP or other forms of nosocomial pneumonia (282–284).
In select patients with infections caused by MDR strains, aerosolized colistin has proved
beneficial as supplemental therapy (285).
The non-fermenting gram-negative rod,A. baumannii,has been held responsible for the
recent rise in VAP. This bacterium is intrinsically resistant to many antimicrobial agents, and
the agents found to be most active against it are carbapenems, sulbactam, and polymyxins
(56,58). In effect, intravenous carbapenem is the treatment of choice today for MDR isolates of
A. baumannii(286). In patients with strains resistant to carbapenems, intravenous colistin has
been successfully used (59).
Adequate Dosing
To ensure the best outcome, it is essential that the dosing of initial antibiotics for suspected
MDR pathogens is adequate (274). All too often, agents are initially underdosed. For example,
vancomycin should not be routinely given at a dose of 1 g q12h, but rather the dose should be
calculated by weight in mg/kg (a dose that needs adjusting for renal impairment).
Retrospective pharmacokinetic modeling has suggested that the failures described for
vancomycin could be the result of inadequate dosing. Many physicians aim for a trough
vancomycin concentration of at least 15 to 20 mg/L, although, as mentioned in the previous
section, the success of this strategy has not been prospectively confirmed. Only one matched
cohort study exists in which continuous vancomycin infusion was associated with reduced
mortality (287).
Some antibiotics penetrate well and achieve high local concentrations in the lungs, while
others do not. For example, most beta-lactam antibiotics achieve less than 50% of their serum
concentration in the lungs, while fluoroquinolones and linezolid attain equivalent or higher
concentrations than blood levels in bronchial secretions. Table 7 shows how to adjust the
antibiotic dose in patients with renal impairment.
Aerosolized Antibiotics
All patients with VAP should initially receive antibiotics intravenously, but conversion to
oral/enteral therapy may be possible in certain responding patients. The direct aerosol
Nosocomial Pneumonia in Critical Care 193