Ventilator-associated pneumonia (VAP) is one of the most dreaded nosocomial infection. VAP appears to have a low attributable mortality although episodes caused by multi-drug resistant (MDR) pathogens is associated with a significant attributable mortality [
1,
2]. Potential MDR pathogens include:
P. aeruginosa,
Acinetobacter spp, extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae,
Klebsiella-producing carbapanamase strains,
Stenotrophomonas maltophilia, and methicillin-resistant
S. aureus (MRSA).
In critically ill patients, the susceptibility of the bacteria isolated in a VAP depends on the duration of stay in the ICU and on mechanical ventilation as well as the previous use of antibiotics [
3]. VAP has been conventionally classified into early and late onset. Early-onset VAP occurs within less than 96 hours of ICU admission and is generally due to antimicrobial-sensitive bacteria. Late-onset VAP occurs after 96 hours of ICU admission and may be caused by MDR pathogens. Other risk factors of MDR pathogens include prior antibiotic use within the preceding 90 days, frequency of antibiotic resistance in the community or hospital, and the immunocompromised state [
4]. However, different studies have described a high rate of VAP due to MDR pathogens in episodes occurring in the first days of mechanical ventilation highlighting the importance of local ecology [
5‐
7].
Diagnosing of VAP is difficult because it requires a thorough assessment of clinical data, radiological findings, and microbiological results. There are no foolproof tools to determine whether the patient has a VAP. When the clinical suspicion of VAP is high, empirical antimicrobial therapy must be initiated promptly because both delayed and inadequate treatments have been associated with increased rate of morbidity and mortality [
4]. Nevertheless, one third of the patients with VAP only exhibit clinical criteria of sepsis [
8]. In patients with no signs of severe sepsis or septic shock and no organisms present on Gram’s staining, antimicrobial therapy can be withheld pending culture results [
9,
10].
Current guidelines recommend empirical coverage of Gram-negative bacilli (GNB) with a third or forth generation cephalosporin, piperacillin-tazobactam or a carbapenem in combination with a fluoroquinolone or an aminoglycoside [
11]. However, the problem arises when a high proportion of the GNB are resistant to these antibiotics. One of the consequences of a greater prevalence of antimicrobial resistance is an increased recognition of inadequate antimicrobial treatment of infection. Few alternatives are available for treatment of these multi-drug resistant GNB.
Antibiotics for resistant Gram-positive cocci
Empirical coverage of MRSA is less troublesome. Vancomycin has been considered the treatment of choice for pneumonia due to MRSA [
4]. Almost all MRSA isolates are susceptible to vancomycin and only anecdotal cases of MRSA resistant to this glycopeptide have been reported. However, an interesting issue to keep in mind is the MIC of MRSA to vancomycin. Several studies in patients with MRSA pneumonia or bacteremia (mainly from lung source) have observed a higher rate of treatment failure and mortality in episodes with MIC ≥ 1.5 mg/L treated with vancomycin [
50,
51]. Lung infection has been identified as an independent predictor of treatment failure in MRSA bacteremia treated with vancomycin and not explained by MIC [
52], perhaps reflecting the poor penetration of this antibiotic into the lung tissue [
53].
Current guidelines recommend a loading dose of 25-30 mg/kg followed by vancomycin dosages of 15-20 mg/kg given every 8-12 hours for patients with normal renal function [
54]. Monitoring of trough concentrations is necessary after the forth dose to maintain serum trough concentrations of 15-20 mg/L increase efficacy and improve clinical outcomes. An AUC to MIC ratio ≥400 has been shown to predict more favorable microbiological and clinical outcomes in cases of
S. aureus pneumonia [
55].
Teicoplanin might be an acceptable alternative to treat pneumonia caused by MRSA. However, the administration of high teicoplanin doses (12 mg/kg teicoplanin every 12 h the first 2 days followed by 12 mg/kg once daily) is needed to reach sufficient antibiotic concentrations in lung tissues at steady state [
56]. We do not recommend teicoplanin for VAP due to the uncertainties about the correct doses, impossibility of level measurements, and the availability of alternatives such as vancomycin or linezolid.
Linezolid has been shown to have a better pharmacokinetic profile than vancomycin [
57]. The
post hoc analysis of two randomized, double-blind studies concluded that linezolid therapy was associated with significantly better clinical cure and survival rates than therapy with vancomycin in the subgroup of patients with MRSA VAP [
58]. In a recent double-blind, controlled trial, linezolid, compared with vancomycin, achieved a higher clinical and microbiological response rate (the latter was not statistically significant) despite vancomycin dose optimization, together with a lower incidence of all types of renal adverse effects in patients with MRSA pneumonia. However, mortality was unaffected [
59]. Limitations of this study include imbalanced distribution of medical comorbidities and the number of patients excluded to reach the per-protocol group.
Although tigecycline is active against MRSA, clinical cure of cases of MRSA was lower with tigecycline than with the comparator in the clinical trial that evaluated this antibiotic in hospital-acquired pneumonia [
42]. Therefore, we do not advocate the use of tigecycline for MRSA pneumonia and a specific antibiotic against this Gram-positive bacterium is necessary.
Ceftaroline is a cephalosporin with broad gram-positive activity, including MRSA. Its gram-negative activity includes common respiratory pathogens and members of the Enterobacteriaceae. However, ceftaroline is currently only approved for acute bacterial skin infections and community-acquired pneumonia. This new cephalosporin has a promising role in the treatment of VAP but clinical data are not currently available. It should be used in combination with another antimicrobial to cover GNB such as P aeruginosa or ESBL-producing Enterobacteriaceae.
Nebulized antibiotics
The administration of nebulized antibiotics has been proposed to provide high levels of the drug in the lung and to reduce the systemic toxicity associated with intravenous antibiotics. The concentration in the respiratory secretion of the nebulized antibiotic may be 20 to 100 fold greater than the
in-vitro MIC of the organisms being treated [
60]. Large randomized trials are needed to define the impact on clinical outcomes of nebulized antibiotics as adjunctive therapy in MDR-VAP.
Although diverse antibiotics have been nebulized, the most extensive experience exists with aminoglycosides and colistin. The use of appropriate devices is essential to assure clinical and microbiological utility of nebulized antibiotics. During mechanical ventilation, high amounts of the particles dispersed by conventional nebulizers remain in the ventilatory circuits and the tracheobronchial tree and, therefore, less drug is available in the alveolar compartment.
The use of aerosolized colistin for multi-drug resistant GNB pneumonia increases cure rates and may be reasonably efficacious and safe [
61]. The use of inhaled colistin was independently associated with clinical cure in a retrospective study (OR 2.53, 95% CI 1.11-5.76) although mortality was unaffected. Nevertheless, other studies have concluded that the use of aerosolized colistin in conjunction with intravenous colistin did not provide additional therapeutic benefit to patients with MDR VAP due to gram-negative bacteria [
62]. Moreover, a randomized controlled trial of nebulized CMS as adjunctive therapy of ventilator-associated pneumonia caused by GNB failed to demonstrate beneficial effect on clinical outcome [
63]. Regarding aminoglycosides, several studies have evaluated tobramycin or amikacin with promising results [
64,
65].
Duration of treatment
There is no consensus regarding the duration of antibiotic treatment for patients with VAP due to MDR. In a randomized clinical trial that included patients with VAP and adequate empirical antimicrobial therapy, short-course (8 days) treatment of VAP has no difference in terms of mortality compared to long-course (15 days) treatment. In VAP caused by non-fermenting gram-negative bacilli including
P aeruginosa, rate of recurrence was significantly higher (40.6%
vs 25.4%) in patients receiving 8 days of treatment [
66]. A recent meta-analysis of four RCTs also concluded that a short-course of antibiotic may be enough to treat VAP although the issue of length of therapy in MDR VAP has not been specifically evaluated [
67]. A prospective study showed that a procalcitonin-based strategy (recommending that physicians stop antibiotics when the procalcitonin concentration was <0.5 ng/mL, or had decreased by ≥80%) did not negatively influence outcomes although the subgroup of patients with MDR-VAP was not specifically assessed [
68].