Ventilator-associated pneumonia is common in patients in intensive care units. As treatment usually cannot wait until the causative organism has been identified, empirical antibacterial therapy should be initiated based on risk factors for virulent and/or resistant microorganisms.

Ventilated patients at high risk

Ventilator-associated pneumonia (VAP) is defined as pneumonia occurring in patients with acute respiratory failure supported by invasive mechanical ventilation and which was absent at the time of endotracheal intubation.[1] VAP affects ≈10–20% of ventilated patients and is associated with high costs and increased morbidity and mortality in patients in the intensive care unit (ICU). This article summarizes the review by Vincent et al.[1] on the treatment and prevention of VAP.

Pneumonia in critically ill patients results from aspiration of nasal, oropharyngeal or gastric microorganisms and is complicated by impaired host defences, which facilitate colonization of the normally sterile lower respiratory tract and lung tissue.[1] The presence of an endotracheal tube in patients receiving mechanical ventilation helps bypass normal defence mechanisms, such as mucociliary clearance and cough, creates an unnatural passage between the trachea and upper airway, and may act as a source of contaminated secretions.[1]

Causative organism depends on time of onset and resistance patterns

The causative organism in VAP is influenced by a number of factors, including the duration of mechanical ventilation, length of ICU and hospital stay, presence of co-morbidities, prior antibacterial therapy and geographical location.[1] Despite these variables, generalizations can be made about common probable pathogenic organisms depending on the presence or absence of risk factors (table I). The most commonly isolated causative microorganisms causing VAP are Gram-negative enteric bacilli, Staphylococcus aureus and Pseudomonas aeruginosa.[1] Viral and fungal pathogens may also cause VAP, but are relatively uncommon in immunocompetent patients.[2,3]

Table I
figure Tab1

Common causative organisms of ventilator-associated pneumonia (VAP)[2]

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The presence of antibacterial resistance complicates treatment and is associated with increased mortality.[1] As resistance patterns of pathogens differ with early- and late-onset VAP, the time of occurrence should be considered when selecting empirical drug therapy for VAP.[4] ‘Community’ organisms tend to be the cause of early-onset VAP, whereas late-onset VAP is more likely to be caused by more virulent pathogens (table I).

Initiate empirical therapy until causative organism identified

Treatment of VAP centres principally on antibacterial therapy and should be started as early as possible.[1] As inappropriate or delayed therapy is associated with poorer outcomes, local infection and susceptibility patterns should initially be used to guide the choice of empirical antibacterial therapy.[1] However, guidelines for treatment have been developed to aid selection of the most appropriate antibacterial therapy based on the time of onset and other risk factors for multi-drug resistant organisms ( Patient care guidelines ).[2,4] Once bacterial culture and sensitivity information is available, broad-spectrum therapy should be de-escalated to more specific, narrow-spectrum cover.[1]

figure U1

Empirical antibacterial therapy for patients with ventilator-associated pneumonia (VAP) according to risk factors for multi-drug resistant (MDR) organisms, as suggested by Vincent et al.(1)

Single-agent therapy generally preferred

Most data suggest that combination therapy has no benefits over single-agent therapy for VAP and is associated with increased costs and risk of adverse effects.[1] Indeed, a meta-analysis of 41 studies evaluating parenteral antibacterial regimens in adult patients with VAP concluded that the rates of mortality (relative risk [RR] 0.94; 95% CI 0.76, 1.16) and treatment failure (RR 0.88; 95% CI 0.72, 1.07) were similar for monotherapy and combination therapy, although the quality of the studies was generally poor.[5] US and European guidelines generally recommend single-agent therapy in patients with early-onset VAP, but combination therapy in patients at risk of multi-drug resistant pathogens[2,4] ( Patient care guidelines ).

Response determines therapy duration

US guidelines for the management of VAP recommend that the treatment duration be determined by the severity of disease, clinical response and causative organism.[2] For example, a course of 7–14 days is recommended for VAP caused by S. aureus or Haemophilus influenzae, whereas 14–21 days is more appropriate for infection caused by P. aeruginosa.[2] A multivariate analysis concluded that the duration of therapy was not an independent predictor of infection recurrence or death at 28 days.[6]

Dose affected by a number of factors

The efficacy of an antibacterial depends on its mode of action and ability to penetrate lung tissue. A number of factors need to be taken into account when considering drug dosing in ICU patients. These include renal or hepatic dysfunction, haemodilution, hypoalbuminaemia and drug interactions.[1] Patients in the ICU may need higher or more frequent doses than other patient populations; continuous infusions may even be required.[1]

Other possible treatments include aerosolized antibacterials …

Administration of antibacterials via aerosolized formulations may achieve higher concentrations of the drug at the affected site than administration via other routes.[1] Inhaled tobramycin and colistin have been studied in the treatment of VAP, with promising results. A meta-analysis of randomized, controlled trials showed that administration of antibacterials via the respiratory tract (alone or in combination with systemic antibacterials) was associated with greater treatment success than treatment with controls, although there was no effect on mortality rates.[7]

… adjuvant treatment with clarithromycin …

The addition of clarithromycin 1 g/day for 3 days to standard antibacterial therapy in patients with VAP and sepsis was associated with accelerated resolution of VAP and weaning from mechanical ventilation compared with placebo in a randomized, controlled trial.[8] Clarithromycin has anti-inflammatory properties that may be beneficial in patients with VAP.[1]

… and statins

Results of studies assessing the potential effects of HMG-CoA reductase inhibitors (statins) in patients with community-acquired pneumonia have been conflicting; some studies have shown better outcomes in patients who were receiving statins prior to pneumonia onset, whereas other studies have shown no correlation between prior use of statins and pneumonia outcomes.[1] A review of the use of statins in the treatment of sepsis suggested that statins may have beneficial effects on the outcome of infection, but the poor quality of studies did not allow firm conclusions to be drawn.[9] An open-label, randomized trial of the effect of pravastatin 40 mg/day versus control on the incidence and natural course of VAP in patients in the ICU may help resolve this issue, but results have not been made available.[10]

Prevention is an important issue

A number of non-pharmacological strategies have been suggested for the prevention of VAP, including adequate hand hygiene, the use of protective gowns and gloves, semi-recumbent patient positioning, continuous lateral rotation (i.e. kinetic beds), heat and humidification, suctioning of secretions, positive end-expiratory pressure (PEEP) and early tracheotomy.[1] Recent clinical data indicate that reductions in the incidence of VAP were generally shown with semi-recumbent patient positioning,[11] PEEP,[12] suctioning of secretions (although the optimal technique is still a subject of debate)[13,14] and continuous lateral rotation,[15] but that early versus late tracheotomy did not affect VAP rates,[16] and that there are no apparent differences in the effects of heat and moisture exchangers and the more expensive heated humidifiers on the incidence of VAP.[17]

Pharmacological-related strategies to prevent VAP include the following:

  • The use of probiotics (e.g. Lactobacillus). Although some studies have suggested that administration of probiotics can reduce the incidence of VAP,[18,19] results in other studies have been conflicting.[20]

  • The use of aersolized antibacterials. According to a meta-analysis,[21] this strategy reduced the incidence of VAP (odds ratio 0.49; 95% CI 0.32, 0.76), but did not affect mortality rates. There are concerns that the increased use of antibacterials could result in the emergence of resistant bacteria.

  • Treatment of ventilator-associated tracheobronchitis (VAT). The incidence of VAP may be reduced through antibacterial treatment of VAT,[22,23] but further studies are needed, and there are concerns about the possible emergence of resistant bacteria.[24]

  • Reduced sedation. A nurse-implemented sedation protocol significantly reduced the risk of VAP (hazard ratio 0.81; 95% CI 0.62, 0.95) and duration of mechanical ventilation in patients relative to patients managed before the introduction of the protocol, but did not affect mortality rates.[25]

  • Selective digestive or oral decontamination. The use of antibacterials to clear the stomach and oropharynx of potentially pathogenic organisms to reduce the pathogenicity of aspirated contents and, hence, the incidence of VAP, is controversial.[1] Oral decontamination alone has been promoted as being preferable to selective digestive decontamination, as fewer antibacterials are required. A number of randomized, controlled trials have investigated the effect of oral decontamination with various antiseptics (e.g. 0.12–2% chlorhexidine solution or gel used as a rinse or applied once to four times daily,[26–31] iseganan [an antibacterial peptide] solution applied six times daily[32] and 10% povidone-iodine solution used as a rinse every 4 hours followed by aspiration of oropharyngeal secretions[33] ). In most trials, oral decontamination did not have a significant effect on the incidence of VAP,[26–30,32] with the exception of significant (p ≤ 0.03) reduction in the risk of VAP with 2% chlorhexidine solution both with or without 2% colistin versus placebo,[31] as well as when the results of this trial were pooled with those of a trial of 2% chlorhexidine solution versus saline solution[30] (RR 0.53; 95% CI 0.31, 0.90),[30] and a significant (p ≤ 0.03) decrease in incidence of VAP with 10% povidone-iodine solution rinse versus saline or control rinse (8% vs 39% vs 42%).[33] The heterogeneous nature of these trials make it difficult to draw conclusions on the effectiveness of this treatment.[1] In a meta-analysis of seven trials, oral decontamination with antiseptics was associated with a reduced incidence of VAP (RR 0.56; 95% CI 0.39, 0.81), although no effect on the duration of mechanical ventilation or mortality was seen.[34]

‘Bundles’ might be the key

Preventative care ‘bundles’ (i.e. careful implementation of multiple VAP preventive strategies) have been shown to be beneficial in a number of studies.[1] While not all studies have shown bundles to reduce the rate of VAP and none have shown an impact on outcomes, an approach to the prevention of VAP that contains a combination of factors is likely to be the future standard of care.[1]

Disclosure

This review was adapted from Drugs 2010; 70 (15): 1927-44[1] by Adis editors and medical writers. The preparation of these articles were not supported by any external funding.