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Intensive Care Physician,
Pulmonary Care Specialist
Institut Clínic de Pneumologia i Cirurgia Toràcica
Hospital Clínic de Barcelona, Spain
Ventilator-associated pneumonia (VAP) is defined as a nosocomial pneumonia occurring >48 hours after endotracheal intubation and the beginning of mechanical ventilation. It can be further differentiated into early-onset (EOP; less than five days after tracheal intubation) and late-onset (more than five days) pneumonia.(1) EOP often results from aspiration before or within the intubation process, mainly in trauma and surgical patients with a decreased level of consciousness.
In contrast to other nosocomial infections, for which mortality is low (1–4%), the mortality rate for VAP is 24–50% and can reach 76% in certain settings or when lung infection is caused by high-risk microorganisms.(2) Therefore, the prevention of VAP is a very important issue in current clinical practice in critical care medicine. Within the preventive measures of VAP, the pharmacological strategies have focused on the prevention of oropharyngeal or gastric colonisation and the prevention of aspiration of contaminated oropharyngeal or gastric secretions (selective digestive decontamination and antibiotic prophylaxis in a short-term course). Another contentious issue is the relationship between stress-ulcer prophylaxis and respiratory infections in mechanically ventilated patients. Despite abundant literature on recent strategies to prevent nosocomial pneumonia, a number of these preventive measures are still controversial.
This article aims to review current opinions regarding pharmacological prophylaxis strategies of VAP.
The main mechanism in the pathogenesis of VAP is aspiration of oropharyngeal secretions that are colonised by pathogenic endogenous or exogenous flora. The occurrence of VAP implies microaspirations and the invasion of the lower respiratory tract by bacteria that previously colonised the upper airway.(3) In one study, in patients with head injury, the authors concluded that colonisation of the upper airway by Staphylococcus aureus, Haemophilus influenzae or Streptococcus pneumoniae was found to occur very early in the evolution of the illness. In addition, the upper airway represented the main reservoir for subsequent lower airway colonisation.(4) This study also showed that previous antibiotic prophylaxis (short-term) was effective against initial tracheobronchial colonisation but represented a risk factor for subsequent lower airway colonisation by Gram-negative enteric bacilli and Pseudomonas species.
The stomach is a reservoir of nosocomial pathogens with the potential to colonise the upper respiratory tract. When the gastric pH increases from the normal levels to pH >4, microorganisms are able to multiply to high concentrations in the stomach. The gastropulmonary route of infection has therefore been proposed as an important aetiopathogenic factor.(5)
Risk factors and pharmacological prevention
Some of the risk factors for ventilator-associated pneumonia in mechanically ventilated patients have been identified as follows:(2)
A prospective cohort study assessed the risk factors for nosocomial pneumonia.(6) The risk factors for nosocomial pneumonia determined by multivariate analysis were continuous enteral feeding, more than 24 hours of mechanical ventilation, craniotomy, use of positive end-expiratory pressure and corticosteroid therapy. Mortality in the patients with nosocomial pneumonia was significantly higher (43.5%) than mortality in the trauma patients who did not develop nosocomial pneumonia (18.8%).
Sirvent et al studied initial tracheal colonisation in head trauma patients and observed, using a multivariate analysis, that the isolation of S aureus, H influenzae or S pneumoniae in tracheal aspirates on admission was an independent risk factor associated with the development of early-onset ventilator-associated pneumonia [odds ratio (OR): 8.9; 95% confidence interval (95% CI): 1.59-52.5].(7)
Selective digestive decontamination
Selective digestive decontamination (SDD) involves the administration of topical nonabsorbable antibiotics and a systemic antibiotic, for example cefotaxime or ofloxacin, to prevent colonisation and infection in ICU patients. The topical application of the nonabsorbable antibiotics (polymyxin E, tobramycin and amphotericin B) in the oropharynx and the gastrointestinal tract is targeted at nosocomial Gram-negative bacilli, some Gram-positive bacteria and yeast. The systemic antibiotic is used to prevent early-onset pneumonia, and antibiotic administration is continued for three or four days.
Despite several prospective randomised trials and multiple meta-analyses, routine use of SDD is still controversial. In most studies, SDD resulted in significant reductions in respiratory infection rates. However, its efficacy on mortality and length of stay is currently debated. The principal concern regarding SDD use is about the possibility that it increases colonisation and infection with Gram-positive organisms and multidrug-resistant pathogens, mainly in patients in whom SDD has been used for extended periods of time.
SDD regimens using a systemic antibiotic appear to be more effective than those that use only topical ones. This suggests that SDD constitutes early treatment rather than prophylaxis for early-onset pneumonia. In a prospective, randomised, double-blind and placebo-controlled study,(8) topical prophylaxis eradicated colonisation present on admission and prevented acquired oropharyngeal colonisation. Incidences of VAP were 10% in study patients, 31% in the control group and 23% in the other control group (p=0.04). Sanchez-García et al showed that SDD was associated with a significant reduction of morbidity at a reduced cost.(9) These findings support the use of SDD in high-risk patients.
Otherwise, Ferrer et al showed that selective digestive decontamination in mechanically ventilated patients significantly decreased the colonisation rate of Gram-negative bacilli and of Candida species but not of S aureus.(10) It did not decrease the incidence of nosocomial pneumonia, mortality, length of stay or the duration of mechanical ventilation. A recent meta-analysis states that antibiotic prophylaxis with a combination of topical and systemic drugs can reduce respiratory tract infections (OR: 0.35; 95% CI: 0.29–0.41) and overall mortality (OR: 0.8; 95% CI: 0.69–0.93) in critically ill patients.(11) This study shows that the only strategies that had a beneficial effect on survival were those that included systemic antibiotics. In addition, Nathens and Marshall, in a meta-analysis of SDD studies and subgroups of critically ill patients, conclude that SDD notably reduces mortality in critically ill surgical and trauma patients, while critically ill medical patients derive no such benefit (see Figure 1).(12)
Lingnau et al and Verwaest et al demonstrated increased bacterial resistance rates in patients treated with SDD.(13,14) Furthermore, the administration of antibiotics before the onset of pneumonia increases the frequency of late-onset VAP caused by more virulent microorganisms such as Pseudomonas aeruginosa, resulting in higher mortality rates.(15) However, a recently published prospective, randomised, controlled unblended trial showed that the mortality and the colonisation rates with resistant bacteria were lower in the SDD group.(16)
In conclusion, we believe that, until the benefits of selective digestive decontamination have been firmly established, the routine use of this strategy for all intubated patients to prevent ventilator-associated pneumonia is not recommended.
Antibiotic prophylaxis in structural coma
As mentioned earlier, head trauma patients are at increased risk of VAP. Therefore, antibiotic prophylaxis could be effective in these patients. A trial published by Sirvent et al(17) evaluated the effect on the VAP incidence of the use of systemic prophylaxis with cefuroxime before intubation. They studied 100 patients, 50 of whom received one dose of 1.5g of cefuroxime intravenously at the moment of intubation and a second dose 12 hours later. The global incidence of VAP was 37% (n=37): 12 (24%) in the cefuroxime group and 25 (50%) in the control group (p=0.007). They did not observe differences regarding the incidence of enteric Gram-negative bacilli pneumonia between groups. There was no increase in bacterial resistance rates during or after the trial period. It demonstrated that the administration of two doses of intravenous cefuroxime after intubation was an effective prophylactic strategy against VAP in patients with structural coma.
Stress ulcer prophylaxis and VAP
The critically ill patients are at increased risk of GI bleeding from stress ulcers. Respiratory failure and coagulopathy are the strongest risk factors for clinically important gastrointestinal bleeding.(18) The agents used are sucralfate, antacids, H(2)-antagonists and proton pump inhibitors. In theory, patients receiving stress ulcer prophylaxis that does not change gastric acidity should have lower rates of gastric bacterial colonisation and nosocomial pneumonia.
In a 1991 meta-analysis, Tryba found that antacids and H(2)-antagonists were significantly superior to untreated patients in preventing stress bleeding.(19) Sucralfate was superior to H(2)-antagonists. Patients treated with antacids or H(2)-antagonists showed a significantly higher risk for the development of nosocomial pneumonia. Later, Cook et al demonstrated the trend toward reduced clinically important bleeding with H(2)-antagonists and antacids compared with sucralfate.(20) There was a trend towards an increased risk of pneumonia associated with H(2)-antagonists, as compared with no prophylaxis, and a significantly higher risk as compared with sucralfate. Finally, the last meta- analysis(21) concluded that ranitidine is ineffective in the prevention of gastrointestinal bleeding and might increase the risk of pneumonia. Studies on sucralfate do not provide conclusive results. Currently, there are insufficient data to be able to conclude anything one way or the other.
VAP is a severe pathology with high mortality rates. Therefore, it is vital to implement preventive strategies to decrease its incidence. Antimicrobial-based preventive strategies are used to diminish aerodigestive tract colonisation. SDD has been demonstrated to decrease respiratory infection rates in high-risk patients, but its effect on mortality rates is controversial. The routine clinical use of SDD cannot be recommended at the present time.
Equally, the consequences of stress ulcer prophylaxis on VAP development are not clear, but there is a trend towards higher VAP rates in H2-antagonist- treated patients. On the other hand, there is evidence to suggest that short-term antibiotic prophylaxis is an effective strategy to prevent VAP in patients with structural coma.