By William H. Thompson, MD
Associate Professor of Medicine, University of Washington, Seattle
Dr. Thompson reports no financial relationships relevant to this field of study.
Ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) account for approximately 22% of all hospital-acquired infections.1 While the National Healthcare Safety Network reports declining rates of VAP, others cite a rate of approximately 10% of all ventilated patients with no declining trend.2-4 Because VAP and HAP can significantly increase mortality rates, prolong ventilation duration, lead to longer hospital stays, create more serious complications, and increase the cost of care, all efforts leading to prevention and better treatment of VAP and HAP can improve outcomes in ICUs.5-7
When discussing VAP prevention, it is important to acknowledge that the literature revolves around a set of definitions that differ from the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) definitions of VAP. These definitions, introduced by the CDC, emphasize the need for standardization of metrics used to assess the quality of care for ventilated patients.8,9 As such, the CDC definitions are better tools for surveillance, quality improvement, and benchmarking quality of care rather clinical criteria for VAP diagnosis and treatment. The CDC definitions for ventilator-associated events (VAEs), as outlined by Klompas et al, include:
- Ventilator-associated conditions (VAC): Two or more days of stable or declining minimum positive end-expiratory pressure (PEEP) or minimum FiO2, followed by a rising minimum PEEP (by 3 cm H2O) or FiO2 (by 0.2 points) for two or more days;
- Infection-related ventilator-associated complication (IVAC): Presence of possible infection indicators concurrent with VAC onset (temperature < 36° C or > 38° C or white blood cell count < 4,000 or > 12,000) and initiation of a new antibiotic that is continued for four or more days;
- Possible VAP: An IVAC and Gram stain evidence of purulent sputum or pathogenic pulmonary culture;
- Probable VAP: An IVAC and either: 1) Gram stain evidence of purulent sputum and quantitative or semiquantitative growth of pathogenic organisms or 2) a positive test for respiratory viruses, Legionella species, pleural fluid cultures, or suggestive histopathology with or without abnormal Gram stain results.9
VAC and IVAC were developed for public reporting. However, it remains unclear how preventable VAC and IVAC are and how comparable they are from institution to institution. On the other hand, possible and probable VAP are meant for internal institutional quality improvement purposes and are not suitable for public reporting or benchmark comparisons. The Society for Healthcare Epidemiology of America recommends surveillance for VAE and all of the above definition tiers for all adult patients on the ventilator for four or more days, knowing that much of the data on VAP prevention come from literature using traditional definitions of VAP rather than CDC definitions of VAE.9 Further, VAC may be a surveillance marker for broader nosocomial acute lung injury, including pneumonia, pulmonary edema, atelectasis, and acute respiratory distress syndrome (ARDS). As such, approaches shown to decrease VACs in general may be efficacious through means other than pneumonia prevention.
Specific recommendations for preventing VAP and the quality of evidence to support them are outlined in Table 1. Many of these focus on minimizing ventilator days; others focus on reducing the risk of introducing microbes into the trachea and lower airways. Data to support elevation of the head of the bed are mixed. Still, combining the studies in a meta-analysis demonstrated a positive effect on VAP rate.10 Elevating the head of the bed is especially important for those receiving enteral nutrition. Some methods have been shown to improve outcomes but have not been strongly recommended or adopted because of concerns of potential risks. Included in this group is selective decontamination of the oropharynx, which has been shown to decrease mortality rates but in theory could increase the risk of antibiotic resistance or Clostridioides difficile infections.11
Other measures with unclear risk vs. benefit ratios that have not been strongly recommended include chlorhexidine oral care, prophylactic probiotics, ultrathin polyurethane endotracheal tube cuffs, and mechanical tooth brushing. Measures generally not recommended for prevention of VAP are silver-coated endotracheal tubes, kinetic beds, early tracheotomy, and early parenteral nutrition. In fact, initiation of early parenteral nutrition is associated with a higher risk of nosocomial infection and mortality compared to delaying it until day 8.12
In reviewing the literature on the treatment rather than the prevention of HAP and VAP, one must return to the more traditional definitions of pneumonia. Definitions of VAP and HAP were left largely unchanged in the 2016 IDSA/ATS guidelines update.13 Pneumonia is defined as a “new lung infiltrate plus clinical evidence that the infiltrate is of an infectious origin, which includes the new onset of fever, purulent sputum, leukocytosis, and decline in oxygenation.” HAP is a pneumonia that develops in the hospital and was not incubating at the time of admission. VAP is a pneumonia developing more than 48 hours after intubation. Without a gold standard for the diagnosis of pneumonia, there remains room for clinical judgment. In the IDSA/ATS guidelines, VAP is not included in the definition of HAP; thus, they are mutually exclusive groups, a definition of HAP that is not always consistent when reviewing the literature on the subject.13
On the other hand, the term healthcare-associated pneumonia (HCAP) has been excluded from the updated VAP/HAP guidelines. This is, in large part, because of increasing evidence showing that many patients previously defined as having HCAP are not at high risk for multidrug-resistant (MDR) pathogens and do not warrant exposure to broader antibiotic coverage. Instead, emphasis is placed on identifying risk factors for MDR pathogens in VAP and HAP. Similarly, while community-acquired pneumonia (CAP) is not covered in this review, the authors of the 2016 guidelines believed that specific risk factors for MDR pathogens (rather than simply looking at previous contact with the healthcare system) should be part of the guidelines for managing CAP.13 In contrast, coma at the time of ICU admission decreases the chances of finding an MDR organism in VAP, probably related to the propensity for neurotrauma patients to develop VAP early in their hospitalization. MDR organisms in HAP, methicillin-resistant S. aureus (MRSA) in VAP or HAP, and resistant Pseudomonas organisms in VAP or HAP all share the risk factor of prior IV antibiotic use within 90 days. However, consistent data supporting other risk factors for these three scenarios are lacking. Besides prior IV antibiotic use within 90 days, other indications for treatment of MDR in VAP include septic shock, ARDS, five or more days of hospitalization prior to VAP onset, and acute renal replacement therapy prior to VAP onset.
What is the best way to obtain cultures in the patient with a new infiltrate? The IDSA/ATS guidelines recommend noninvasive sampling in VAP/HAP with semiquantitative cultures rather than bronchoalveolar lavage (BAL), protected specimen brush, or blind bronchial sampling (mini-BAL).13 However, the European Respiratory Society and other international societies recommend using the invasive sampling techniques for VAP.14,15 If someone happens to obtain invasive quantitative cultures, the IDSA/ATS guidelines recommend withholding antibiotics if the cultures return below the diagnostic threshold for VAP.
When VAP is suspected and before diagnostic microbiologic results have returned, empiric treatment is required. This treatment should include coverage for Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacilli.13 Empiric coverage for methicillin-sensitive S. aureus (MSSA) should include piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem. MRSA rather than MSSA empiric coverage would be required for those with risk factors for MRSA (prior IV antibiotic use within 90 days, ICUs with > 10-20% S. aureus isolates resistant to methicillin) and would include vancomycin or linezolid. Empiric coverage for resistant Pseudomonas or other gram-negative organisms should include two antipseudomonal agents: one from the beta-lactam class (e.g., aztreonam, cefepime piperacillin-tazobactam, imipenem, ceftazidime, meropenem) and one from the nonbeta-lactam class (e.g., amikacin, colistin, ciprofloxacin, levofloxacin, polymyxin, gentamicin, tobramycin). The only double beta-lactam combination that could be considered is aztreonam with another beta-lactam, as aztreonam has a different bacterial cell wall target.13 If the risk of resistant gram-negative organisms is low, then only one gram-negative agent is required, preferably an agent also effective against MSSA (if there are no risk factors for MRSA).
To avoid potential costs and side effects, such as renal failure and C. difficile infection, caveats to these recommendations include avoiding aminoglycosides and colistin when alternative agents are available. Generally, antibiotics to which the patient has been exposed recently should be avoided, with preference given to an agent from a different class of antibiotics. In addition, empiric coverage for both VAP and HAP should be guided by local antibiograms, which should be generated regularly and made available to clinicians.
Empiric coverage for HAP is similar to that of VAP. However, patients who are at high risk of mortality receive coverage for MRSA and MDR Pseudomonas — even if the MDR risk factors are not present. “High risk of mortality” is defined as the need for ventilator support due to HAP or the presence of septic shock.13 Otherwise, clinicians should use double antipseudomonal coverage if the patient has bronchiectasis, cystic fibrosis, or another structural lung disease that raises the risk of resistant gram-negative infection.
Recommendations for coverage of specific organisms identified in VAP and HAP include using both inhaled and systemic antibiotics for treating gram-negative bacilli sensitive only to aminoglycosides or polymyxins (colistin or polymyxin B). P. aeruginosa VAP/HAP with known antibiotic susceptibility should be treated with two antibiotics if the patient is still in septic shock or at high risk of death. Otherwise, monotherapy with an agent to which the organism is susceptible is recommended. The exception is that aminoglycosides should not be used as a sole antipseudomonal agent due to concerns about lung penetration.
Acinetobacter species are treated preferentially with a carbapenem or ampicillin/sulbactam if they are susceptible. Tigecycline is not recommended when Acinetobacter is the known pathogen. If sensitive only to polymyxins, Acinetobacter and other carbapenem-resistant pathogens should be treated with IV polymyxin (colistin or polymyxin B) and with inhaled colistin. If MSSA is the confirmed sole causative organism, coverage can be narrowed to oxacillin, nafcillin, or cefazolin. Nosocomial Legionella spp. VAP or HAP would be much less common but would require coverage to be tailored to include appropriate antibiotics (fluoroquinolones or azithromycin). Similarly, anaerobes are a less likely cause of VAP and HAP. However, in the setting of aspiration or recent abdominal surgery, one could consider including anaerobic coverage in the selection of antibiotics, knowing that adding specific anaerobic coverage for aspiration pneumonia may offer no clinical benefit.16
Generally, therapy duration is seven to eight days rather than a longer course for both VAP and HAP. However, for VAP due to nonfermenting, gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, Burkholderia cepacia, Sphingomonas paucimobilis, Achromobacter xylosoxidans, etc.), the risk of recurrence is higher with the seven-day course vs. the longer 10-15 day course.13,17 Other situations in which a longer course of antibiotics should be considered include inadequate initial antibiotic treatment and severely immunocompromised patients.15 Recently, Klompas et al suggested that VAP in stable patients on minimal ventilator support may perform just as well with a three-day course of antibiotics.18 However, these findings need to be replicated before making firm recommendations to use the very short course. Because the clinical definitions of VAP and HAP as discussed earlier are very sensitive but have poor specificity, it is reasonable to consider a shortened course of antibiotics. Culture data and the patient’s clinical course often can often help inform the diagnostic suspicion of VAP/HAP and early de-escalation of broad-spectrum antibiotic therapy. Still, differentiation between airway colonization and lower respiratory tract infection can be challenging.
In addition to clinical criteria, biomarkers (chiefly procalcitonin) may help guide length of therapy as well as timing of de-escalation. When possible, antibiotic therapy should be narrowed when culture and sensitivity results are available.
Considering the frequent difficulty in distinguishing bacterial pneumonia from viral pneumonia or other pulmonary insults, interest in the use of biomarkers to help guide VAP and HAP management has increased in recent years. Biomarkers include procalcitonin (PCT), C-reactive protein (CRP), copeptin, soluble triggering receptor expressed on myeloid cells (sTREM-1), and others.
In general, sensitivity, specificity, and positive and negative predictive values of none of these biomarkers are adequate to make any of them useful in deciding whether to initiate antibiotic therapy.13 Some have suggested that PCT may be helpful to decide when to stop empiric antibiotics when cultures return negative or to shorten the course of antibiotics in a patient who otherwise appears to be responding adequately. To reduce antibiotic use, some research supports stopping antibiotics when the PCT level declines to < 0.5 ng/mL or by more than 80% of the peak level, but the cohorts in those studies were relatively small.19-22 Thus, the IDSA/ATS guidelines make a weak recommendation for using PCT levels in addition to clinical criteria to assist in deciding when to stop antibiotics.13 Meanwhile, the 2017 European and Latin American society guidelines recommend considering PCT levels only if the anticipated duration of antibiotic therapy is longer than seven to eight days.14,15 Other biomarkers, such as CRP, may not be as useful because of persistent elevation from noninfectious inflammatory disorders seen in the ICU, but may be considered when PCT testing is not available. If PCT levels remain elevated, one must consider that nonbacterial infections (such as Pneumocystis jirovecii, Candida species, and some parasites), as well as noninfectious conditions such as shock, burns, trauma, and chronic renal disease, can cause elevated PCT levels.
VAP and HAP pose significant risks to hospitalized patients and increase the cost of care. It is essential to institute measures to reduce the risk of these pneumonias and to recognize and treat them early when they occur. Treatment is a balance of ensuring adequate antimicrobial coverage in those who already are seriously ill while not unduly exposing them to the risks of medication side effects and higher rates of resistant organisms that come with the use of broad-spectrum antibiotics. Following established guidelines discussed will lead to improved outcomes in ICUs and hospital wards.
- Magill SS, et al. Survey of healthcare-associated infections. N Engl J Med 2014;370:2542-2543.
- Dudeck MA, et al. National Healthcare Safety Network (NHSN) report, data summary for 2012, device-associated module. Am J Infect Control 2013;41:1148-1166.
- Metersky ML, et al. Trend in ventilator-associated pneumonia rates between 2005 and 2013. JAMA 2016;316:2427-2428.
- Wolkewitz M, et al. Changes in rates of ventilator-associated pneumonia. JAMA 2017;317:1580-1581.
- Muscedere JG, et al. Mortality, attributable mortality, and clinical events as end points for clinical trials of ventilator-associated pneumonia and hospital-acquired pneumonia. Clin Infect Dis 2010;51:S120-S125.
- Sopena N, et al. Multicenter study of hospital-acquired pneumonia in non-ICU patients. Chest 2005;127:213-219.
- Kollef MH, et al. Economic impact of ventilator-associated pneumonia in a large matched cohort. Infect Control Hosp Epidemiol 2012;33:250-256.
- Hayashi Y, et al. Toward improved surveillance: The impact of ventilator-associated complications on length of stay and antibiotic use in patients in intensive care units. Clin Infect Dis 2013;56:471-477.
- Klompas M, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:915-936.
- Alexiou VG, et al. Impact of patient position on the incidence of ventilator-associated pneumonia: A meta-analysis of randomized controlled trials. J Crit Care 2009;24:515-522.
- De Smet AM, et al. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med 2009;360:20-31.
- Casaer MP, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506-517.
- Kalil AC, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016;63:e61-e111.
- Torres A, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J 2017;50. pii: 1700582. doi: 10.1183/13993003.00582-2017.
- Torres A, et al. Summary of the international clinical guidelines for the management of hospital-acquired and ventilator-acquired pneumonia. ERJ Open Res 2018;4. pii: 00028-2018. doi: 10.1183/23120541.00028-2018.
- Dragan V, et al. Prophylactic antimicrobial therapy for acute aspiration pneumonitis. Clin Infect Dis 2018;67:513-518.
- Pugh R, et al. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev 2015;CD007577.
- Klompas M, et al. Ultra-short-course antibiotics for patients with suspected ventilator-associated pneumonia but minimal and stable ventilator settings. Clin Infect Dis 2017;64:870-876.
- Stoltz D, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: A randomized study. Eur Respir J 2009;34:1364-1375.
- Schuetz P, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2017;10:CD007498.
- Schuetz P, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: A patient level meta-analysis. Lancet Infect Dis 2018;18:95-107.
- Bouadma L, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): A multicenter randomized controlled trial. Lancet 2010;375:463-474.