Nosocomial Pneumonia: Aetiology, Diagnosis and Treatment
Pieter Depuydt; Dries Myny; Stijn Blot 

Curr Opin Pulm Med.  2006;12(3):192-197.  ?2006 Lippincott Williams & Wilkins
Posted 04/18/2006

Abstract and Introduction

Abstract

Purpose of Review: This review highlights recent advances in the aetiology of nosocomial pneumonia, and in strategies to increase accuracy of diagnosis and antibiotic prescription while limiting unnecessary antibiotic consumption.
Recent Findings: Bacterial pathogens still cause the bulk of nosocomial pneumonia and are of concern because of ever-rising antimicrobial resistance. Yet, the pathogenic role of fungal and viral organisms is increasingly recognized. Since early appropriate antimicrobial therapy is the cornerstone of an effective treatment, further studies have been conducted to improve appropriateness of early antibiotic therapy. De-escalation strategies combine initial broad-spectrum antibiotics to maximize early antibiotic coverage with a subsequent focusing of the antibiotic spectrum when the cause is identified. Invasive techniques probably do not alter the immediate outcome but have the potential to reduce unnecessary antibiotic exposure. Decisions to stop or change antibiotic therapy are hampered due to a lack of reliable parameters to assess the resolution of pneumonia.
Summary: Increasing antimicrobial resistance in nosocomial pneumonia both challenges treatment and mandates limitation of selection pressure by reducing antibiotic burden. Treating physicians should be both aggressive in initiating antimicrobials when suspecting nosocomial pneumonia but willing to discontinue antimicrobials when diagnostic results point to an alternative diagnosis. Efforts should be made to limit duration of antibiotic therapy when possible.

Introduction

Pneumonia is the second most frequent nosocomial infection. The incidence ranges from four to 50 cases per 1000 hospital admissions. This figure increases five to 10-fold when patients are referred to the intensive care unit (ICU), and more than 20-fold when they receive invasive mechanical ventilation.[1,2,3*,4] The 2004 updated joint American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines expanded the spectrum of nosocomial pneumonia to include healthcare related pneumonia, which is pneumonia occurring in healthcare settings other than the acute care hospital.[5**] Since most episodes of nosocomial pneumonia occur in ventilated patients, however, the bulk of the literature has focused on ventilator-associated pneumonia (VAP), and this bias continues in the most recent literature reviewed below. Although pneumonia appears as the most lethal of nosocomial infections, some controversy remains as to whether it causes excess mortality when treated appropriately.[3,6**,7,8,9**] The attributable mortality of pneumonia depends for a certain extent on the microbial cause[10,11**] and on the type of patient population studied.[3*] For example, in a recent study focusing on respiratory tract microbiology in the first 24 h following diagnosis of acute respiratory distress syndrome (ARDS), mortality was not higher in the subset of patients who fulfilled clinical and microbiological criteria of pneumonia.[12**] In contrast, a matched cohort analysis identified VAP as the only risk factor for mortality in ventilated chronic obstructive pulmonary disease patients.[13*] More consistently, nosocomial pneumonia is known to add to morbidity and to increase medical consumption in terms of antibiotic use and length of hospital stay.[14**,15,16**]

Microbial Aetiology of Nosocomial Pneumonia

Treatment of nosocomial pneumonia is complicated by the frequent involvement of potentially multi-drug resistant (MDR) organisms. Antibiotic exposure and a hospital stay of more than a week are well established risk factors for infection with these organisms.[17,18**,19,20] Interestingly, a similarly dichotomized risk pattern for the cause of multi-drug resistance was found in a study of nursing-home acquired pneumonia (which is now firmly included in the spectrum of nosocomial pneumonia): risk factors for MDR organisms were prior antibiotic exposure and the Activity of Daily Living score as a marker of dependency.[21*] In early nosocomial pneumonia, community-acquired organisms such as Streptococcus pneumoniae, Mycoplasma pneumoniae and Chlamydia pneumoniae are prevalent.[22**] On the other hand, depending on locally prevailing microbial ecology, MDR organisms, such as methicillin-resistant Staphylococcus aureus and resistant Pseudomonas aeruginosa, may be involved in early VAP.[23**] Patients admitted from long-term care facilities should be suspected of harbouring potentially MDR organisms, especially when previously exposed to antibiotics.[24*] Legionella spp. is a significant cause of nosocomial pneumonia in acute care hospitals and probably also in long-term care facilities.[25*] The role of viruses is difficult to ascertain in nosocomial pneumonia but is probably limited.[26*] Herpes simplex virus (HSV) was found in lower respiratory tract specimens of a high proportion of ventilated patients: this occurred mostly in the patients with severe illness and probably represented reactivation due to immune suppression. Although the patients with HSV infection fared worse, it is unclear whether HSV contributed to this deterioration.[27] Similarly, cytomegalic virus reactivation with antigenemia was found in 17% of critically ill patients with persisting fever and negative bacteriological cultures.[28*] Finally, a recent study[29] identified presence of adenovirus in bronchoalveolar lavage (BAL) fluid of 50 patients without clinical viral illness; again viral load was higher in immunosuppressed patients.[29] To a certain extent, viral replication or reactivation may be a marker of immunosuppression rather than a true pathogen of pneumonia. Fungal infections are generally omitted from studies dealing with nosocomial pneumonia. Yet, invasive aspergillosis is increasingly recognized in ICU patients without apparent immune deficiency and often manifests itself as pulmonary disease.[30*,31*] Candida spp. on the other hand is frequently found in respiratory samples of ICU patients but is probably very rarely the cause of pneumonia;[32,33] hence, isolation of Candida in airway samples represents colonization in most cases. Highly variable practice regarding Candida management in general ICU patients reflects the uncertainty about its clinical significance in airway specimens.[34**] Interestingly, in a recent autopsy series of 71 bone marrow transplant patients, a population at the highest risk of invasive fungal disease, Candida bronchopneumonia was diagnosed in only one patient.[35*]

Pathogenesis of Nosocomial Pneumonia

It is assumed that most episodes of nosocomial and ventilator-associated pneumonia are caused by micro-aspiration of oral and pharyngeal content. The oral cavity is increasingly recognized as a reservoir of potentially pathogenic MDR organisms.[36**] In patients with poor oral hygiene, a microbial cause of VAP could be traced back to dental plaque harbouring pathogens such as S. aureus, Gram-negative enteric bacilli and P. aeruginosa.[37*] Applying gingival and dental plaque antiseptic decontamination decreased oropharyngeal colonization in ventilated patients, although this did not reduce the incidence of pneumonia nor eradicate highly resistant organisms.[38*] Apart from endogenous reservoirs, exogenous transmission can serve as a route for acquisition of MDR pathogens, as shown by the simultaneous isolation of the same P. aeruginosa pulsotypes in stomach cultures and tap water in a Spanish study.[39] A third route of acquisition of bacterial pathogens at the ICU is patient-to-patient transmission, which is probably rather limited when standard hand hygiene precautions are applied.[40*]

Diagnosis of Nosocomial Pneumonia

Approaches to diagnosis of nosocomial pneumonia are variable, which is mainly due to the lack of a uniformly accepted gold standard and, consequently, to differences in medical culture or belief between ICUs and countries. To illustrate this, invasive microbiological sampling, more precisely the use of quantitative culturing of BAL fluid in clinically suspected VAP was performed in only half of 29 inquired ICUs in Germany.[41**] A similar but larger survey in 395 French ICUs found a 90% use of quantitative culture techniques, and a 60% use of bronchoscopical sampling.[42] A wide divergence in practice of bronchoscopy in pneumonia in ICU patients (including both community-acquired and nosocomial pneumonia) was also observed in Australian and New Zealand ICUs, which did not translate in outcome differences.[43]

Although a clinical diagnosis of VAP is unreliable and suffers from a lack of specificity, with unnecessary antibiotic treatment as a potential hazardous consequence,[44,45*] a clinical estimation of the probability of pneumonia remains essential in the interpretation of microbiological results. In a small prospective study in patients with prolonged mechanical ventilation but otherwise being stable without antibiotic therapy, bacterial growth in respiratory samples often exceeded the commonly accepted threshold of 104 CFU/ml for diagnosing VAP.[46**] On the other hand, quantitative cultures probably have a lower sensitivity for diagnosis of VAP as compared with qualitative cultures,[47**] and a study in trauma patients suggests that the quantitative culturing threshold for diagnosing VAP should depend on severity of injury and the type of pathogen recovered.[48**] Invasive and quantitative microbiological investigation is probably also prone to sampling variability, as the return in instilled BAL saline and hence dilution of the sample may influence bacterial counts of BAL fluid culture,[49**] and as bilateral blind or bronchoscopically guided sampling may yield different results compared with unilateral blind sampling.[50]

This continuing pro-con debate over whether, and which, invasive techniques should be used for diagnosing VAP was partially concluded by the recent meta-analysis of four randomized controlled trials which could not identify a survival benefit associated with the use of invasive techniques.[51**] In the updated ATS-IDSA guidelines, both invasive (i.e. bronchoscopical) and non-invasive sampling, and both quantitative and semiquantitative culturing techniques were considered acceptable to establish a microbiological diagnosis. In conclusion, both clinical and microbiological data should be integrated in a holistic diagnostic approach to nosocomial pneumonia.[5**] New and promising biomarkers of pneumonia, such as soluble TREM-1, will undoubtedly increase the discriminative power of diagnostic strategies in VAP but should again preferably be used within this clinical-microbiological framework, and not as a single test.[52**,53]

Treatment

Clinical signs and symptoms of severe infection in general, and nosocomial pneumonia in particular, should always prompt antimicrobial therapy. Antimicrobial therapy should be adequate (i.e. cover the causative pathogen) and effective (i.e. adequately administered and dosed).[54-57,58**,59]

Controversy remains over whether diagnosis of nosocomial pneumonia should be microbiologically centred and initial antibiotic therapy directed, based on the results of (invasive) microbiological sampling, or whether diagnosis should be clinical and initial antibiotic therapy empirical, with use of broad-spectrum antibiotics to minimize the risk of an initially insufficient spectrum. Authors favouring the directed approach point to the lack of specificity of a clinical diagnosis of nosocomial pneumonia, leading to excessive antibiotic consumption and a further fuelling of selection of MDR organisms. On the other hand, proponents of the empirical broad-spectrum approach stress the excess mortality in severe infection associated with delayed or initially inappropriate antibiotic therapy. This effect is most pronounced in bacteremia, and less conclusive, but probably present, in nosocomial pneumonia.[60*]

In a prospective observational study of 68 episodes of ventilator-associated pneumonia, antibiotic prescription based on clinical diagnosis of pneumonia together with Gram staining and early culture results of blind protected aspirate was adequate within 24 h of sampling in 28 of 35 of patients with subsequently proven VAP. The same strategy limited antibiotic prescription to 12 of 33 patients with unconfirmed pneumonia.[61*] The reliability of immediate microbiological examination may not be readily extrapolated to other centres, however, as a retrospective study in trauma patients suggested. In this study, Gram staining identified cause in only 63% of Gram-negative VAP and 72% of Gram-positive VAP, which led the authors to recommend that Gram-negative organisms should be covered empirically irrespective of the results of Gram staining.[62**] Again, it can be noted that the aforementioned meta-analysis by Shorr et al.[51**] concluded that invasive microbiological sampling led to more changes in antibiotic therapy without affecting mortality.

On the other hand, it appears that empirical choices should at least be guided by microbiological results, as purely empirical choices still carry a risk of missing the etiologic pathogen in a setting of highly prevalent and variable multi-drug resistance. For example, in a French study, imipenem resistance was observed in a quarter of episodes of nosocomial pneumonia.[63**] In late nosocomial bacteremic pneumonia, imipenem resistance was observed in 21% of patients and resistance to both a broad-spectrum betalactam and a fluoroquinolone or an aminoglycoside in 25%.[20] Surveillance of respiratory tract samples has a moderate to good prediction of cause in VAP and can be used to minimize the risk of inappropriate initial antibiotic therapy in patients at risk for MDR infection.[20,64*]

Downsizing the initial antibiotic spectrum to a narrower one still including the causative pathogen, once this has been identified, is a possible way to limit antibiotic exposure, with the benefit of cost savings and potentially decreased selection pressure. Rello et al.[65**] and Colardyn[66**] estimated that this so-called de-escalation of antibiotic therapy could be performed in a third of the VAP episodes. If the clinical suspicion of VAP is high but the pathogen remains elusive, de-escalation is problematical, which is the major limitation of this approach.

Finally, resolution of nosocomial pneumonia should be monitored to predict individual outcome, to assess the need for change or to limit the duration of antibiotic therapy, or to reconsider diagnosis. A daily rigorous clinical assessment formalized in a protocol is shown to be helpful to limit duration of antibiotic therapy.[67**] Whereas classical clinical signs used to identify a favourable evolution of pneumonia, such as defervescence and improvement in oxygenation, are present within 48 h in the majority of ICU patients, these may be more difficult to interpret and slower to evolve in patients with ARDS.[68**] In this study, radiological resolution appeared to be a poor indicator for improvement both in patients with and without ARDS, and hence a lack of radiological improvement should not defend a prolonged antibiotic course. Serial evaluation of CRP may be helpful to identify a subgroup with a poor prognosis: in a Portuguese study, both a fast and a slow but continuous decrease of CRP predicted ultimate survival (100%) whereas a non-responsive and a biphasic CRP curve were associated with >70% mortality.[69**] Procalcitonin measurement on days 1, 3 and 7 was superior to CRP measurement (as indicated by better ROC characteristics) to discriminate survivors from non-survivors in a French study,[70**] but procalcitonin assessment is more expensive and not widely available.

Conclusion

The diagnosis of nosocomial pneumonia remains challenging and should be made by a careful clinical assessment combined with a critical evaluation of microbiological results; the integration of clinical probability and microbiological data is more important than the choice of technique for obtaining and respectively culturing respiratory samples, as each of these techniques has intrinsic limitations. A high suspicion of nosocomial pneumonia should lead to immediate antibiotic therapy likely to cover the offending pathogen. When clinical risk factors for multi-drug resistance cause are present or when MDR pathogens are endemic, the spectrum of the empirical antibiotic therapy should be broadened to include these likely pathogens. Microbiological data should be integrated to guide this initial therapy, firstly by adapting empirical therapy to local ecology and resistance patterns, and secondly by tailoring this therapy to the individual colonization status in selected patients at high risk for MDR organism infection. Downgrading initial antibiotic therapy to the narrowest spectrum possible once the microbial cause is identified should be aimed at as much as possible. In patients failing to improve after several days of antibiotic therapy, efforts should be made to try to discriminate between clinical failure due to inappropriately chosen or inadequately dosed antibiotics, persistent ARDS or an alternative diagnosis.

References

Papers of particular interest, published within the annual period of review, have been highlighted as:

* of special interest
** of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 245-246).

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    * The review is based on a PubMed search from 1997 to 2004 focusing on papers dealing with appropriate therapy.
  61. Brun-Buisson C, Fartoukh M, Lechapt E, et al. Contribution of blinded, protected quantitative specimens to the diagnostic and therapeutic management of ventilator-associated pneumonia. Chest 2005; 128:533-544.
    * This prospective study focused on the impact of immediate microbiological processing of blind and directed protected aspiration on adequacy of early antibiotic therapy.
  62. Davis KA, Eckert MJ, Lawrence R, et al. Ventilator-associated pneumonia in injured patients: do you trust your Gram's stain? J Trauma 2005; 58:462-467.
    ** This retrospective study focused on microbiologically proven VAP in trauma patients. Overall accuracy of Gram's stain was 88%, but accuracy declined to 63% and 72% for predicting specific cause in Gram-negative and Gram-positive pneumonia respectively.
  63. Leroy O, d'Escrivan T, Devos P, et al. Hospital-acquired pneumonia in critically ill patients: factors associated with episodes due to imipenem-resistant organisms. Infection 2005; 33:129-135.
    ** This observational study included 168 patients with hospital-acquired pneumonia. Imipenem resistance was observed in 25%. Imipenem resistance was associated with prior use of fluoroquinolones, aminoglycoside and severity of pneumonia, as expressed by the need for invasive monitoring and the presence of bilateral infiltrates on chest radiograph.
  64. Michel F, Francescini B, Berger P, et al. Early antibiotic treatment for BAL-confirmed ventilator-associated pneumonia: A role for routine endotracheal aspirate cultures. Chest 2005; 127:589-597.
    * Thirty-four of 41 cases of VAP proven by BAL culture had a prior endotracheal aspirate growing the same organism. In this study, surveillance endotracheal aspirate cultures were performed twice weekly in all ventilated patients. Antibiotic prescription based on this surveillance was more adequate than a hypothetical prescription based on clinical factors.
  65. Rello J, Vidaur L, Sandiumenge A, et al. De-escalation therapy in ventilator-associated pneumonia. Crit Care Med 2004; 32:2183-2190.
    ** This was a study of the feasibility of a de-escalation approach in a single ICU.
  66. Colardyn F. Appropriate and timely empirical antimicrobial treatment of ICU infections: a role for carbapenems. Acta Clin Belg 2005; 60:51-62.
    ** This is a review of the concept or early appropriate antimicrobial therapy in ICUacquired infection.
  67. Micek ST, Ward S, Fraser VJ, et al. A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia. Chest 2004; 125:1791-1799.
    ** This prospective trial randomized patients with VAP for having duration of antibiotic therapy determined by a formal antibiotic discontinuation guideline or by clinical decision by the treating physician. Overall duration of antibiotic treatment was reduced in the guideline arm: median duration was 6 versus 8 days in the conventional arm.
  68. Vidaur L, Gualis B, Rodriguez A, et al. Clinical resolution in patients with suspicion of ventilator-associated pneumonia: a cohort study comparing patients with and without acute respiratory distress syndrome. Crit Care Med 2005; 33:1248-1253.
    ** This was a prospective study on the evolution of clinical factors during the course of VAP in patients with and without ARDS.
  69. Povoa R, Coelho L, Almeida A, et al. C-reactive protein as a marker of ventilator-associated pneumonia resolution: a pilot study. Eur Respir J 2005; 25:804-812.
    ** Serial CRP analyses in 47 patients with VAP were used to predict outcome. A CRP of >0.6 times the initial level on day 4 was predictive of a poor outcome with a sensitivity of 0.92 and a specificity of 0.59. On the other hand, both a fast (identified as a <0.4 decrease of CRP on day 4 as compared to day 0) and a slow but continuous decrease in CRP levels were associated with survival.
  70. Luyt CE, Gu?in V, Combes A, et al. Procalcitonin kinetics as a prognostic marker of ventilator-associated pneumonia. Am J Respir Crit Care Med 2005; 171:48-53. Procalcitonin kinetics predicted outcome in this prospective observational study of 63 patients with VAP.
    ** Procalcitonin kinetics predicted outcome in this prospective observational study of 63 patients with VAP.

Abbreviation Notes

ARDS = acute respiratory distress syndrome; BAL = bronchoalveolar lavage; HSV = herpes simplex virus; ICU = intensive care unit; MDR = multi-drug resistant; VAP = ventilator-associated pneumonia

Reprint Address

Correspondence to Pieter Depuydt, Department of Intensive Care, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium Tel: +32 9 240 2808; fax: +32 9 240 3849; e-mail: pieter.depuydt@ugent.be
Pieter Depuydt,a Dries Myny,b Stijn Blot,a

aDepartment of Intensive Care, De Pintelaan, Belgium
bNursing Department, Ghent University Hospital, De Pintelaan, Belgium