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Nosocomial Pneumonia in the ICU—Year 2000 and Beyond^*

^* From the Department of Internal Medicine (Pulmonary and Critical Care) and Anesthesiology (Critical Care), Wake Forest University School of Medicine, Winston-Salem, NC.

	Abstract

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 
Diagnostic and treatment strategies in ICU patients with ventilator-associated pneumonia (VAP) remain controversial, largely because of the paucity of well-controlled comparison trials using clinically important end points. Recent studies indicating that early appropriate antibiotic therapy significantly lowers mortality underscore the urgent need for well-designed comparative trials. When quantitatively cultured, bronchial specimens obtained by noninvasive techniques may provide clinically useful information and avoid the higher costs and risks of invasive bronchoscopic diagnostic techniques. Previous antibiotic use before onset of nosocomial pneumonia raises the likelihood of infection with highly virulent organisms, such as Pseudomonas aeruginosa and Acinetobacter sp. Thus, the empiric antibiotic regimen should be active against these Gram-negative pathogens as well as other common Gram-negative and Gram-positive causative organisms. Promising preventive modalities for nosocomial VAP include use of a semirecumbent position, endotracheal tubes that allow continuous aspiration of secretions, and heat and moisture exchangers. Rotating their standard empiric antibiotic regimens and restricting the use of third-generation cephalosporins as empiric therapy may help hospitals reduce the incidence of nosocomial pneumonia caused by resistant Gram-negative pathogens.

Key Words: antibiotic regimen • culture • ventilator-associated pneumonia

	Introduction

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 
Nosocomial pneumonia is the second most common nosocomial infection and, along with primary bacteremia, the leading cause of death from infection acquired in the hospital.¹ In mechanically ventilated patients, the incidence of nosocomial pneumonia ranges from 9 to 68%, and mortality rates range from 33 to 71%.² Despite the frequency of ventilator-associated pneumonia (VAP) and the threat it poses to patient survival, consensus on an appropriate diagnostic strategy for VAP has yet to be established. The uncertainty is compounded by a lack of well-controlled comparisons of specific treatment regimens and their impact on relevant outcomes, such as morbidity, mortality, and cost. This article will briefly review the key data and suggest approaches to the diagnosis, treatment, and prevention of nosocomial pneumonia in ICU patients.

	Diagnostic Strategies

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 
The difficulties for clinicians facing patients with suspected pneumonia were underscored in 1971, when the investigations of Barrett-Connor³ questioned the diagnostic utility of sputum cultures in the diagnosis of community-acquired pneumonia. The value of sputum cultures in community- and hospital-acquired pneumonias is still being debated. The controversies surrounding VAP are particularly animated. In 1988, the findings of Fagon and colleagues⁴ ignited a flame of controversy that has yet to be doused. In this study of 147 mechanically ventilated patients, a clinical diagnosis of bacterial pneumonia was strongly suggested by the presence of fever, leukocytosis, pulmonary infiltrates, and purulent sputum. Yet less than half of these patients had positive cultures from specimens obtained bronchoscopically by protected catheter brushing (PCB).⁴ In the 10 years following this report, numerous studies have evaluated the performance characteristics of a variety of techniques for obtaining and culturing specimens. Nevertheless, the utility of these techniques in directing appropriate patient care remains controversial.

Much of the controversy about the clinical relevance of various diagnostic strategies arises from lack of a gold standard against which the techniques can be compared. As a result, the reported sensitivity or specificity of quantitative cultures of either PCB or BAL specimens have ranged from 31 to 96%.^{4 ,5 ,6 ,7 ,8} This wide range reflects the fact that some studies used clinical criteria as end points (eg, response to antibiotics or withholding antibiotic treatment), some directly compared the two diagnostic techniques, some used postmortem biopsy cultures, and others used histologic criteria. Unfortunately, none of the end points can withstand the scrutiny required for acceptance as a "gold standard."⁹ Even histologic findings are problematic because there are no widely accepted criteria for their interpretation. This difficulty is underscored by a prospective autopsy study in which histologic samples from 39 patients were reviewed to determine the presence or absence of VAP. A positive diagnosis of pneumonia was made in 9 patients (23%) by consensus of four independent pathologists-reviewers; later, classification by one of these pathologists, using specific histologic criteria proposed by Johanson et al,¹⁰ diagnosed pneumonia in 14 (36%) of the patients.¹¹

Current thresholds used to define a positive PCB or BAL culture have been based on factors that maximize test performance rather than on clinical outcomes. In the clinical arena, however, outcomes are paramount since mortality rates are lower when appropriate antibiotic therapy is used.^{1 ,2} Underdiagnosing nosocomial pneumonia increases the risk of not treating patients with this serious infection. To avoid missed diagnoses, it is necessary to accept a lower threshold for positive culture of PCB, ie, 10² rather than 10³ cfu/mL, in patients with a high pretest clinical suspicion of pneumonia.⁹ The 10² cfu/mL threshold minimizes underdiagnosis of pneumonia while only modestly reducing the performance characteristics of the test. Well-designed outcome trials addressing the effect of a given diagnostic technique on survival or hospital or ICU length of stay would provide much needed clinical guidance. Unfortunately, there is a paucity of methodologically sound studies examining these issues. Bregeon and colleagues¹² employed a case-matched study design to compare mortality in mechanically ventilated patients suspected of having VAP. In their study, the diagnosis was made either by invasive PCB or one of several other invasive or noninvasive sampling methods, each coupled with quantitative cultures.¹² They, and others, found that mortality from presumed VAP was independent of any specific sampling strategy and suggest that invasive bronchoscopic sampling techniques need not be employed in most situations. Quantitatively cultured samples obtained noninvasively, eg, by blind bronchial sampling or mini-BAL, can provide clinically useful information.^{12 ,13}

	Impact of Prior Antibiotic Use on Etiology and Outcome of Nosocomial Pneumonia

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 
Previous antibiotic use in the ICU has widespread effects on etiology, diagnosis, and outcome of nosocomial pneumonia. Antibiotic therapy before bronchoscopic diagnostic studies appears to impair the diagnostic validity of both PCB and BAL cultures. However, the reported effect varies widely. Some studies have excluded subjects who received prior antibiotic therapy and others have not, because in the "real world," empiric antibiotic administration is commonplace and accepted. Therefore, assessments of diagnostic strategies must take this into account if they are to be broadly applicable.

Antibiotic administration before onset of pneumonia has been linked to an increased frequency of VAP caused by highly virulent organisms such as Pseudomonas aeruginosa and Acinetobacter sp^{14 ,15} which, in turn, have been associated with an increased mortality rate, as reported in several studies.^{1 ,14 ,15 ,16} While data thus far are only inferential, it would appear that empiric antibiotic regimens employed in the ICU should, in general, be used with circumspection after adequate culture data have been obtained, be highly active against P aeruginosa and Acinetobacter sp, be used no longer than necessary, and be modified if less virulent, broadly sensitive organisms are isolated.

	Empiric Antibiotic Therapy for Nosocomial Pneumonia

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 
Mortality attributable to VAP is significant in most patient populations and prompt administration of appropriate empiric antibiotic therapy in these groups is associated with improved outcomes, as demonstrated by studies using quantitative culture of bronchoscopically obtained specimens or growth in sterile fluids (blood, pleural or lung aspirate) to identify the etiologic agent.^{1 ,2 ,17} For example, Celis and colleagues¹ reported a mortality rate of 92% in a small group of patients with nosocomial pneumonia receiving inappropriate antibiotic therapy compared with 31% in the larger group receiving appropriate antibiotics. In mechanically ventilated patients, Torres and associates² reported a mortality rate of 52% in patients receiving inappropriate antibiotics vs 23% in those with appropriate antibiotic therapy. When the administration of appropriate antibiotic therapy was delayed, however, a favorable impact on outcome was not observed.¹⁷ Hence, despite the difficulties in distinguishing the presence or absence of pneumonia and the desire to avoid indiscriminate antibiotic use, in most patients at the time of presentation there will be insufficient data for physicians to be confident about either the diagnosis or the microbiological etiology. Administration of antibiotics should not be delayed pending "the answer" from culture data and will, thus, be empiric.

	Appropriate Antibiotic Regimens

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 
Appropriate empiric antibiotic therapy must be directed at the most prevalent and virulent pathogens. Prevalence of particular nosocomial pathogens and prevailing antibiotic resistance levels vary from one ICU to another, depending on many factors. In most ICUs, effective empiric therapy will require activity against Gram-negative bacilli, especially Pseudomonas and Acinetobacter, as well as Gram-positive organisms. Thus, at least initially, multidrug therapy will be required.

There are scant data suggesting the superiority of any particular regimen for the initial therapy of nosocomial pneumonia. In a prospective randomized trial, Joshi and colleagues¹⁸ compared piperacillin/tazobactam (PIP/TAZO) with ceftazidime (CTAZ) in patients with hospital-acquired lower respiratory tract infections (n = 78 and 58, respectively). At study end point, patients in the PIP/TAZO group displayed significantly higher rates of clinical improvement (Fig 1 ). This difference was accounted for by a significantly greater improvement for patients with nosocomial pneumonia, who made up the bulk of the study population. In addition, the mortality rate in the group receiving PIP/TAZO was significantly lower than that in the CTAZ group (7.7% vs 16.6%, p = 0.03). However, insufficient data on severity of illness among groups were provided. The findings of Sieger and colleagues,¹⁹ who used the criterion of clinical resolution or bacterial eradication, suggested that meropenem was superior to CTAZ with tobramycin. However, nonquantitative culture methods were used, insufficient data on the severity of illness among groups were provided, and in the CTAZ group, 40% of the patients with Pseudomonas isolates received an inadequate course of tobramycin (ie, fewer than six doses).

View larger version (44K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Clinical improvement in nosocomial lower respiratory tract infection for patients treated with PIP/TAZO or CTAZ.18

	Potential Preventive Modalities

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

Ventilator circuits are rapidly colonized with bacteria, and the condensate within these circuits can have very high bacterial counts. Aspiration of circuit condensate may play a role in the development of nosocomial pneumonia.²² Heat and moisture exchangers (HMEs) are not associated with the same degree of formation of condensate, and, further, many have filtration capabilities that inhibit the movement of bacteria across the HME to the patient. Dreyfuss and colleagues²² examined the effects of using HMEs or heated humidifiers on the incidence of circuit colonization and nosocomial pneumonia in 131 patients admitted to their medical/surgical ICU. Circuit colonization was reduced with HME, but the incidence of pneumonia, defined rigorously by quantitative culture techniques, was similar in both groups. More recently, Kirton and associates,²³ using an HME with greater filtration capabilities, demonstrated a significant (p < 0.05) reduction in the incidence of nosocomial VAP in ICU trauma patients randomized to receive HME compared with those receiving heated humidifiers (Fig 2 ). Although this trial used clinical criteria to diagnose pneumonia, the length of stay in the ICU was shorter and circuit costs associated with mechanical ventilatory support were reduced in the HME group.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Incidence of VAP in patients receiving ventilation using an HME or heated humidifier.23

	Comments and Recommendations

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

Clinicians and hospitals are concerned that their patients have good outcomes, and that these are obtained at the lowest feasible cost. Such costs include not only antibiotic acquisition, but length of stay, need for ancillary support (mechanical ventilation, respiratory care, bedside nursing), and impact on the care of other patients within the ICU. While much remains to be learned, increased understanding of the effects of prior antibiotic use on incidence and outcome of nosocomial pneumonia can probably help reduce the incidence of pneumonia caused by highly antibiotic-resistant organisms. Institutional prescribing practices place important selection pressures on the native microbial flora and their degree of sensitivity to commonly used antibiotics. In a group of postcardiac surgery patients, Kollef and colleagues²⁴ demonstrated that a scheduled change of antibiotic class used for empiric treatment of nosocomial Gram-negative infections resulted in a significantly reduced incidence of VAP, especially VAP caused by antibiotic-resistant Gram-negative organisms. In this study, the standard empiric regimen was changed from a third-generation cephalosporin to a quinolone. Interestingly, there was also a nonsignificant trend toward a reduction in bacteremia attributable to resistant Gram-negative organisms. Other studies, both in the community and in the hospital, have suggested that rotating standard antibiotic regimens or restricting overused antibiotics (such as third-generation cephalosporins) may reverse or ameliorate the incidence of drug-resistant pathogens.^{25 ,26}

We clinicians should strongly encourage pharmaceutical companies to undertake the difficult and expensive comparative studies needed to effect improvements in both prevention and management of nosocomial pneumonia. The following suggestions for the design of future comparative studies of nosocomial pneumonia can help provide a framework for these studies.

1. The diagnosis of pneumonia should be based on quantitative cultures of airway secretions. While any arbitrary cutoff for these cultures will exclude some subjects who do have pneumonia, the added specificity will help assure the comparability of the treatment groups by reducing the chance that a disproportionate share of one treatment group contains subjects without pneumonia. Bronchoscopically obtained specimens, for the purposes of these studies, do not confer sufficient additional benefit to warrant either their cost or the small but real risk of the procedure.

2. The study population should be homogenous or homogenously heterogeneous because incidence and outcomes of nosocomial pneumonia vary widely among patient populations. Homogenous ICU populations are difficult to define, especially in multicenter trials. Hence, randomization should stratify patients according to patient type (trauma, nontrauma surgical, medical) and disease severity (APACHE [acute physiology and chronic health evaluation] II or similar system).

3. Potentially confounding variables should be standardized including, but not limited to, use of HMEs, elevation of the head of the bed, and choice of stress-ulcer prophylaxis. The continuous aspiration of subglottic secretions should also be addressed.

4. The most important outcome to evaluate in these critically ill patients is survival. While assessing this outcome requires large numbers of patients, all other end points pale in significance. Total cost of patient care (ICU and hospital length of stay) and antibiotic-related cost are also important. Microbiological outcome must, of course, be assessed but it is less important than clinical factors such as survival and shortened hospital stay.

	Appendix 1

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 
Dr. Campbell: Is there any evidence that scoring systems, such as the Clinical Pulmonary Infection Scoring System, are useful in improving the detection of nosocomial pneumonia?

Dr. Bowton: We have not used scoring systems for evaluating or ascribing risk for nosocomial pneumonia, but I believe they might be useful, especially for systematically standardizing risk factor evaluations in large, cross-ICU clinical trials.

Dr. Weber: Our experience suggests that scoring systems are more useful in some patient populations than others. For example, in one of our studies, scoring using APACHE II was predictive of pneumonia in surgical ICU patients but not predictive in medical ICU patients. We also found that age was not, in itself, a predictor of mortality from pneumonia once other explanatory variables were factored in.

Dr. Bowton: It appears that for a scoring system to be an effective predictor, it would have to have the patients’ underlying risk factors explicitly laid out. At this time, such systems have not been tested in large enough groups of ICU patients to establish their usefulness.

Dr. Campbell: What empiric regimens are you currently recommending for use in your ICUs?

Dr. Bowton: We discourage the use of cephalosporins as empiric therapy because of their tendency to select out resistant Pseudomonas and vancomycin-resistant enterococci. For nosocomial pneumonia, we prefer broad-spectrum penicillins, such as piperacillin, combined with an aminoglycoside, since studies suggest that penicillins are significantly less likely than cephalosporins to exert selective pressure.

Dr. Murthy: Another important resistance problem in some hospitals is the emergence of extended-spectrum ß-lactamases following routine use of empiric CTAZ. When, at our institution, we started encountering bacteremias with CTAZ-resistant Escherichia coli resulting from production of extended-spectrum ß-lactamases—combined with the more common resistance problems—we moved away from empiric use of CTAZ.

Dr. File: The new quinolone, trovafloxacin, was recently approved for therapy of nosocomial pneumonia. Might broad-spectrum agents be useful for empiric monotherapy for nosocomial pneumonia in the ICU?

Dr. Bowton: We would be reluctant to use any quinolone as monotherapy. Monotherapy did not work with ciprofloxacin—we started to see problems with resistant Pseudomonas following use of this drug.

Dr. Burgess: The 300-mg dose of trovafloxacin will provide a peak concentration of 4 to 4.5 µg/mL. Since the maximal effect for fluoroquinolones is a peak 10 to 12 times the minimal inhibitory concentration (MIC) or an area under the curve/MIC > 125, the MIC₉₀ would need to be about 0.5 µg/mL. However, the MIC₉₀ for trovafloxacin against Pseudomonas is 1 to 2 µg/mL.

Dr. Bernstein: There has been little clinical experience with quinolones combined with antibiotics other than CTAZ.

Dr. Burgess: We have compared the in vitro activity of penicillins plus quinolones, penicillins plus aminoglycosides, and quinolones plus aminoglycosides and have found the quinolone/aminoglycoside combinations to be less active against Pseudomonas than the other combinations.

	Footnotes

 
Correspondence to: David L. Bowton, MD, FCCP, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157-1054; e-mail: dbowton@wfubmc.edu

Abbreviations: CTAZ = ceftazidime; HME = heat and moisture exchanger; MIC = minimal inhibitory concentration; PCB = protected catheter brushing; PIP/TAZO = piperacillin/tazobactam; VAP = ventilator-associated pneumonia

	References

TOP Abstract Introduction Diagnostic Strategies Impact of Prior Antibiotic... Empiric Antibiotic Therapy for... Appropriate Antibiotic Regimens Potential Preventive Modalities Comments and Recommendations Appendix 1 References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bowton, D. L. Search for Related Content PubMed PubMed Citation Articles by Bowton, D. L.