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(Chest. 2005;128:533-544.)
© 2005 American College of Chest Physicians

Contribution of Blinded, Protected Quantitative Specimens to the Diagnostic and Therapeutic Management of Ventilator-Associated Pneumonia*

Christian Brun-Buisson, MD; Muriel Fartoukh, MD; Emmanuelle Lechapt, MD; Stéphanie Honoré, MD; Jean-Ralph Zahar, MD; Charles Cerf, MD and Bernard Maitre, MD

* From Service de Réanimation Médicale (Drs. Brun-Buisson, Fartoukh, and Zahar), Service d’Anatomie Pathologique (Dr. Lechapt), Service de Microbiologie (Dr. Honoré), Service de Réanimation Chirurgicale (Dr. Cerf), and Antenne de Pneumologie (Dr. Maitre); Hôpital Henri Mondor, Créteil, France.

Correspondence to: Christian Brun-Buisson, MD, Service de Réanimation Médicale, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, 51, Avenue du Mal de Lattre de Tassigny, 94010 Créteil Cedex, France; e-mail: christian.brun-buisson{at}hmn.ap-hop-paris.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: Sampling techniques for microbiological diagnosis of ventilator-associated pneumonia (VAP) remain debated, and it is unclear to what extent invasive diagnostic techniques impact the management of patients.

Design: A prospective observational study of 68 first episodes of suspected pneumonia in which specimens were obtained blindly (endotracheal aspirate [EA] and blinded protected telescoping catheter [PTC]) and via bronchoscopy (directed PTC bronchoscopy and BAL), and in sequence, and the results were provided to the attending physicians in the same order. Therapeutic plans resulting at each step were examined, and their adequacy was assessed using quantitative BAL fluid culture as the diagnostic standard.

Participants: Sixty-eight patients with clinically suspected VAP hospitalized in two ICUs in a tertiary care university hospital.

Results: There were 35 patients (51%) with VAP confirmed by BAL fluid culture (13 early onset and 22 late onset). EA specimens grew organisms (light growth or more) in all BAL-confirmed VAP cases and 59% of nonconfirmed cases, whereas the sensitivity and specificity of blinded PTC quantitative cultures were 77% and 97%, and did not differ from those of directed PTC cultures (77% and 94%, respectively). Antibiotic therapy based on the clinical severity and likelihood of VAP, Gram stain results, and early blinded PTC culture results was adequate in 54% (19 of 35 VAP patients) within 2 h of sampling and 80% (28 of 35 patients) within 24 h; therapy was revised in only 3 more patients following BAL culture results. New antibiotics were introduced within the first 24 h in 14 of 33 nonconfirmed episodes (42%), and antibiotics were withheld or withdrawn within 48 h in 23 episodes (70%); three of these patients—with both blinded PTC and BAL growing organisms below the threshold—had early subsequently confirmed pneumonia with the same organism.

Conclusions: A therapeutic approach guided by quantitative cultures of blinded specimens helps achieve early adequate management of approximately 90% of patients suspected of having VAP.

Key Words: antimicrobial therapy • bronchoscopy • cohort studies • diagnosis • intensive care • mechanical ventilation • microbiology • nosocomial pneumonia


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Ventilator-associated pneumonia (VAP) is a common and potentially lethal infection, with a median prevalence of 20% (range, 6 to 52%) in patients receiving mechanical ventilation.12 The diagnosis of VAP is therefore often clinically suspected in these patients. However, the diagnostic approach and management of VAP remain a challenge for the ICU physician. It is well accepted that clinical features suggestive of VAP (ie, purulent tracheal secretions, fever, leukocytosis, change in PaO2/fraction of inspired oxygen [FIO2] ratio, and new or persistent lung infiltrates) are nonspecific for the diagnosis of pneumonia in patients receiving mechanical ventilation.34

Accurately diagnosing VAP is important because of its potential impact on antibiotic prescribing and on a patient’s outcome.5 Since the adverse consequences of VAP can be reduced in part by early adequate antibiotic therapy,678 many ICU patients receive empiric therapy for suspected VAP. However, increased antibiotic prescribing leads to increased antimicrobial resistance problems, and poorer outcome of subsequent infections.9 Prudent antimicrobial usage is therefore a current major objective in ICUs.10 Using accurate diagnostic tools may help reduce antibiotic usage, without exposing patients to adverse outcomes.111 However, controversy persists on which respiratory tract secretions specimens should be used in routine practice to help achieve this goal. Endotracheal aspirate (EA) cultures are nonspecific, because of rapid and widespread airways colonization in intubated patients, especially with Gram-negative bacilli.12 Although no sampling method will ensure 100% diagnostic accuracy, the invasive (bronchoscopic) techniques, especially BAL, are currently viewed as the most accurate for diagnosing VAP.113 However, the invasive techniques have not gained universal acceptance because of persisting controversy on the potential impact of this diagnostic approach on the outcome of patients, and of the difficulties and costs associated with performing routine bronchoscopy in patients suspected of having VAP.131415 Alternatives methods, such as nonbronchoscopic protected specimens, which are simpler and less costly and can be obtained "blindly" via the endotracheal tube by nursing personnel, and be processed by quantitative culture, are available.16171819 In the current study, we examined the diagnostic accuracy of protected distal sampling (protected telescoping catheter [PTC]), obtained blindly or directed via bronchoscopy, compared to BAL in a series patients receiving mechanical ventilation suspected of having VAP, and analyzed antibiotic management based on quantitative culture results in these patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
The population included in this study has been described previously.20 Briefly, patients receiving mechanical ventilation for > 48 h in whom VAP was clinically suspected were eligible for inclusion. The clinical suspicion of VAP was based on the usual clinical, radiologic, and biological criteria320: an increase in body temperature, blood leukocyte count, purulent tracheal secretions, and decrease in the PaO2/fraction of inspired oxygen (FIO2) ratio, plus a new or persistent lung infiltrate. Only the first episode of suspected VAP was analyzed in the present study. Data recorded for each patient included demographics, primary organ failure, and severity score (simplified acute physiology score II) on ICU admission,21 date of intubation or tracheostomy, duration of mechanical ventilation, and antibiotics received prior to, ongoing, or recently introduced before the day of samplings. The study was approved by the Ethical Committee of the Société de Réanimation de Langue Française, and informed consent was waived, since current recommendations for respiratory tract secretion samplings in France include both protected specimen brush and BAL in patients clinically suspected of having VAP.

Respiratory tract secretions samplings were obtained in sequence, as described below, and their results were provided to the physicians in charge in the same order. Physicians were then asked at each step to provide their therapeutic plans according to these results, and antibiotics administered were recorded, focusing on the early steps of therapy.

Sampling Procedures and Processing
Nonbronchoscopic samples were obtained first, followed by bronchoscopic samples. The nonbronchoscopic "blinded" specimens were obtained by the nurse as described previously,1820 and consisted of an EA using a sputum suction trap (Vygon; Ecouen, France), followed by a blinded, single-sheathed, plugged telescopic catheter (Ventimed; Neuilly sur Seine, France) sampling. The directed samplings were performed within 3 h via bronchoscopy (BF2B; Olympus; New Hyde Park, NY) by the same pulmonologist (B.M.),20 starting with directed PTC, then standard BAL, using 3 aliquots of 50-mL sterile isotonic saline solution. After the procedures, the EA and the blinded PTC and directed PTC specimens were immediately transported to the microbiology laboratory, as well as the second BAL fluid aliquot. Gram stain analysis of a cytocentrifuged layer was performed on all specimens except EA. The third BAL aliquot was sent to the cytology laboratory for cytocentrifugation, cell identification, and differential count; the percentage of polymorphonuclear cells containing intracellular bacteria was determined on at least 50 cells.

Cultures of Samples
Cultures were performed using standard media. After homogenization, a calibrated loop sample of the EA specimen was plated on agar media using the four-quadrant streak technique. After vortexing, 1/10 dilution of fluid samples from blinded PTC, directed PTC, and BAL was performed, and 1/10 mL of each sample was plated on agar culture media. Colony counts were read after 24- and 48-h cultures. PTC and BAL cultures were reported as colony forming units per milliliter for PTC and BAL, after correction for the initial dilution. All organisms recovered were identified, and their susceptibility was tested using standard techniques. EA cultures were read semiquantitatively (EAsq) using the following scale: + (rare growth) = growth on the first quadrant with < 10 colonies; 2+ (light growth) = growth of between 101 and 102 colonies on the first and second quadrants; 3+ (moderately numerous, <103) = growth > 102 colonies in the first and second quadrants, and light growth on the third quadrant; 4+ (numerous, 103 to 104) = heavy growth on the first, second, and third quadrants; 5+ (heavy growth, 105) = confluent growth on the first, second, and third quadrants with heavy growth on the fourth quadrant.

Impact of Sampling on Antibiotic Management
The therapeutic strategy was based on the protocol outlined in Figure 1 .22 One of the investigators interviewed the physician in charge of the patient to prospectively assess the contribution of respiratory tract specimens to antibiotic management at each step of the diagnostic procedure and notification of microbiological results. This was done four times: (1) at the time of obtaining specimens (ie, initial empiric therapy); (2) when the direct examination of blinded PTC was available (approximately 2 h after sampling), then of the BAL sample; (3) at 24 h, with the quantitative cultures results of the blinded PTC, and then of BAL; and (4) at 48 h with the final results of the cultures of the blinded PTC and the susceptibility profile of the microorganisms recovered on BAL fluid culture. Therapeutic plans were recorded at each step, as well as the efficacy and adequacy of therapy, taking the latter results as reference.



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  		Figure 1.. Approach to diagnosis and antibiotic management of VAP, integrating severity of presentation, clinical likelihood of pneumonia, and early microbiological information. In patients not presenting with severe sepsis/shock, administration of antibiotic therapy is based on clinical likelihood of pneumonia, direct examination, and adapted on results of quantitative cultures. In those with low likelihood of infection and negative Gram stain results (eg, CPIS Gram ≤ 6),20 therapy can await culture results unless associated infection mandates therapy. Q. culture = quantitative culture; Rx = therapy.

 
Definitions
VAP and Thresholds for Positivity: VAP was considered confirmed when BAL fluid culture yielded ≥ 104 cfu/mL of at least one microorganism, or the presence of > 2% cells containing intracellular bacteria on direct examination.1 The threshold for positivity of quantitative PTC culture was 103 cfu/mL of any single species1820; the semiquantitative culture of an EA specimen (EAsq) was considered positive with a score ≥ 4+.

Concordance Rates Between Specimens: Taking BAL fluid culture as the reference, the concordance rates between blinded and directed samples were defined qualitatively and quantitatively. A concordance between two samples was defined when the same species were recovered above or below the thresholds for positivity on both specimens, and was scored 0. Cases with discordance were classified according to their potential impact on antibiotic therapy: (1) qualitatively minor discordance, with different bacterial species recovered below the thresholds of both specimens, or above the threshold of both specimens, but with no impact on therapy; (2) quantitatively major discordance (the same bacterial species in the two specimens) below the threshold for one specimen and above the threshold for the other specimen; (3) and both qualitative and quantitative major discordance (different bacterial species recovered above and below the thresholds of the two specimens).

Efficacy of Antibiotics: An antibiotic regimen was deemed adequate when its spectrum of activity encompassed all the microorganisms recovered in significant amount from BAL fluid culture. Two effective antibiotics were required for therapy of Pseudomonas aeruginosa.

Analysis
Data are shown as mean ± SD and medians, unless otherwise stated. The concordance rates between samples and the diagnostic accuracy of EA, blinded PTC, and directed PTC were assessed by comparison to BAL fluid culture taken as the reference standard. The contribution of the respiratory tract specimens to antibiotic management plans were analyzed in terms of efficacy at each step of the results provided to the physicians. Comparisons used the Student t test and the Man Whitney U test; p < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Population
The clinical characteristics of the 68 patients studied are shown Table 1 . On the day of sampling, patients had received mechanical ventilation for 10.0 ± 7.2 days (median, 8 days; interquartile range, 3 to 24 days). There were 22 episodes (32%) occurring early (< 7 days of mechanical ventilation) and 46 episodes occurring later; two patients underwent a tracheostomy. A new pulmonary infiltrate was present on the chest radiograph in 41 episodes (60%), and others had persistent infiltrates. Severe sepsis (n = 4) or septic shock (n = 7) were recorded in 11 episodes (16%). The clinical suspicion of VAP was microbiologically confirmed in 35 episodes (51%), based on a BAL fluid culture yielding ≥ 104 cfu/mL of at least one pathogen or on the presence of > 2% cells containing intracellular bacteria. There was no significant difference in the characteristics of episodes with or without microbiologically confirmed VAP,20 although patients without confirmed pneumonia tended to have more severe underlying diseases. Patients with early onset pneumonia also had higher severity and a lower PaO2/FIO2 ratio (p = 0.03) than corresponding patients without confirmed pneumonia (Table 1).


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  		Table 1.. Clinical Characteristics of the 68 Patients at ICU Admission and at the Time of Clinical Suspicion of Pneumonia, According to Time of Onset*

 
Respiratory tract specimens were obtained while patients were free of antibiotics in 28 of 68 suspected episodes (41%) [Table 2 ]. Ongoing antibiotic therapy (administered for > 72 h before the day of samplings) was administered to 37 patients (54%); in 3 patients, a new antibiotic regimen had been introduced within the past 48 h, before samplings for suspected sepsis or another nonpulmonary infectious episode.


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  		Table 2.. Antibiotic Received Prior to Sampling, Stratified by Time of Onset of Suspected VAP in 68 Patients*

 
Respiratory Specimen Gram Stains and Cultures
A count > 2% of leukocytes containing intracellular bacteria in BAL fluid was recorded in 14 of 64 samples (22%) examined in this regard (4 samples not done), and in only one patient with bacterial count below the 104 threshold. Results of Gram stain of cytocentrifuged BAL fluid were positive in 39 patients (57%), including 30 of the 35 patients (86%) with confirmed VAP. Results of Gram stain of blinded PTC samples were positive in 24 episodes (35%), including 21 patients (60%) with confirmed VAP (Table 3 ).


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  		Table 3.. Results of Direct Examination and Cultures of Specimens, Stratified by Time of Onset of Suspected VAP in 68 Patients

 
EA culture results were positive in 60 of 66 samples (91%; 2 samples missing) [Table 3]. By EAsq, 79% of samples grew ≥ 1+; EAsq were positive at ≥ 4+ in 27 of 35 patients (77%) with BAL-confirmed VAP and in 6 of 31 patients (19%) with nonconfirmed VAP. Results of blinded PTC cultures were positive in 27 of 35 VAP patients (77%), and in only 1 of 33 patients (6%) with nonconfirmed VAP; corresponding figures were identical for directed PTC cultures (Table 3). Fifty-eight microorganisms were recovered from BAL cultures in VAP patients (Fig 2 ); 15 patients (43%) had monomicrobial infection. Gram-negative bacilli accounted for 74% of all organisms recovered. Pseudomonas sp was the most frequent of these (17 of 43 organisms, 40%), and was recovered in 49% of VAP patients, especially in late-onset cases (13 of 22 organisms vs 4 of 13 organisms, p = 0.2).



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  		Figure 2.. Organisms recovered in BAL fluid cultures in patients with confirmed VAP (n = 35). Infection was monomicrobial (dotted bars) in 15 (43%) patients and polymicrobial (closed bars) in 20 patients (57%). MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-susceptible S aureus; E coli = Escherichia coli.

 
Qualitative and Quantitative Concordance Between Respiratory Specimen Cultures
Blinded PTC was either concordant or had a minor qualitative discordance (ie, scores 0 to 1) with BAL and directed PTC in 55 of 68 patients (81%) and 52 of 68 patients (76%), respectively. EA culture was concordant with BAL in 40 of 66 patients (61%); when considering a 4+ score for positivity of EAsq, the rate rose to 76% (Fig 3 ).



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  		Figure 3.. Concordance scores between specimen cultures (all 68 patients). Scores were defined as follows: 0 (open bars) = total concordance between samples; 1 (hatched bars) = minor qualitative discordance; 2 or 3 (filled bars) = major quantitative discordance or major qualitative and quantitative discordance. Two EA samples were missing for comparison.

 
Initial Empiric Therapy
In addition to the three patients who received antibiotics within 48 h before sampling, empiric therapy was administered to eight additional patients (12%) at the time of sampling (including all those associated with septic shock). Of these 11 patients, 7 had BAL-confirmed VAP, 6 of whom were treated adequately. Four of these patients had associated infection documented within 48 h. The empiric regimen was maintained in eight patients (adapted in two patients) and stopped within 72 h in the three others after culture results were available (Table 4 ).


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  		Table 4.. Timing of Early Antibiotic Therapy Administered and Outcome of Patients With and Without BAL-Confirmed Pneumonia

 
Therapeutic Plans According to Results of Gram Stains and Cultures
After results of direct examination of blinded PTC were obtained, new antibiotics were introduced in 19 other patients, 16 of whom had subsequently confirmed pneumonia; the prescribed regimen was effective in 13 of these 16 patients (81%). Altogether, 23 of 35 patients (66%) with subsequently confirmed pneumonia received a new antimicrobial therapy within the first 2 h of sampling (Table 4), which was effective in 19 of 23 of these patients (83%), including all those associated with severe sepsis/shock. At 24 h, culture results of blinded PTC specimens led to a modification of the initial empirical therapy in two patients, and to the prescription of new antibiotics in nine other confirmed cases, all effective. Knowledge of BAL fluid culture results led to the prescription of new antibiotics in three additional patients (effective and adequate therapy) [Table 4]. Finally, a change in the regimen occurred in only three remaining confirmed cases (9%) when full antibiotic susceptibility was reported at 48 h. The proportion of patients receiving effective therapy for pneumonia was therefore 17% (6 of 35 patients) at inclusion, increased a few hours later to 54% (19 of 35 patients) after direct examination with blinded PTC, and was 83% (29 of 35 patients) and 91% (32 of 35 patients) within 24 h at the time of availability of cultures of blinded PTC and BAL fluid, respectively (Fig 4 ).



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  		Figure 4.. Proportion of patients adequately treated at each step of the diagnostic procedure. The number of new patients receiving effective therapy (open bars) and the total number of patients receiving effective therapy (black bars) at each step are shown.

 
In the 33 patients with nonconfirmed VAP, empiric therapy was prescribed in 4 patients (including 1 patient in whom therapy was administered within 24 h before sampling), and 3 other patients received therapy after positive direct examination of specimens and a high clinical probability of VAP. Four of these seven regimens were stopped after 48 h because of low-count (or sterile in one case) cultures in all samples, and three were maintained or adapted because of high likelihood of pneumonia or associated infection (Table 4). Five patients and two other patients were treated after early or complete culture results, respectively (although both blinded PTC and BAL cultures were below thresholds); all were treated on clinical grounds or because of newly documented associated infection. New antibiotics were thus introduced within the first 48 h in 14 of 33 patients (42%), and maintained beyond that in only 10 patients (33%) [Table 4].

Eight of the 23 patients (35%) in whom antibiotic therapy was withheld or withdrawn subsequently acquired VAP; the corresponding rate was nonsignificantly higher in the subgroup in which antibiotics were maintained (5 of 10 patients, 50%; p = 0.46) and was twice higher than in patients with BAL-confirmed pneumonia (5 of 35 patients, 14%; p = 0.13) [Table 5 ]. Six of these eight cases of VAP occurred within the following 7 days, with four cases due to the same organisms found in low counts on the previous inclusion (Table 4). Two of these six patients died, respectively, 24 days and 45 days later from unrelated causes (postanoxic coma and mediastinitis due to another microorganism).


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  		Table 5.. Outcome of Patients With and Without BAL-Confirmed Pneumonia*

 
Overall, new antibiotics (including empiric therapy) were introduced within the 24-h period following sampling in 31 of 35 patients (89%) with confirmed VAP and in 12 of 33 patients (36%) with nonconfirmed episodes (p < 0.001). The overall hospital mortality rate was 43% (29 of 68 patients) and was similar in patients with BAL-confirmed or nonconfirmed VAP (40% vs 45%, respectively) [Table 5]. Of the 19 patients with VAP receiving effective therapy within the first hours (including all patients with severe sepsis or shock), 12 patients (63%) eventually died; only 2 of 16 patients (12%; p = 0.005) receiving ineffective therapy within the first 24 h died, 14 days and 40 days later, respectively, from unrelated causes (mesenteric infarction and hepatorenal syndrome).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our data suggest that blind, protected sampling techniques with quantitative cultures may be a suitable alternative to bronchoscopic sampling as an aid to diagnosis and management of antibiotic therapy in patients clinically suspected of having VAP. Together with clinical judgment, making optimal use of early microbiological data, including Gram stains and early quantitative cultures of specimens (Fig 1), allows physicians to prescribe effective therapy within the first 2 to 24 h of diagnosis of VAP in > 80% of patients, while allowing to withhold or withdraw new antibiotics in approximately two thirds of patients who do not need therapy for pneumonia.

Lower respiratory tract infection is the primary cause of nosocomial infection and acquired sepsis in the ICU, and therefore accounts for a majority of antibiotic prescriptions.1023 In addition, several studies have documented a high rate of inappropriate antibiotic therapy for pneumonia—mostly due to antimicrobial resistance710—potentially associated with increased morbidity and mortality.67824 This context induces clinicians to liberally prescribe broad-spectrum antibiotics early in suspected VAP because of a high index of suspicion and the fear of resistance.1025 Moreover, antibiotics are often initiated before obtaining specimens,2627 a strategy that confounds the interpretation of culture results and entails major difficulties in subsequent antibiotic management.13 Overall, these approaches may eventually be more harmful than beneficial, and may contribute to the ever-increasing rate of antibiotic resistance in ICUs and hospitals.1222528 In this context, there is a need for diagnostic tests that help physicians manage antibiotic prescriptions in a timely fashion, ie, to effectively treat early patients who need such therapy, and to reduce antibiotic use in patients in whom it is not necessary.

It is well accepted that VAP poses a difficult diagnostic challenge because of the limited value of the clinical variables available at time of suspicion3132930 and the lack of a universally accepted reference test. Evidence accumulated from 2 decades of research in this field, however, suggest that BAL processed by quantitative culture is the sampling technique providing the best currently available compromise between a high sensitivity and an acceptable specificity.113 Therefore, BAL was taken in this study as the reference test, not ignoring that both false-positive and false-negative results may occasionally occur. However, bronchoscopy is invasive, time consuming, and costly, and is not available on a daily basis in all ICUs, and may be poorly tolerated in severely hypoxemic patients. Therefore, alternative procedures providing acceptable diagnostic accuracy are needed. In addition, it remains unclear whether the diagnostic accuracy of "invasive procedures" is more dependent on the fact that samplings are directed under visual guidance, on the protection of the sampling device, on quantitative culture of specimens, or any combination of the above. A recent consensus conference however suggested that quantitative cultures might be more important.13

Our data confirm that qualitative EA cultures have a high sensitivity but a high proportion (> 80%) of false-positive results when compared to BAL.13 Although this noninvasive technique remains the most widely used worldwide, its lack of specificity can hardly help fulfill the objective of antibiotic stewardship if its results are used to guide antibiotic therapy.14 Using simple semiquantitative cultures and a threshold corresponding to approximately 104cfu/mL markedly improved the diagnostic accuracy of EAsq relative to BAL and increased its specificity to 82%, while its sensitivity decreased to 77% (Table 3). However, results of previous studies313233 looking at the best threshold for positivity of quantitative EA cultures have been inconsistent, with recommended values ranging from 104 to 106 cfu/mL.

Comparisons of the diagnostic accuracy of the blinded sampling techniques tested in this study are consistent with others.161718 Similarly to our previous results comparing blinded and directed PTC quantitative cultures to bronchoscopic protected brush sampling,18 we found similar accuracies of the directed and blinded techniques in the current study comparing these to BAL. Protected samplings (blinded PTC and directed PTC) were associated with a similar sensitivity (77%) and an excellent specificity (97%) as compared with the nonprotected techniques, especially nonquantitative EA (Table 3). In our study, only 1 of 35 patients without BAL-confirmed VAP was "overtreated" using blinded PTC culture results to guide therapy. By contrast, using EA or even EAsq would have been associated with substantially more patients being overtreated (57% and 18%, respectively) [Table 3], therefore favoring blinded PTC as a noninvasive technique to help decide whether antimicrobial therapy should be prescribed or maintained in patients clinically suspected of having VAP.

Blinded PTC specimens, however, appeared to have a suboptimal sensitivity, with 8 of 35 false-negative culture results (23%) in our series, as compared to BAL. We cannot exclude that some of these patients actually had a false-positive BAL result, just as well as a few patients might have had false-negative BAL results, as suggested by the early recurrence of VAP in some patients (Table 4). However, therapy was started empirically or at 24 h in several of these patients and maintained in most. Only three patients might have been treated earlier using BAL-guided therapy rather than blinded PTC cultures (Fig 3). A quality control of PTC specimens may be available through direct examination, since "false-negative" PTC specimens all showed epithelial/bronchial cells on direct examination, with few polymorphonuclear cells (data not shown). When such features are present, or as suggested, when no visible secretions are present,17 and the clinical likelihood of VAP is high, repeated sampling should be considered.

Altogether, our study comparing the diagnostic accuracy of various sampling techniques (whether qualitative or quantitative, protected or nonprotected, blinded or directed) relatively to BAL tends to confirm that reporting quantitative culture results is more important than directing sampling via bronchoscopy for the microbiological diagnosis of VAP.13 Several authors32333435 have also argued that quantitative culture of nondirected, nonprotected specimens such as EA could have a diagnostic accuracy comparable to that of BAL.

Equal to or even more important than the specific test used is the way its results are interpreted and used to help manage antibiotic therapy. Our current approach to diagnosis and antibiotic management of VAP, integrating severity of presentation, clinical information (which can be summarized by the modified clinical pulmonary infection score [CPIS]20), and results of direct examination of specimens is depicted Figure 1. The empiric approach to therapy is mainly guided by the clinical likelihood of pneumonia and the severity of presentation. In the patients with more severe disease, antibiotics will be initiated early and maintained whatever the results may be, at least until results of a complete workup and follow-up under therapy are available, as occurred in our patients. Of note, the outcome was much worse in our patients with severe presentation of infection than in other patients, despite early and adequate therapy in the former group (Table 5). In the latter patients, which account for a majority of those suspected of VAP (84% in our series), antibiotic therapy can be guided safely by clinical likelihood of pneumonia and results of direct examination of specimens and early culture. Although early therapy is clearly warranted in patients with symptoms of severity, it should be noted that a delay in therapy of a few hours in patients not having a severe presentation was not associated with adverse consequences on clinical outcomes of patients (Tables 4, 5), as previously noted by Bonten et al.1136

In evaluating outcome of initial (empiric) antibiotic therapy, it is important to assess both subgroups of patients with and without eventually confirmed infection. Few studies provide such information. Our results show the following: (1) all patients with severe infection were adequately treated early, and > 80% of all patients with BAL-confirmed VAP were treated adequately within 24 h; and (2) antibiotic therapy could be withheld or withdrawn in two thirds of patients without BAL-confirmed pneumonia. Nevertheless, only 54% of patients with BAL-confirmed pneumonia received adequate therapy within 2 h of clinical suspicion of VAP, which may be viewed as suboptimal. However, there are few other data in the literature reporting higher rates within this short time window, since almost all reports focus on a 24-h time window or do not clearly specify the time window of evaluation relative to clinical suspicion and respiratory tract samplings. For example, Kollef et al37 reported a 26.8% overall rate of inadequate initial therapy of documented nosocomial infections during a 17-month study of antibiotic rotation; in this study, the precise timing of "initial" therapy relative to clinical suspicion of infection was not specified. Iregui et al38 reported a 31% rate of delayed (> 24 h) adequate antibiotic therapy for VAP. Only Ibrahim et al,39 from the same group, reported a 94% rate of adequate therapy within 12 h of sampling after implementation of a guideline recommending a combination of vancomycin, imipenem, and ciprofloxacin for initial therapy of VAP with subsequent deescalation; however, there was no impact on outcomes as compared to a historical control group, where the adequacy rate was only 48%; in addition, what was the antibiotic management in patients with a clinical suspicion of pneumonia in whom the diagnosis was not eventually confirmed—at least part of whom likely received empiric therapy—was not reported. Thus, our strategy provides rates of appropriate management for most patients with suspected VAP comparable to or better than most recent series, while allowing antibiotic stewardship. Limiting unnecessary duration of therapy is an important additional step to control antibiotic use and resistance.4041

Limitations of our study include the relatively small number of episodes studied, which limits its power, and the fact that it was conducted in a center with a long-standing tradition of using this method for sampling, and particular emphasis in the appropriate and prudent use of antimicrobials. Our results in terms of adequacy of antibiotics may not be applicable to other centers. In fact, the adequacy of initial (empiric) therapy administered for any given ICU-acquired infection is critically dependent on a thorough evaluation of the prior history of the patient, antibiotics administered, and local epidemiology.91042 Although microbiological specimens provide an aid to decide whether or not to initiate antibiotic therapy through direct examination4344 and thus help targeting therapy, none will ensure the adequacy of initial therapy. The latter will largely depend on knowledge of the above mentioned factors and clinical skills. However, it is essential to obtain reliable samples before initiating therapy, so that therapy can be subsequently tailored, and when appropriate, withdrawn.1113

Providing early adequate antimicrobial coverage while avoiding overprescribing of antibiotics is currently a major objective in the management of ICU patients with suspected pneumonia.1710 However, prescribing before sampling should be avoided.13 Using blinded PTC sampling, a simple and readily available test, is one way to overcome this problem. Using this test as a guide to therapy, effective therapy was administered to > 80% patients with BAL-confirmed pneumonia within 24 h of diagnosis. Such rates are substantially higher than those recorded in several recent series.6782729 Blinded samplings with quantitative (or possibly semiquantitative) culture may thus be proposed as an alternative tool for the routine management of suspected VAP, especially where and when bronchoscopy is not readily available.

Antibiotic management based on the use of bronchoscopic techniques has been shown in one randomized trial14 to reduce overall antibiotic use and to improve outcomes of patients as compared to management based on EA. It should be noted that only qualitative EA cultures were used in the control arm of this study, therefore favoring excess antibiotic use in the latter. Our results suggest that a randomized controlled trial comparing a diagnostic approach using bronchoscopic BAL to blind (semi-)quantitative culture of protected specimens is warranted to examine whether the two diagnostic approaches result in comparable antibiotic use and outcomes of patients.


   Footnotes
 
Abbreviations: CPIS = clinical pulmonary infection score; EA = endotracheal aspirate; EAsq = semiquantitative culture of endotracheal aspirate specimen; FIO2 = fraction of inspired oxygen; PTC = protected telescoping catheter; VAP = ventilator-associated pneumonia

Received for publication December 4, 2003. Accepted for publication January 27, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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