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Impact of Invasive Strategy on Management of Antimicrobial Treatment Failure in Institutionalized Older People with Severe Pneumonia

Division of Pulmonary, Critical Care, and Sleep Medicine and Division of Geriatrics, James P. Nolan Clinical Research Center, Department of Medicine, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York

Correspondence and requests for reprints should be addressed to Ali El-Solh, M.D., M.P.H., Division of Pulmonary, Critical Care, and Sleep Medicine, Erie County Medical Center, 462 Grider Street, Buffalo, NY 14215. E-mail: solh{at}buffalo.edu

ABSTRACT

The aim of the study was to investigate the etiology and the impact of invasive quantitative sampling on the management of severe pneumonia in institutionalized older people with antimicrobial treatment failure. Fifty-two institutionalized patients aged 70 years and older hospitalized with a presumptive diagnosis of severe pneumonia and failure to respond to treatment after 72 hours of initiation of outpatient antimicrobial therapy were enrolled. Microbial investigation included blood culture, serology, pleural fluid, and bronchoalveolar samples. A definite etiology could be established in 24 of 52 (46%) patients. Methicillin-resistant Staphylococcus aureus (33%), enteric Gram-negative bacilli (24%), and Pseudomonas aeruginosa (14%) accounted for most isolates. Atypical infections (2%) were uncommon. Invasive bronchial sampling directed a change of microbial therapy in 8 (40%) and discontinuation of antibiotics in 2 of 20 cases (10%) of definite pneumonia. Overall hospital mortality was 42%. There was no difference in mortality among definite or unverified cases or those who had invasive bronchial sampling–guided change in therapy. We conclude that antimicrobial therapy should be targeted toward "nosocomial" pathogens in those institutionalized patients who received prior antibiotic treatment. When combined with microbial investigation, direct visualization of the tracheobronchial tree might be useful in determining the presence of bacterial pneumonia.

Key Words: antimicrobial failure • older people • pneumonia

Nursing home–acquired pneumonia (NHAP) continues to be the major reason for transfer to an acute-care facility (1, 2) and the major cause of death in the institutionalized older population (3, 4). Factors predisposing to NHAP include serious comorbid illnesses, a waning immune system, and increased bacterial colonization of the oropharynx with antibiotic-resistant bacteria (5, 6) such as Staphylococcus aureus and aerobic Gram-negative bacilli. Recent studies indicate that infection rates in these facilities by respiratory pathogens are rising in association with an increase in the level of care required by patients (7, 8). As a result, the number of cases of pneumonia occurring in long-term care will undoubtedly increase in the foreseeable future.

Prescription of antibiotics in nursing home settings is often empiric and initiated in the absence of fever or culture results (9). Recent literature surveys indicated that many cases of NHAP could be treated successfully with oral antibiotics in the nursing homes at considerable cost savings when compared with hospitalizations (10). However, it has been estimated that approximately 30% of patients with NHAP fail treatment (11) and up to 10% may experience progressive life-threatening pneumonia (12). Most of the treatment failures have been attributed to risk factors such as decreased functional status, type of diet received, or frequency of visits by physician or nurse practitioner (11). Much less attention has been paid to the description of the microbial causes of progressive NHAP. Overall, little information is available about the role of infective pathogens and microbial susceptibility in patients with treatment failures.

We, therefore, conducted an interventional prospective study to assess the causes of antimicrobial failures in hospitalized patients with severe NHAP and the impact of invasive diagnostic techniques on antimicrobial therapy.

METHODS

Study Population
A prospective cohort study was performed in our medical intensive care units (ICUs) between November 1999 and November 2001 after obtaining approval from the institutional review board. Patients admitted from nursing homes with the diagnosis of severe pneumonia requiring mechanical ventilation were included in the study if they met the following criteria: (1) the presence of radiographic infiltrate compatible with pneumonia together with symptoms suggestive of lower respiratory tract infection; (2) the presence of any two of the following clinical parameters: temperature of 38°C or more, leukocytosis of 10,000 mm³ or more, or purulent respiratory secretions; and (3) treatment failure defined as clinical deterioration or absence of clinical improvement after 72 hours of antimicrobial therapy for pneumonia in the nursing home entailing worsening or persistent fever or hypothermia, purulent secretion, worsening of pulmonary infiltrates, or hypoxemia. Patients with severe immunosuppression (solid-organ transplantation or steroid therapy of 20 mg/day or more for more than 2 weeks), witnessed aspiration, or an expected terminal event from metastatic cancer were excluded. Similarly, patients who were transferred to the ICU after 24 hours of initial admission to the ward or who were hospitalized within 30 days of admission were also excluded.

Data Collection
Demographic data included age, sex, activity of daily living score (13), comorbid illnesses (14), prior hospitalizations, and antimicrobial therapy in the preceding 12 months (see online data supplement). In addition, the following parameters were recorded on ICU admission: clinical symptoms, vital signs, laboratory data, the Acute Physiology and Chronic Health Evaluation II score (15), and antibiotic coverage. At the clinical endpoints of hospital discharge or death, the length of mechanical ventilation and ICU stay and modification of antimicrobial therapy were recorded. The decision of continuing or withholding antimicrobial treatment was the responsibility of the primary health care provider.

Microbiological Evaluation
Initial microbial investigation included two sets of blood cultures, serology, and respiratory samples obtained by flexible bronchoscopy with (1) protected brush specimen, (2) bronchoalveolar lavage (BAL), or (3) distally blindly placed catheter for protected BAL (see online data supplement). Paired sera (at admission and after 4 weeks) were performed. These were tested for serologic evidence of infection with Chlamydia species, Legionella pneumophila, as well as respiratory viruses (influenza viruses A and B, parainfluenza viruses 1 to 3, and respiratory syncytial virus). Fiberoptic bronchoscopy was performed within 24 hours of inclusion in the study. A standardized reporting form about the visual inspection of the trachea and proximal bronchi for erythema and endobronchial obstruction and appearance of the distal bronchi for the presence and quality of secretions after aspiration was conducted. Urinary samples were assayed for the Legionella and pneumococcus antigens.

Diagnostic Criteria
Infectious etiology of pneumonia was considered present if one of the following criteria was met: (1) blood cultures or pleural fluid yielding a bacterial or fungal pathogen in the absence of an apparent extrapulmonary focus; (2) seroconversion, a fourfold increase in immunoglobulin G titers for Chlamydia pneumoniae, L. pneumophila, and respiratory viruses (influenza viruses A and B, respiratory syncytial virus, and parainfluenza viruses 1 to 3); (3) positive urinary antigen for L. pneumophila type 1 or for Streptococcus pneumoniae; and (4) bacterial growth of 10³ or more colony-forming units/ml of a pathogenic microorganism from a protected brush specimen or growth of 10⁴ or more colony-forming units/ml of a pathogenic microorganism from BAL or a distal blindly placed catheter for protected BAL (see online data supplement). Isolation of fungi from respiratory samples was considered diagnostic only in the presence of a positive concomitant blood culture growing the same organism. For the purpose of this article, we have defined the term "definite pneumonia" as those cases in which an infectious etiology was identified. A noninfectious etiology indicated a definite alternative diagnosis. The term "unverified pneumonia" was used otherwise. The term "negative microbial investigation" was used to refer to cases where the diagnostic work up did not reveal the presence of a microbial pathogen (i.e., it referred to patients with noninfectious etiology plus those with unverified pneumonia).

Statistical Analysis
Results were expressed as means ± SD. Continuous variables were compared using Student's t test for normally distributed variables and the Mann-Whitney test for nonnormally distributed variables. Proportions were compared using the chi-square test with Yates correction or Fisher's exact test when necessary. Multivariate analysis to predict infection with nosocomial pathogens was performed by stepwise logistic regression. All reported p values are two tailed. The level of significance was set at 5%.

RESULTS

Study Population
Sixty-one patients met the eligibility criteria for enrollment. Informed consent could not be obtained from seven subjects, and two refused participation. For those patients with more than one ICU admission during the study period, only the first ICU admission was included in the analysis to ensure independence of observations. Patient characteristics are shown in Table 1 . Thirty eight (72%) had at least two comorbidities, including 12 (23%) who had more than three. Dementia was the most common comorbidity (48%), followed by pulmonary (35%), diabetes mellitus (17%), and cardiac comorbidities (17%).

Etiology of Treatment Failure
A definite etiology of treatment failure could be established in 24 of 52 patients (46%). A causative pathogen was recovered in 20 subjects (39%). There were no significant differences in terms of demographic, functional status, Acute Physiology and Chronic Health Evaluation II, or the Fine score between those who had a definite pneumonia and those with unverified pneumonia (Table 3) . A detailed list of the pathogens involved is shown in Table 4 . Methicillin-resistant S. aureus (MRSA) represented 33% of the total isolates (7 out of 21) and was the predominant pathogen isolated from six institutionalized older persons with treatment failure. Four out of the six patients with MRSA had been hospitalized on at least one occasion in the year before their recent admission. Enteric Gram-negative bacilli were the second most frequent pathogens recovered (24%), followed by P. aeruginosa (14%). Anaerobic infection with Bacteroides fragilis was documented in one patient, whereas none of the 39 participants tested for the presence of C. pneumoniae were positive. An empyema secondary to S. pneumoniae was diagnosed in one patient after the urine antigen for streptococcus turned out positive. In two cases, the etiology of pneumonia was considered polymicrobial: S. plus P. aeruginosa in the first and Escherichia coli plus Enterobacter sp. in the second.

The appearance of the trachea and proximal bronchi was not significantly different between those with definite or unverified pneumonia. However, the presence of persistent purulent secretions emanating from distal bronchi was present in 16 of 20 definite pneumonia cases (80%) compared with 5 of 32 with negative microbial investigation (16%) (p < 0.001). In comparison, Gram stains of bronchial secretions were positive in 15 out of 20 patients with definite pneumonia and in 6 out of 32 with negative microbial investigation, yielding a sensitivity of 75% (95% confidence interval, 51 to 91%) and a specificity of 81.3% (95% confidence interval, 64 to 93%).

Antimicrobial Treatment
Table 6 compares the antimicrobial treatment prescribed in the nursing homes with the American Thoracic Society (16, 17) and Infectious Diseases Society of America guidelines (18). The antimicrobial regimens consisted of amoxicillin/clavulanic acid (n = 13), ceftriaxone (n = 14), ciprofloxacin (n = 4), levofloxacin (n = 12), clindamycin (n = 1), trimethoprim sulfamethoxazole (n = 7), and doxycycline (n = 1). All but ceftriaxone were administered either orally or through a feeding tube. The mean duration of antibiotic therapy was 5.4 ± 2.2 days (Table 7) . Five patients failed outpatient antimicrobial therapy despite adequate antibiotic coverage. All five were receiving oral formulation. There was no significant difference with regard to activities of daily living, presenting symptoms, or clinical parameters to distinguish those patients from those who had inadequate antimicrobial coverage at the nursing home.

Invasive bronchial samplings directed a change of antimicrobial therapy in 8 of 20 patients (40%) in which an etiology was identified (Figure 1) . The antibiotics most often introduced based on culture results were vancomycin in five cases and fourth-generation cephalosporin in four cases. The patient who had M. tuberculosis was started initially on four antituberculous drugs; however, he died before the sensitivity was available. Alternately, antibiotics were discontinued on two patients whose bronchial samplings tested positive for influenza A viral antigens and on three of four patients with noninfectious etiology (Figure 1). Five of 28 cases (18%) of unverified pneumonia had their antibiotics changed empirically because of clinical deterioration, and 11 had their antimicrobial therapy discontinued for lack of documented respiratory infection. None of the 11 cases with unverified pneumonia had documented persistent purulent secretion during exhalation on bronchoscopy or a positive Gram stain on bronchial specimens.

View larger version (23K): [in this window] [in a new window]   Figure 1. A flow diagram detailing the study population enrolled, the Gram-stain results of invasive bronchial samplings, and the therapeutic changes instituted (BOOP = bronchiolitis obliterans organizing pneumonia, CAP = community-acquired pathogens, D/C = discontinued, FB = foreign body, GS = Gram stain, NP = nosocomial pathogens, PE = pulmonary embolism).

DISCUSSION

This study is the first to evaluate the etiology of antimicrobial failure in institutionalized older persons with severe pneumonia. It provides three important findings: (1) "nosocomial" pathogens were likely to be responsible for severe NHAP in those who have received prior antimicrobial therapy. (2) Invasive diagnostic approach in institutionalized patients with treatment failure might be helpful in streamlining antibiotic coverage. (3) Visualization of the tracheobronchial tree when combined with microbial investigation might be useful in determining the presence of bacterial pneumonia.

One previous study has assessed the impact of diagnostic strategy on antibiotic use and outcome in community acquired pneumonia with antimicrobial treatment failure. On the basis of a prospective study evaluating 49 patients with nonresponding community-acquired pneumonia, Arancibia and colleagues (19) reported a definite etiology of treatment failure in 65% and a probable etiology in another 18%. Treatment failures were mainly infectious and were attributed mostly to microbial resistance to the initial antimicrobial treatment. However, the study had important limitations related to the lack of inclusion of institutionalized older persons and the inclusion of subjects with in-hospital treatment failure. The recent American Thoracic Society guidelines for the management of adults with community-acquired pneumonia recognized the uniqueness of patients with nursing home pneumonia in terms of the diversity of microbial pathogens and the importance of local antibiotic susceptibility of offending agents (17). The guidelines pointed out that MRSA, enteric Gram-negative bacteria, and viral microbes are particularly more recognizable in this group and should be considered when antimicrobial coverage is prescribed. Our study confirms the validity of these statements and appears even more relevant for those institutionalized older persons who failed outpatient antimicrobial therapy. Indeed, MRSA and enteric Gram-negative bacilli infection represented 50% of the microbial etiologies of those confirmed with pneumonia and accounted for the majority of treatment failures.

The controversy over the use of quantitative invasive techniques in the evaluation of patients with clinical suspicion of pneumonia has been the subject of continuous debate. Some researchers who advocate the use of bronchoscopic techniques argue that visualization of the tracheobronchial tree is useful for the diagnosis of pneumonia. Timsit and colleagues (20) described three factors that are highly predictive of ventilator-associated pneumonia during bronchoscopy. Among these factors, the persistence of the distal purulent secretion from distal bronchi during exhalation was found to be useful in confirming the presence of pneumonia in 80% of those who had positive bronchial cultures in our study. Furthermore, the addition of bronchoscopic techniques to the diagnostic criteria for pneumonia resulted in adjustment of empirical antibiotic coverage in 40% of patients and withholding of antimicrobial therapy in another 10% of cases with definite pneumonia.

The impact of quantitative bronchoscopic sampling on mortality remains controversial. In a randomized trial of 91 patients with suspected ventilated-associated pneumonia, Solé Violán and colleagues (21) found no mortality difference between invasive quantitative techniques and noninvasive qualitative approach. Recently, Fagon and coworkers (22) reversed that trend by reporting an improved outcome in the group investigated by an invasive diagnostic approach. Small sample size and a lack of standardized approach to treatment among study designs have been the major limitations. A similar case could be made here; however, the objective of this study was not intended to address this question.

The yield of microbial recovery in our study was lower than previously reported in patients with antimicrobial treatment failure (19). Prior antimicrobial therapy is known to affect the results of bacterial tests and may preclude the recovery of organisms from respiratory secretions (23, 24). In this situation, the diagnostic accuracy may be increased if antibiotic treatments are discontinued 48 hours before sample collection (25). However, antibiotic discontinuation may pose undue risks particularly when delay of therapy is associated with increased mortality (26). A delay in mounting a serologic response for Chlamydia and Legionella might have also accounted for the low yield of atypical pathogens. In one study of 42 culture-proven L. pneumophila, 41% of the patients did not seroconvert within 4 to 6 weeks (27). Another potential factor implicated in the lower yield rate pertains to the higher incidence of aspiration in the older population that could mimic the manifestation of pneumonia. Kikuchi and coworkers (28) investigated the occurrence of "silent" aspiration during sleep in 14 older patients with community-acquired pneumonia compared with age-matched control subjects by applying a paste containing indium-111 wrapped in a gauze and fixed to the teeth. After scanning the thorax, aspiration was documented in 71% of the study patients compared with 10% of the control subjects (p < 0.02).

The percentage of MRSA and Pseudomonas in our study was relatively high. This observation is of crucial significance because most common initial empirical regimens were targeted toward community-acquired endogenous pathogens. Several factors may explain the high prevalence of "nosocomial" pathogens in our study population. Methicillin-resistant S. aureus is classically found in older adults with underlying diseases, particularly those with pulmonary comorbidity (29). It frequently colonizes the nares of nursing home residents at a rate that is similar to those in hospitals through out the United States (30). More significantly, it is estimated that the persistence of MRSA carriage can be as high as 70% at 30 or less months after hospital discharge with a half-life of 40 months among readmitted patients (31). In this study, 67% of patients with confirmed MRSA infection were hospitalized in the year before their admission. Prior use of antibiotics remains the most significant risk factor linked to the isolation of drug-resistant organisms. In a study of ventilator-associated pneumonia caused by S. aureus, Rello and coworkers (32) found that all patients with MRSA ventilator-associated pneumonia had recently received antibiotics compared with 21% of those with methicillin-sensitive S. aureus. In another study, the same investigators noted that the rate of pneumonia caused by P. aeruginosa was significantly higher in patients who had received prior antimicrobial treatment (33). In agreement with these studies, our data strongly support the observation that prior use of antibiotics is a strong determinant in selecting potentially resistant organisms with an odds ratio of 24.5 (95% confidence interval, 3.3 to 118.7). Another potential risk factor for the high frequency of nosocomial pathogens lies in the delay of oral clearance of oropharyngeal pathogens (34) in a severely compromised population with a high incidence of pulmonary comorbidity and malnutrition (17). At this time and until more data become available, antimicrobial therapy for antimicrobial treatment failure in institutionalized older patients hospitalized with severe pneumonia should consider two antipseudomonal agents with selected ß-lactam and antipseudomonal quinolone in addition to vancomycin in those with prior antibiotic exposure until results of sputum and blood cultures are available.

Several limitations should be considered when interpreting the results of this study. First, we do not know whether these data are broadly applicable to other long-term care facilities. Nonetheless, there is growing concern regarding the rise of "nosocomial" pathogens in long-term care settings, and our results seem to echo this trend. Second, patient-related advance care directives and patient choices on hospitalization and therapeutic interventions might have interjected a bias on the microbiology profile that we have reported. The selection bias could have been introduced by the health care providers in referring patients for aggressive treatment while restricting others in whom aggressive treatment would have been considered futile. Third, prior antibiotic therapy could have altered the results of the microbial investigations raising potential concern of discontinuing therapy on those patients with negative cultures and no documented purulent secretions on bronchoscopy. The favorable outcome of those patients, however, argues in favor of this approach. Nonetheless, further studies are needed to confirm these observations.

In summary, we found that invasive diagnostic methods in institutionalized older persons with treatment failure may give information that could lead to modification of antibiotic regimen. Treatment with prior antibiotics should alert for the possibility of nosocomial pathogens in institutionalized older patients hospitalized with antimicrobial failure.

FOOTNOTES

Supported by a grant from the Research for Health in Erie County.

This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form February 18, 2002; accepted in final form July 18, 2002

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This Article Abstract Full Text (PDF) Online Data Supplement All Versions of this Article: 200202-123OCv1 166/8/1038    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by El-Solh, A. A. Articles by Davies, J. Search for Related Content PubMed PubMed Citation Articles by El-Solh, A. A. Articles by Davies, J.