Community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis

The study was approved by the Ethics Committee of our institution, but written informed consent was waived due to the non-interventional design.

The present cohort included 362 consecutive adult patients with CAP admitted to the ICU within 24 hours of admission to the emergency department in an 850-bed tertiary care university hospital (Hospital Clinic of Barcelona, Spain) between January 2003 and December 2010. The decision for admission to an ICU was made by the attending physician in all cases.

Pneumonia was defined as a new pulmonary infiltrate found on the hospital admission chest radiograph with symptoms and signs of lower respiratory tract infection. We excluded patients with immunosuppression (for example, patients with neutropaenia after chemotherapy or bone marrow transplantation, patients with drug-induced immunosuppression as a result of solid-organ transplantation or corticosteroid (> 10 mg/day) or cytotoxic therapy, and all HIV-infected patients) and healthcare-associated pneumonia patients.

The following parameters were recorded at admission: age, sex, tobacco use, alcohol and drug consumption, co-morbidities (chronic respiratory disease, including chronic obstructive pulmonary disease, asthma and bronchiectasis among others, diabetes mellitus, chronic cardiovascular disease, neurological disease, chronic renal disease and chronic liver disease), antibiotic treatment in the previous 30 days before hospital admission, treatment with corticosteroids, clinical symptoms and features (fever, cough, pleuritic chest pain, dyspnoea, mental confusion and aspiration), clinical signs (blood pressure, body temperature, respiratory rate and heart rate), arterial blood gas measurements, chest radiograph findings (number of lobes affected, pleural effusion and atelectasis), laboratory parameters (haemoglobin level, white blood cell count, platelet count, serum creatinine level, C-reactive protein level and other biochemical parameters), diagnostic procedures, empiric antibiotic therapy, ventilatory support, pulmonary complications (empyema, acute respiratory distress syndrome (ARDS) criteria, pleural effusion and surgical pleural draining) and other clinical events (cardiac arrhythmias, septic shock, and acute renal failure). The duration of treatment, length of hospital stay and 30-day in-hospital mortality were noted. We also calculated the pneumonia severity index (PSI) at admission [8].

Microbiological examination was performed in sputum, urine, two samples of blood and nasopharyngeal swabs. Pleural puncture, tracheobronchial aspirates and bronchoalveolar lavage (BAL) fluid, when available, were collected. Conventional tests were used to evaluate the presence of bacterial, parasitic and fungal agents, and of respiratory viruses. Sputum, Bronchial aspirate sample (BAS) and BAL specimens were stained using the Gram and Ziehl-Neelsen methods for bacterial and mycobacteria detection, respectively. In BAL samples, the following additional stains were used: May-Grünwald Giemsa for fungal detection and cellular differential count, and Gomori methenamine silver for Pneumocystis jirovecii. Sputum and pleural fluid samples were qualitatively cultured for bacterial pathogens, fungi and mycobacteria. Bronchial aspirate sample (BAS) and BAL samples were homogenised and processed for quantitative culture by serial dilutions for bacterial pathogens; undiluted cultures for Legionella spp., fungi and mycobacteria were also carried out.

Nasopharyngeal swabs and BAL specimens were processed for antigen detection by immunofluorescence assay and for isolation of viruses in cell culture (influenza virus A, influenza virus B, human parainfluenza viruses 1 to 3, adenovirus and respiratory syncytial virus). In addition, two independent multiplex-nested RT-PCR assays able to detect from 1 to 10 copies of viral genomes were performed for the diagnostics of respiratory viruses. One RT-PCR assay detected influenza virus types A, B and C, respiratory syncytial viruses A and B, and adenovirus. Another RT-PCR assay studied parainfluenza viruses 1, 2, 3 and 4, coronaviruses 229E and OC43, rhinoviruses and enteroviruses. All positive results were subsequently confirmed by a second independent assay.

Sputum and blood samples were obtained for bacterial culture before the start of antibiotic therapy in the emergency department. Nasopharyngeal swab for respiratory virus detection and urine samples for Streptococcus pneumoniae and Legionella pneumophila antigen detection were obtained within 24 hours after hospital admission. Blood samples for serology of atypical pathogens and respiratory virus were taken at admission and within the third and sixth week thereafter.

The aetiology was considered definite if one of the following criteria was met: blood culture positive (in the absence of an apparent extrapulmonary focus); positive bacterial culture of pleural fluid or transthoracic needle aspiration samples; elevated serum levels of IgM against Chlamydophila pneumoniae (≥ 1:64), Coxiella burnetii (≥ 1:80) and Mycoplasma pneumoniae (any positive titre); seroconversion (that is, a fourfold increase in IgG titres) for C. pneumoniae and L. pneumophila > 1:128, C. burnetii > 1:80 and respiratory viruses (influenza viruses A and B, parainfluenza viruses 1 to 3, respiratory syncytial virus and adenovirus); positive urinary antigen for L. pneumophila (Binax Now L. pneumophila urinary Antigen Test; Trinity Biotech, Bray, Ireland); positive urinary antigen for S. pneumoniae (Binax Now S. pneumoniae urinary Antigen Test; Emergo Europe, The Hague, The Netherlands); bacterial growth in cultures of tracheobronchial aspirates (≥ 10⁵ cfu/ml), in a protected specimen brush (≥ 10³ cfu/ml) and in BAL (≥ 10⁴ cfu/ml); and detection of antigens by immunofluorescence assay plus virus isolation or detection by RT-PCR testing for respiratory virus (influenza viruses A and B, parainfluenza viruses 1 to 3, respiratory syncytial virus, rhinovirus and adenovirus).

The aetiology of pneumonia was classified as presumptive when a predominant microorganism was isolated from a purulent sample (leukocytes > 25 per high-power microscopic field and few epithelial cells < 10 per high-power microscopic field) and the findings of Gram staining were compatible. For the purpose of the present study, presumptive and definitive diagnostics were analysed together.

Polymicrobial pneumonia was defined as pneumonia due to more than one pathogen. Severe CAP was defined when at least one major criterion or three minor criteria of the Infectious Disease Society of America/American Thoracic Society (IDSA/ATS) guidelines were present [9]. Appropriateness of empiric antibiotic treatment was defined when the isolated pathogens were susceptible in vitro to one of the antimicrobials administrated according to current European guidelines for microbiological susceptibility testing [10]. For Pseudomonas aeruginosa infection, adequate treatment needed a combination of two active antibiotics against the isolated strain.

Univariate and multivariate logistic regression analyses were performed to identify variables predictive of patients with polymicrobial pneumonia (dependent variable). The independent variables analysed were: age, gender, smoking, alcohol consumption, previous antibiotic, influenza vaccine, pneumococcal vaccine, inhaled corticosteroids, systemic corticosteroids, chronic cardiovascular disease, chronic renal failure, diabetes mellitus, chronic liver disease, neurological disease, chronic pulmonary disease, fever, C-reactive protein level, white blood cell count, creatinine, PSI, multilobar infiltration, ARDS criteria, shock and mechanical ventilation. Univariate and multivariate logistic regression analyses were performed to predict 30-day mortality (dependent variable). The independent variables were the previous plus the number of aetiologies and adequacy of empirical treatment, with the exception of ARDS, shock and mechanical ventilation. Variables that showed a significant result univariately (P < 0.1) were included in the multivariate logistic regression backward stepwise model. The Hosmer-Lemeshow goodness-of-fit test was performed to assess the overall fit of the model [11]. All tests were two-tailed and significance was set at 5%. All analyses were performed with SPSS version 16.0 for Windows (SPSS Inc., Chicago, IL, USA).

During the study period, 2,200 patients were hospitalised with a diagnosis of CAP. Of these, 362 (16%) patients were admitted to the ICU. The main characteristics of patients and the outcome variables are shown in Table 1.

Among the 67 patients who had received antimicrobial treatment prior to hospital admission, the median duration of treatment was 2.8 days. The types of antibiotics received were: 25 (8%) β-lactams, 20 (6%) fluoroquinolones, six (2%) macrolides and 16 (5%) unknown.

The specimens obtained included blood cultures from 330 (91%) patients, urine from 345 (95%) patients, acute and follow-up sera from 150 (41%) patients, sputum from 285 (79%) patients, bronchoscopically obtained lower respiratory secretions from 84 (23%) patients, pleural fluid in 62 (17%) patients, and nasopharyngeal and oropharyngeal swabs from 180 (50%) patients.

The aetiology of CAP could be established in 196 (54%) ICU patients. The proportion of patients with defined aetiology was higher in those with available lower respiratory tract samples, which included sputum and bronchoscopically obtained secretions (Table 2). Patients with lower respiratory tract samples were more severe, assessed by higher PSI risk classes, more frequent septic shock, ARDS criteria and the need for mechanical ventilation.

Monomicrobial infection was detected in 157 cases and polymicrobial infection in 39 cases (11% of the overall population and 20% of those with defined aetiology only), with two pathogens isolated in 33 cases and three pathogens in six cases. As shown in Table 3, the most frequently identified pathogens were S. pneumoniae, respiratory viruses, P. aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative enteric bacilli (GNEB) and L. pneumophila.

Patients with polymicrobial aetiology had previously received antibiotics less frequently, had a higher proportion of chronic respiratory and neurological diseases, less frequently presented fever at admission, had higher rates of PSI risk class V, had severe CAP according to the IDSA/ATS definition, and fulfilled ARDS criteria. The length of hospital stay and hospital mortality tended to be higher in these patients (Table 4).

As regards the aetiologic pathogens, the proportion of respiratory viruses-particularly influenza A, MRSA, P. aeruginosa, GNEB, Haemophilus influenzae and Moraxella catarrhalis - were more frequently isolated in patients with polymicrobial pneumonia, without differences in the remaining pathogens (Table 3).

Data on antibiotic treatment were available in 347 (96%) patients. The most frequent regimens were fluoroquinolones plus β-lactam (n = 217, 63%), β-lactam plus macrolide (n = 73, 21%), fluoroquinolone monotherapy (n = 39, 11%) and β-lactam monotherapy (n = 18, 5%). These regimens were similarly administered in patients with monomicrobial or polymicrobial aetiology.

The empirical antibiotic treatment was more frequently inappropriate in patients from the polymicrobial aetiology group (Table 4). When respiratory viruses were not taken into account, the pathogens most frequently associated with inadequate treatment were MRSA in 10 cases, and S. pneumoniae, P. aeruginosa and GNEB in nine cases each. None of our patients received antiviral therapy.

Several variables were significantly associated with polymicrobial pneumonia in the univariate logistic regression analyses (Table 5). Among these variables, chronic respiratory disease and ARDS criteria at hospital admission were independent predictors of polymicrobial aetiology in the multivariate analysis.

The univariate logistic regression analyses revealed several variables significantly associated with hospital mortality (Table 6). Although polymicrobial pneumonia (that is, two or more pathogens identified) was associated with increased mortality compared with the absence of defined aetiology, the differences between monomicrobial and polymicrobial aetiology were not significant, as shown in Table 4.

Among these variables, age ≥ 65 years, neurological disease, chronic liver disease and inappropriate antimicrobial treatment were independently associated with increased hospital mortality in the multivariate analysis.