INTRODUCTION

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Viridans streptococci comprise a heterogeneous group of facultatively anaerobic, gram-positive cocci that do not produce catalase or coagulase, and rarely produce -hemolysis on sheep blood agar (1). As an important part of the normal microbial flora of humans, these organisms are indigenous to the upper respiratory tract, the female genital tract, and the gastrointestinal tract (2). Infections caused by viridans streptococci usually result from spread of the organisms outside of their normal habitat. Although strains of viridans streptococci are known to be the most common etiologic agents in bacterial endocarditis, their involvement in diseases other than endocarditis has not received much attention (2).

Although primary pneumonia due to viridans streptococci has rarely been described (3, 4), early reports had documented the recovery of these organisms in specimens of empyema and lung abscess (5). In these studies, however, the organisms were regarded as minor pathogens, although several of the strains appeared as pure isolates. Despite the demonstration that viridans streptococci are capable of elaborating potentially toxic and damaging extracellular proteases that may cause apparent clinical disease (9), most microbiology laboratories do not identify these organisms in clinical specimens to the species level because of their uncertain role in the pathogenesis of the diseases in which they are found, as well as the difficulty in identifying viridans streptococci with conventional biochemical tests. Since the introduction of schemes for species identification (10, 11), the S. milleri group of viridans streptococci have received attention because of their frequent isolation from various suppurative infections (12), but there are only a few reports describing the clinical features of pleuropulmonary diseases caused by species of viridans streptococci other than those of the S. milleri group (16).

The Microbiology Laboratory of National Taiwan University Hospital began identifying the species of viridans streptococci isolated from specimens collected from normally sterile sites in 1984. To determine the role of these organisms in the pathogenesis of empyema and lung abscesses in patients at our hospital, we retrospectively reviewed the clinical features of patients with empyema and/or lung abscesses as well as the antimicrobial susceptibility of the isolates seen in a 12-yr period. We found that species of viridans streptococci were frequently isolated from patients with empyema and/or lung abscess, and were associated with a high mortality rate. Patients infected with non-S. milleri species had significantly higher mortality and deserved clinical attention.

	METHODS

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We retrospectively analyzed the medical records of patients with empyema and/or lung abscesses treated at National Taiwan University Hospital (NTUH) from January 1984 to September 1996. NTUH, a major teaching hospital in northern Taiwan, had 1,200 beds before 1991 and 1,500 beds as of 1991. Case records were selected through a computerized search of diagnoses codified at hospital discharge. The diagnosis of empyema was established clinically when thick, purulent- appearing (puslike) pleural effusion was recovered by thoracocentesis or tube thoracostomy, and light microscopic/routine examination of the specimen revealed a white blood cell (WBC) count of more than 15,000/µl with neutrophil predominance (19). The diagnosis of lung abscess was made clinically when there was radiographic evidence of a pulmonary parenchymal infiltrate with an air-fluid level indicating a cavity at least 2 cm in diameter. Only the records of patients that were available for review and contained additional proof of isolation and identification of viridans streptococci to the species level from the pleural effusion or aspirate of the lung abscess were included.

The following data were collected for each patient: age and sex; predisposing factors, including important underlying disease and associated medical conditions; clinical symptoms; peripheral WBC counts and differential counts; strains of pathogens isolated from cultures of the pleural effusion or lung abscess; antibiotic susceptibility tests of the viridans streptococci isolated; the regimen and duration of antibiotic therapy; use of intrapleural fibrinolytic therapy; invasive drainage procedures or surgery; duration of hospitalization; and outcome.

Evaluation of the etiopathogenesis of each patient's disease was based on the history and clinical picture described in the medical records. A patient was considered to have pneumonia prior to the development of empyema or lung abscess if there was radiographic evidence of a parenchymal infiltrate adjacent to the location of the empyema thoracis or lung abscess, and/or there were fever and apparent productive cough with purulent sputum as initial manifestations. The diagnosis of aspiration pneumonia was made when there were symptoms and radiographic evidence suggestive of pneumonia and the patient had clinical illness with a proneness to vomiting and/or aspiration.

Specimens were collected under aseptic conditions: pleural fluid specimens were obtained by thoracentesis or during tube thoracostomy; lung abscess specimens were obtained by ultrasound-guided percutaneous needle aspiration or during surgical intervention (lobectomy). The specimens were processed according to standard procedures (20), and were cultured for both aerobic and anaerobic bacteria. In most cases, the specimens were examined microscopically and were also cultured for mycobacteria and fungi. All isolates were considered significant if their colonies showed moderate or heavy growth on a primary isolation plate, corresponding to more than 10⁵/ml to 10⁷/ml of bacteria in the specimen, and were identified to the species level on the basis of methods described previously (1) as well as with the API20 STREP (bioMerieux, Marcy l'Etoile, France) system. The antimicrobial susceptibility of the strains isolated, and of all coisolates, was determined with the disc diffusion technique according to National Committee for Clinical Laboratory Standards (NCCLS) guidelines (21). In 1996, the minimum inhibitory concentrations (MICs) of penicillin for the isolated strains of viridans streptococci were determined with the standard agar dilution method (22).

Patients with empyema underwent standard tube thoracostomy or continuous closed drainage with an indwelling pigtail catheter unless the clinical condition or scarcity of effusion ruled out invasive procedures. Patients received intrapleurally instilled streptokinase or had open drainage if there was radiographic or sonographic evidence of loculation of pleural effusion with poor drainage, and the clinical condition suggested persistent inflammation. Patients with lung abscess underwent further surgical intervention if the abscess, evaluated by follow-up of its size on serial radiographs, responded poorly to appropriate antibiotic therapy, with persistent symptoms and signs of systemic inflammation.

Proportions of age, sex, underlying conditions, bacterial isolates, and leukocyte count were compared with the chi-square test. Multivariate analysis was performed with the logistic regression model of the SAS software package (SAS Institute Inc., Cary, NC). A value of p < 0.05 was considered significant.

	RESULTS

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Clinical Characteristics of Patients

From January 1984 to September 1996, 387 patients with a clinical diagnosis of empyema and/or lung abscess were eligible for the present study. Of the 255 patients with microbiologically documented diagnoses, 72 (28%) had viridans streptococci identified to the species level, including 53 patients (32%) with empyema, 14 (19%) with lung abscess, and five (38%) with both empyema and lung abscess (Table 1). Two cases of lung abscess were proved microbiologically by lobectomy. The other 70 cases were proved microbiologically by diagnostic thoracocentesis, tube thoracostomy, or transthoracic needle aspiration.

The demographic and clinical features of the 72 patients with proven viridans streptococci infections, separated into three groups, are summarized in Table 2. Sixteen patients (22%) were over 65 yr of age. The mean age of the group with both empyema and lung abscess (68 yr) was greater than that of the empyema or lung abscess groups. Male patients predominated in all groups, especially in the lung abscess group (93%). Underlying diseases or associated medical conditions were present in 46 (64%) of the 72 patients, especially in patients with both diseases (80%). Among the 72 patients, the most common underlying condition was malignancy, including lung cancer (five patients), colorectal cancer (three patients), hepatocellular carcinoma (two patients), esophageal cancer (two patients), and ovarian cancer, cervical cancer, nasopharyngeal cancer, lymphoma, and brain tumor (one patient each). In the lung abscess group, however, only one patient (7%) had an underlying malignancy (esophageal cancer). Medical records of evaluation for periodontal diseases were not available for most of our patients. Among the 72 patients, the most common manifestations of pulmonary infection were fever (76%), leukocytosis (67%), chest pain (65%), cough (70%), and expectoration (61%). There was a wide range of leukocyte counts among the patients in all three groups.

Microbiology

A total of 76 strains of viridans streptococci were isolated from the 72 patients and were identified to the species level (Table 3); four patients had more than one strain of viridans streptococci isolated. In 38 (53%) of the patients, viridans streptococci were found to be the sole pathogens isolated. Species belonging to the S. milleri group accounted for the majority of isolates in all grous. Fifty-five strains of pathogens other than viridans streptococci were isolated from 34 patients, representing mixed infections (Table 4). There was an average of 1.8 different bacterial species in each case. Among all coisolates, anaerobic pathogens accounted for the majority (68%) of strains, with the most common pathogen in mixed infections being Bacteroides spp., followed by Veilonella spp., and Peptostreptococcus spp. During the course of their hospitalization, none of the 72 patients had bacteremia caused by viridans streptococci. All isolates of viridans streptococci were uniformly susceptible to penicillin according to the disc diffusion method. Fifty strains were available for determination of the MIC of penicillin, with the range being  0.03 to 0.25 µg/ml.

Treatment and Outcome

Treatment and outcome of the 72 patients with viridans streptococcal infections are summarized in Table 5. All patients received antibiotic therapy, and the regimens were adjusted according to the microbiologic findings. Beta-lactam (penicillin and cephalosporins) antibiotics were used in 71 (99%) of the patients. Thirteen (17%) patients were treated with penicillin G as a single regimen throughout their hospital course, whereas three (4%) patients received a cephalosporin alone. The rest of the patients (79%) were treated with additional antimicrobial agents combined with penicillin or cephalosporins, with the most common agents being aminoglycosides (43%), followed by clindamycin (33%) and metronidazole (24%). For all patients, antimicrobial agents were used for at least 4 wk unless the patient died within 4 to 6 wk. The median hospital stay was 30 d (mean: 32 d; range: 5 to 180 d), and was similar in the three groups (means: 32, 31, and 30 d for empyema, lung abscess, and both entities, respectively). Fifteen (21%) patients died: 10 had underlying malignancies and nine had polymicrobial infections. Of the 10 patients with empyema who received antibiotic alone or in combination with simple thoracentesis, three (30%) died, whereas six (28%) of the 21 patients with empyema who underwent tube thoracostomy died. Of the 27 patients who received intrapleurally instilled streptokinase and/or had surgery for apparent loculation, five (19%) died, all of whom underwent surgical procedures.

The clinical, epidemologic, microbiologic, and laboratory variables studied, as well as their relative influence on mortality (univariate and multivariate analysis) of patients with empyema alone are summarized in Table 6. This table shows that underlying malignancy (odds ratio [OR] = 16.0, p = 0.023) and non-S. milleri isolates (OR = 3.72, p = 0.030) were significantly and independently associated with death.

	DISCUSSION

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Our findings were that viridans streptococci were significant pathogens in empyema and lung abscess, and that in a significant portion of isolates these organisms were recovered as the sole pathogens. Although all isolates of viridans streptococci were sensitive to penicillin, the mortality rate from pleuropulmonary infections due to viridans streptococci was surprisingly high. Although species belonging to the S. milleri group accounted for two thirds of the viridans streptococcal isolates, we found that patients with empyema and non-S. milleri isolates had a significantly and independently greater risk of death than patients with other viridans streptococcal isolates.

For decades, viridans streptococci have been isolated in cultures from empyema and lung abscess in humans. Owing to the extensive changes that have occurred in microbiologic nomenclature and taxonomy, however, it is not easy to collate the literature pertaining to bronchopulmonary diseases caused by the viridans group of streptococci. In early reports of the microbiology of empyema and lung abscess, in which "viridans streptococci" might have indicated -hemolytic and nonhemolytic streptococci, and different terms such as microaerophilic streptococci or even simply streptococci were also used, these organisms accounted for up to 18% of cases of empyema and 8% of cases of lung abscess (6, 8). With the application of species identification of viridans streptococci, recent studies found that strains of viridans streptococci accounted for 3% to 15% of isolates in cases of empyema (23, 24) and 18% of isolates in cases of lung abscess (25). In our present series of patients, viridans streptococci were more frequently isolated. One reason for this might have been that patients with complicated, nonpurulent-appearing parapneumonic effusions were not included in our study. Viridans streptococci may be less frequently encountered in patients with acute parapneumonic effusions, since their involvement in primary pneumonia has rarely been described. Pleuropulmonary infections caused by pathogens other than viridans streptococci might, however, produce more acute symptoms, and current treatment of the infections is usually effective. Thus, progression to empyema caused by pathogens other than viridans streptococci of parapneumonic effusions might be encountered less often than previously. Although serious infections due to penicillin-resistant strains of nonviridans streptococci have been reported (26), the higher frequency of viridans streptococcal pleuropulmonary infections in our series was not caused by penicillin resistance, which was not found.

The clinical characteristics of pleuropulmonary infections with viridans streptococci in our series included a male preponderance, varying clinical presentations, and frequent requirement of intrapleurally instilled streptokinase or open drainage for loculated pleural effusion. Since detection of true loculation of pleural effusion requires specific imaging studies, such as computed tomography (CT) or sonography, and the use of instilled streptokinase or drainage in our patients was determined mainly by clinical judgment, we have no data concerning the true incidence of pleural loculation in this series. Most of the patients in our series had no underlying chronic pulmonary disease, suggesting that viridans streptococci may be of low virulence as bacterial colonizers of the lower respiratory tract. Our finding in this regard is compatible with the fact that viridans streptococci isolated from the sputum of patients with chronic pulmonary diseases have been uniformly regarded as contaminants rather than true pathogens.

Nearly 63% of our patients with polymicrobial infection had anaerobes as coisolates. Although anaerobic bacteria have been known for their pathogenic role in empyema and lung abscess, it has also been noted that viridans streptococci are frequently isolated together with anaerobic organisms in patients with lung abscess or empyema, suggesting infection from an oropharyngeal source and an aspiration mechanism. Although it has been proposed that species of the S. milleri group may act in synergy with anaerobic pathogens in causing tissue damage and spread of infection (27), the clinical features of pleuropulmonary infection caused by viridans streptococci in our series did not differ from those of pleuropulmonary infection of polymicrobial etiology, including that in which anaerobes were among the causative organisms.

Recently, viridans streptococci have become a major concern in neutropenic patients undergoing chemotherapy, since they may be responsible for up to 39% of cases of bacteremia in this patient population (28), and resistance to penicillin has been found in up to 50% of the isolated strains (29). Although underlying malignancy was the most common factor predisposing to viridans streptococci empyema or lung abscess in the present study, no patients had neutropenia or bacteremia during their episodes of empyema and/or lung abscess. The majority of the etiologic pathogens in our patients, belonging to S. milleri group, were also different from the species of viridans streptococci causing bacteremia in neutropenic patients, in whom the most commonly isolated species are S. sanguis and S. mitis (28).

Treatment of empyema in our series of patients appeared more problematic than that of lung abscess. Because all isolates of viridans streptococci in the series were susceptible to penicillin, most of the patients with lung abscess alone responded well to antibiotic therapy alone. Empyema due to viridans streptococci with or without lung abscess tended to have a higher mortality rate than that due to other organisms, although the difference was not statistically significant. As the patients with empyema in this series were characterized by a frequent requirement for intrapleural streptokinase or open drainage, treatment for possible loculated empyema due to viridans streptococci may be important. Previous reports had shown that intrapleural instillation of streptokinase is effective for managing loculated pleural empyema (30, 31). In cases of empyema due to viridans streptococci, the detection of loculation, followed by early aggressive treatment, may be needed, but the timing of treatments and their efficacy must be further evaluated.

In the group of patients in our study who had empyema alone, those with non-S. milleri infections had a significantly and independently increased risk of death. This finding has never previously been reported in the English literature. In fact, although at least 17 non-S. milleri species are currently recognized as belonging to the viridans group of streptococci, literature on the bronchopulmonary disease caused by these species of organisms remains scarce. In our study, 24 strains of viridans streptococci belonging to five different non-S. milleri species were isolated. To elucidate the pathogenic role of each non-S. milleri species, identification of viridans streptococci to the species level is strongly indicated in patients with pleuropulmonary diseases, and may also be indicated in patients with diseases involving other systems. Since the case numbers of non-S. milleri-caused diseases remain limited, a universal scheme of species identification of viridans streptococci may be important. However, the species defined by different identification schemes, including the frequently used American scheme (10) and the British scheme (11), were not identical. Analysis of the pathogenic role and clinical significance of different species of viridans streptococci remains difficult. Although genetic studies have recently been used to identify these organisms to the species level (32), the possibility of their widespread use requires further evaluation.

In summary, we found that viridans streptococci were significant pathogens in empyema and lung abscess, and that they were associated with considerable morbidity and mortality. Patients with lung abscess alone had good responses to appropriate antibiotic therapy. In patients with empyema thoracis, however, early aggressive drainage may be needed in addition to appropriate antibiotic treatment. Non-S. milleri isolates are significantly and independently associated with death. Identification of viridans streptococci to the species level, based on a universal scheme, is necessary for elucidation of the pathogenic role of the organism causing pleuropulmonary disease in a particular patient.