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Infections Caused by Viridans Streptococci in Patients with Neutropenia

  1. Allan R. Tunkel1 and
  2. Kent A. Sepkowitz2
  1. 1Division of Infectious Diseases, Department of Medicine, MCP Hahnemann University, Philadelphia, Pennsylvania
  2. 2Clinical Infectious Disease Section, Memorial Sloan-Kettering Cancer Center, New York, New York
  1. Reprints or correspondence: Dr. Allan R. Tunkel, Dept. of Medicine, MCP Hahnemann University, 3300 Henry Ave., Philadelphia, PA 19129 (allan.tunkel{at}drexel.edu).
 
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Abstract

The frequency of isolation of viridans streptococci from the blood of neutropenic patients with cancer has significantly increased over the course of the last 10–15 years. Risk factors in this patient population include severe neutropenia, oral mucositis, administration of high-dose cytosine arabinoside, and antimicrobial prophylaxis with either trimethoprim-sulfamethoxazole or a fluoroquinolone. In some patients with cancer and neutropenia who develop viridans streptococcal bacteremia, a toxic shock–like syndrome has been described; Streptococcus mitis has been the causative species in most cases. Because resistance of viridans streptococci to a variety of antimicrobial agents is increasingly recognized, penicillin susceptibility cannot be assumed, and empirical vancomycin therapy should be used to treat neutropenic patients with cancer who have shock or are developing acute respiratory distress syndrome. Given the seriousness of septicemia caused by viridans streptococci and the potential for selection of other resistant microorganisms, the routine practice of antimicrobial prophylaxis for neutropenic patients with cancer should be reconsidered.

Over the course of the last several decades, the frequency with which gram-positive bacteria have been isolated from neutropenic patients with cancer has increased. Data from the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer documented that 29% of 145 single-microorganism blood culture isolates recovered during 1973–1976 were gram-positive bacteria, compared with 67% of 161 such microorganisms isolated during 1991–1993 [1]. Similar trends have also been documented in other centers. Gram-positive bacteria isolated have included Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus species. In addition, viridans streptococci have emerged as an important cause of bacteremia in neutropenic patients with cancer.

Viridans streptococci are part of the normal microbial flora of humans [2]. In the past, the terminology applied to the viridans group of streptococci was confusing and inconsistent, and recovered species were often identified as "nonhemolytic" or "α-hemolytic," rather than by a specific species designation. In the 1970s, 2 schemes for identification of the viridans streptococci were proposed. Colman and Williams suggested classification into 5 species (Streptococcus mutans, Streptococcus milleri, Streptococcus sanguis, Streptococcus salivarius, and Streptococcus mitior), and the scheme of Facklam recognized 10 physiological species (S. sanguis I and II, Streptococcus mitis, S. salivarius, S. mutans, Streptococcus uberis, Streptococcus acidominimus, Streptococcus morbillorum, Streptococcus anginosus-constellatus, and Streptococcus MG-intermedius) [reviewed in 2]. More recently, a molecular approach has been used to define the taxonomy of the viridans streptococci on the basis of genetic relatedness (table 1).

The viridans streptococci are most prevalent in the oral cavity but also reside in the upper respiratory tract, the female genital tract, and all regions of the gastrointestinal tract; they also are occasionally found as part of the skin flora. Although they are commensal organisms in these sites, these microorganisms may also invade sterile body sites, which can lead to life-threatening diseases (e.g., endocarditis, meningitis, and pneumonia). They typically cause significant infection only when the oral mucosa is significantly disrupted and host defense mechanisms are compromised, for example, in neutropenic patients with cancer [3, 4].

The first cases of viridans streptococcal bacteremia in neutropenic patients with cancer were described in 1978, when 29 episodes of bacteremia were observed in adults and children at the National Cancer Institute in Bethesda [5] and 6 episodes were reported in children at the M. D. Anderson Cancer Center in Houston [6]. Since then, the isolation of these microorganisms has become more frequent. On the basis of these findings, it is critical for physicians to consider the diagnosis of serious infection caused by viridans streptococci in patients with cancer who have neutropenia and fever. We review the epidemiological factors that increase risk of infection and the clinical manifestations and management of this emerging infectious disease.

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Epidemiology

The frequency at which viridans streptococci are isolated from the blood of neutropenic patients with cancer has significantly increased over the course of the last 10–15 years [3, 4]. At the M. D. Anderson Cancer Center, the incidence of viridans streptococcal bacteremia increased from 1 case per 10,000 admissions in 1972 to 47 cases per 10,000 admissions in 1989 (P ≤; .0001) [7]. In another study, from Switzerland (carried out during 1988–1991), viridans streptococci accounted for 30% of all episodes of bacteremia in hospitalized neutropenic patients [8]. Infection caused by viridans streptococci also has been a significant problem after bone marrow transplantation. In one study, viridans streptococci were recovered from the blood of 35 (17.5%) of 200 consecutive patients who were undergoing autologous stem cell transplantation [9]; bacteremia occurred a median of 6 days after transplantation. Similarly, of 320 patients who were undergoing bone marrow transplantation in Barcelona, Spain, during 1986–1992, 38 (12%) had viridans streptococcal bacteremia during episodes of severe neutropenia [10]. All of these studies indicate that these microorganisms have emerged as an important cause of bacteremia in immunocompromised patients.

A number of risk factors are associated with an increased incidence of viridans streptococcal bacteremia in neutropenic patients with cancer (table 2) [3, 4, 7–18]. Because the selection criteria for the control populations varied depending on the individual study and because not all studies were case controlled, published reports have identified a variety of risk factors in univariate analyses. The factors identified as significant in various multivariate analyses are discussed in more detail below.

Severe neutropenia has been identified as an important risk factor for viridans streptococcal bacteremia. In one study, 87% of case patients (patients with viridans streptococcal infection) had severe neutropenia (<100 neutrophils/mm3), compared with only 20% of control patients (patients with bacteremia caused by other gram-positive bacteria) (P < .0001) [7]. Although the association between severe neutropenia and viridans streptococcal bacteremia has been confirmed in some studies, others have indicated that bacteremia can occur in patients with less-severe neutropenia [13, 14, 19].

Mucositis, particularly in the oral cavity, appears to be another important factor predisposing patients to viridans streptococcal bacteremia [11, 15, 17]. In an analysis of data from 25 neutropenic patients with viridans streptococcal bacteremia [15], viridans streptococci with the same ribotype as the strain responsible for the bacteremia were recovered from the mouths of all patients before the onset of bacteremia. This demonstrates that the oral cavity is an important source of this microorganism and strongly suggests that disruption of the oral mucosa may lead to development of bacteremia. In one study, oropharyngeal lesions were more frequently observed in case patients than in case-matched control subjects without bacteremia (82% vs. 55%; P = .02) [8]. In another study of 24 patients with neutropenia and viridans streptococcal bacteremia, 62% had ulcerative mucositis, compared with 36% of control subjects (P < .05) [17]. Localized oral infection with herpes simplex virus may also be important; this was found to be a risk factor in a study that showed that the incidence of viridans streptococcal bacteremia decreased in allogeneic bone marrow transplant recipients after administration of acyclovir [20]. However, oral infection with herpes simplex virus has not been identified as a risk factor in other studies.

In addition to the oral cavity, the stomach may be an important point of entry for viridans streptococci. The presence of ulcers induced by chemotherapeutic regimens may allow streptococci to grow in an environment that has been made relatively more alkaline by the administration of antacids or histamine type 2 receptor antagonists. A study found a 7-fold increase in risk in patients treated with one of these agents (P < .0001), whereas the risk was not increased when sucralfate was used (P = .65) [7]. However, this finding has not been confirmed by other studies [3].

Administration of high-dose cytosine arabinoside has been implicated as another important risk factor for viridans streptococcal bacteremia [8, 12, 16]. In a study of patients with acute leukemia, 43% of patients with viridans streptococcal bacteremia, compared with 14% of patients with gram-negative bacteremia, had received high doses of this agent (P ≤; .01) [12]. Similar results were demonstrated in another study (64% for case patients vs. 14% for control subjects; P < .001) [8], although administration of this drug was not identified as a risk factor in another report [7]. In addition, repeated administration of high-dose chemotherapy may increase the risk, as was demonstrated in an analysis in which the risk of developing viridans streptococcal bacteremia was found to be 21 times higher for patients who were repeatedly exposed to high-dose chemotherapy than it was for patients receiving a first course of chemotherapy [15].

Antimicrobial prophylaxis may also play an important role in the increase in the incidence of viridans streptococcal bacteremia. Use of either trimethoprim-sulfamethoxazole or a fluoroquinolone as oral prophylaxis against gram-negative infections has been significantly associated with increased risk (P < .0001) [7]. This is not surprising, because viridans streptococci typically are resistant to these antimicrobial agents, and use of these agents would select for viridans streptococcal colonization. In one study, 75% of case patients with viridans streptococcal bacteremia had received prophylaxis with a fluoroquinolone, compared with only 22% of patients with bacteremia due to gram-negative rods (P ≤; .01) [12].

A consensus is lacking for several other potential risk factors (table 2). In some studies, children appear to be at higher risk than adults for viridans streptococcal sepsis [10, 19, 21, 22]. Similarly, bone marrow transplantation may also be a risk factor. In one study [7], 54% of patients with viridans streptococcal bacteremia had undergone autologous bone marrow transplantation, compared with only 2% of those with bacteremia caused by other gram-positive organisms (P < .0001). However, case patients were more likely to have received intravenous hyperalimentation and prophylaxis with trimethoprim-sulfamethoxazole or a fluoroquinolone and were more likely to have stayed in a laminar flow room than were control subjects. In the multivariate analysis, hyperalimentation, a stay in a laminar flow room, and bone marrow transplantation were not significant risk factors for viridans streptococcal bacteremia.

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Clinical Manifestations

As is true of the majority of types of bacteremia that are seen in patients with cancer and neutropenia, fever is the first clinical sign of viridans streptococcal bacteremia (in 83%–100% of cases) [3, 4, 9, 12]. In one case study, fever appeared an average of 9.8 days after the onset of neutropenia (<1000 neutrophils/mm3) or 6.4 days after severe neutropenia (<100 neutrophils/mm3) [8]. Fever may persist for days, even though blood culture results rapidly become negative. Other findings include flushing, chills, stomatitis, and pharyngitis. The species usually implicated in this syndrome include S. mitis, S. sanguis, Streptococcus oralis, S. salivarius, Streptococcus constellatus, S. mutans, and Streptococcus intermedius. In one report, 41% of isolates were S. mitis, 22% were S. sanguis, and 13% were Gemella morbillorum [7].

Although the majority of patients with neutropenia and viridans streptococcal bacteremia recover, a toxic shock–like syndrome (characterized by hypotension, rash, palmar desquamation, and acute respiratory distress syndrome [ARDS]) has been observed in as many as 25% of patients and in 13%–21% of children after bone marrow transplantation [3, 4, 10, 19, 23]. This syndrome is seldom encountered in patients without neutropenia. Viridans streptococcal shock syndrome may occur early or within 2–3 days after presentation and progresses to respiratory failure within 48 h [3, 4, 7, 10, 18]. Shock may appear despite rapid clearance of viable bacteria from the bloodstream [22]. In severe cases, ARDS may be observed, usually 2–3 days after the onset of bacteremia. It is unusual, however, to find localized sites of infection. Rash and desquamation of the palms and soles have also been reported (usually 8–14 days after the onset of infection) [7]. The rash, when it occurs, is maculopapular, beginning at the trunk and spreading to the face and extremities centrifugally.

The causative species in patients with viridans streptococcal shock syndrome has been S. mitis in the majority of studies [7, 11, 18]; in one analysis, all patients with ARDS had received high doses of cytosine arabinoside and had bacteremia caused by S. mitis [8]. The pathogenesis of this syndrome is not entirely clear. In vitro studies have shown that clinical isolates of viridans streptococci from patients with shock were able to induce production of TNF-α in murine macrophages [24]. Increased serum concentrations of IL-6, TNF-α, IL-1 receptor antagonist, and IL-2 receptors have also been described in patients with this syndrome [25]. Although it has been postulated that some viridans streptococcal strains might produce a toxin similar to pyrogenic toxin A, which is produced by group A streptococci [22], no exotoxin or other virulence factor of viridans streptococci has been directly implicated in this syndrome.

Pulmonary infiltrates are frequent in severe cases of viridans streptococcal bacteremia [4]. In some cases, this may be related to ARDS, to the pulmonary toxicity of cytosine arabinoside, or to other factors. However, these microorganisms must be considered to be a potential cause of primary pneumonia (in one study, viridans streptococci were the causative organism in 31% of patients [12]). A postmortem study of 3 patients who died after viridans streptococcal shock syndrome demonstrated 2 morphological phases [10]: an early phase, consisting of diffuse alveolar-interstitial damage characterized by congestion, alveolar-interstitial edema, hyperplasia of type II pneumocytes, sloughing of alveolar lining cells, and hyaline membrane formation, and a later phase, characterized by progressive interstitial and alveolar fibrosis.

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Therapy and Outcome

Initial reports of viridans streptococcal bacteremia in patients with cancer and neutropenia revealed that these microorganisms were uniformly susceptible in vitro to penicillin. However, resistance of viridans streptococci to a number of antimicrobial agents has been increasingly recognized, and penicillin susceptibility can no longer be assumed. Among 352 isolates of α-hemolytic streptococci from 43 centers in the United States, 13% exhibited high-level penicillin resistance (MIC, ≥4.0 μg/mL), and 43% had intermediate resistance to penicillin (MIC, 0.25–2.0 μg/mL); high-level penicillin resistance was more common among strains of S. mitis (16%) and S. salivarius (17%) than among S. milleri strains (2%) [26]. Furthermore, 20% of strains were resistant to cefuroxime, 17% were resistant to ceftriaxone, and ã33% were resistant to erythromycin. In patients with cancer, neutropenia, and viridans streptococcal bacteremia, similar patterns of resistance have been reported (table 3) [18, 27, 28]. At Memorial Sloan-Kettering Cancer Center, during calendar year 2000, 44% of 50 viridans streptococcal isolates causing bacteremia were resistant to penicillin; 26% exhibited intermediate resistance (penicillin MIC, 0.5 μg/mL), and 18% exhibited high-level resistance (penicillin MIC, ã0.5 μg/mL) (K.A.S., unpublished data).

In vitro resistance of viridans streptococci to vancomycin has not been reported. Other antimicrobial agents with excellent in vitro activity against viridans streptococci (100% susceptibility) include quinupristin-dalfopristin, teicoplanin, and telithromycin [29–32], although further studies are needed before these agents can be used to treat neutropenic patients with viridans streptococcal bacteremia. The fluoroquinolones, including the newer agents, are not sufficiently active against viridans streptococci to warrant use in treatment or prophylaxis.

Antimicrobial selection for treatment of viridans streptococcal infections must take into account the local in vitro pattern of antimicrobial susceptibility. As a result of the increased incidence of viridans streptococcal bacteremia in neutropenic patients and the widespread resistance of these microorganisms to various β-lactam agents, some cancer centers now routinely include vancomycin in their initial empirical antimicrobial regimens for neutropenic patients [3, 4]. In a study of neutropenic patients with cancer who had bacteremia caused by α-hemolytic streptococci, mortality was higher when vancomycin was not included in the initial empirical antimicrobial regimen (14% vs. 0%; P = .04) [33]. Although this approach may successfully decrease the mortality associated with viridans streptococcal disease, the potential that infections caused by other resistant pathogens, such as vancomycin-resistant Enterococcus species, may be promoted must be carefully considered. As always, each medical center should develop its own guidelines, but we believe that empirical therapy with vancomycin should be used only for those neutropenic patients with cancer who have shock or are developing ARDS.

Despite early initiation of appropriate antimicrobial therapy, the mortality for viridans streptococcal bacteremia in neutropenic patients with cancer has ranged from 0% to 18% [7–9, 11, 14, 16, 18]. However, bacteremia may not always be the only factor leading to the patient's death. In small series of patients with viridans streptococcal shock syndrome, mortality was quite high, ranging from 60% to 100% [10, 15, 18, 22].

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Prevention

Because viridans streptococci are now an important emerging pathogen among patients with neutropenia, especially those who are undergoing bone marrow transplantation, some centers are using antimicrobial agents that have in vitro activity against these microorganisms to decrease colonization and, it is hoped, to prevent infection [3, 4]; the agents used have included penicillin, ampicillin, vancomycin, and roxithromycin. At one center, the incidence of streptococcal bacteremia was reduced from 11.5% in 1989 to <2.5% in 1995 after the introduction of penicillin prophylaxis for neutropenic patients, although streptococcal resistance increased [34]. In another study, 22 (8.5%) of 259 patients who received fluoroquinolone prophylaxis developed viridans streptococcal bacteremia, compared with 3 (3.7%) of 82 patients who received prophylaxis with a fluoroquinolone and penicillin (P = .07); however, the 3 episodes of viridans streptococcal bacteremia in the latter group were caused by strains with decreased susceptibility to penicillin [8]. Furthermore, those patients who received a fluoroquinolone and penicillin had an even higher rate of oropharyngeal colonization with viridans streptococci than did patients who received a fluoroquinolone alone. These results contrast with those of another study, in which prophylactic use of ampicillin failed to decrease the incidence of viridans streptococcal sepsis among bone marrow transplant recipients [9].

Although the published data generally suggest that prophylactic administration of antimicrobial agents that have in vitro activity against the viridans streptococci reduces the incidence of significant infection, further development of resistance in viridans streptococci and other microorganisms is of great concern [18, 28]. In addition, case-fatality rates may be higher among neutropenic patients with penicillin-resistant viridans streptococcal bacteremia than among those with infection caused by penicillin-susceptible strains [27, 34]. Given the serious nature of septicemia caused by viridans streptococci and the potential for selection of resistant microorganisms (including viridans streptococci, enterococci, and gram-negative bacilli) that may cause significant disease and increased morbidity and mortality in neutropenic patients with cancer, we believe that the routine practice of using antimicrobial prophylaxis for this patient group should be reconsidered.

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Figures and Tables

Table 1.
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Table 1.

Current taxonomic names of species of viridans streptococci.

Table 2.
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Table 2.

Factors reported to predispose individuals to development of viridans streptococcal bacteremia.

Table 3.
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Table 3.

In vitro susceptibility of viridans streptococci isolated from neutropenic patients with cancer to selected antimicrobial agents.

  • Received September 22, 2001.
  • Revision received January 9, 2002.
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  1. Clin Infect Dis. (2002) 34 (11): 1524-1529. doi: 10.1086/340402
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