Population-Based Study of Invasive Disease Due to b-hemolytic Streptococci of Groups Other than A and B

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1 MAJOR ARTICLE Population-Based Study of Invasive Disease Due to b-hemolytic Streptococci of Groups Other than A and B Laura N. Broyles, 1 Chris Van Beneden, 2 Bernard Beall, 2 Richard Facklam, 2 P. Lynn Shewmaker, 2 Paul Malpiedi, 3 Pamala Daily, 4 Arthur Reingold, 4,5 and Monica M. Farley 1,3 1 Division of Infectious Diseases, Emory University School of Medicine, 2 Respiratory Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, and 3 Atlanta Veterans Affairs Medical Center, Atlanta, Georgia; and 4 California Emerging Infections Program, Oakland, and 5 University of California at Berkeley School of Public Health, Berkeley Background. b-hemolytic streptococci of groups other than A and B (NABS) are increasingly recognized as causes of clinically significant disease, but precise information about this heterogeneous group is lacking. We report the incidence of NABS infection and describe the epidemiologic and clinical characteristics. Methods. Active, population-based surveillance for invasive NABS was performed over a 2-year period in the 8-county metropolitan Atlanta, Georgia, area and the 3-county San Francisco Bay, California, area. Clinical records were reviewed, and available isolates were sent to the Centers for Disease Control and Prevention (Atlanta) for additional microbiologic characterization. Incidences were calculated using year-appropriate US Census Bureau data. Results. A total of 489 cases of invasive NABS infection were identified (3.2 cases per 100,000 population). The median age of patients was 55 years; 64% of patients were males, and 87% had underlying diseases. The incidence was higher among black persons than white persons (4.0 vs. 2.5 cases per 100,000 population; P!.01) and increased with age among all races. Infections were community acquired in 416 cases (85%). Among the 450 patients (94%) with NABS infection who were hospitalized, 55 (12%) died. Of 266 isolates (54%) speciated at the Centers for Disease Control and Prevention, 212 (80%) were dysgalactiae subspecies equisimilis; 46 (17%) were members of the anginosus group. S. dysgalactiae subspecies equisimilis primarily presented as skin and soft-tissue infection in older patients, whereas individuals with invasive S. anginosus group infections were more likely to be younger patients with intra-abdominal infections. Conclusions. NABS comprise multiple distinct species that cause a significant number of community-acquired invasive infections. Clinical manifestations differ by species. Thus, speciation of invasive NABS may be warranted in clinical settings. Although Lancefield group A streptococci (GAS) and group B streptococci are considered the major pathogenic b-hemolytic streptococci, other non group A or B b-hemolytic streptococci (NABS) that are frequently normal inhabitants of the oropharynx, skin, and gastrointestinal and genitourinary tracts [1] are also ca- Received 4 August 2008; accepted 15 November 2008; electronically published 2 February Reprints or correspondence: Dr. Laura N. Broyles, Emory University School of Medicine, Grady Infectious Diseases Program, 341 Ponce de Leon Ave. NE, Atlanta, GA (lbroyle@emory.edu). Clinical Infectious Diseases 2009; 48: by the Infectious Diseases Society of America. All rights reserved /2009/ $15.00 DOI: / pable of causing significant disease. These include groups C, G, F, and L, of which the most common are groups G and C [1, 2]. Several studies have reported an increasing incidence of disease due to b-hemolytic group G streptococci, which have surpassed GAS as a leading cause of invasive streptococcal infection in some medical centers [3 5]. The true burden of these infections in the United States is unknown, however, and an accurate description of their clinical manifestations is lacking. Traditionally, the identification of b-hemolytic streptococci was based on hemolytic reaction and Lancefield group carbohydrate antigen. Streptococcal taxonomy has undergone significant changes in recent years [6 8], however, and general phenotypic characteristics are 706 CID 2009:48 (15 March) Broyles et al.

2 often inadequate for providing accurate identification because of a substantial overlap between species. For example, the b- hemolytic large-colony forming species, dysgalactiae subspecies equisimilis, may possess Lancefield group A, C, G, or L carbohydrate antigens [6]. b-hemolytic small-colony forming strains of the S. anginosus group may possess Lancefield groups A, C, F, or G or no group and are considered members of the viridans group streptococci [9]. The S. anginosus group is classically associated with Lancefield group F and with invasive pyogenic infections, which distinguishes them from other viridans streptococci [9 12]. Given the microbiologic heterogeneity of NABS, the classification, nomenclature, and identification of these b-hemolytic streptococci are not widely understood, especially in the clinical setting. Most studies in the medical literature categorize NABS on the basis of Lancefield group alone, and clinical laboratories rarely identify NABS isolates to the species level. Therefore, it has been difficult to determine the true burden of NABS infection and to achieve a clear understanding of the clinical characteristics of such infections. We sought to determine the incidence of b-hemolytic NABS infections and to further elucidate their epidemiologic, laboratory, and clinical characteristics. METHODS Figure 1. Annual incidence of invasive non-a, non-b b-hemolytic streptococcal infection, by sex, race, and age group. Table 1. Surveillance. Active laboratory- and population-based surveillance for invasive b-hemolytic NABS infection was performed at 2 sites in the Centers for Disease Control and Prevention s (CDC s) Active Bacterial Core surveillance (ABCs), a core component of the Emerging Infections Program. Surveillance was conducted for 2 years in the 8-county metropolitan Atlanta, Georgia, area (1 July June 2004; population, 4,464,200 persons in 2003) and in the 3-county San Francisco Bay, California, area (1 January December 2004; population, 3,213,848 persons in 2003). A case was defined as isolation of NABS from a normally sterile site (e.g., blood, CSF, or bone) for a resident of the surveillance area. Isolates were initially identified as NABS at local hospital laboratories using standard, commercially available latex agglutination kits. Detailed, standardized chart reviews of clinical and laboratory records were completed. All available isolates were sent to the CDC (Atlanta) for additional characterization based on Lancefield group, speciation, and M protein gene (emm) type and for antibiotic susceptibility testing. Laboratory methods. Isolates were identified at the CDC using conventional biochemical tests [13], enzymatic tests from the Rapid ID32 Strep system (biomérieux) [14], and identification schemes, as described elsewhere [6]. The emm types were determined as described elsewhere [15 17]. All emm type specific sequences described here are downloadable from the CDC database (ftp://ftp.cdc.gov/pub/infectious_diseases/biotech/ tsemm/). Antimicrobial susceptibility testing was performed, as described by the Clinical Laboratory Standards Institute for testing streptococci other than pneumoniae [18], with use of the microdilution method in Mueller-Hinton broth, which was supplemented with 3% lysed horse blood in customized panels (PML Microbiologicals). Species identification of invasive non-a, non-b b-hemolytic streptococcal isolates, by Lancefield group. Species Lancefield group C F G L No antigen Unknown group All isolates dysgalactiae subspecies equisimilis equi subspecies zooepidemicus canis iniae anginosus group S. anginosus constellatus, no subspecies S. constellatus subspecies constellatus S. constellatus subspecies pharyngis Total Invasive Disease Due to b-hemolytic Streptococci CID 2009:48 (15 March) 707

3 Table 2. Demographic characteristics, underlying conditions, and clinical syndromes in patients with invasive non-a, non-b b-hemolytic streptococcal infection, combined and by species group No. (%) of patients Characteristic Overall (n p 489) dysgalactiae subspecies equisimilis (n p 212) anginosus group (n p 126) Demographic characteristic Male sex 314 (64) 145 (68) 79 (63).28 Age, years!20 30 (6) 3 (1) 16 (13)! (14) 27 (13) 22 (17) (45) 98 (46) 47 (37) (35) 84 (40) 41 (33).19 Race a Black 139 (33) 69 (36) 33 (31).4 White 246 (58) 103 (54) 62 (59).42 Other 42 (10) 18 (9) 10 (10).99 Hospitalized 450 (92) 204 (96) 113 (90).02 Admitted from Home 370 (83) 152 (76) 106 (94)!.01 Patient was homeless 35 (8) 22 (11) 2 (2)!.01 Nursing home 18 (4) 13 (6) 1 (1).02 Patient died b 55 (11) 31 (15) 11 (9).12 Underlying condition c None 64 (13) 8 (4) 34 (27)!.01 Atherosclerotic cardiovascular disease 169 (35) 94 (44) 23 (18)!.01 Diabetes mellitus 151 (31) 90 (42) 32 (25)!.01 Obesity 121 (25) 63 (30) 23 (18).02 Chronic skin condition d 103 (21) 64 (30) 10 (8)!.01 Smoker 78 (16) 28 (13) 19 (15).63 Congestive heart failure 69 (14) 46 (22) 8 (6)!.01 Malignancy 59 (12) 23 (11) 19 (15).25 Cerebrovascular accident 49 (10) 25 (12) 10 (8).26 Chronic obstructive pulmonary disease 45 (9) 22 (10) 15 (12).66 Alcohol abuse 42 (9) 23 (11) 5 (4).03 HIV infection 30 (6) 15 (7) 2 (2).03 Injection drug use 24 (5) 12 (6) 3 (2).16 Cirrhosis 23 (5) 13 (6) 2 (2).05 Asthma 21 (4) 12 (6) 5 (4).49 End-stage renal disease 20 (4) 16 (8) 3 (2).05 Use of immunosuppressive medications 19 (4) 7 (3) 8 (6).19 Organ transplantation 3 (1) 2 (1) 0 (0).53 Clinical syndrome c Bacteremia without focus 106 (22) 56 (26) 27 (21).3 Cellulitis 134 (27) 87 (41) 6 (5)!.01 Peritonitis 65 (13) 6 (3) 28 (22)!.01 Appendicitis 42 (9) 1 (0.5) 22 (17)!.01 Abscess (not skin) 40 (8) 6 (3) 24 (19)!.01 Osteomyelitis 38 (8) 20 (9) 9 (7).47 Pneumonia 32 (7) 14 (7) 12 (10).33 Septic arthritis 29 (6) 12 (6) 4 (3).3 Streptococcal toxic shock syndrome 23 (5) 19 (9) 1 (1)!.01 Endocarditis 13 (3) 7 (3) 2 (2).34 P (continued)

4 Table 2. (Continued.) Characteristic Overall (n p 489) No. (%) of patients dysgalactiae subspecies equisimilis (n p 212) anginosus group (n p 126) Empyema 10 (2) 0 (0) 9 (7)!.01 Necrotizing fasciitis 5 (1) 3 (1) 2 (2).9 Meningitis 2 (0.5) 1 (0.5) 1 (1).71 P Table 3. NOTE. Patients from the San Francisco Bay, California, metropolitan area were older than were those from the Atlanta, Georgia, metropolitan area (mean age, 57 vs. 51 years; P!.01), whereas those from Atlanta were more likely to be black (46% vs. 24%; P!.01). Basic demographic characteristics were otherwise similar between the 2 populations. a Race data were known for 427 patients overall, 190 patients in the S. dysgalactiae subspecies equisimilis group, and 105 patients in the S. anginosus group. b Case-fatality rates differed significantly between the Atlanta and San Francisco Bay metropolitan areas (17% and 8%, respectively; P!.01). c Patient could have 11 underlying condition or clinical syndrome. d Examples include chronic diabetic foot ulcer, decubitus ulcer, venous stasis, and chronic lymphedema. Analysis. Incidences were calculated with year-appropriate data from the US Census Bureau. For species-level analysis, group F isolates unavailable for speciation were considered to be part of the S. anginosus group. Analysis was performed with SAS software, version 9.1 (SAS Institute). Demographic characteristics of patients in the 2 surveillance sites were compared using the paired Student s t test. Patient characteristics, clinical manifestations, and outcomes were compared between the S. dysgalactiae subspecies equisimilis group and the S. anginosus group the 2 major species groups identified using the x 2 test. RESULTS During the combined 2-year study periods, 489 cases of invasive NABS infection (175 in the Atlanta metropolitan area and 314 in the San Francisco Bay metropolitan area) were identified. Isolates were available for 266 cases (54%) and were sent to Antimicrobial susceptibility of invasive non-a, non-b b-hemolytic streptococci, by species group. Antibiotic or antibiotic class dysgalactiae subspecies equisimilis (n p 212) anginosus group (n p 19) canis (n p 5) Penicillin, ampicillin, and first-, second-, and third-generation cephalosporins No resistance No resistance No resistance Erythromycin Resistance, 61 isolates Resistance, 1 isolate (5%) No resistance (29%); intermediate, 1 isolate (0.5%) Fluoroquinolones Resistance, 2 isolates (1%) No resistance No resistance Tetracycline Clindamycin Intermediate, 123 isolates (58%) Resistance, 9 isolates (4%); intermediate, 3 isolates (1%) the CDC for further characterization. Lancefield grouping and/ or speciation was performed in the clinical laboratories for 208 (93%) of 223 cases for which isolates were unavailable. The combined annual incidence of invasive NABS infection was 3.17 cases per 100,000 population, with a higher incidence in the San Francisco Bay metropolitan area than in the Atlanta metropolitan area (4.89 vs cases per 100,000 population; P!.01). The overall incidence of invasive NABS infection was higher among black persons than white persons (3.95 vs cases per 100,000 population; P!.01) and among men than women (6.23 vs cases per 100,000 population; P!.01) and increased with age (figure 1). Isolate speciation. Species, Lancefield group, or both were available for 474 (97%) of 489 cases; 15 isolates were listed only as non-a, non-b b-hemolytic. Table 1 presents data on microbiologic characterization of isolates by Lancefield group and species among isolates that were sent to Resistance, 1 isolate (5%); intermediate, 7 isolates (37%) No resistance Intermediate, 1 (33%) of 3 isolates No resistance Vancomycin No resistance No resistance No resistance Invasive Disease Due to b-hemolytic Streptococci CID 2009:48 (15 March) 709

5 Table 4. emm Types for 217 cases of invasive non-a, non-b b- hemolytic streptococcal infection, by species. emm Type dysgalactiae subspecies equisimilis (n p 212) stg6 31 stg stg stg stg stg10 12 stg stg stg stc74a 7 stg653 6 stg stg840 6 stc stc stg11 3 stg166b 3 stg stc stg stc7901, stc7934, stc839, stg3442, stg7860, stg97, and stl1929 canis (n p 5) stg Nontypeable 4 No. of isolates 1 each the CDC. Definitive species information was known only for 266 (54%) of 489 isolates evaluated at the CDC, because clinical laboratories frequently did not perform speciation. The majority of speciated group G isolates were S. dysgalactiae subspecies equisimilis, all group F isolates were S. anginosus group, and the bulk of group C isolates were S. dysgalactiae subspecies equisimilis or S. anginosus group. Forty-two isolates were speciated by clinical laboratories only to the level of S. anginosus group and were not available for further speciation at the CDC. Patient characteristics, clinical presentations, and disease outcome by species group. Table 2 presents patient characteristics and outcomes for all cases and for the 2 largest microbiologic categories, S. dysgalactiae subspecies equisimilis and S. anginosus group. The combined median age of patients was 55 years (range, 1 day to 101 years); patients with S. anginosus group infection were significantly younger than were those with S. dysgalactiae subspecies equisimilis infection ( P!.01). Patients with S. dysgalactiae subspecies equisimilis infection were significantly more likely than those with S. anginosus group infection to be homeless or nursing home residents but were less likely to be hospitalized. In 416 cases (85%), NABS infection was community acquired; in 30 (7%) of 450 cases, NABS infection was nosocomial (which was defined as infection for which the first sample to yield a positive culture result was obtained 148 h after hospital admission). No significant differences in species distribution or in site of positive culture were noted between patients with nosocomial infection and those with community-onset infection. Underlying conditions were present in the majority (87%) of patients with invasive NABS infection, although these were more common among patients with invasive S. dysgalactiae subspecies equisimilis infection. Several common underlying medical conditions were distributed differently between the 2 species groups (table 2). Patients with S. dysgalactiae subspecies equisimilis infection often presented with skin and soft-tissue infection and streptococcal toxic shock syndrome, whereas those with S. anginosus group infection were more likely to have intra-abdominal infections, such as peritonitis and appendicitis. Although the majority of all cases were bacteremic, patients infected with S. dysgalactiae subspecies equisimilis were significantly more likely than those infected with S. anginosus group to have positive culture results only for blood samples (94% vs. 62%; P!.01). S. anginosus group was more frequently cultured from other sites, such as peritoneal fluid (21% vs. 1%; P!.01), and was more often polymicrobial (44% vs. 17%; P!.01); the most frequently isolated other organisms were Escherichia coli, Staphylococcus aureus, and Bacteroides fragilis. The NABS infections in the subset of 30 patients (6%) aged!20 years differed clinically from those in older patients. Only 7 patients (23%) had underlying medical conditions, of which the most common was asthma (2 patients [7%]). The most common clinical manifestation was peritonitis (23 patients [77%]); all patients but 1 presented with appendicitis, and most infections (20 patients [67%]) were polymicrobial. There were no deaths among pediatric patients. Unlike isolates recovered from older patients with NABS infection, isolates recovered from pediatric patients were most often group F (40%), followed by group G (36%) and group C (24%). Of 19 cases for which the isolate was speciated, 16 (84%) were caused by S. anginosus group. Antibiotic susceptibility. Antibiotic susceptibility testing was performed for all 266 isolates sent to the CDC. Results, by species group, are summarized in table 3. The antimicrobials for which resistance was noted were erythromycin, clindamycin, fluoroquinolones, and tetracycline. No penicillin or cephalosporin resistance was found. There were no statistically significant differences in antibiotic resistance by site. emm Types. emm Typing was limited to S. dysgalactiae subspecies equisimilis isolates ( n p 212) and canis isolates ( n p 5), because emm genes have never been docu- mented in other NABS species. A total of 28 emm sequence 710 CID 2009:48 (15 March) Broyles et al.

6 types were identified (table 4). The emm type stg1389 was originally seen in a S. canis isolate recovered from a dog in 1999 (unpublished data) and was subsequently reported by an independent source in another dog S. canis isolate recovered in Australia (GenBank accession number EU ). The other 4 S. canis isolates were emm nontypeable. DISCUSSION This is, to our knowledge, the first population-based study of the epidemiology and burden of NABS infection in North America and demonstrates the substantial morbidity and mortality associated with these infections. The burden of NABS infection is comparable to that caused by invasive GAS infection during the same study period and at the same ABCs sites: the incidence of invasive GAS infection was 2.89 cases per 100,000 population overall (4.48 cases per 100,000 population in the San Francisco Bay metropolitan area; 1.76 cases per 100,000 population in the Atlanta metropolitan area [ABCs; unpublished data]). Both NABS and GAS affect similar adult populations, tend to be community acquired, and affect primarily persons with underlying medical conditions [3, 19 21]. The clinical manifestations of NABS infection and the affected risk groups in our study are similar to those described in previous studies [3, 4, 20, 22, 23], although the frequency of underlying malignancies in our study was lower than in other studies [5, 21], most likely as a result of our population-based approach. The mortality rate was similar to that (8% 21%) reported elsewhere [4, 21, 24]. We have shown that S. dysgalactiae subspecies equisimilis and S. anginosus group infections present with distinct clinical manifestations and in different populations. Pediatric S. dysgalactiae subspecies equisimilis infection was uncommon, whereas infection due to the S. anginosus group was associated with younger age, intra-abdominal sites, and abscess formation a propensity described elsewhere [12, 25]. We found that most pediatric S. anginosus group infections in children were polymicrobial and represented sequelae of perforated appendicitis and associated peritonitis; this finding is supported by the fact that S. anginosus group isolates have been recovered from 20% 40% of healthy appendices [12]. The NABS recovered from our surveillance were uniformly susceptible to penicillins and cephalosporins, although a-hemolytic viridans group streptococci have shown increasing resistance to penicillin and other b-lactams [26]. In contrast, the resistance to erythromycin and tetracycline among S. dysgalactiae subspecies equisimilis is similar to rates in other b-hemolytic streptococci, such as GAS [27 29]. In other reports, as many as 40% of isolates of S. dysgalactiae subspecies equisimilis were resistant to tetracycline [25, 28, 30]. In this study, many NABS identified in clinical laboratories were members of the S. anginosus group. Because we only analyzed isolates that demonstrated b-hemolysis, it remains unclear what clinical differences, if any, exist between a-, b-, and nonhemolytic S. anginosus group isolates and what the true burden of infection is for cases involving S. anginosus group. Previous studies have shown that non b-hemolytic strains of S. anginosus are more common than b-hemolytic strains [6]. Under current protocols in many clinical laboratories, additional characterization of NABS, including antimicrobial susceptibility testing, is uncommon. However, we have shown that these b-hemolytic strains can cause significant infections that can lead to substantial morbidity and mortality, suggesting that speciation and susceptibility testing may be warranted if NABS are isolated from a sterile site. There are several limitations to our study. Only two-thirds of isolates were available for full characterization, and isolates recovered from blood samples were more likely to be sent to the CDC than were isolates recovered from other body sites; therefore, isolates recovered from patients infected with S. dysgalactiae subspecies equisimilis were more likely to be fully characterized. In addition, because ABCs collects only sterile site isolates, the burden of noninvasive disease (e.g., cellulitis) due to NABS is underestimated. However, this study is, to our knowledge, the largest reported collection of invasive NABS infections to date; incorporates data from 2 geographically distinct, major US metropolitan areas; and includes extensive characterization of the isolates. Population-based surveillance also allowed us to calculate incidences by site and age group and among other subpopulations. NABS comprise a number of distinct species that cause significant community-acquired invasive infection with substantial morbidity and mortality. Classification of streptococci in clinical laboratories based on hemolytic reaction and/or Lancefield group is inadequate for accurate identification. Speciation and antimicrobial susceptibility testing are needed to provide sufficient information for clinical decision-making. Given the incidence of invasive NABS infection, the distinct clinical presentations, and potential for increasing antibiotic resistance to macrolides and tetracycline, speciation of this heterogeneous group of bacteria is important for optimal clinical management and to improve understanding of NABS epidemiology. Acknowledgments We thank Rajesh Sathy, Susan Ray, Wendy Baughman, Pat Martell- Cleary, Suzanne Segler, Jamie Howgate, Christina Payne, Janine Ladson, Kathryn Arnold, Tim Bailiff, Tami Skoff, Carolyn Wright, Delois Jackson, Ruth Franklin, Zhongya Li, and Varja Sakota for their assistance. We are grateful to the hospitals and laboratories in the surveillance areas for their assistance in identifying cases. We thank Lane Pucko for assistance with manuscript preparation. Financial support. Support for the ABCs is provided by the CDC s Emerging Infections Program. Potential conflicts of interest. All authors: no conflicts. Invasive Disease Due to b-hemolytic Streptococci CID 2009:48 (15 March) 711

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