Eur J Clin Microbiol Infect Dis DOI 10.1007/s10096-014-2092-0
REVIEW
Streptococcus dysgalactiae subsp. equisimilis bacteremia: an emerging infection S. Rantala
Received: 19 December 2013 / Accepted: 10 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract The importance of group C and G Streptococcus dysgalactiae subspecies equisimilis (S. dysgalactiae subsp. equisimilis) as a significant pathogen has recently been better recognized. S. dysgalactiae subsp. equisimilis disease can range in severity from milder skin and soft-tissue conditions such as wound infection, erysipelas, and cellulitis, to lifethreatening necrotizing fasciitis and streptococcal toxic shock syndrome, thus sharing the clinical picture with S. pyogenes. The most common clinical manifestation of bacteremia is cellulitis. An increase in the incidence of S. dysgalactiae subsp. equisimilis bacteremia has been recognized. Invasive forms of this infection are most commonly found in elderly patients with underlying comorbidities and skin breakdown. The case fatality in bacteremia has been reported to be 15– 18 %. In this review, the epidemiology, clinical characteristics, and emm types of S. dysgalactiae subsp. equisimilis bacteremia are summarized.
Introduction Streptococcus dysgalactiae subspecies equisimilis (S. dysgalactiae subsp. equisimilis) belongs to the group of beta-hemolytic streptococci. Their identification has been based on hemolytic reaction and Lancefield group carbohydrate antigen, which is a part of the cell wall [1]. Vandamme et al. [2] divided S. dysgalactiae into two subspecies: S. dysgalactiae subsp. equisimilis, human large colonyforming group C and G streptococci, and S. dysgalactiae subsp. dysgalactiae, animal origin group C streptococci. The Lancefield group G carbohydrate may be encountered in S. Rantala (*) Department of Internal Medicine, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland e-mail: [email protected]
several beta-hemolytic streptococcal species, including S. anginosus and S. canis, but mainly in S. dysgalactiae subsp. equisimilis. This subspecies has Lancefield group C or G antigens and rarely A antigen. The species was determined by gene sequencing of the group C species, formerly named S. equisimilis, which showed it to be indistinguishable from group G S. dysgalactiae [3]. In the new taxonomy, all large colony-forming group C and G streptococci are classified as S. dysgalactiae subsp. equisimilis [4]. The phenotype of S. dysgalactiae subsp. equisimilis on sheep blood agar comprises grayish colonies surrounded by large beta-hemolysis. The phenotypic characteristics of human beta-hemolytic streptococci are presented in Table 1. S. dysgalactiae subsp. equisimilis causes a diversity of diseases similar to that caused by S. pyogenes [5]. The spectrum of S. dysgalactiae subsp. equisimilis diseases ranges from pharyngitis and skin and soft-tissue infections, such as wound infection, erysipelas, and cellulitis, to severe invasive infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome (STSS) [6]. S. dysgalactiae subsp. equisimilis is increasingly recognized as a bacteria causing not only severe soft-tissue infections but also severe systemic infections comprising STSS [7]. Some studies report an association with pharyngitis and acute poststreptococcal glomerulonephritis, and an association with acute rheumatic fever and S. dysgalactiae subsp. equisimilis isolation from the upper respiratory tract [8, 9]. The global burden of diseases caused by S. dysgalactiae subsp. equisimilis is unknown, as it is not common practice to identify group C and G streptococci to the species level in clinical laboratories. In addition, populationbased data on S. dysgalactiae subsp. equisimilis bacteremia are limited [6, 10, 11]. In this review, the incidence, predisposing factors, clinical characteristics, and outcome in S. dysgalactiae subsp. equisimilis bacteremia are summarized, along with the distribution of emm types in S. dysgalactiae subsp. equisimilis causing invasive infections. In addition, the
Eur J Clin Microbiol Infect Dis Table 1 Phenotypic characteristics of human beta-hemolytic streptococci. Adapted from (Takahashi et al. [15])
Species
Lancefield group
Hemolysis type
Colony size
S. pyogenes S. agalactiae S. dysgalactiae subsp. equisimilis S. equi subsp. zooepidemicus S. anginosus group
A B A, C, G C A, C, G, F, none
β β β β β, α, none
Large Large Large Large Small
severity of invasive infections caused by S. dysgalactiae subsp. equisimilis and S. pyogenes is compared.
Clinical manifestations of bacteremia caused by S. dysgalactiae subsp. equisimilis Skin and soft-tissue infections are particularly common in patients with S. dysgalactiae subsp. equisimilis bacteremia [6, 10–14]. Cellulitis is the most common presenting clinical manifestation [6, 11, 13]. In S. dysgalactiae subsp. equisimilis bacteremia, the infection focus can be arthritis, osteomyelitis, pneumonia, deep abscess, endocarditis, meningitis, or peritonitis, or it may remain unknown [5, 6]. It can also cause puerperal sepsis [10]. Cellulitis is more common in S. dysgalactiae subsp. equisimilis and S. pyogenes bacteremia as compared to group B streptococcal bacteremia [10, 11, 15]. Septic arthritis, again, is more common in S. dysgalactiae subsp. equisimilis bacteremia as compared to group B streptococcal bacteremia [10, 11, 15]. Osteomyelitis may accompany septic arthritis. Bacteremia is life-threatening in combination with pneumonia, necrotizing fasciitis, septic shock, or STSS. In a population-based study of invasive beta-hemolytic streptococci other than group A and B from the United States, cellulitis (41 %), bacteremia without focus (26 %), and osteomyelitis (9 %) were the three most common clinical manifestations, followed by pneumonia (7 %) and septic arthritis (6 %) [6]. Pneumonia is more frequently observed in patients with S. pyogenes bacteremia (10 %) than in those with S. dysgalactiae subsp. equisimilis bacteremia (5 %) [10]. Deep abscesses are more common in patients with S. pyogenes bacteremia (10 %) as compared to S. dysgalactiae subsp. equisimilis infection (1 %) [15]. Necrotizing fasciitis and STSS are rare in S. dysgalactiae subsp. equisimilis bacteremia [10, 16–18]. A comparison of studies reporting on the clinical manifestations and outcome of beta-hemolytic group C and G streptococcal bacteremias in the last 10 years is presented in Table 2. We can compare S. dysgalactiae subsp. equisimilis and group G streptococci isolates, as most S. dysgalactiae subsp. equisimilis isolates possess the Lancefield group G carbohydrate, and a significant minority have the group C carbohydrate. A recent French study of invasive S. dysgalactiae subsp. equisimilis infection also included
non-bacteremic patients and isolates from non-sterile sites with clinical signs of necrotizing fasciitis and STSS, and is, for those reasons, excluded from Table 2 [19]. Loubinoux et al. studied invasive infections and found the three most common clinical manifestations to be skin and soft-tissue infections (44 %), bacteremia without focus (20 %), and bone and joint infections (20 %) [19]. The figures for necrotizing fasciitis (18 %) and STSS (16 %) were much higher than in previous studies [6, 10, 15, 16]. A high incidence of necrotizing fasciitis and STSS in the paper by Loubinoux et al. can be potentially partly explained by the inclusion of isolates from non-sterile sites [19]. In addition, the study was not population-based, in contrast to the earlier studies [6, 10, 11]. A high rate of recurrence in group G streptococcal bacteremia has been reported. Cohen-Poradosu et al. found that 14 % of patients had recurrent group G streptococcal bacteremia, and that lymphatic drainage disorders were a risk factor for recurrence [13]. Cellulitis is the most common clinical manifestation in recurrence [20, 21]. Recurrences of infection in an individual patient are commonly caused by an identical strain [20, 21]. Vartian et al. reported polymicrobial bacteremia to be a prominent feature, Staphylococcus aureus being the co-pathogen most frequently isolated, probably because both pathogens can cause skin and soft-tissue infections [22].
Epidemiology of S. dysgalactiae subsp. equisimilis bacteremia An increase in the number of cases of bacteremia due to group C and G streptococci has been recognized [10, 11, 23]. The overall incidence of invasive S. dysgalactiae subsp. equisimilis infection is higher among men than women and increases with age [6]. In Denmark, a three-fold increase in group G streptococcal infections was noted during 1999–2002 [10]. In Norway, the mean annual incidence of invasive group A streptococcal disease and invasive group C and G streptococcal disease was 5.0 per 100,000 and 4.1 per 100,000 population during 2006–2009 [17]. In the Pirkanmaa area in Finland, the incidence of S. dysgalactiae subsp. equisimilis bacteremia increased from 2.05 cases per 100,000 in 1995 to 4.75 cases per 100,000 in 2004 [11], and that of group G streptococcal bacteremia has continued to increase, with 6.2 cases per 100,000 in 2009 [24]. The explanation for the
Retrospective cohort
n (%)
Study design
Clinical manifestationa Cellulitis Pneumonia Arthritis ND ND ND 13 (3) 9 (2) 4 (1) 109 (28) 18 %
ND 0 3 (3) 0 ND ND 18 (19)
5%
134 (34) 19 (5) 41 (10)
Prospective population-based cohort
N=397 GGS
Ekelund et al. 2005 [10]
3%
ND 4 (4) 1 (1) 4 (22) ND ND 34 (37)
48 (52) 1 (1) 2 (2)
Retrospective observational
N=92 GGS
Liao et al. 2008 [20]
15 %
20 (9) 6 (3) 7 (3) 1 (1) 19 (9) 3 (1) 56 (26)
87 (41) 14 (7) 12 (6)
15 %
6 (5) 2 (2) 2 (2) 1 (1) 4 (3) 1 (1) 21 (16)
73 (57) 12 (9) 11 (9)
N=212 N=128 S. dysgalactiae subsp. GGS equisimilis Prospective Retrospective population-based population-based cohort cohort
Broyles et al. 2009 [6] Rantala et al. 2009 [11, 16]
Tsai et al. 2013 [45]
13 %
2 (1) 2 (1) 4 (2) 5 (2) 2 (1) 9 (4) 98 (42)
52 (23) 12 (5) 4 (4)
2%
ND ND ND ND 1 (2) 1 (2) 12 (24)
30 (60) 0 ND
12 %
ND ND ND ND 6 (15) ND 22 (54)
14 (34) 3 (7) 1 (2)
N=231 N=50 N=40 S. dysgalactiae S. dysgalactiae S. dysgalactiae subsp. equisimilis subsp. equisimilis subsp. equisimilis Retrospective cohort Retrospective cohort Retrospective cohort
Takahashi et al. 2010 Kittang et al. 2011 [15] [17]
a
A patient may have one or more clinical manifestations
Values are presented as number (percentage). We can compare Lancefield group G streptococci and S. dysgalactiae subsp. equisimilis isolates since most S. dysgalactiae subsp. equisimilis isolates are Lancefield group G streptococci
GGS Lancefield group G beta-hemolytic streptococci; ND not determined
Osteomyelitis Deep abscess Endocarditis Meningitis STSS Fasciitis Bacteremia without focus 30-day case fatality
N=94 GGS
Patients, N
56 (60) 3 (3) 4 (4)
Cohen-Poradosu et al. 2004 [13]
Author, year [reference]
Table 2 Comparison of studies reporting on the clinical manifestations and outcome of beta-hemolytic group C and G streptococcal bacteremias in the last 10 years
Eur J Clin Microbiol Infect Dis
Eur J Clin Microbiol Infect Dis
increase in S. dysgalactiae subsp. equisimilis infections remains unclear. Prolonged survival of adults with underlying chronic conditions such as heart disease, diabetes mellitus, and cancer may be one contributing factor [14]. Also, S. dysgalactiae subsp. equisimilis virulence factors probably have a role [25]. The burden of invasive S. dysgalactiae subsp. equisimilis infections approximates that of invasive group A streptococcal disease in North America [6]. In Finland, S. dysgalactiae subsp. equisimilis is isolated from blood culture as frequently as S. pyogenes [26].
Contacts and human carriage of S. dysgalactiae subsp. equisimilis S. dysgalactiae subsp. equisimilis (group C and G streptococci) is a common colonizer of the pharynx, gastrointestinal and female genital tracts, and the skin [12, 22]. Its transmission usually occurs through direct contact with respiratory secretions or by aerosolized droplets, or via skin contact, especially contact with infected skin lesions. Sites of colonization and focal infections are principal reservoirs for transmission and infections are transmitted from person to person.
Predisposing factors in S. dysgalactiae subsp. equisimilis bacteremia Almost all (90–96 %) S. dysgalactiae subsp. equisimilis bacteremia patients carry some underlying disease [6, 10, 12–14, 22, 27]. Group C and G streptococcal bacteremias are linked to diabetes mellitus, cardiovascular disease, malignancy, immunosuppression, and breakdown of the skin [12–14, 22, 27, 28]. In one large American study, cardiovascular disease (44 %), diabetes mellitus (42 %), obesity (30 %), and chronic skin disease (30 %) were the most common underlying disorders among patients with S. dysgalactiae subsp. equisimilis bacteremia [6]. Breakdown of the skin is one of the most common predisposing factors in bacteremia [10, 11, 14]. A comparison of studies reporting underlying diseases in betahemolytic group C and G streptococcal bacteremias in last decade is presented in Table 3. A recent French study of invasive S. dysgalactiae subsp. equisimilis infection also included non-bacteremic patients and isolates from non-sterile sites with clinical signs of necrotizing fasciitis and STSS, and is excluded from Table 3 [19]. Group G streptococcal bacteremia occurs most commonly in patients over 65 years of age [10]. In Japan, the median age among patients with invasive disease has been 75 years [15]. In contrast, in an American study covering invasive disease, 59 % of adults were less than 65 years old and there were high proportions of diabetes (42 %) and obesity (30 %) [6]. One possible reason for this is that the prevalence of diabetes has
more than doubled among US adults, and diabetes is a risk factor for skin and soft-tissue infections [29]. S. dysgalactiae subsp. equisimilis bacteremia is uncommon in children [10].
Virulence factors and emm types of S. dysgalactiae subsp. equisimilis There is an overlap in the virulence properties of S. pyogenes and S. dysgalactiae subsp. equisimilis, which is mainly explained by horizontal gene transfer from the former to the latter [25, 30]. This involves the M-protein gene, which is important in the pathogenesis of S. pyogenes infection and is a tool in epidemiologic typing (emm typing) [31]. S. dysgalactiae subsp. equisimilis is also emm-typeable. Based on multilocus sequence analysis (MLSA), significant interspecies recombination between S. pyogenes and S. dysgalactiae subsp. equisimilis has been reported [32, 33]. The M protein shared by these two subspecies confers resistance to phagocytosis [34]. The mechanism here may lie in preventing complete opsonization of the Streptococcus by interfering with the activation of the alternative complement pathway on the bacterial surface [35]. Based on the variability of the N-terminal end of the emm gene (encoding the M protein), more than 60 different emm types of S. dysgalactiae subsp. equisimilis have, thus far, been recognized [36]. Broyles et al. identified stG6, stG245, and stG2078 as the three most common emm types, covering 39 % of 212 American isolates [6]. A group under Rantala reported stG480, stG6, and stG485 as the three most common emm types, covering 51 % of 138 Finnish isolates [21]. Takahashi et al. found stG6792, stG485, and stG6 to be the three most common emm types, covering 49 % of 231 Japanese isolates [15]. The dominant emm types in Japan were different from those in the United States and Finland. Predominant emm types tend to vary depending on the geographic region and over time, as does group A Streptococcus [37–39]. In France, a group under Loubinoux recently found stG6, stG485, and stG6792 to be the three most common emm types [19]. One recent Finnish study revealed that the case fatality was higher in S. dysgalactiae subsp. equisimilis bacteremia caused by rare emm types than that attributable to common emm types [21]. One reason for this might be that patients encounter prevailing bacterial strains (so-called common emm types) more often, and prior antigen challenge and development of antibodies may protect against infection. Severe disease (defined as death or admission to the intensive care unit) has also been caused more frequently by rare than by common emm types [21]. In contrast, a recent study from Japan found the most common emm type stG6792 to be associated with poor outcome [15]. The strain might have spread from India to Japan. emm types stG485, stG480, and stG6 are associated with invasive S. dysgalactiae subsp. equisimilis infections
GGS Lancefield group G beta-hemolytic streptococci; ND not determined
The values are presented as number (percentage). We can compare Lancefield group G streptococci and S. dysgalactiae subsp. equisimilis isolates since most S. dysgalactiae subsp. equisimilis isolates are Lancefield group G streptococci
ND
ND 5 (10)
3 (6) 48 (21)
ND 18 (14) 7 (3)
8 (4)
ND
4 (22)
10 (10)
10 (13) 8 (9) No underlying disease
Alcoholism
Immunosuppression ND
ND
Skin condition
23 (11) ND
13 (10)
ND
ND 2 (4) ND
13 (33)
11 (11)
15 (12)
31 (62)
13 (26) 35 (16)
ND 68 (53) ND
33 (35)
ND
Malignancy
64 (30)
23 (11) 35 (38) 24 (20)
26 (36)
30 (23)
13 (33)
10 (25) 19 (38)
6 (12) 36 (16)
28 (12) 51 (40) 96 (44)
90 (42)
20 (22)
16 (17)
5 (8) ND
33 (35) Diabetes
n (%) Underlying disease
Cardiac diseases
29 (16)
31 (24)
Retrospective cohort Retrospective cohort Retrospective cohort Retrospective populationbased cohort Prospective populationbased cohort Prospective populationbased cohort Retrospective cohort Study design
Retrospective observational
N=40 S. dysgalactiae subsp. equisimilis N=50 S. dysgalactiae subsp. equisimilis N=231 S. dysgalactiae subsp. equisimilis N=128 GGS N=92 GGS N=397 GGS Patients, N
N=94 GGS
N=212 S. dysgalactiae subsp. equisimilis
Tsai et al. 2013 [45] Kittang et al. 2011 [17] Takahashi et al. 2010 [15] Rantala et al. 2009 [11, 16] Broyles et al. 2009 [6] Liao et al. 2008 [20] Ekelund et al. 2005 [10] Cohen-Poradosu et al. 2004 [13] Author, year [reference]
Table 3 Comparison of studies reporting on the underlying diseases of group C and G streptococcal bacteremias in the last 10 years
Eur J Clin Microbiol Infect Dis
[40, 41]. More studies are called for on the association between emm types and disease severity. emm type surveillance remains important for the rapid detection of changes in type distribution which might lead to an increase in incidence and mortality. Horizontal genetic transfer among group A, C, and G streptococci is evident concerning both emm gene and Sag genes [42]. Clinically isolated S. dysgalactiae subsp. equisimilis strains have many important virulence factors present in group A Streptococcus, including streptolysin S (saga), streptolysin O (slo), streptokinase (ska), and antiphagocytic surface M proteins [25]. Several important group A streptococcal virulence factors are missing from the S. dysgalactiae subsp. equisimilis genome, including SpeB, a chromosomally encoded cysteine protease, and a hyaluronic acid capsule [43, 44]. In a Chinese study, several nonsuperantigenic toxic genes, including scpA, ska, saga, and slo genes were commonly found in invasive S. dysgalactiae subsp. equisimilis isolates, but superantigenic toxic genes (speC, speG, speH, speL, speK, smez, and ssa genes) were not detected in any strains [45]. The speA gene was found in only one of six patients with STSS (17 %) and it may not play a significant role in the pathogenesis of STSS caused by S. dysgalactiae subsp. equisimilis [45]. S. dysgalactiae subsp. equisimilis lacks superantigenic activity because its speG gene does not show superantigenic activity [44]. The low content of superantigen genes detected in S. dysgalactiae subsp. equisimilis reflects the fact that these virulence factors are not a prerequisite for the development of necrotizing softtissue infection by this bacteria [5, 46]. The role of virulence factors in increasing the incidence of S. dysgalactiae subsp. equisimilis bacteremia is unclear. Also, the host factors age and underlying diseases are contributing factors. The following complete genome sequencing of a human S. dysgalactiae subsp. equisimilis strain has been determined: group C S. dysgalactiae subsp. equisimilis 167, group A S. dysgalactiae subsp. equisimilis AC-2713, group G S. dysgalactiae subsp. equisimilis ATCC 12394, group G S. dysgalactiae subsp. equisimilis GGS 124, and group G S. dysgalactiae subsp. equisimilis RE378 [43]. Watanabe et al. have presented the main findings of these complete genome sequencing analyses [43].
Mortality The case fatality rate due to bacteremias caused by S. dysgalactiae subsp. equisimilis varies between 2 and 18 % [6, 10, 16, 17]. Some large studies report a case fatality of 15–18 %, being as high as in group A streptococcal bacteremia [6, 10, 16]. S. dysgalactiae subsp. equisimilis patients are older and have more underlying diseases than group A streptococcal patients [6, 10, 38]. Group G streptococcal
Eur J Clin Microbiol Infect Dis
bacteremia patients are treated in an intensive care unit more seldom than group A streptococcal bacteremia patients [10, 16]. Possibly, the infection itself is less severe than in group A streptococcal bacteremia. For instance, disseminated intravascular coagulation, multiorgan failure, and STSS are observed more frequently among group A streptococcal bacteremia patients as compared to group G streptococcal patients [10, 16]. Group A Streptococcus is possibly more virulent than group G Streptococcus, since group A streptococcal patients are generally younger and often previously healthy [10]. Mortality associated with S. dysgalactiae subsp. equisimilis bacteremia is influenced by clinical aspects such as age and underlying diseases. This may explain why the case fatality rates are similar in bacteremias caused by S. dysgalactiae subsp. equisimilis and S. pyogenes. The number of population-based studies describing predictors of case fatality in group C and G streptococcal bacteremia is limited [10]. Chronic heart or lung disease, alcohol abuse, and immune dysfunction were factors associated with increased case fatality in one Danish study [10]. In the case of STSS, the mortality rates were very high [10].
Treatment Bacteremia being a life-threatening condition, the rapid initiation of effective intravenous empirical antibiotic therapy is essential. S. dysgalactiae subsp. equisimilis has remained sensitive to penicillin and other beta-lactam antibiotics. Penicillin G remains the first-line treatment of choice. Second- and third-generation cephalosporins are alternatives in patients with mild to moderate penicillin allergy, and in type I allergic patients, vancomycin and clindamycin is a sensible alternative. Resistance to macrolides in S. dysgalactiae subsp. equisimilis has been shown in many countries. In one multicenter surveillance in the United States, 28.8 % of isolates were found to be resistant to erythromycin [6]. The resistance rate for clindamycin was 4.2 % and for fluoroquinolones, it was 0.9 % [6]. In the presence of a high inoculum and stationary growth phase of the organism, the addition of clindamycin with high-dose penicillin has proved to be effective [47, 48]. There is a lack of high-quality clinical evidence on the addition of clindamycin to penicillin on the most severe S. dysgalactiae subsp. equisimilis infections. However, it is sensible to treat S. dysgalactiae subsp. equisimilis patients as S. pyogenes patients, meaning the inclusion of clindamycin along with penicillin in patients with necrotizing fasciitis, STSS, or severe cellulitis with a suspected high inoculum of bacteria and bacteremia [47, 48]. For life-threatening infections (e.g., meningitis and endocarditis), aminoglycoside can be considered in addition to penicillin, as the aminoglycoside– penicillin combination shows in vitro bactericidal synergy [49]. Older clinical observations have been suggested to
improve outcomes in patients treated with combination therapy [50, 51], but no well-conducted studies exist. However, several guidelines recommend the addition of aminoglycoside to the penicillin therapy of streptococcal endocarditis during the first 2 weeks [52]. Aminoglycosides penetrate very poorly the cerebrospinal fluid (CSF). An alternative in meningitis is third-generation cephalosporin, because it penetrates better the CSF. Patients with group A Streptococcus receiving intravenous immunoglobulin (IVIG) in STSS have improved outcomes [53], but data on S. dysgalactiae subsp. equisimilis STSS are still lacking. There is only one prospective study on the topic, which did not show any significant reduction in the 28-day mortality in group A streptococcal STSS [54]. Hence, the evidence of IVIG on group A Streptococcus STSS will remain a matter of discussion. Adequate supportive measures (intensive fluid resusCitation, vasopressors, ventilatory support) are a prerequisite for effective antimicrobial therapy. When tissue necrosis or gangrene is suspected, surgical exploration is essential, along with rapid debridement of the affected tissue. The drainage of abscesses is essential when loculated fluid is present. Amputation of a limb may be necessary in case of severe necrotizing infection. In case of prosthetic joint infection, debridement or removal of the prosthetic joint is essential. Surgery is more commonly needed in patients with S. pyogenes bacteremia (42 %) than among those with S. dysgalactiae subsp. equisimilis bacteremia (18 %) [17]. In a Japanese study, insufficient white blood cell responses due to neutropenia (
REVIEW
Streptococcus dysgalactiae subsp. equisimilis bacteremia: an emerging infection S. Rantala
Received: 19 December 2013 / Accepted: 10 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract The importance of group C and G Streptococcus dysgalactiae subspecies equisimilis (S. dysgalactiae subsp. equisimilis) as a significant pathogen has recently been better recognized. S. dysgalactiae subsp. equisimilis disease can range in severity from milder skin and soft-tissue conditions such as wound infection, erysipelas, and cellulitis, to lifethreatening necrotizing fasciitis and streptococcal toxic shock syndrome, thus sharing the clinical picture with S. pyogenes. The most common clinical manifestation of bacteremia is cellulitis. An increase in the incidence of S. dysgalactiae subsp. equisimilis bacteremia has been recognized. Invasive forms of this infection are most commonly found in elderly patients with underlying comorbidities and skin breakdown. The case fatality in bacteremia has been reported to be 15– 18 %. In this review, the epidemiology, clinical characteristics, and emm types of S. dysgalactiae subsp. equisimilis bacteremia are summarized.
Introduction Streptococcus dysgalactiae subspecies equisimilis (S. dysgalactiae subsp. equisimilis) belongs to the group of beta-hemolytic streptococci. Their identification has been based on hemolytic reaction and Lancefield group carbohydrate antigen, which is a part of the cell wall [1]. Vandamme et al. [2] divided S. dysgalactiae into two subspecies: S. dysgalactiae subsp. equisimilis, human large colonyforming group C and G streptococci, and S. dysgalactiae subsp. dysgalactiae, animal origin group C streptococci. The Lancefield group G carbohydrate may be encountered in S. Rantala (*) Department of Internal Medicine, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland e-mail: [email protected]
several beta-hemolytic streptococcal species, including S. anginosus and S. canis, but mainly in S. dysgalactiae subsp. equisimilis. This subspecies has Lancefield group C or G antigens and rarely A antigen. The species was determined by gene sequencing of the group C species, formerly named S. equisimilis, which showed it to be indistinguishable from group G S. dysgalactiae [3]. In the new taxonomy, all large colony-forming group C and G streptococci are classified as S. dysgalactiae subsp. equisimilis [4]. The phenotype of S. dysgalactiae subsp. equisimilis on sheep blood agar comprises grayish colonies surrounded by large beta-hemolysis. The phenotypic characteristics of human beta-hemolytic streptococci are presented in Table 1. S. dysgalactiae subsp. equisimilis causes a diversity of diseases similar to that caused by S. pyogenes [5]. The spectrum of S. dysgalactiae subsp. equisimilis diseases ranges from pharyngitis and skin and soft-tissue infections, such as wound infection, erysipelas, and cellulitis, to severe invasive infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome (STSS) [6]. S. dysgalactiae subsp. equisimilis is increasingly recognized as a bacteria causing not only severe soft-tissue infections but also severe systemic infections comprising STSS [7]. Some studies report an association with pharyngitis and acute poststreptococcal glomerulonephritis, and an association with acute rheumatic fever and S. dysgalactiae subsp. equisimilis isolation from the upper respiratory tract [8, 9]. The global burden of diseases caused by S. dysgalactiae subsp. equisimilis is unknown, as it is not common practice to identify group C and G streptococci to the species level in clinical laboratories. In addition, populationbased data on S. dysgalactiae subsp. equisimilis bacteremia are limited [6, 10, 11]. In this review, the incidence, predisposing factors, clinical characteristics, and outcome in S. dysgalactiae subsp. equisimilis bacteremia are summarized, along with the distribution of emm types in S. dysgalactiae subsp. equisimilis causing invasive infections. In addition, the
Eur J Clin Microbiol Infect Dis Table 1 Phenotypic characteristics of human beta-hemolytic streptococci. Adapted from (Takahashi et al. [15])
Species
Lancefield group
Hemolysis type
Colony size
S. pyogenes S. agalactiae S. dysgalactiae subsp. equisimilis S. equi subsp. zooepidemicus S. anginosus group
A B A, C, G C A, C, G, F, none
β β β β β, α, none
Large Large Large Large Small
severity of invasive infections caused by S. dysgalactiae subsp. equisimilis and S. pyogenes is compared.
Clinical manifestations of bacteremia caused by S. dysgalactiae subsp. equisimilis Skin and soft-tissue infections are particularly common in patients with S. dysgalactiae subsp. equisimilis bacteremia [6, 10–14]. Cellulitis is the most common presenting clinical manifestation [6, 11, 13]. In S. dysgalactiae subsp. equisimilis bacteremia, the infection focus can be arthritis, osteomyelitis, pneumonia, deep abscess, endocarditis, meningitis, or peritonitis, or it may remain unknown [5, 6]. It can also cause puerperal sepsis [10]. Cellulitis is more common in S. dysgalactiae subsp. equisimilis and S. pyogenes bacteremia as compared to group B streptococcal bacteremia [10, 11, 15]. Septic arthritis, again, is more common in S. dysgalactiae subsp. equisimilis bacteremia as compared to group B streptococcal bacteremia [10, 11, 15]. Osteomyelitis may accompany septic arthritis. Bacteremia is life-threatening in combination with pneumonia, necrotizing fasciitis, septic shock, or STSS. In a population-based study of invasive beta-hemolytic streptococci other than group A and B from the United States, cellulitis (41 %), bacteremia without focus (26 %), and osteomyelitis (9 %) were the three most common clinical manifestations, followed by pneumonia (7 %) and septic arthritis (6 %) [6]. Pneumonia is more frequently observed in patients with S. pyogenes bacteremia (10 %) than in those with S. dysgalactiae subsp. equisimilis bacteremia (5 %) [10]. Deep abscesses are more common in patients with S. pyogenes bacteremia (10 %) as compared to S. dysgalactiae subsp. equisimilis infection (1 %) [15]. Necrotizing fasciitis and STSS are rare in S. dysgalactiae subsp. equisimilis bacteremia [10, 16–18]. A comparison of studies reporting on the clinical manifestations and outcome of beta-hemolytic group C and G streptococcal bacteremias in the last 10 years is presented in Table 2. We can compare S. dysgalactiae subsp. equisimilis and group G streptococci isolates, as most S. dysgalactiae subsp. equisimilis isolates possess the Lancefield group G carbohydrate, and a significant minority have the group C carbohydrate. A recent French study of invasive S. dysgalactiae subsp. equisimilis infection also included
non-bacteremic patients and isolates from non-sterile sites with clinical signs of necrotizing fasciitis and STSS, and is, for those reasons, excluded from Table 2 [19]. Loubinoux et al. studied invasive infections and found the three most common clinical manifestations to be skin and soft-tissue infections (44 %), bacteremia without focus (20 %), and bone and joint infections (20 %) [19]. The figures for necrotizing fasciitis (18 %) and STSS (16 %) were much higher than in previous studies [6, 10, 15, 16]. A high incidence of necrotizing fasciitis and STSS in the paper by Loubinoux et al. can be potentially partly explained by the inclusion of isolates from non-sterile sites [19]. In addition, the study was not population-based, in contrast to the earlier studies [6, 10, 11]. A high rate of recurrence in group G streptococcal bacteremia has been reported. Cohen-Poradosu et al. found that 14 % of patients had recurrent group G streptococcal bacteremia, and that lymphatic drainage disorders were a risk factor for recurrence [13]. Cellulitis is the most common clinical manifestation in recurrence [20, 21]. Recurrences of infection in an individual patient are commonly caused by an identical strain [20, 21]. Vartian et al. reported polymicrobial bacteremia to be a prominent feature, Staphylococcus aureus being the co-pathogen most frequently isolated, probably because both pathogens can cause skin and soft-tissue infections [22].
Epidemiology of S. dysgalactiae subsp. equisimilis bacteremia An increase in the number of cases of bacteremia due to group C and G streptococci has been recognized [10, 11, 23]. The overall incidence of invasive S. dysgalactiae subsp. equisimilis infection is higher among men than women and increases with age [6]. In Denmark, a three-fold increase in group G streptococcal infections was noted during 1999–2002 [10]. In Norway, the mean annual incidence of invasive group A streptococcal disease and invasive group C and G streptococcal disease was 5.0 per 100,000 and 4.1 per 100,000 population during 2006–2009 [17]. In the Pirkanmaa area in Finland, the incidence of S. dysgalactiae subsp. equisimilis bacteremia increased from 2.05 cases per 100,000 in 1995 to 4.75 cases per 100,000 in 2004 [11], and that of group G streptococcal bacteremia has continued to increase, with 6.2 cases per 100,000 in 2009 [24]. The explanation for the
Retrospective cohort
n (%)
Study design
Clinical manifestationa Cellulitis Pneumonia Arthritis ND ND ND 13 (3) 9 (2) 4 (1) 109 (28) 18 %
ND 0 3 (3) 0 ND ND 18 (19)
5%
134 (34) 19 (5) 41 (10)
Prospective population-based cohort
N=397 GGS
Ekelund et al. 2005 [10]
3%
ND 4 (4) 1 (1) 4 (22) ND ND 34 (37)
48 (52) 1 (1) 2 (2)
Retrospective observational
N=92 GGS
Liao et al. 2008 [20]
15 %
20 (9) 6 (3) 7 (3) 1 (1) 19 (9) 3 (1) 56 (26)
87 (41) 14 (7) 12 (6)
15 %
6 (5) 2 (2) 2 (2) 1 (1) 4 (3) 1 (1) 21 (16)
73 (57) 12 (9) 11 (9)
N=212 N=128 S. dysgalactiae subsp. GGS equisimilis Prospective Retrospective population-based population-based cohort cohort
Broyles et al. 2009 [6] Rantala et al. 2009 [11, 16]
Tsai et al. 2013 [45]
13 %
2 (1) 2 (1) 4 (2) 5 (2) 2 (1) 9 (4) 98 (42)
52 (23) 12 (5) 4 (4)
2%
ND ND ND ND 1 (2) 1 (2) 12 (24)
30 (60) 0 ND
12 %
ND ND ND ND 6 (15) ND 22 (54)
14 (34) 3 (7) 1 (2)
N=231 N=50 N=40 S. dysgalactiae S. dysgalactiae S. dysgalactiae subsp. equisimilis subsp. equisimilis subsp. equisimilis Retrospective cohort Retrospective cohort Retrospective cohort
Takahashi et al. 2010 Kittang et al. 2011 [15] [17]
a
A patient may have one or more clinical manifestations
Values are presented as number (percentage). We can compare Lancefield group G streptococci and S. dysgalactiae subsp. equisimilis isolates since most S. dysgalactiae subsp. equisimilis isolates are Lancefield group G streptococci
GGS Lancefield group G beta-hemolytic streptococci; ND not determined
Osteomyelitis Deep abscess Endocarditis Meningitis STSS Fasciitis Bacteremia without focus 30-day case fatality
N=94 GGS
Patients, N
56 (60) 3 (3) 4 (4)
Cohen-Poradosu et al. 2004 [13]
Author, year [reference]
Table 2 Comparison of studies reporting on the clinical manifestations and outcome of beta-hemolytic group C and G streptococcal bacteremias in the last 10 years
Eur J Clin Microbiol Infect Dis
Eur J Clin Microbiol Infect Dis
increase in S. dysgalactiae subsp. equisimilis infections remains unclear. Prolonged survival of adults with underlying chronic conditions such as heart disease, diabetes mellitus, and cancer may be one contributing factor [14]. Also, S. dysgalactiae subsp. equisimilis virulence factors probably have a role [25]. The burden of invasive S. dysgalactiae subsp. equisimilis infections approximates that of invasive group A streptococcal disease in North America [6]. In Finland, S. dysgalactiae subsp. equisimilis is isolated from blood culture as frequently as S. pyogenes [26].
Contacts and human carriage of S. dysgalactiae subsp. equisimilis S. dysgalactiae subsp. equisimilis (group C and G streptococci) is a common colonizer of the pharynx, gastrointestinal and female genital tracts, and the skin [12, 22]. Its transmission usually occurs through direct contact with respiratory secretions or by aerosolized droplets, or via skin contact, especially contact with infected skin lesions. Sites of colonization and focal infections are principal reservoirs for transmission and infections are transmitted from person to person.
Predisposing factors in S. dysgalactiae subsp. equisimilis bacteremia Almost all (90–96 %) S. dysgalactiae subsp. equisimilis bacteremia patients carry some underlying disease [6, 10, 12–14, 22, 27]. Group C and G streptococcal bacteremias are linked to diabetes mellitus, cardiovascular disease, malignancy, immunosuppression, and breakdown of the skin [12–14, 22, 27, 28]. In one large American study, cardiovascular disease (44 %), diabetes mellitus (42 %), obesity (30 %), and chronic skin disease (30 %) were the most common underlying disorders among patients with S. dysgalactiae subsp. equisimilis bacteremia [6]. Breakdown of the skin is one of the most common predisposing factors in bacteremia [10, 11, 14]. A comparison of studies reporting underlying diseases in betahemolytic group C and G streptococcal bacteremias in last decade is presented in Table 3. A recent French study of invasive S. dysgalactiae subsp. equisimilis infection also included non-bacteremic patients and isolates from non-sterile sites with clinical signs of necrotizing fasciitis and STSS, and is excluded from Table 3 [19]. Group G streptococcal bacteremia occurs most commonly in patients over 65 years of age [10]. In Japan, the median age among patients with invasive disease has been 75 years [15]. In contrast, in an American study covering invasive disease, 59 % of adults were less than 65 years old and there were high proportions of diabetes (42 %) and obesity (30 %) [6]. One possible reason for this is that the prevalence of diabetes has
more than doubled among US adults, and diabetes is a risk factor for skin and soft-tissue infections [29]. S. dysgalactiae subsp. equisimilis bacteremia is uncommon in children [10].
Virulence factors and emm types of S. dysgalactiae subsp. equisimilis There is an overlap in the virulence properties of S. pyogenes and S. dysgalactiae subsp. equisimilis, which is mainly explained by horizontal gene transfer from the former to the latter [25, 30]. This involves the M-protein gene, which is important in the pathogenesis of S. pyogenes infection and is a tool in epidemiologic typing (emm typing) [31]. S. dysgalactiae subsp. equisimilis is also emm-typeable. Based on multilocus sequence analysis (MLSA), significant interspecies recombination between S. pyogenes and S. dysgalactiae subsp. equisimilis has been reported [32, 33]. The M protein shared by these two subspecies confers resistance to phagocytosis [34]. The mechanism here may lie in preventing complete opsonization of the Streptococcus by interfering with the activation of the alternative complement pathway on the bacterial surface [35]. Based on the variability of the N-terminal end of the emm gene (encoding the M protein), more than 60 different emm types of S. dysgalactiae subsp. equisimilis have, thus far, been recognized [36]. Broyles et al. identified stG6, stG245, and stG2078 as the three most common emm types, covering 39 % of 212 American isolates [6]. A group under Rantala reported stG480, stG6, and stG485 as the three most common emm types, covering 51 % of 138 Finnish isolates [21]. Takahashi et al. found stG6792, stG485, and stG6 to be the three most common emm types, covering 49 % of 231 Japanese isolates [15]. The dominant emm types in Japan were different from those in the United States and Finland. Predominant emm types tend to vary depending on the geographic region and over time, as does group A Streptococcus [37–39]. In France, a group under Loubinoux recently found stG6, stG485, and stG6792 to be the three most common emm types [19]. One recent Finnish study revealed that the case fatality was higher in S. dysgalactiae subsp. equisimilis bacteremia caused by rare emm types than that attributable to common emm types [21]. One reason for this might be that patients encounter prevailing bacterial strains (so-called common emm types) more often, and prior antigen challenge and development of antibodies may protect against infection. Severe disease (defined as death or admission to the intensive care unit) has also been caused more frequently by rare than by common emm types [21]. In contrast, a recent study from Japan found the most common emm type stG6792 to be associated with poor outcome [15]. The strain might have spread from India to Japan. emm types stG485, stG480, and stG6 are associated with invasive S. dysgalactiae subsp. equisimilis infections
GGS Lancefield group G beta-hemolytic streptococci; ND not determined
The values are presented as number (percentage). We can compare Lancefield group G streptococci and S. dysgalactiae subsp. equisimilis isolates since most S. dysgalactiae subsp. equisimilis isolates are Lancefield group G streptococci
ND
ND 5 (10)
3 (6) 48 (21)
ND 18 (14) 7 (3)
8 (4)
ND
4 (22)
10 (10)
10 (13) 8 (9) No underlying disease
Alcoholism
Immunosuppression ND
ND
Skin condition
23 (11) ND
13 (10)
ND
ND 2 (4) ND
13 (33)
11 (11)
15 (12)
31 (62)
13 (26) 35 (16)
ND 68 (53) ND
33 (35)
ND
Malignancy
64 (30)
23 (11) 35 (38) 24 (20)
26 (36)
30 (23)
13 (33)
10 (25) 19 (38)
6 (12) 36 (16)
28 (12) 51 (40) 96 (44)
90 (42)
20 (22)
16 (17)
5 (8) ND
33 (35) Diabetes
n (%) Underlying disease
Cardiac diseases
29 (16)
31 (24)
Retrospective cohort Retrospective cohort Retrospective cohort Retrospective populationbased cohort Prospective populationbased cohort Prospective populationbased cohort Retrospective cohort Study design
Retrospective observational
N=40 S. dysgalactiae subsp. equisimilis N=50 S. dysgalactiae subsp. equisimilis N=231 S. dysgalactiae subsp. equisimilis N=128 GGS N=92 GGS N=397 GGS Patients, N
N=94 GGS
N=212 S. dysgalactiae subsp. equisimilis
Tsai et al. 2013 [45] Kittang et al. 2011 [17] Takahashi et al. 2010 [15] Rantala et al. 2009 [11, 16] Broyles et al. 2009 [6] Liao et al. 2008 [20] Ekelund et al. 2005 [10] Cohen-Poradosu et al. 2004 [13] Author, year [reference]
Table 3 Comparison of studies reporting on the underlying diseases of group C and G streptococcal bacteremias in the last 10 years
Eur J Clin Microbiol Infect Dis
[40, 41]. More studies are called for on the association between emm types and disease severity. emm type surveillance remains important for the rapid detection of changes in type distribution which might lead to an increase in incidence and mortality. Horizontal genetic transfer among group A, C, and G streptococci is evident concerning both emm gene and Sag genes [42]. Clinically isolated S. dysgalactiae subsp. equisimilis strains have many important virulence factors present in group A Streptococcus, including streptolysin S (saga), streptolysin O (slo), streptokinase (ska), and antiphagocytic surface M proteins [25]. Several important group A streptococcal virulence factors are missing from the S. dysgalactiae subsp. equisimilis genome, including SpeB, a chromosomally encoded cysteine protease, and a hyaluronic acid capsule [43, 44]. In a Chinese study, several nonsuperantigenic toxic genes, including scpA, ska, saga, and slo genes were commonly found in invasive S. dysgalactiae subsp. equisimilis isolates, but superantigenic toxic genes (speC, speG, speH, speL, speK, smez, and ssa genes) were not detected in any strains [45]. The speA gene was found in only one of six patients with STSS (17 %) and it may not play a significant role in the pathogenesis of STSS caused by S. dysgalactiae subsp. equisimilis [45]. S. dysgalactiae subsp. equisimilis lacks superantigenic activity because its speG gene does not show superantigenic activity [44]. The low content of superantigen genes detected in S. dysgalactiae subsp. equisimilis reflects the fact that these virulence factors are not a prerequisite for the development of necrotizing softtissue infection by this bacteria [5, 46]. The role of virulence factors in increasing the incidence of S. dysgalactiae subsp. equisimilis bacteremia is unclear. Also, the host factors age and underlying diseases are contributing factors. The following complete genome sequencing of a human S. dysgalactiae subsp. equisimilis strain has been determined: group C S. dysgalactiae subsp. equisimilis 167, group A S. dysgalactiae subsp. equisimilis AC-2713, group G S. dysgalactiae subsp. equisimilis ATCC 12394, group G S. dysgalactiae subsp. equisimilis GGS 124, and group G S. dysgalactiae subsp. equisimilis RE378 [43]. Watanabe et al. have presented the main findings of these complete genome sequencing analyses [43].
Mortality The case fatality rate due to bacteremias caused by S. dysgalactiae subsp. equisimilis varies between 2 and 18 % [6, 10, 16, 17]. Some large studies report a case fatality of 15–18 %, being as high as in group A streptococcal bacteremia [6, 10, 16]. S. dysgalactiae subsp. equisimilis patients are older and have more underlying diseases than group A streptococcal patients [6, 10, 38]. Group G streptococcal
Eur J Clin Microbiol Infect Dis
bacteremia patients are treated in an intensive care unit more seldom than group A streptococcal bacteremia patients [10, 16]. Possibly, the infection itself is less severe than in group A streptococcal bacteremia. For instance, disseminated intravascular coagulation, multiorgan failure, and STSS are observed more frequently among group A streptococcal bacteremia patients as compared to group G streptococcal patients [10, 16]. Group A Streptococcus is possibly more virulent than group G Streptococcus, since group A streptococcal patients are generally younger and often previously healthy [10]. Mortality associated with S. dysgalactiae subsp. equisimilis bacteremia is influenced by clinical aspects such as age and underlying diseases. This may explain why the case fatality rates are similar in bacteremias caused by S. dysgalactiae subsp. equisimilis and S. pyogenes. The number of population-based studies describing predictors of case fatality in group C and G streptococcal bacteremia is limited [10]. Chronic heart or lung disease, alcohol abuse, and immune dysfunction were factors associated with increased case fatality in one Danish study [10]. In the case of STSS, the mortality rates were very high [10].
Treatment Bacteremia being a life-threatening condition, the rapid initiation of effective intravenous empirical antibiotic therapy is essential. S. dysgalactiae subsp. equisimilis has remained sensitive to penicillin and other beta-lactam antibiotics. Penicillin G remains the first-line treatment of choice. Second- and third-generation cephalosporins are alternatives in patients with mild to moderate penicillin allergy, and in type I allergic patients, vancomycin and clindamycin is a sensible alternative. Resistance to macrolides in S. dysgalactiae subsp. equisimilis has been shown in many countries. In one multicenter surveillance in the United States, 28.8 % of isolates were found to be resistant to erythromycin [6]. The resistance rate for clindamycin was 4.2 % and for fluoroquinolones, it was 0.9 % [6]. In the presence of a high inoculum and stationary growth phase of the organism, the addition of clindamycin with high-dose penicillin has proved to be effective [47, 48]. There is a lack of high-quality clinical evidence on the addition of clindamycin to penicillin on the most severe S. dysgalactiae subsp. equisimilis infections. However, it is sensible to treat S. dysgalactiae subsp. equisimilis patients as S. pyogenes patients, meaning the inclusion of clindamycin along with penicillin in patients with necrotizing fasciitis, STSS, or severe cellulitis with a suspected high inoculum of bacteria and bacteremia [47, 48]. For life-threatening infections (e.g., meningitis and endocarditis), aminoglycoside can be considered in addition to penicillin, as the aminoglycoside– penicillin combination shows in vitro bactericidal synergy [49]. Older clinical observations have been suggested to
improve outcomes in patients treated with combination therapy [50, 51], but no well-conducted studies exist. However, several guidelines recommend the addition of aminoglycoside to the penicillin therapy of streptococcal endocarditis during the first 2 weeks [52]. Aminoglycosides penetrate very poorly the cerebrospinal fluid (CSF). An alternative in meningitis is third-generation cephalosporin, because it penetrates better the CSF. Patients with group A Streptococcus receiving intravenous immunoglobulin (IVIG) in STSS have improved outcomes [53], but data on S. dysgalactiae subsp. equisimilis STSS are still lacking. There is only one prospective study on the topic, which did not show any significant reduction in the 28-day mortality in group A streptococcal STSS [54]. Hence, the evidence of IVIG on group A Streptococcus STSS will remain a matter of discussion. Adequate supportive measures (intensive fluid resusCitation, vasopressors, ventilatory support) are a prerequisite for effective antimicrobial therapy. When tissue necrosis or gangrene is suspected, surgical exploration is essential, along with rapid debridement of the affected tissue. The drainage of abscesses is essential when loculated fluid is present. Amputation of a limb may be necessary in case of severe necrotizing infection. In case of prosthetic joint infection, debridement or removal of the prosthetic joint is essential. Surgery is more commonly needed in patients with S. pyogenes bacteremia (42 %) than among those with S. dysgalactiae subsp. equisimilis bacteremia (18 %) [17]. In a Japanese study, insufficient white blood cell responses due to neutropenia (
