Emerging gram-positive bacterial infections

Clin Lab Med 24 (2004) 587–603

Emerging gram-positive bacterial infections Sameer Elsayed, MDa,b,c,*, Kevin B. Laupland, MDa,d,e a

Department of Pathology and Laboratory Medicine, University of Calgary, 9, 3535 Research Road NW, Calgary, Alberta T2L 2K8, Canada b Department of Microbiology and Infectious Diseases, University of Calgary, 9, 3535 Research Road NW, Calgary, Alberta T2L 2K8, Canada c Division of Microbiology, Calgary Laboratory Services, 9, 3535 Research Road NW, Calgary, Alberta T2L 2K8, Canada d Department of Medicine, University of Calgary, 9, 3535 Research Road NW, Calgary, Alberta T2L 2K8, Canada e Centre for Antimicrobial Resistance, Calgary Health Region, 9, 3535 Research Road NW, Calgary, Alberta T2L 2K8, Canada

Gram-positive bacteria are a phylogenetically diverse group of ubiquitous microorganisms that are involved in a wide variety of human infectious diseases. Over the last 20 to 30 years, several species belonging to this group have demonstrated a remarkable ability to produce striking human illnesses never seen or only seldom encountered in the past. Furthermore, a number of newly described species of gram-positive bacteria have also emerged as important human pathogens during this period. According to the United States Centers for Disease Control and Prevention [1] and the Harvard Working Group on New and Resurgent Diseases [2], emerging infectious diseases are those that are occurring with increasing frequency or that are associated with more severe clinical manifestations, symptoms distinct from those of any previous disease, new patient populations or geographic areas, or newly described human pathogens. Host-specific, pathogen-specific, and environmental factors are all believed to contribute to disease emergence. Conditions such as staphylococcal and streptococcal toxic shock syndromes, streptococcal necrotizing fasciitis, and invasive infections caused by the newly described bacterium Streptococcus iniae are typical examples of important emerging gram-positive bacterial diseases that have recently garnered a great deal of attention in lay and medical circles. This review discusses the clinical and microbiologic aspects of these and other emerging gram-positive bacterial infections. * Corresponding author. Division of Microbiology, Calgary Laboratory Services, 9, 3535 Research Road NW, Calgary, Alberta, Canada T2L 2K8. E-mail address: [email protected] (S. Elsayed). 0272-2712/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cll.2004.05.007

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Emerging infections caused by Staphylococcus aureus Background Staphylococcus aureus is one of the chief bacterial causes of human suffering and death worldwide [3]. This organism was first described by Ogston [4] in 1880, who recognized that a ‘‘cluster-forming coccus was the cause of certain pyogenous abscesses in man.’’ Two years later, Ogston named the organism ‘‘staphylococcus’’ based on its characteristic microscopic morphology [4]. Since then, S aureus has come to be widely recognized as a principal cause of an impressive spectrum of human illnesses, ranging from relatively mild skin and soft tissue infections to more severe conditions such as pneumonia, osteomyelitis, septic arthritis, septicemia, endocarditis, and toxigenic states such as food poisoning, scalded skin syndrome, toxic shock syndrome, and neonatal toxic shock syndrome–like exanthematous disease [4–7]. The highly pathogenic nature of this organism stems from its remarkable ability to harbor and express potent virulence factors such as coagulase, protein A, hyaluronidase, and various cytolytic or superantigenic exotoxins [4,5,8]. Hospital epidemics, intrafamilial outbreaks, and sporadic infections caused by virulent strains of this pathogen gained notoriety on a global scale during the 1950s and 1960s [9]. From that period on, S aureus was an important cause of hospital- and community-acquired human illness; it is now one of the principal causes of nosocomial catheter-related bacteremia, surgical wound infection, and pneumonia [10]. The emergence of antibiotic-resistant strains, including methicillin-resistant S aureus (MRSA) and glycopeptide-resistant S aureus, continues to present a therapeutic challenge to clinicians [11]. Since the late 1970s, however, a number of unique, highly pathogenic strains of S aureus expressing potent superantigenic exotoxins have emerged as causes of novel or previously rare vivid conditions such as staphylococcal toxic shock syndrome (TSS) and neonatal toxic shock syndrome–like exanthematous disease (NTED). Natural habitat and microbiologic features Staphylococcus aureus is ubiquitous in nature and may be found as part of the normal bacterial flora of humans and other mammals [8]. Strains have a predilection for colonizing the anterior nares but may also be found at other anatomic sites, including the skin, mucous membranes, and the upper respiratory, gastrointestinal, and genitourinary tracts [8]. A constellation of host factors is believed to play a role in the ability of an individual to carry this organism asymptomatically [8,9,12]. Most infectious and toxinmediated diseases caused by this organism are endogenous in nature and arise from these colonizing strains. Microbiologically, S aureus is a grampositive, catalase-positive, coagulase-positive, facultatively-anaerobic, nonmotile, non–spore-forming spherical bacterium, approximately 0.5 to 1.0 lm

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in diameter, which typically forms irregular ‘‘grape-like’’ clusters [8]. On blood agar media, colonies are usually large (6–8 mm in diameter after 24 hours of incubation), creamy-yellow, smooth, and slightly raised, and often demonstrate b-hemolysis [8]. All strains produce thermostable nuclease (DNase) and protein A (cell wall–associated antiphagocytic immunoglobulin-binding protein), both of which can serve as the basis for additional identification tests [8]. Phenotypic or molecular detection of exotoxins produced by strains implicated in toxin-mediated diseases may be useful for clinical or epidemiologic purposes. Isolates are commonly susceptible to several antimicrobial agents, including vancomycin, cloxacillin, first-generation cephalosporins, carbapenems, b-lactam/b-lactamase inhibitor combinations, clindamycin, macrolides, and trimethoprim-sulfamethoxazole [8]. Strains harboring the mecA gene are resistant to all b-lactam agents [13]. Vancomycin resistance is extremely rare [8]. Clinical syndromes Staphylococcal toxic shock syndrome TSS is an acute, potentially life-threatening superantigenic toxinmediated disease characterized by fever, hypotension, multisystem organ dysfunction, and an erythematous rash with desquamation occurring in convalescence [5,14–16]. It was first described in 1978 by Todd [14], who reported the condition in previously healthy children aged 8 to 17 years. Shortly afterward, numerous reports of superabsorbent tampon–associated staphylococcal TSS in young, healthy menstruating women (prevalence of 10 per 100,000 young women) gained much publicity. The disease was found to be primarily caused by vaginal colonization with S aureus strains and led to the discovery of an exotoxin termed toxic shock syndrome toxin 1 (TSST-1) [17]. While rates of TSST-1–mediated TSS declined after the withdrawal of superabsorbent tampons from the market, the incidence of nonmenstrual TSS (NMTSS) cases increased (prevalence of 1 per 100,000) following their initial identification in the early 1980s [5,15,16]. Most NMTSS cases are hospital-acquired and occur postoperatively (eg, as surgical wound infection or following rhinoplasty with nasal packing) or in association with various skin, respiratory, bone, dental, genital, and other focal S aureus infections [5,15,16]. In NMTSS, TSST-1 or one of several potent staphylococcal enterotoxins, particularly staphylococcal enterotoxin B, is produced by S aureus strains causing the disease [5,15,16]. TSST-1 and the staphylococcal enterotoxins are superantigens that act as potent nonspecific T-cell mitogens. This widespread immune system activation (between 5% and 30% of the entire T-cell population) causes the release of massive amounts of cytokines that ultimately lead to the clinical manifestations of TSS [5,15,16]. The diagnosis of staphylococcal TSS illness is based on the United States Centers for Disease Control and Prevention case definition as shown in Box 1 [18]. Less than 10% of cases of TSS are associated with S aureus

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Box 1. Case definition of staphylococcal toxic shock syndrome All of: Fever (temperature 38.9(C) Rash (diffuse macular erythroderma) Desquamation (1–2 weeks after onset of illness, particularly palms and soles) Hypotension (systolic blood pressure 90 mm Hg for adults or \5th percentile by age for children, or orthostatic syncope) AND Involvement of three or more of the following organ systems: (A) Gastrointestinal (vomiting or diarrhea at onset of illness) (B) Muscular (severe myalgia or creatine phosphokinase level  twice upper limit of normal) (C) Mucous membrane (vaginal, oropharyngeal, or conjunctival hyperemia) (D) Renal (blood urea nitrogen or creatinine  twice upper limit of normal, or urinary sediment with pyuria [5 leukocytes per high power field] in absence of urinary tract infection) (E) Hepatic (total bilirubin or hepatic transaminases  twice upper limit of normal) (F) Hematologic (platelets \100,000/mm3) (G) Central nervous system (disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent) AND Negative results on the following tests, if obtained: (A) Blood, throat, or cerebrospinal fluid cultures (blood culture may be positive for Staphylococcus aureus) (B) Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles (Modified from Centers for Disease Control and Prevention. Case definitions for public health surveillance. MMWR Recomm Rep 39[RR-13]:1–43.)

bacteremia [5,15,16]. Treatment of TSS may involve supportive measures, antimicrobial agents, surgery (for associated focal or systemic infection), and possibly intravenous immunoglobulin [5,15,16]. High-dose intravenous cloxacillin, clindamycin (in b-lactam–allergic patients), or vancomycin (in areas with high rates of MRSA) should be used empirically until susceptibility testing results are available to guide antimicrobial choice [5,15,16]. The case-fatality rate for staphylococcal TSS ranges from 3% to 9% [16].

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Neonatal toxic shock syndrome–like exanthematous disease NTED is a newly emerging superantigen-mediated infectious disease of neonates first described by Takahashi et al [6] in 1998. This condition is characterized by the presence of fever, rash, thrombocytopenia, and mildly elevated serum C–reactive protein levels [6]. Virtually all of the neonates in the initial reports were colonized with MRSA strains that selectively produced TSST-1 [19]. However, the disease does not fulfill the clinical criteria for TSS. NTED has been observed in over 70% of the major neonatal care units in Japan, although the condition has not been described elsewhere except for a single case in France [6,19,20]. The condition resolves spontaneously without antibiotic therapy in full-term neonates, but most preterm neonates develop severe symptoms, with two deaths in the latter group reported to date [6,19]. Treatment involves supportive measures and, in the case of premature neonates, antistaphylococcal antibiotics. Emerging infections caused by coagulase-negative staphylococci Background Before the 1980s the coagulase-negative staphylococci (CoNS) were regarded as nonpathogenic or minimally pathogenic commensal bacteria that were typically discounted as contaminants when isolated from human clinical specimens [8,21,22]. It was not until 1981 that investigators became cognizant of the striking ability of various strains of these microbes to produce an extracellular polysaccharide material commonly referred to as ‘‘slime,’’ which facilitated adherence to bioprosthetic material surfaces such as intravenous catheters and was believed to act as a barrier to antimicrobial agents [21–23]. This observation was shortly followed by reports of central venous catheter–associated sepsis caused by slime-producing CoNS [21–23]. Since then, the CoNS have emerged as important human pathogens in both hospitalized and ambulatory patients, and they are now among the most frequently isolated microorganisms in the clinical microbiology laboratory [8]. These opportunistic pathogens have been associated with infectious processes in patients with various indwelling or implanted medical devices such as urinary catheters and ureteral stents (pyelonephritis), peritoneal dialysis catheters (peritonitis), hemodialysis or other vascular grafts and central venous catheters (sepsis), biliary stents (cholangitis), breast implants (cellulitis), prosthetic joints (septic arthritis), heart valves (endocarditis), pacemakers (pocket infection), and central nervous system shunts (meningitis). They have also caused severe infections in immunocompromised patients and premature neonates [8,21–23]. Natural habitat and microbiologic features CoNS are widespread in nature and constitute a major component of the normal integumentary, upper respiratory, gastrointestinal, and urogenital

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microbiota of humans and other mammals. Approximately 30 species of CoNS have been described to date, with S epidermidis being the most common colonizer and cause of infection in humans. The other medically important CoNS indigenous to humans include S saprophyticus, S capitis, S cohnii, S haemolyticus, S hominis, S lugdunensis, S schleiferi (subspecies schleiferi only), S simulans, and S xylosus, although infections due to other species have been documented [8]. Most bioprosthesis-associated infections caused by this group of organisms are endogenous in nature and arise from colonizing strains [21–23]. Microbiologically, CoNS are gram-positive, catalase-positive, coagulase-negative, facultatively anaerobic, nonmotile, non–spore-forming spherical bacteria, approximately 0.5 lm to 1.0 lm in diameter, which typically form irregular ‘‘grape-like’’ clusters similar in appearance to S aureus [8]. On blood agar media, colonies are medium-sized (2–6 mm in diameter after 24 hours of incubation), nonpigmented, smooth, and sticky and, except in the case of S hemolyticus, do not usually demonstrate b-hemolytic activity [8]. They are easily distinguished from S aureus by their lack of free coagulase, DNase, and protein A. The CoNS are not known to produce any potent exotoxins [8,21,22]. This group of organisms is commonly susceptible to several antimicrobial agents, including vancomycin, clindamycin, macrolides, and trimethoprim-sulfamethoxazole [8]. However, up to 80% of strains carry the mecA gene [8,24], rendering them resistant to all b-lactam agents, including cloxacillin, cephalosporins, carbapenems, and b-lactam/b-lactamase inhibitor combinations. Vancomycin resistance has been reported in S hemolyticus and S epidermidis but is extremely rare [8]. Clinical syndromes Indwelling prosthetic material–related infections The introduction and increasing use of bioprosthetic devices such as artificial joints, heart valves, central nervous system shunts, and central venous catheters (CVCs) in acutely or chronically ill patients have revolutionized modern medicine over the last several decades. The use of these devices has, in many cases, resulted in improved patient outcomes and increased quality of life. However, the foreign materials used to manufacture these devices are susceptible to colonization (often permanent) by biofilm-producing microorganisms, leading to local or systemic infection or to failure of the device. While the use of CVCs is associated with lower morbidity compared with other implanted devices, they will be the focus of this review because they are by far the most commonly used of all devices. CVCs allow for the parenteral administration of various antimicrobials, chemotherapeutic agents, blood products, inotropic agents, and nutritional support in very ill patients. Their increased use, however, has been accompanied by an increase in the frequency of bacteremia and sepsis [21,23]. The first reports of vascular catheter–related infection caused by

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CoNS were published in the early 1980s; these infections were due to slimeproducing S epidermidis strains [21–23]. Since then, other species of CoNS and many nonstaphylococcal bacteria have been implicated as causes of these infections [21,25,26]. Of the more than 5 million CVCs placed annually in the United States, about 10% are associated with infection [21,25,26]. Data from the National Nosocomial Infection Surveillance system between January 1992 and February 1998 revealed that bloodstream infections (most of which were CVC-related) were the third most common cause of hospitalacquired infection and accounted for 14% of all nosocomial infections [27]. The CoNS were responsible for approximately 40% of cases, with over half caused by S epidermidis [27]. Microorganism-specific, host-specific, and various extrinsic and environmental factors are believed to modulate the risk of catheter-related infection [21,25,26]. The source of colonization (on either the external or internal catheter surface) is usually the patient’s own permanent or transient normal bacterial skin flora at the site of catheter insertion, but colonization may also occur from an extrinsically or endogenously contaminated catheter hub or contaminated infusate, or secondary to hematogenous seeding from a remote site of infection [21,25,26]. In short-term catheters (8 days), catheter colonization usually arises from skin microorganisms (75%–90% of cases), followed by the catheter hub/lumen (10%–20%), the bloodstream (3%–10%, up to 50% in ICU patients), and infusate (2%–3%). For long-term catheters (>8 days), the source of colonization is generally the hub/lumen (66% of cases), followed by the skin (26%) [21,25]. Once catheters are colonized, bacteremia and septicemia may ensue. Clinical criteria for CVC-related infections are nonspecific and often rely on the absence of any other explanation for the patient’s sepsis. Diagnosis is facilitated by semiquantitative culture of the distal catheter tip using one or more methods (eg, roll-plate, catheter flushing, or sonication) [8,21,25,26]. CVC-related bacteremia may also be diagnosed by simultaneous culture of blood obtained peripherally and by means of the catheter, with earlier positivity of cultures drawn through the catheter [25,26]. Without adequate management, the case-fatality rate for CVC-related sepsis may be as high as 10% to 20% [25,26]. Management of CVC-related bacteremia caused by CoNS involves early administration of vancomycin (or antistaphylococcal b-lactam agent, depending on susceptibility testing results), given the antibiotic resistance profile of this group of organisms [25]. Catheter removal may be required to effect a cure, particularly if antibiotic therapy is delayed [25].

Group A b-hemolytic streptococcal infections Background Streptococcus pyogenes (Lancefield group A b-hemolytic streptococcus or GABHS) is one of the most important and frequently encountered bacterial

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pathogens of humans worldwide [28]. It was first described by Billroth in the late 1800s as a cause of erysipelas and wound infection and was later recognized by Pasteur as the cause of puerperal sepsis, although written works of ancient physicians and other historical accounts suggest that this organism has caused human disease for thousands of years [28]. The landmark discovery of the Lancefield group A antigen in S pyogenes in the early 1930s facilitated an improved understanding of the spectrum of infections caused by this virulent microbe and led to its recognition as the principal cause of acute bacterial pharyngitis, scarlet fever, and concomitant nonsuppurative sequelae, specifically acute rheumatic fever (ARF) and poststreptococcal glomerulonephritis [28]. Epidemics of scarlet fever and ARF occurred in Europe and the United States before the early 1900s and were associated with high morbidity and mortality. However, the incidence of these and other severe GABHS infections subsequently declined, particularly in developed countries—a decline that was believed to be secondary to reduced expression of virulence factors in infecting strains [29]. Over the last 2 decades, however, there has been an emergence of invasive and potentially life-threatening infections caused by highly virulent, epidemic strains of GABHS that have cocirculated with less virulent endemic strains [28–31]. Conditions such as necrotizing fasciitis (streptococcal gangrene or ‘‘flesh-eating disease’’), myositis, and streptococcal toxic shock syndrome (STSS) have been documented with increasing frequency during this period, particularly in industrialized nations [14,15,28–34]. These strains harbor an impressive armamentarium of tissue-destructive and superantigenic virulence factors leading to the clinical manifestations of these severe diseases [14,15,28–34]. Natural habitat and microbiologic features Humans are the natural reservoir for Streptococcus pyogenes. This organism may be found as part of the pharyngeal, vaginal, and transient skin flora of asymptomatic individuals. A number of factors besides carriage or contact with a virulent strain are believed to modulate the risk of invasive disease. Nevertheless, invasive disease is virtually always associated with positive blood and tissue cultures for streptococcal TSS and necrotizing fasciitis/myositis, respectively [28,29,32–34]. GABHS is easily identified in the clinical microbiology laboratory using standard phenotypic tests [35]. Like other members of the genus Streptococcus, it grows well on nonselective blood agar media, is nonmotile and catalase-negative, and appears as gram-positive cocci in chains on microscopic examination [35]. This organism is facultatively anaerobic and typically forms large (0.5-mm diameter after 24 hours of incubation), nonpigmented colonies surrounded by a pronounced zone of b-hemolysis (enhanced by anaerobic incubation), mediated by streptolysins S (oxygen stable) and O (oxygen labile) [35]. Streptococcus pyogenes is leucine animopeptidase (LAP) and

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pyrrolidonlyarylamidase (PYR) positive, Voges-Proskauer negative, bacitracin sensitive, and Christie Atkins Munch-Peterson (CAMP) test negative; it reacts with Lancefield group A–specific antisera [35]. The ability of strains to produce one or more superantigenic streptococcal pyrogenic exotoxins (SPEs), namely SPE-A, SPE-B, and SPE-C, can usually be determined by polymerase chain amplification of the respective genes. GABHS is universally sensitive to penicillin G, ampicillin, ureidopenicillins, first-generation cephalosporins, carbapenems, b-lactam/b-lactamase inhibitor combinations, and vancomycin [35]. Most strains are sensitive to clindamycin and the macrolides, although resistance to these agents is increasingly encountered [35]. Clinical syndromes Streptococcal necrotizing fasciitis Necrotizing fasciitis (NF) caused by S pyogenes is an acute, rapidly progressive, life-threatening, deep-seated infection of the subcutaneous tissue, usually of an extremity, that results in extensive destruction of superficial and deep fascia and fat while initially sparing the skin and underlying muscle [28,29,31–33]. The condition is often preceded by blunt or penetrating skin trauma, chronic skin disease, varicella infection, or surgery and is more common in the elderly [28,29,31–33]. Patients typically present with excruciating pain that is out of proportion to the observed clinical findings [28,29,31–33]. Over the ensuing 24 to 72 hours, the skin characteristically becomes dusky and cyanotic and may be accompanied by clear or hemorrhagic bullae [28,29,31–33]. Unless aggressive surgical and other supportive measures are rapidly employed, disease may further progress to cutaneous gangrene, myositis, septicemia, STSS, and death [28,29,31–33]. Therapy involves aggressive surgical debridement and removal of all necrotic material, intravenous antibiotics usually consisting of high-dose penicillin G and clindamycin, and fluid and nutritional support [28,29,31– 33]. The mortality, even with the best of care, ranges from 10% to 50% and is usually secondary to shock and multisystem organ failure [28,29,31–33]. Streptococcal toxic shock syndrome STSS is defined as isolation of GABHS from blood or another normally sterile body site in the presence of shock and multiorgan failure (Box 2) [36]. It is believed to be mediated by the production of SPEs that function as superantigens causing massive nonspecific T-cell activation and cytokine release [15,16,28,32–34]. In about 50% of cases, STSS is associated with NF, with or without myositis [15,16,28,32–34]. The source of GABHS is commonly the skin, pharynx, or vaginal mucosa [15,16,28,32–34]. Patients may initially present with flu-like symptoms, including fever, chills, malaise, myalgia, nausea, vomiting, and diarrhea, followed shortly by severe sequelae that include necrotizing soft tissue infection, shock, adult respiratory distress

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Box 2. Case definition of streptococcal toxic shock syndrome A) Hypotension (systolic blood pressure 90 mm Hg for adults or \5th percentile by age) AND B) Two or more of the following: Renal impairment (creatinine 177 lmol/L for adults or  twice upper limit of normal for age or compared with baseline in chronic renal insufficiency) Coagulopathy (platelets 100,000 or disseminated intravascular coagulation) Hepatic involvement (transaminases or bilirubin  twice upper limit of normal or compared with baseline in pre-existing liver impairment) Adult respiratory distress syndrome Generalized erythematous macular rash Soft tissue necrosis (necrotizing fasciitis, myositis, or gangrene) Definite case: clinical criteria plus isolation of group A streptococci from a normally sterile site Probable case: clinical criteria plus isolation of group A streptococci from a non-sterile site (Modified from The Working Group on Severe Streptococcal Infections. Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition. JAMA 1993;269[3]:390–1.)

syndrome, and renal failure [15,16,28,32–34]. Treatment must be prompt and includes hemodynamic stabilization with inotropic agents and intravenous fluids, use of potent antistreptococcal antibiotics (usually consisting of high-dose penicillin G plus clindamycin), and, in the case of concurrent soft tissue infection/NF, aggressive surgical debridement [15,16]. About 30% to 70% of patients die from STSS despite these measures [15,16]. Emerging group B streptococcal infections Background Streptococcus agalactiae (Lancefield group B streptococcus, GBS) is an important and well-documented cause of human infection in patients of all ages. It was first characterized in the early 1930s as a unique b-hemolytic member of the genus Streptococcus, partly based on its capsular polysaccharide antigenic specificity [37]. At that time, it was recognized as an important cause of bovine mastitis but had not been recovered from

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human sources. A few years later, however, it was isolated from the vaginas of healthy postpartum women, a finding that was soon followed by reports of GBS-related postpartum endometritis and sepsis [37]. In the 1960s and 1970s, this organism emerged as a major cause of neonatal bacteremia and septicemia, and it continues to be the leading cause of serious bacterial infection among neonates in the United States [37,38]. Over the last 3 decades, however, GBS has emerged as an important human pathogen in nonpregnant adults, causing a clinical spectrum of disease ranging from skin and soft tissue infection to more severe conditions such as pneumonia, septic arthritis, osteomyelitis, endocarditis, meningitis, and septicemia, which are associated with high morbidity and mortality [39–41]. Natural habitat and microbiologic features Humans and various domestic animals are the natural reservoirs for S agalactiae. This organism may be found as part of the normal gastrointestinal and genitourinary tract bacterial flora in 20% to 35% of individuals and may occasionally be found as part of the transient flora of the skin and upper respiratory tract [35,38]. The source of GBS causing infections in adults is usually one of these sites of colonization. GBS is easily identified in the clinical microbiology laboratory using standard phenotypic tests. Like other members of the genus Streptococcus, it grows well on nonselective blood agar media, is nonmotile and catalase-negative, and appears as gram-positive cocci in chains on microscopic examination [35]. It is facultatively anaerobic and typically forms large (0.5-mm diameter after 24 hours of incubation), nonpigmented colonies that are usually surrounded by a modest zone of b-hemolysis [35]. S agalactiae is LAP, CAMP test, and hippurate positive but PYR negative, Voges-Proskauer negative, and bacitracin resistant; it reacts with Lancefield group B–specific antisera [35]. Isolates are universally sensitive to penicillin G, ampicillin, ureidopenicillins, first-generation cephalosporins, carbapenems, b-lactam/b-lactamase inhibitor combinations, and vancomycin. Most strains are sensitive to clindamycin and macrolides, although resistance to these agents is emerging [35,38]. Clinical syndromes Group B streptococcal infections in nonpregnant adults Group B streptococci are capable of causing a wide array of infections in nonpregnant adult patients. Diseases caused by GBS in this patient population usually arise from colonizing strains and include conditions such as urinary tract infections, skin and soft tissue infections, post–surgical wound infections, pneumonia, osteomyelitis, septic arthritis, peritonitis, meningitis, central venous catheter–related infection, and septicemia [39– 41]. Underlying conditions that predispose these patients to GBS disease

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include diabetes mellitus, malignancy, congestive heart failure, liver disease, alcohol abuse, and bedridden state [39–41]. Empiric therapy for GBS infections includes prompt administration of intravenous penicillin G or ampicillin (or an alternative agent such as clindamycin or vancomycin in blactam allergic patients) [39–41]. Despite treatment, the case-fatality rate for invasive (bacteremic) GBS disease is about 25% [39–41].

Emerging groups C and G b-hemolytic streptococcal infections Background Large colony (0.5-mm diameter) b-hemolytic streptococci belonging to Lancefield serologic groups C and G have emerged as important human pathogens in recent years. These organisms, by virtue of their ability to produce a number of tissue-destructive enzymes and other virulence factors, have been responsible for a spectrum of human disease almost identical to that of group A streptococci (S pyogenes), including conditions such as pharyngitis, epiglottitis, skin and soft tissue infections, septic arthritis, osteomyelitis, endocarditis, septicemia, meningitis, and TSS [35,42,43]. Most infections due to group C streptococci (GCS) are associated with exposure to animals carrying these microbes as part of their commensal flora, although endogenous infection from human colonizing sources may also occur [35,42,43]. Infections due to group G streptococci (GGS) are usually endogenous in nature [35,42]. Natural habitat and microbiologic features Group C and G streptococci are b-hemolytic, a-hemolytic, or nonhemolytic bacteria of human or animal origin that are further differentiated based on their ability to form either large (0.5 mm in diameter) or small (\0.5 mm in diameter) colony variants in the laboratory [35,43]. Human strains of b-hemolytic large-colony GCS belong to the subspecies S dysgalactiae subspecies equisimilis, whereas those isolated from animals belong to S dysgalactiae subspecies dysgalactiae, S equi subspecies equi, or S equi subspecies zooepidemicus [35,42]. S dysgalactiae subspecies equisimilis may be found as part of the normal human nasopharyngeal, skin, and vaginal flora [35,42]. The other species are commensals or pathogens of various animals, including horses, cattle, sheep, swine, and guinea pigs [35,42,44]. GGS, which belong to the equisimilis subspecies of S dysgalactiae, are indigenous to humans, being commensals of the skin, the oropharynx, and the upper respiratory, gastrointestinal, and female genital tracts [35,42]. Isolates of b-hemolytic GCS and GGS are uniformly sensitive to penicillin G, ampicillin, first-generation cephalosporins, expanded spectrum cephalosporins, and vancomycin [35]. Strains are usually sensitive to clindamycin and macrolides, but resistance to these agents is emerging [35].

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Clinical syndromes Invasive b-hemolytic group C and G streptococcal infections Invasive diseases caused by b-hemolytic GCS and GGS include empyema, peritonitis, osteomyelitis, septic arthritis, endophthalmitis, pericarditis, endocarditis, meningitis, septicemia, and TSS [35,42,43]. Most of these infections are associated with GCS or GGS bacteremia, although these organisms account for less than 1% of all bacteremias and less than 10% of bacteremias caused by b-hemolytic streptococci [42,44,45]. Infections caused by these organisms are usually community-acquired and are frequently associated with one or more underlying health problems such as cardiovascular disease, diabetes mellitus, alcoholism, intravenous drug use, chronic venous insufficiency, renal disease, prosthetic joints or heart valves, immunosuppression, and malignancy, with the latter being the most significant underlying disorder associated with GGS infections [42–45]. The portal of entry for GCS is usually the upper respiratory or gastrointestinal tract, a fact explained by the high proportion of patients with GCS infection related to animal exposure [42,44]. In contrast, most cases of group G disease are associated with a cutaneous source of the organism [42,44]. Treatment of patients with invasive GCS or GGS infections is often problematic. Mortality as high as 25% for GCS and 39% for GGS has been reported and is related to the underlying disease state as well as to the severity of infection [42]. Penicillin G is the treatment of choice for GCS and GGS infections, although the addition of gentamicin is recommended for serious infections (eg, meningitis, endocarditis), because strains (especially of GCS) tolerant to the bactericidal action of penicillin G have been described [35,42]. Alternative antibiotic choices include first-generation cephalosporins, clindamycin, and vancomycin [35,42].

Streptococcus iniae infections Background Streptococcus iniae was first described in 1976 as a cause of subcutaneous abscesses in an Amazon freshwater dolphin [46]. It was later implicated as a cause of invasive disease with high mortality among freshwater fish such as tilapia, salmon, rainbow trout, and bass, but was not recognized as a human pathogen until the mid-1990s [47]. Natural habitat and microbiology Various freshwater fish, particularly tilapia (reported to be the fastestgrowing aquaculture crop in the United States and around the world), serve as the reservoir for S iniae. Like other members of the genus

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Streptococcus, the organism grows readily in vitro on nonselective blood agar media, is nonmotile and catalase-negative, and appears as grampositive cocci in chains on microscopic examination of smears [35,47–50]. On 5% sheep blood agar, S iniae forms large (0.5 mm in diameter after 24 hours of incubation) colonies with a narrow zone of b-hemolysis (enhanced by anaerobic incubation) surrounded by a larger a-hemolytic zone [35,47–50]. The organism is LAP and PYR positive, Voges-Proskauer negative, and variably susceptible to bacitracin [47–50]. Arginine is variably hydrolyzed, and acid is produced from glucose, sucrose, trehalose, and salicin [48–50]. Like S agalactiae, S iniae is CAMP test positive. However, it does not possess any Lancefield group antigens [35]. Commercial identification systems may misidentify S iniae strains as S uberis [47]. Definitive identification can be achieved by means of sequencing of the 16S ribosomal RNA gene [49]. Phylogenetically, S iniae displays the closest relationships with S parauberis, S dysgalactiae, and S agalactiae [49]. The organism demonstrates in vitro sensitivity to penicillin G, cefazolin, ceftriaxone, cefepime, erythromycin, clindamycin, tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin, and vancomycin [48,49]. Clinical syndromes Several Asian patients from Toronto, Canada developed invasive S iniae infection shortly after handling freshly killed or live fish, particularly tilapia [47,48]. Cases of human S iniae infection also have been reported in the United States [48] and China [49], including a case in 1991 in the United States that was identified by retrospective surveillance [48]. Worldwide, about 15 cases of human S iniae infection have been reported to date, with most patients being over 40 years of age and about half having underlying diseases such as diabetes mellitus or rheumatic heart disease [47–49]. An over-representation of S iniae infection in patients of Asian origin has been observed and is believed to be related to the method of preparing and cooking fish. Most affected individuals reported an episode of percutaneous trauma from a fish bone or knife during the handling and preparation of fish [47–49]. Cellulitis of the hand is the most common clinical presentation, usually developing within 16 to 24 hours after percutaneous injury, and is often accompanied by fever, lymphangitis, and bacteremia [47–49]. Occasionally, septic arthritis, osteomyelitis, endocarditis, and meningitis may occur from bacteremic spread [47–49]. Invasive human S iniae infections are readily diagnosed by culture of peripheral blood specimens and occasionally from other sterile body sites in cases of metastatic infection [47–49]. Penicillin G is considered the treatment of choice. Based on accumulated experience, a 10-day course of therapy appears to be sufficient for localized disease. There are no reports of clinical failure or death due to S iniae infection in humans.

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Summary The last 30 years have witnessed the emergence or re-emergence of a number of serious gram-positive bacterial infections of humans that have been caused predominantly by members of the Staphylococcus and Streptococcus genera. Although this review addresses key emerging grampositive bacterial infectious diseases, emerging diseases due to other grampositive bacterial genera are also significant. Members of the Listeria, Clostridium, and Nocardia genera have emerged as important pathogens in immunocompromised patients, such as individuals with transplants or those receiving cancer chemotherapy. Infections caused by these and other known bacterial agents will continue to pose a therapeutic challenge to clinicians caring for such individuals. Future advances in molecular diagnostics may pave the way for the discovery of new agents of human disease and improve our understanding of the known disease threats.

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