Infection due to coagulase-negative staphylococci: Clinical manifestations

INTRODUCTION — Coagulase-negative staphylococci (CoNS) are a major constituent of human skin and mucosal commensal flora [1,2]. Once considered relatively avirulent and a likely contaminant when isolated from a clinical specimen, these organisms have increasingly been recognized as a cause of clinically significant nosocomial bloodstream infections. Patients at particular risk include those with prosthetic valves, pacemakers, defibrillators, ventricular assist devices, intravascular catheters, or other foreign bodies as well as neonates and immunocompromised hosts. These infections are inherently difficult to treat given the propensity of these organisms to colonize foreign material, to form a biofilm, and to display resistance to multiple antibiotics [3].

The following discussion will emphasize the issues specific to both native valve endocarditis and prosthetic valve endocarditis caused by CoNS. Discussion of CoNS infections at other sites is also included. General discussions related to the diagnosis and treatment of infective endocarditis and to the epidemiology, microbiology, pathogenesis, and antibiotic resistance patterns of CoNS are presented separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Antimicrobial therapy of left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis" and "Antimicrobial therapy of prosthetic valve endocarditis" and "Infection due to coagulase-negative staphylococci: Epidemiology, microbiology, and pathogenesis" and "Infection due to coagulase-negative staphylococci: Treatment".)

CLINICAL MANIFESTATIONS

Intravascular catheter infection — CoNS remains the most common cause of catheter-related infections; in addition, most episodes of CoNS bacteremia are catheter related [4]. For short-term catheters, infection most commonly results from CoNS originating on the patient's skin, migrating via the cutaneous surface of the catheter to gain access to the bloodstream. For longer-term catheters, hub colonization and migration of organisms via the luminal surface is also important.

Clinical manifestations may be absent or include local findings (catheter site erythema and/or drainage) and/or systemic findings (fever, hypotension). Diagnosis and management of intravascular catheter infection are discussed further separately. (See "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis" and "Intravascular non-hemodialysis catheter-related infection: Treatment".)

Distinguishing true infection from skin contamination is important; this is discussed separately. (See "Infection due to coagulase-negative staphylococci: Epidemiology, microbiology, and pathogenesis", section on 'Distinguishing infection from contamination'.)

Endocarditis — CoNS are emerging as an important cause of native valve endocarditis (NVE) in both community and healthcare settings [5,6]. In addition, CoNS are among the most frequent causes of prosthetic valve endocarditis (PVE) within the first year after surgery [7-11].

Native valve — The clinical presentation of NVE due to CoNS is similar to endocarditis due to viridans streptococci in that a prolonged duration of symptoms is common, although vascular and immunologic manifestations including Osler nodes, Janeway lesions, and Roth spots are somewhat less common with CoNS [6].

In the past, NVE due to CoNS was primarily a community-acquired infection [12]; more recent studies identify a high frequency of healthcare-associated infections [6]. This includes infections acquired in the hospital as well as infections in patients with extensive recent healthcare contact.

Data from one large study including more than 1500 cases of NVE noted that approximately 6 percent were caused by CoNS [5]. Compared with NVE due to Staphylococcus aureus, patients with NVE due to CoNS had lower rates of brain embolization (5 versus 24 percent) but higher rates of intracardiac abscess formation (15 versus 8 percent) and surgical intervention (54 versus 35 percent).

Compared with NVE due to viridans group streptococci, patients with NVE due to CoNS had higher rates of [5]:

●Nosocomial endocarditis (40 versus 1 percent)

●A long-term intravascular catheter (20 versus 1 percent)

●Heart failure (49 versus 31 percent)

●Pulmonary embolus (5 versus 0.5 percent)

●Surgical intervention (54 versus 35 percent)

●In-hospital mortality (19 versus 6.6 percent)

Another study noted that, among NVE cases not associated with injection drug use, CoNS were responsible for nearly 8 percent of cases, and nearly half were acquired in a healthcare setting [6]. Patients with NVE due to CoNS had a longer duration of symptoms prior to diagnosis as compared with patients with NVE due to S. aureus; despite this apparent delay in diagnosis, embolic events were less frequent among patients with NVE caused by CoNS. When compared with patients with NVE due to S. aureus, a larger proportion of patients with NVE due to CoNS had a pacemaker or implantable defibrillator [6].

Laboratory abnormalities including leukocytosis, anemia, and elevated inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) are common. In one study, vegetations were demonstrated by echocardiogram in 89 percent of patients [6]. In another review of 21 patients, 14 developed complications including systemic embolization, heart failure, or new conduction system abnormalities, and 9 required surgical intervention [12].

The majority of isolates are S. epidermidis, although a variety of other species can be causative agents, including S. lugdunensis, S. schleiferi, S. hominis, S. capitis, and others [5,6,13]. Although most patients respond to antibiotic therapy, mortality rates of 13 to 25 percent have been reported [5,6,12,14-16].

S. lugdunensis is an aggressive pathogen in the setting of NVE [17]. Its virulence is similar in many ways to that of S. aureus. In one series of 11 cases of S. lugdunensis IE, native valves were involved in 8 cases; valve destruction with abscess formation was observed in half of cases, with a mortality rate of 70 percent [18]. In another report, four patients presented with rapidly progressive valve destruction requiring prompt valve replacement [19]. (See "Staphylococcus lugdunensis".)

The approach to treatment for NVE due to CoNS is discussed separately. (See "Antimicrobial therapy of left-sided native valve endocarditis".)

Prosthetic valve — CoNS are the second most common cause of prosthetic valve endocarditis, after S. aureus [20,21]. In a series of 69 cases of PVE due to CoNS, 33 occurred between 60 and 365 days, and 82 percent of strains were S. epidermidis; 57 percent underwent surgery [21]. Early cases occurring within the first year are thought to result from introduction of bacteria at the time of surgery. Coagulase-negative staphylococci were also the most frequent isolates in cases of transcatheter implanted aortic valve endocarditis [22].

The infecting isolates in early PVE usually have a phenotype characteristic of nosocomial acquisition; they tend to form biofilm and to be resistant to multiple antibiotic families. CoNS have been isolated from numerous sources in the operating room, including bypass equipment, bone saws, and the prosthesis itself, and surgeons have been implicated as the source of contamination in point-source outbreaks for both wound infections and PVE [23,24].

Early PVE due to CoNS is often locally destructive. In one series of 55 patients, prosthetic valve dysfunction due to annular infection was found in 38 patients and perivalvular extension resulting in abscess formation in 17 patients [25].

The main challenge in interpreting blood cultures positive for CoNS in patients with PVE is distinguishing infection from contamination. Obtaining multiple blood cultures, separated over time, with assiduous attention to sterile technique to minimize culture contamination, is crucial in making this distinction. If a patient with a prosthetic valve has sporadically positive cultures, evaluation of antimicrobial susceptibility and techniques for determining the clonal origin of CoNS isolates should be applied. (See "Infection due to coagulase-negative staphylococci: Epidemiology, microbiology, and pathogenesis", section on 'Identification'.)

The mortality associated with PVE remains high despite earlier diagnosis of infection and the use of a combined surgical and medical approach for early infections. Treatment choices for staphylococcal PVE are the same regardless of whether the pathogen is coagulase negative or S. aureus. (See "Antimicrobial therapy of prosthetic valve endocarditis".)

Cardiac devices — CoNS (predominantly S. epidermidis) account for at least 25 percent of cardiac device infections and may occur via inoculation at the time of device placement or by hematogenous seeding from another site. The microbiology, clinical presentation, diagnosis, and treatment of these infections are discussed further separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Vascular graft infection — Prosthetic vascular graft infection rates range from 1 to 6 percent, depending on the graft location; infrainguinal grafts deriving from the groin have the highest rates of infection [26]. CoNS are common causes of these infections. In early-onset infections (≤4 months), fever and local signs of infection are often present. Late-onset infections are frequently more difficult to diagnose. Symptoms may be clinically occult with patients having fever and fatigue but with few localizing findings [27]. Diagnosis is generally made by physical examination and radiographic imaging with demonstration of a sinus tract or pseudoaneurysm at the vascular anastomosis site. Positron emission tomography (PET) scans may be useful in establishing the diagnosis, but more study is needed [27].

Orthopedic infection — CoNS are a common cause of infection of prosthetic orthopedic devices. The organisms are frequently inoculated at the time of the arthroplasty, and infection may present indolently. The clinical manifestations, diagnosis, and treatment of prosthetic joint infections are discussed further separately. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Prosthetic joint infection: Treatment".)

Central nervous system shunt infection — About half of shunt infections are due to CoNS. These infections are discussed further separately. (See "Infections of cerebrospinal fluid shunts".)

Breast implant infections — Coagulase-negative staphylococci are also among the most common causes of infection following breast implant and reconstructive surgery. Early infections may present with localized signs of erythema, drainage, and pain as well as fever, while the more indolent late infections may present with drainage, chronic pain, and, infrequently, capsular contracture [28]. (See "Breast implant infections".)

Surgical site infection — CoNS are an important cause of surgical site infection (SSI). In some surgical procedures (such as coronary artery bypass surgery and some orthopedic procedures), CoNS are the second most common cause of SSI after S. aureus [29].

CoNS are more often cultured from superficial incisional wounds than deeper wounds and are more likely to cause infections in "clean" procedures. Diagnosis is made by culture of CoNS as the predominant isolate or repeated isolation of the same organism in serial cultures [30].

CoNS are among the most common causes of the endophthalmitis that can complicate approximately 0.1 percent of cataract surgeries. It is also a cause of postinjection endophthalmitis following the intravitreal injection of antivascular endothelial growth factor to treat macular degeneration [31-33].

Animal bite wound — Staphylococcus intermedius is a common part of animal oral flora and is an important pathogen in bite wounds [34].

Urinary tract infection — Staphylococcus saprophyticus is a common cause of urinary tract infection; it is almost always methicillin-susceptible [35].

INFECTION IN NEONATES — Neonates are at particularly high-risk for infection due to CoNS [36-38]. CoNS are the most frequently isolated organisms associated with late-onset neonatal sepsis. Risk factors include prematurity, very low birth weight, central line placement, receipt of total parenteral nutrition, and prolonged hospitalization [39,40]. Clinical features are often nonspecific and may include temperature instability, hypoxemia, apnea, bradycardia, gastrointestinal disturbances, and lethargy or irritability [39-41].

The extent to which neonatal CoNS infections are associated with increased morbidity, including sequelae such as neurodevelopmental impairments, remains unclear [37,40,42]. Our understanding of the outcomes of CoNS sepsis has been hampered by the lack of a uniform approach to diagnosis, particularly in terms of distinguishing clinically relevant isolates from contaminants [39,40].

SUMMARY

●Coagulase-negative staphylococci (CoNS) are a major constituent of human skin flora. These organisms have become increasingly recognized as agents of nosocomial bloodstream infections. Patients at risk include those with prosthetic devices and immunocompromised hosts. (See 'Introduction' above.)

●Most CoNS bloodstream infections are related to intravascular catheters. Clinical manifestations may include fever, hypotension, and leukocytosis. (See 'Intravascular catheter infection' above.)

●CoNS are emerging as an important cause of native valve endocarditis in both community and healthcare settings. In addition, CoNS are the most frequent cause of prosthetic valve endocarditis within the first year after surgery. (See 'Endocarditis' above.)

●CoNS (predominantly Staphylococcus epidermidis) account for at least 25 percent of cardiac device infections and may occur via inoculation at the time of device placement or by hematogenous seeding from another site. (See 'Cardiac devices' above.)

●CoNS are a common cause of vascular graft infection. In early-onset infections, local signs of infection are often present, while late-onset infections may be clinically occult and difficult to diagnose. (See 'Vascular graft infection' above.)

●CoNS are a common cause of infection of prosthetic orthopedic devices. The organisms are frequently inoculated at the time of the arthroplasty, and infection may present indolently. (See 'Orthopedic infection' above.)

●Surgical site infections due to CoNS are second only to S. aureus as an etiologic agent. CoNS are more often cultured from superficial incisional wounds than deeper wounds and are more likely to cause infections in "clean" procedures. (See 'Surgical site infection' above.)

●Neonates are a particularly high-risk group for CoNS infection. Risk factors include prematurity, very low birth weight, central line placement, receipt of total parenteral nutrition, and prolonged hospitalization. Clinical manifestations may include temperature instability, hypoxemia, apnea, bradycardia, gastrointestinal disturbances, and lethargy or irritability. (See 'Infection in neonates' above.)