Infectious Diseases

Coagulase negative Staphylococci

OVERVIEW: What every clinician needs to know

Pathogen name and classification

There are more than 45 recognized species of coagulase-negative staphylococci (CoNS). CoNS are gram-positive cocci that divide in irregular "grape-like" clusters and are differentiated from S. aureus by their inability to produce coagulase and coagulate rabbit plasma. Species of CoNS that have important traits and are more frequently associated with clinical disease are S. epidermidis (biomaterial-based and prosthetic device infections), S. lugdunensis (skin and soft-tissue infections, bacteremia, endocarditis), S. saprophyticus (uncomplicated urinary tract infections in sexually active women), and S. haemolyticus (often less-susceptible to vancomycin).

What is the best treatment?

  • Vancomycin is generally the cornerstone for treatment of infections due to S. epidermidis and other CoNS, because 80-90% of strains responsible for nosocomial infections are resistant to semi-synthetic, penicillinase-stable penicillins, such as oxacillin and nafcillin. Dosing of vancomycin is based on actual weight and renal function. The benefit of higher-dose vancomycin (trough levels of 15-20 ug/mL) is not well-defined for CoNS infections and may lead to increased risk of nephrotoxicity. Many clinicians add rifampin (600 mg/day) to regimens containing vancomycin when treating a biomaterial-based infection (prosthetic joint infection, prosthetic valve endocarditis, etc.).

  • A characteristic of CoNS infections involving medical devices (intravascular catheters, vascular grafts, prosthetic joints, CSF shunts, etc.) is the presence of biofilm and "persister" cells. Biofilm-associated CoNS are generally much less susceptible to antibiotics than planktonic cells, and, oftentimes, effective therapy of biomaterial-based infections requires removal of the device.

  • CoNS responsible for nosocomial infections are almost always resistant to multiple classes of antimicrobial agents.

    • Approximately 95% of strains of S. epidermidis isolated from well-defined healthcare-associated infections are resistant to penicillins due to production of beta-lactamase. Most strains are also resistant to methicillin due to mecA-mediated production of PBP2A. Further complicating the picture is the fact that phenotypic expression of methicillin resistance is much more heterotypic than observed in S. aureus. In addition, resistance to other classes of antibiotics is common, including resistance to fluoroquinolones, macrolides, lincosamides, and trimethroprim-sulfamethoxazole.

    • To detect heterotypic oxacillin-resistance in CoNS, the MIC breakpoint is lower for CoNS (except S. lugdunensis) than S. aureus (0.5 ug/mL versus 4 ug/mL, respectively). Commercial assays are available for detection of mecA or PBP2A. The commercially available automated identification and susceptibility testing systems (e.g., MicroScan, Vitek, etc.) perform adequately in defining susceptibility to other classes of antibiotics.

    • Fortunately, several newer antibiotics have been introduced that have activity against multiple-resistant CoNS. These newer antibiotics include linezolid, daptomycin, tigecycline quinupristin-dalfopristin, televancin, and ceftaroline.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology

    • CoNS are commensal flora of the human skin and mucous membranes and rarely cause primary disease. Their pathogenic potential resides in their ability to colonize biomaterials and cause medical device infections. CoNS, largely S. epidermidis, are the leading cause of nosocomial bloodstream infections and are responsible for approximately 30% of these infections, which are chiefly due to intravascular catheters. Similarly, CoNS are a leading cause of various other device-associated infections, including vascular grafts, cerebro-spinal fluid (CSF) shunts, prosthetic joints, and artificial heart valves. As the use of such devices has increased in developed countries, the incidence of infection due to CoNS has increased in tandem.

    • Pulse field gel electrophoresis (PFGE) is generally regarded as the best test to address questions of short-term molecular epidemiology. There is great diversity in pulse-field patterns. Finding indistinguishable PFGE patterns in the context of an outbreak or in complex clinical situations is a reliable indicator of clonality. Longer-term population analysis is better addressed by multi-locus sequence typing (MLST).

  • Infection control issues

    • CoNS are ubiquitously present on human skin and lack the intrinsic virulence of S. aureus. Standard infection control measures (hand hygiene, routine environmental cleaning and disinfection) are adequate.

    • Prevention of infection due to CoNS becomes more relevant in the setting of surgical implantation of prosthetic medical devices and insertion and care of intravascular catheters. Central venous catheters should be inserted using full sterile barrier precautions following disinfection of the skin with chlorhexidine. Catheter insertion and maintenance can be successfully introduced using a "bundle" approach. In the operating room, when a prosthetic device is to be placed, great care should be exercised in preparing the skin at the operative site with emphasis placed on adequate disinfection of the skin and removal of hair, if necessary, through use of surgical clippers. Many surgeons elect to use vancomycin as a prophylactic antibiotic when placing a prosthetic device in which contamination and infection due to CoNS is relevant (heart valve, prosthetic joint, vascular graft, etc).

    • Although efforts to develop a vaccine against S epidermidis are in progress, there is currently no commercially available vaccine for CoNS.

What host factors protect against this infection?

  • The key immune system factor that protects against invasion by CoNS is intact skin and mucosal barriers and functional neutrophils.

  • Patients at higher risk of infection because of CoNS are those with intravascular catheters and prosthetic medical devices. In addition, neonates and neutropenic patients are at higher risk of infection. S. saprophyticus causes urinary tract infection in pre-menopausal, sexually active women. S. lugdunensis behaves more similarly to S. aureus than other CoNS and can cause invasive infection in normal hosts.

  • Histopathology of CoNS biomaterial-associated infections often reveals evidence of acute and chronic inflammation, as well as foreign body reaction (multi-nucleated giant cells). In animal models of antibiotic treated CoNS biomaterial-associated infection, organisms are often cleared from the immediate interface between the device and tissue but persist in the peri-implant tissues. In addition, viable organisms are often recovered from the biofilm that is a hallmark of CoNS biomaterial-based infections.

What are the clinical manifestations of infection with this organism?

S. epidermidis ismost commonly associated with medical device infections. Infections are often indolent and may be clinically difficult to define. Differentiating culture contamination from true infection may be challenging.

Intravascular Catheter Infections: CoNS, usually S. epidermidis, are the most common cause of intravascular catheter infections. Although patients with infected intravascular catheters may present with signs of sepsis (bacteremia, hypotension, etc.), the catheter site itself usually appears innocuous. Occasionally, there are local signs of inflammation or purulent drainage at the catheter site. In general, short-term, non-tunneled, central venous catheters (CVCs) infected with CoNS should be removed. In patients with infected long-term CVCs who do not have signs of severe sepsis, it is reasonable to attempt treatment with the catheter in-situ.

Prosthetic Valve Endocarditis (PVE): CoNS cause 15-40% of cases of PVE. Patients may present acutely or in an amore indolent fashion. Clinical manifestations include fever and evidence of valve dysfunction. The diagnosis is confirmed by documenting persistently positive blood cultures and finding evidence of endocarditis via transesophageal echocardiogram. Surgery is almost always required, and antibiotic treatment usually consists of a combination of vancomycin and rifampin, often with gentamicin for the first 2 weeks.

Pacemaker Infection: CoNS account for 50-60% of pacemaker endocarditis. Patients generally present with evidence of inflammation at the generator pocket site along with positive blood cultures. Transesophageal echocardiography is recommended for all patients with suspected pacemaker infection, and successful treatment usually requires complete removal of the device.

Vascular Graft Infection: 20-30% of vascular graft infections are caused by CoNS. Infections usually present in an indolent fashion over weeks to months with a false aneurysm, fistula, or sinus track at the graft site. Blood cultures may be negative, because the infection may not extend into the graft lumen. Surgery is needed for cure and prolonged antibiotic therapy is often employed.

Orthopedic Infections: CoNS cause 30-45% of prosthetic joint infections. Although it is believed that most of these infections stem from contamination of the device at the time of implantation, the presentation of infection may be delayed for months or years. Joint pain is usually the only symptom, and fever or other systemic signs or symptoms are rare. The diagnosis is supported by finding elevated inflammatory markers (erythrocyte sedimentation rate, C-reactive protein). Cure is best assured with a two-step exchange procedure and 6-8 weeks of antibiotic therapy.

Cerebrospinal Fluid Shunt Infections: CoNS cause approximately one-half of infections of CSF shunts. Signs and symptoms of CSF shunt infection usually develop within 2-3 months of shunt implantation and consist of local signs of inflammation, as well as fever, nausea, vomiting, shunt malfunction, and increased intracranial pressure. The diagnosis is confirmed by recovery of CoNS from CSF obtained from the shunt. As is true of most prosthetic device infections, surgical removal is generally required and antibiotic treatment with agents active against methicillin-resistant strains is employed. In the case of CSF shunt infections, vancomycin and gentamicin are often given intraventricularly and rifampin is administered orally.

Peritoneal Dialysis Catheter-Associated Peritonitis: CoNS account for 25-50% of peritoneal dialysis-associated peritonitis. Manifestations of infection include abdominal pain and tenderness, fever, nausea, and vomiting. Unlike other prosthetic device infections, peritoneal catheter-associated peritonitis can often be successfully treated with antibiotics in the dialysate fluid without removal of the catheter. Recalcitrant peritonitis is, however, an indication for catheter removal.

Other common CoNS prosthetic device infections:

  • Endophthalmitis following intraocular lens implantation

  • Breast implant infection

  • Penile prosthesis infection

  • Left-ventricular assist device and other cardiac device infections

  • Orthopedic hardware and fracture fixation device infection

  • Surgical mesh infection

Infections due to S. lugdunensis present in an acute fashion similar to infections due to S. aureus. Common infections include skin and soft tissue infection (e.g., cellulitis, furunculosis) and native valve endocarditis.

S. saprophyticus is a common cause of urinary tract infection in pre-menopausal women and presents with typical signs and symptoms, such as urgency, frequency, dysuria, and pelvic discomfort. Pyuria and hematuria are common. For unknown reasons, S. saprophyticus urinary tract infection has a late summer and fall seasonal predilection and often follows sexual intercourse or menstruation.

What common complications are associated with infection with this pathogen?

  • Complications of infection due to CoNS are usually due to direct extension of infection in peri-medical device tissues and/or device malfunction. For example, as CoNS prosthetic valve endocarditis progresses, valvular dysfunction, heart failure, and cardiac conduction abnormalities develop. Because CoNS do not produce exotoxins or other pro-inflammatory compounds (as does S. aureus), rarely do patients develop overt signs of severe sepsis or septic shock, even with endovascular infections associated with high-grade bacteremia. Rarely, patients exhibit immunologic phenomena associated with chronic bacteremia; immune complex deposition in the kidneys causes shunt nephritis. More specific information regarding complications can be found in sections addressing specific organ system infection topics.

How should I identify the organism?

CoNS are gram-positive cocci that divide in "grape-like" clusters and are catalase-positive. CoNS are readily recovered from biologic specimens with use of commercially-available automated blood culture systems or standard solid or broth media (sheep blood agar, Mueller-Hinton, brain-heart-infusion, trypticase soy, etc).

Because of the number of biochemical tests needed, it is difficult to routinely identify all of the CoNS to species level. However, the majority of systems used in modern clinical microbiology laboratories can accurately identify those species most commonly associated with clinical disease, S. epidermidis, S haemolyticus,and S sapophyticus. A method to rapidly identify S. lugdunensis from other CoNS involves documenting a positive L-pyrrolidonyl-beta-naphyhylamide (PYR) test and ornithine decarboxylase test. Molecular methods that identify CoNS to the species level have been developed based on phylogenetic analysis of several conserved DNA sequences.

The recovery of CoNS from biofilms and biomaterial-based infections has been enhanced by sonication of devices and PCR protocols. However, because CoNS are normal commensal organisms of the skin and mucous membranes, detecting low numbers of CoNS by polymerase chain reaction (PCR) from surgically removed devices and peri-device aspirates often raises the question of whether the finding is consistent with contamination or true infection.

In the situation of recovery of CoNS from blood cultures, the clinician is often faced with determining whether the culture result represents true infection or contamination. Factors that can assist in this determination include host situation (is the patient at higher risk of infection due to CoNS [neonate, neutropenic, presence of an intravascular prosthetic device, such as a cardiac valve, vascular graft, or ventral venous catheter?]); multiple positive blood cultures with the same strain of CoNS (same species, same phenotype - antibiogram or biotype - same genotype - indistinguishable PFGE pattern); culture positivity within 24 hours (indicative of larger numbers of organisms); and positive differential time to positivity test (DTP).

The DTP test is helpful in patients with a CVC and is predicated on the principle that a blood sample from an infected CVC will have a higher number of microbes present than an equal amount of blood obtained from the periphery. If the blood culture obtained from the periphery "turns positive" greater than 2 hours longer than blood obtained from the CVC, it is a reasonably sensitive and specific indicator of a CoNS CVC-associated infection.

How does this organism cause disease?

CoNS are able to cause disease because of two features: their natural niche on human skin, resulting in ready access to medical devices implanted or inserted across the skin, and their ability to adhere to biomaterials and to elaborate biofilm. S. epidermidis possesses genetic elements, such as Arginine Catabolic Mobile Element (ACME) that are important in its ability to thrive in the relatively dry and acidic conditions found on human skin. It produces antibiotics (e.g., epidemin, epilancin, epicidin) that may play a role in bacterial interference and successful persistence on the skin.

In contrast to S aureus that produces a large number adhesins, toxins, and factors to avoid host defense, CoNS possess relatively few defined virulence factors. The ability of S epidermidis to adhere to biomaterials and to form biofilm appears to be the most important virulence trait. Also, the ability to secrete poly-gamma-DL-glutamic acid (PGA) and phenol soluble modulins (PSM) appear to aid in the capacity to cause disease.

Adherence: Biomaterials placed within the human host are quickly coated with a "conditioning film" consisting of various host serum matrix proteins, such as fibrinogen, fibronectin, and elastin. S. epidermidis is able to bind directly to plastics because of action of autolysins and to interact with the conditioning film due to various adhesins.

Biofilm: CoNS growing in a biofilm are much less susceptible to antibiotics and are more resistant to host defense than unattached planktonic cells. In addition, it is thought that metabolically quiescent cells found in biofilms allow for tolerance to antibiotics and persistence of infection that is hallmark of a CoNS biomaterial-based infection. Extracellular DNA (eDNA) and polysaccharide intercellular adhesin (PIA) appear to be major functional components of S. epidermidis biofilm. In addition, alternative proteinaceous biofilm components, such as Accumulation-Associated Protein (AAP) and Biofilm-associated protein (Bap), have been described. S epidermidis produces PSMs under quorum-sensing global regulation and are important in the ability of the organisms to detach from the biofilm and disperse to other sites. Multiple species of CoNS produce PGA that appears to inhibit host defense and facilitate colonization of human skin.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Daroucihe, RO. "Treatment of infections associated with surgical implants". N Engl J Med. vol. 350. 2004. pp. 1422-9.

(CoNS are a major cause of infection of surgical implants. This review article outlines principles of treatment and the need for surgical intervention.)

Fey, PD, Olson, ME. "Current concepts in biofilm formation of Staphylococcus epidermidis". Future Microbiol. vol. 5. 2010. pp. 917-33.

(This review article discusses current knowledge of S. epidermidis adherence, biofilm formation, and virulence.)

Hall, KK, Lyman, JA. "Updated review of blood culture contamination". Clin Microbiol Rev. vol. 19. 2006. pp. 788-802.

(Approximately 1-5% of blood cultures yield contaminants, and 70-80% of blood culture contaminants are CoNS. Hall and Lyman discuss the clinical significance of blood culture contamination, how to differentiate contamination from true infection, and how to prevent contamination.)

Lewis, K, Spoering, AL, Kaldalu, N, Keren, I, Shah, D, Pace, JL, Rupp, ME, Finch, RG. "Persisters: specialized cells responsible for biofilm tolerance". Biofilms, infection, and antimicrobial therapy. CRC Press. 2006. pp. 241-56.

(This source is a review of biofilm infections, antibiotic tolerance, and persister cells.)

Mermel, LA, Allon, M, Bouza, E. "Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America". Clin Infect Dis. vol. 49. 2009. pp. 1-45.

(CoNS are the most common cause of nosocomial bacteremia and intravascular catheter infections. In this evidence-based guideline from the Infectious Diseases Society of America [IDSA], the diagnosis and treatment of intravascular-catheter related infections due to CoNS are discussed.)

Raad, I, Hanna, HA, Alakech, B, Chatzinikolaou, I, Johnson, MM, Tarrand, J. "Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections". Ann Intern Med. vol. 140. 2004. pp. 18-25.

(The use of the differential-time-to-positivity test is put to the test in this study.)

Rogers, KL, Fey, PD, Rupp, ME. "Coagulase-negative Staphylococcal infections". Infect Dis Clin N Am. vol. 23. 2009. pp. 73-98.

(This is an overview of pathogenesis, clinical features, and treatment of infections due to CoNS.)

Sader, HS, Jones, RN. "Antimicrobial susceptibility of Gram-positive bacteria isolated from US medical centers". Diagnos Microbiol Infect Dis. vol. 65. 2009. pp. 158-62.

(This is a large surveillance study from 27 US medical centers testing 1153 strains of CoNS recovered from patients in 2007 and 2008. This study documents the multi-resistant phenotype common in isolates recovered from patients with healthcare-associated infections.)
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