What are coagulase-negative staphylococci?
The human skin is the first line of defence between the body and the outside world. As a result, the skin is physiologically colonised by a host of microorganisms, including at least 47 species of coagulase-negative staphylococci . Coagulase-negative staphylococci are gram-positive, aerobic organisms distinguished from the closely related Staphylococcus aureus by the group's inability to form coagulase, an enzyme that promotes thrombus formation via the conversion of fibrinogen into fibrin . They were first identified by the microbiologists Louis Pasteur and Alexander Ogston in the 1880s .
Coagulase-negative staphylococci are an important part of normal skin microbiota, and they also colonise mucous membranes in adults and children from a few weeks of age . Staphylococci prefer humid areas and are therefore commonly found in the axillae, gluteal, and inguinal regions as well as anterior nares and the conjunctiva .
Below is a list of common coagulase-negative staphylococcal species and their preferred sites of colonisation.
- S. epidermidis tends to occur in the axillae, groin, perineum, toe webs, anterior nares, and conjunctiva.
- S. haemolyticus and S. hominis both occur in the axillae and pubic areas high in apocrine glands.
- S. capitis tends to surround the sebaceous glands on the forehead and scalp following puberty.
- S. lugdunensis occurs in the axillae, pelvis and perineum regions, groin & lower extremities.
Until two decades ago, coagulase-negative staphylococci were commonly perceived as contaminants in clinical specimens. Now, with the increasing use of implanted medical equipment, they have become leading pathogens for nosocomial infections owing to their ability to form biofilms on foreign material [1,2]. The S. epidermidis group of coagulase-negative staphylococci are of particular importance.
- There are between 10 and 24 strains of S. epidermidis on healthy adult skin.
- This group comprises predominantly of S. epidermidis, S. haemolyticus, S. capitis, S. hominis, S. simulans and S. warneri .
- S. epidermidis accounts for > 50% of staphylococci isolated from human skin and > 75% of coagulase-negative staphylococci in all clinical specimens .
- Collectively, S. epidermidis and S. haemolyticus account for the majority of foreign body and premature neonatal infections due to coagulase-negative staphylococci .
Skin conditions associated with staphylococci
Coagulase-negative staphylococcal skin conditions
S. epidermidis can induce miliaria, a disorder characterised by the retention of sweat within the eccrine glands. Skin biopsies have shown that periodic acid–Schiff (PAS)–positive material tends to block the upper eccrine sweat ducts. Miliaria is associated with:
- Overgrowth of commensal bacteria, especially coagulase-negative staphylococci
- An occlusive environment (occlusive dressings and thermal stimulation)
- S. epidermidis strains that produce PAS-positive extracellular polysaccharide substances (EPS) .
Miliaria is not associated with non-EPS producing strains of S. epidermidis or another coagulase-negative staphylococcus, such as S. haemolyticus and S. hominis. Of note, up to 62% of S. epidermidis strains on the forehead and back produce EPS [4,5].
Coagulase-negative staphylococci are implicated in the 'double-hit' phenomenon, a theory used to explain the cause of atopic dermatitis. The abnormal stratum corneum (skin surface) is attributed to the combined effects of an abnormal FLG gene and an unknown environmental trigger. The specific environmental trigger may be subclinical miliaria, as PAS-positive material has been discovered in the eccrine ducts of patients with atopic dermatitis. The PAS-positive material may arise from S aureus and EPS–producing strains of S. epidermidis. Rather than causing the usual miliaria lesions, in patients with a FLG defect, occlusion of the eccrine ducts may trigger a flare of atopic dermatitis by activating the innate immune system .
In the study described above, all skin samples from patients with atopic dermatitis contained drug-resistant staphylococci. S. aureus accounted for 42% and S. epidermidis in 20%, and all were positive for EPS and biofilms .
Competing against pathogens
Coagulase-negative staphylococci are competitors against S. aureus, a common pathogen, on the surface of normal skin. All organisms use quorum–sensing systems in which virulence factors are only expressed in a dense population of bacteria that is adapting to a changing environment. The quorum-sensing system for staphylococci is known as the accessory gene regulator (agr) system. Each staphylococcal subspecies has pheromones that can block the agr system of foreign species.
- S. epidermidis produces a pheromone that inhibits the agr response in three subgroups of S. aureus; therefore, inhibiting the expression of many virulence factors .
- It is also thought that the serine protease produced by S. epidermidis destroys any biofilm formed by S. aureus .
Skin samples from patients with atopic dermatitis patients are colonised with greater proportion of S. aureus than healthy controls, which are colonised with S. epidermidis . Skin colonisation by S. epidermidis may confer protection against atopic dermatitis, particularly in patients with the FLG gene defect.
Who gets coagulase-negative staphylococcal infections?
Despite their abundance on the skin, coagulase-negative staphylococci rarely cause disease in intact skin. The main risk factor for coagulase-negative staphylococcal infection is a medical implant on which the organism can colonise, proliferate, and gain access to the systemic circulation [1,2,8].
Specific risk factors for coagulase-negative staphylococcal infection are:
- Prosthetic heart valves (metallic and porcelain), pacemakers, defibrillators, cardiac stents and prosthetic joints 
- Neutropenic, systemic immunosuppressive therapy [1,2]
- Intravascular devices, such as central venous catheters, peripherally inserted central venous catheters and arterial lines, which are associated with up to 40% of nosocomial bloodstream infections [1,9].
- Orthopaedic implants — risks include previous joint surgery, prolonged surgery, concurrent infection at the time of implant, and rheumatoid arthritis 
- Prematurity, very low birth weight (< 1500 g at birth), and the use of umbilical or central catheters in neonates (accounting for 31% of all neonatal intensive care infections in the United States) .
What are the symptoms and signs of coagulase-negative staphylococcal infections?
Clinical signs such as fever, hypotension and leukocytosis are helpful in differentiating between true infections from coagulase-negative staphylococcal contamination .
Certain microbiological findings can support a diagnosis of infection, as opposed to contamination.
- Incubation time to a positive culture occurs in ≤ 25 hours .
- Growth occurs in both aerobic and anaerobic culture bottles [2,10].
- There are ≥ two positive cultures with identical species. If there are two isolates with different genetic makeup, contamination is likely [2,10].
- Positive results appear more quickly from blood drawn from a suspected catheter than from a peripheral blood sample. A ≥ 2–hour difference in positivity is considered a sensitive and specific marker of catheter-associated bacteraemia .
How are coagulase-negative staphylococci identified and infection diagnosed?
Coagulase-negative staphylococci are identified in the laboratory.
- Clinical specimens are first cultured on non–selective blood agar plates and an enrichment broth.
- The organism group is then identified via examining morphology, physiological testing results and antibiotic susceptibility .
- Clonal diversity among coagulase-negative staphylococci is discerned through multilocus sequence typing (MLST) of housekeeping genes and whole-genome sequencing with 70–90% accuracy in identifying specific staphylococcal species [1,2].
Surgical site infections
Coagulase-negative staphylococci are more often cultured from superficial incisional wounds than from deeper wounds. A diagnosis is obtained by finding they are the predominant microorganisms or by repeated isolation of the same organism in serial cultures .
Two sets of blood cultures should be obtained in a patient with fever and signs of bacteraemia . If the patient has an indwelling central catheter, one of the blood cultures should be collected through the catheter .
Intravascular device infection
Diagnosis is achieved by a positive culture of the catheter tip, which is considered the gold standard .
Prosthetic vascular graft infections
Prosthetic vascular graft infection is most commonly associated with grafts distal to the inguinal region (1–6%). Infection can occur within 30 days of grafting, but more commonly occurs months to years later. It is diagnosed by physical examination and imaging, which shows sinus tracts or pseudo-aneurysms (pockets of blood in the bloodstream) at the site of vascular anastomosis (a connection between blood vessels) .
Prosthetic valve endocarditis
Endocarditis is due to S. epidermidis in 15–40% cases. Diagnosis is achieved via repeated positive blood cultures with suggestive transthoracic echo findings (80% will have valve dysfunction and intracardiac abscess), usually > 12 months after valve placement.
Native valve endocarditis
This form of endocarditis is rarely caused by coagulase-negative staphylococci, occurring in only 8% of cases of endocarditis. It is due to haematogenous seeding of previously damaged or malformed heart valves and endocardium .
Cardiac pacemaker infection
Coagulase-negative staphylococcus, predominantly S. epidermidis, is the culprit pathogen in 25% of pacemaker infections. About 25% of infections occur within 1–2 months of insertion of the device, due to inoculation at the time of placement of the device. Symptoms include inflammation at the pacer pocket site, systemic bacteraemia, and right-sided endocarditis.
Diagnosis is achieved via culture of the generator pocket and of the device itself, or by multiple positive sequential blood cultures with the same strain of bacteria .
Orthopaedic prosthetic device infections
Coagulase-negative staphylococci are usually are inoculated at the time of surgery, but remain indolent and is only present between 3 months and two years later. S. epidermidis is the main pathogen in these infections with a few cases being caused by S. lugdunensis.
Diagnosis is determined through reports of unexplained joint pain together with a high erythrocyte sedimentation rate, positive bone scan findings and culture of the prosthesis. There can be culture-negative prosthetic joint infections, which manifest as aseptic joint loosening .
Central nervous system shunt infections
Coagulase-negative staphylococci are responsible for more than 50% of central nervous system shunt infections. Risk factors are:
- Age < 6 months
- Reinsertion of shunt
- Lack of experience of the surgeon
- A lengthy operation.
Symptoms include unexplained fevers within two months of shunt placement or shunt dysfunction. Definitive diagnosis is determined through positive culture from cerebrospinal fluid drawn from the shunt or ventricles, or positive culture of the shunt .
How do coagulase-negative staphylococci cause systemic infection?
Coagulase-negative staphylococci gain entry through breached skin surfaces, commonly during medical or nursing procedures. The key mechanism is the ability of the bacteria to form biofilms on the surfaces of implanted medical equipment, where the bacteria replicate and disseminate within the systemic circulation .
The key steps are:
- Coagulase-negative staphylococci bind to the biotic surface (the host tissue) or abiotic surface (the medical device), coating it with adhesins (bacterial appendages that attach to the skin surface).
- The bacteria multiply and adhere to each other in multi-layered cell aggregates via the production of cell-wall-anchored proteins and surface-associated proteins, forming a biofilm.
- The biofilm's polysaccharide intercellular adhesion (PIA) helps it to gradually mature into a complex, multi-layered structure with fluid-filled channels ensuring all layers have sufficient nutrients for growth. It is tolerant to antibiotics and can evade host defences, such as phagocytosis [1,8].
- Single cells or groups of cells dissociate from the biofilm and disseminate to other sites via the bloodstream to start colonisation and new biofilm formation [1,8,9].
What is the treatment for the coagulase-negative staphylococcal infection?
When treating coagulase-negative staphylococcal infections, the clinician should consider the:
- Site of infection
- Host's immune status
- Presence of indwelling medical equipment .
The mainstay of treatment is appropriate systemic antibiotic therapy and removal of the culprit implant .
Approximately 90% of infections are resistant to penicillin. Vancomycin is the drug of choice. If the organism is confirmed to be susceptible to methicillin, vancomycin can be replaced by lactamase–resistant penicillin or a first– or second-generation cephalosporin. Newer antibiotics with activity against coagulase-negative staphylococci are daptomycin, linezolid, clindamycin, telavancin, tedizolid and dalbavancin [1,9]. Gentamicin or rifampicin can be added for deep-seated infections.
The duration of treatment depends on the site of infection. (Detailed information on the duration of treatment can be found in guidelines published by the Infectious Diseases Society of America).
- Isolated bacteraemia with no visceral involvement: > 7–14 days 
- Intravascular catheter infection if the offending intravascular catheter is removed, seven days 
- Cardiac pacemaker infection: remove the device and give 4–6 weeks of intravenous antibiotics 
- Central nervous system infection: remove the shunt, drain the ventricles, and give intravenous and intraventricular vancomycin and gentamicin plus oral rifampicin; the new shunt should be inserted after the cerebrospinal fluid has been sterilised
- Prosthetic joint infections — this involves a two-stage replacement procedure with 99% success rate:
- Stage 1: resection of the involved prosthesis and affected tissues with six weeks of antibiotic therapy
- Stage 2: New joint re-implantation after antibiotic treatment .
Due to the correlation between mucosa colonisation and subsequent bacteraemia, treatment can be given to decrease mucosal colonisation with coagulase-negative staphylococci. One suggested the approach is topical mupirocin for nasal decolonisation and an oral glycopeptide, such as ramoplanin, for intestinal decolonisation .
What is the outcome of coagulase-negative staphylococcal infection?
Coagulase-negative staphylococcal bacteraemia is a serious medical condition associated with significant morbidity and mortality.
- Septic shock has been reported in 22% of patients, with a mortality rate of 37%.
- Approximately 50% of deaths in patients with septic shock are secondary to coagulase-negative staphylococcal bacteraemia .
- Coagulase-negative staphylococcal cardiac pacemaker infection also has a high mortality rate of up to 66% .
- Coagulase-negative staphylococcal prosthetic valve endocarditis has a mortality of 24–36% [8,10].
- Although neonatal coagulase-negative infections carry relatively low mortality at 0.3–1.6%, these infections are associated with morbidity and prolonged hospital stays .
- Prosthetic graft infections carry a 17% mortality and 40% morbidity, usually from amputation. The mortality rate for aortic grafts is around 50% .