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Staphylococcus Lugdunensis: The Coagulase-negative Staphylococcus You Don't Want to Ignore

Elizabeth Babu, John Oropello Expert Rev Anti Infect Ther. 2011;9(10):901-907.

Abstract and Introduction

Abstract

Staphylococcus lugdunensis is a virulent coagulase-negative staphylococcus (CoNS) that behaves like Staphylococcus aureus. Toxic shock syndrome, osteomyelitis, septic arthritis and postoperative endopthalmitis have been observed. Endocarditis complicated by heart failure, periannular abscess formation and embolic phenomenon have brought particular attention to this CoNS. Mortality rates for endocarditis appear higher when compared with other CoNS. Owing to the laboratory methods used, identifi cation may be misleading. lactam antimicrobials are recommended pending sensitivities. Evaluation for endocarditis should be pursued in bacteremic patients due to its pathogenic potential.

Epidemiology
According to the most recent SENTRY Antimicrobial Surveillance Program,[1] which monitors predominant pathogens and antimicrobial resistance in the USA, Canada, Latin America and Europe, Staphylococcus lugdunensis was the seventh most common coagulase-negative staphylococcus (CoNS) species isolated in bloodstream infections during the 12-month study period in 1997. To date, the frequency of isolation of S. lugdunensis among CoNS from clinical specimens has been reported in a few isolated studies. Rates range from less than 1% in Denmark[2] and Korea,[3,4] approximately 3% in Japan,[5] 6% in Argentina[6] and from 3 to as high as 7% in the USA.[7,8] S. lugdunensis is normally found as part of human skin flora and has been identified in cultures from the entire body.[9] Studies carried out to look into specific areas of colonization have not been very thorough. The most comprehensive study obtained 525 cultures from eight sites in 75 healthy subjects.[10] Swabs from the groin, toes and axilla yielded S. lugdunensis most frequently. Further studies need to be performed to clarify if the organism has a preferred site of colonization, if the site is different in hospitalized patients and if these sites are a permanent or transient habitat.

History
In 1988, the first description of two new species of Staphylococcus, S. lugdunensis and Staphlococcus schleiferi, was published by Freney et al..[11] These two species were obtained from a collection of unidentified

Staphylococcal strains at The French National Reference Center for Staphylococci. In total, 11 strains were identified as the new genomic species described formally as Staphylococcus lugdunensis. It assumed the Latin name of Lyon, the French city where the organism was first identified. Of the 11 strains, five were obtained from blood, and one each from an intrauterine device, thoracic drain, umbilicus, axillary lymph node, abscess drain and an unknown site. The 11 strains studied were variable depending on the culture medium and the time of incubation. All strains were Gram-positive cocci, 0.81.0 m in diameter, occurring singly, in pairs, small clusters or chains. All strains produced catalase and did not produce coagulase or oxidase. Enterotoxins A, B and C, toxic shock syndrome toxin (TSST) and exfoliative toxin production were not described with this pathogen. All strains were susceptible to oxacillin and penicillin.

Clinical Features
S. lugdunensis has been associated with a wide variety of infections, including cardiovascular infections, osteomyelitis and prosthetic joint infections, bloodstream infections, skin and soft-tissue infections, central nervous infections, peritonitis, endopthalmitis and urinary tract infections. S. lugdunensis has been described as the etiology of cardiovascular infections including severe native and prosthetic valve endocarditis, device-related endocarditis, myocarditis[12] and infected cardiac myxoma.[13] In general, CoNS are unusual causes of native valve endocarditis but are one of the leading causes of prosthetic material-associated endocarditis. The clinical course is subtle, subacute or even chronic without fulminant signs of infection.[14] Infections with CoNS are typically not associated with abscess formation, heart failure or embolic phenomenon. Furthermore, compared with Staphylococcus aureus, CoNS are more amendable to medical and/or surgical therapy and typically have shorter courses with better clinical outcomes.[15] The reports of S. lugdunensis are quite different. S. lugdunensis has been reported as the cause of endocarditis in 67 cases since 1988.[16] Reported cases have been mostly community acquired but not associated with injection drug use. This reporting may represent a significant bias since cases with complicated courses and poor outcomes tend to be published. However, the cases provide a spectrum of complications including acute onset, heart failure,[17] periannular abscess formation,[18] peripheral embolism[19] and shock, which typically is not described in CoNS. In addition, clinical outcomes mimic cases involving S. aureus native and prosthetic valve endocarditis. A prospective cohort study of two centers described their experience with ten cases of S. lugdunensis endocarditis and, in addition, performed a combined analysis of 59 cases in a literature review. [20] Their findings noted that in native valve endocarditis the mitral valve is involved the majority of the time, surgery was required in 51% of the cases and the mortality rate reached as high as 42%. In prosthetic valve endocarditis the aortic valve was most frequently affected, also required surgical intervention, and the mortality rate was 78%. Pacemaker/defibrillator lead endocarditis caused by S. lugdunensis was associated with better prognosis when antibiotic treatment was combined with a surgical removal of the device. Therefore, lead extraction should be performed without delay as recommended by the American Heart Association scientific statement on nonvalvular cardiovascular device-related infections.[21]

Native valve endocarditis has been a consequence of infection originating at other sites, including skin and soft-tissue infections,[9] hemodialysis,[22] vascular catheters,[23,24] coronary angioplasty, vasectomy,[25] kidney transplantation[26] and prosthetic joint infections.[27] Transesophageal echocardiogram (TEE) is the gold standard for identification of intracardiac vegetations with a sensitivity of 96% compared with transthoracic echocardiogram (TTE) of only 30%.[28] TTE can lead to falsenegative results and a delay in appropriate therapy. TEE should be considered as the initial imaging modality in endocarditis.[21] Although uncommon, S. lugdunensis is very destructive and plays a major role in infective endocarditis. Echocardiographic evaluation can change medical and surgical management and may improve clinical outcome in individuals with S. lugdunensis endocarditis. Therefore, evaluation with echocardiography should be pursued. The next most common serious infections are bone and joint infections, both native and prosthetic. Reports have included vertebral osteomyelitis,[29] disk space infection,[30] spondylodiscitis[31] and septic arthritis.[32] Following surgical procedures, both temporal bone osteomyelitis[33] and septic arthritis[34] have been described. Prosthetic joint infections[35,36] have been reported to manifest as early as 6 weeks to as late as 4 years after implantation. In a study looking at S. lugdunensis bacteremia in 63 patients, 15 (23.8%) had clinically significant bacteremia defined as positive blood cultures and systemic inflammatory response syndrome without an alternative explanation.[4] Of those with clinically significant bacteremia, the source was unknown in eight (53%) and associated with central venous catheters in five (33%) patients. In additiona, in this subset of patients, endocarditis was seen in four (26%) patients, two of whom had underlying valvular heart disease. Among the reports of S. lugdunensis, sepsis,[37] septic shock[38] and toxic shock syndrome have been described. A report described septic shock in a 71-year-old man after receiving platelet[39] and red cell transfusions for pancytopenia secondary to myelodysplasia. Blood cultures and cultures of the platelets yielded S. lugdunensis. The transfused blood was sterile and there was no evidence of allergic reaction to the blood products or any other source of infection. Toxic shock syndrome was described in a 33-year-old healthy woman 48 h after a tooth extraction with Gelfoam packing.[40] Blood and purulent maxillary sinus cultures were identified as S. lugdunensis. Tests for coagulase, TSST-1, staphylococcal enterotoxins AE and exfoliatin toxin A were negative. Neither S. aureus nor S. pyogenes were isolated from any samples of blood, urine, sputum, sinus or vaginal specimens from this patient. Fadel et al. examined the outcomes of 29 patients with a single S. lugdunensis positive blood culture.[41] From the chart review, the primary treating physician considered nine (31%) cases clinically significant, did not acknowledge the culture in 14 (48%), and disregarded the culture as a contaminant in six (21%) cases. Fadel et al. reclassified the cases based on defined criteria and found that 13 (45%) patients with a single positive blood culture had clinically significant bacteremia. Therefore, they concluded that all blood cultures for CoNS

should be screened for S. lugdunensis and isolation of this organism from one blood culture should not be assumed to be contamination. Skin and soft-tissue infection account for the majority of infections caused by S. lugdunensis. When isolated from a superficial infection it is more likely to be significant compared with S. epidermidis.[42] S. lugdunensis is well known to cause suppurative skin and soft-tissue infections including furuncles, cellulitis and abscesses.[43] Abscesses have mostly been reported to affect the perineal and inguinal area[44,45] and have usually been associated with surgical procedures. However, abscesses have also been described in nonlactating women.[46,47] One case of a severe acute necrotizing sinusitis complicated by periorbital cellulitis and ulceration through the maxillary sinus through the hard palate has been reported.[48] Pyomyoma after a cesarean section[49] and endometritis[50] has also been described. Infections of the CNS have included abscesses from dental infections, septic emboli from native valve endocarditis, multiple mycotic cerebral aneurysms[51] and meningitis from ventriculostomy and ventriculoperitoneal shunt infections.[52] The ventriculoperitoneal shunt infections occur both with an early and late onset.[53,54] Peritonitis has been described in a patient after cesarean section[55] and in a patient undergoing continuous peritoneal dialysis.[56] In a 4-year multicenter study looking at the species distribution of CoNS in patients with endopthalmitis, S. lugdunensis was the second most common CoNS after S. epidermidis.[57] In a series of postoperative endopthalmitis caused by S. lugdunensis, endopthalmitis was characterized by severe visual loss (hand motion or less) that occurred a mean 7.6 days after cataract surgery and necessitated pars plana viterectomy in three of the five cases.[58] The authors stated that compared with other CoNS, patients infected with S. lugdunensis were characterized by a worse final functional prognosis at 6 months and a higher frequency of viterectomy retinal detachment (60 vs 3%).

Pathogenesis
The toxins produced by S. aureus such as enterotoxins, exfoliatin and TSST have not been identified in any S. lugdunensis isolates despite the syndrome of toxic shock that has been reported. However, various virulence factors have been identified that may explain the similar pathogenic potential to S. aureus. Regions of homology to the S. aureus accessory gene regulator (agr) locus, the regulator of virulence factors, have been identified. This includes heat-stable -like hemolysin, which is similar to toxin in S. aureus. toxin enables the staphylococci to escape killing and digestion by the phagosomes. [59] Another similarity to S. aureus is S. lugdunensis' resistance to lysozyme. Lysozymes, abundant in the cytoplasmic granules of polymorphonuclear neutrophils, are enzymes created by the immune system that damage cell walls. S. lugdunensis possesses in its genome a homologous region to S. aureus that functions in lysozyme resistance. Known as OatA (Oacetyltransferase), this membrane-bound peptidoglycan prevents the binding of lysozyme to the cell wall, thereby averting the immune system.[60]

In addition to averting the immune system, S. lugdunensis has been found to have properties that promote tissue interaction. These properties include adhesins that promote binding to proteins found in host tissue. An investigation to identify these cell surface factors revealed that S. lugdunensis binds to collagen type I found primarily in scar tissue and collagen type IV found on the basal lamina the extracellular matrix on which the epithelial cell sits.[61] Binding to fibronectin, fibrinogen, laminin, vitronectin and plasminogen, key factors in cell adhesion and wound healing, has also been described. The production of von Willebrand factor-binding protein by this organism has been thought to be a contributing factor in the pathogenesis of endocarditis. This protein primarily functions to bind other proteins particularly involved in platelet adhesion following vascular injury. [62] These various adherence factors enable attachment to, and infection of, host tissue as well as synthetic surfaces. S. lugdunensis is also able to protect itself from the immune system via the production of biofilm. [63] Even though organisms may demonstrate susceptibility to an array of antimicrobials, infections can be very difficult to treat if organisms form and proliferate within biofilms. A biofilm is a polymeric matrix of cells, adherence proteins and polysaccharides in which microorganisms can replicate and thrive. This extracellular slime embeds onto host tissues or indwelling medical devices and is difficult to eradicate due to the high level of resistance to antimicrobial therapies as well as the production of factors that interfere with innate immune defenses. One mechanism of this glycocalyx is the ability to stimulate monocyte prostaglandin E2. Prostaglandin E2 modulates the immune system by inhibiting T-cell proliferation.[64]

Diagnosis
In contrast to S. aureus, S. lugdunensis is coagulase negative. Caution should be taken with the latex agglutination test since around 58% of strains of S. lugdunensis produce a bound coagulase.[11,61] Also known as clumping factor, on slide it can suggest that the organism produces coagulase and the technician can falsely identify the organism as S. aureus. S. lugdunensis does not produce coagulase and therefore in the test tube will always be coagulase negative. In addition, some automated identification systems fail to identify S. lugdunensis if the database lacks insufficient discriminatory biochemical reactions, such as ornithine decarboxylase.[65,66] Mateo et al. studied 17 isolates and S. lugdunensis was misidentified most frequently as S. haemolyticus.[67] Species misidentification rates were 5.9, 23.5 and 29.4% with the Crystal (Becton Dickinson, MD, USA), Vitek 2 (bioMrieux, Marcy l'Etoile, France) and Wider (Soria Melguizo SA, Madrid, Spain) systems, respectively. The ATB32-Staph system (bioMrieux) correctly identified all isolates. The Manual of Clinical Microbiology provides the list of systems that have S. lugdunensis in their database.[68] Molecular identification with ribotyping[69] and PCR amplification[70,71] is a rapid and effective alternative to conventional identification strategies. Morphologically, S. aureus and S. lugdunensis have a slight yellow pigmentation and on blood agar plates demonstrate hemolysis. Manual identification demonstrates positive catalase, pyrrolidonyl arylamidases and ornithine decarboxylase tests. Another feature of this organism is that it demonstrates colony variation. [72] Colony variation essentially means that isolates demonstrate mixed morphotypes. Strains can appear both smooth and glossy or rough and dull. In the laboratory this feature may suggest that there exists a mixed population of organisms such as you find in a contamination.

Coagulase-negative staphylococci are among the most frequently isolated bacteria in the clinical microbiology laboratory. These bacteria are normal inhabitants of human skin and mucous membranes and therefore one of the major challenges of daily diagnostic work is to distinguish clinically significant CoNS from contaminant strains. One should have a high degree of suspicion if the clinical course does not correlate with a CoNS organism on culture, especially from a sterile site. Fadel et al. found that 45% of cases with a single positive blood culture for S. lugdunensis were clinically significant.[41] This was defined as having prolonged fever, hypotension, leukocytosis, neutropenia or disseminated intravascular coagulopathy.[2] Many laboratories do not routinely identify CoNS to the species level and presume contamination unless requested. Being aware of these characteristics, including the increased probability of laboratory misidentification, is helpful in earlier recognition and appropriate management of S. lugdunensis infection.

Treatment
Most isolates of S. lugdunensis described have been sensitive to an array of antimicrobial therapy. However, there have been isolated case reports of resistance to erythromycin,[73] streptomycin,[73] tetracycline,[4] penicillin,[74,75] gentamicin,[55] ceftazidime,[55] aminoglycosides[20] and macrolides.[27] Development of resistance to ciprofloxacin[67] and rifampin in a patient on chronic treatment for septic arthritis, vertebral osteomyelitis and aortic and mitral valve endocarditis has been described.[76] -lactamase, the enzyme that confers resistance to -lactam antimicrobials such as penicillin, has been reported in the USA as well as in Europe. [55,77] The frequency of -lactamase in S. lugdunensis is between 7 and 24% in France,[78] 12% in Spain,[9] 15% in Sweden[79] and 2440% in the USA.[80,81] The mecA gene is part of the staphylococcal cassette chromosome that confers resistance to oxacillin and generally all -lactams. The mecA gene has been reported in several reports to date;[8284] the first in a neonate[80] with S. lugdunensis bacteremia associated with an intravascular catheter and the second isolate from a nasal swab.[81] Currently, the Clinical Laboratory and Standards Institute has recommended that S. lugdunensis isolates should be screened for the mecA gene by PCR or penicillinbinding protein 2A (PBP2a) by latex agglutination. Recently, a mecA-negative S. lugdunensis isolate resistant to all -lactams has been described.[85] In 2005, the breakpoints for oxacillin sensitivity were revised to follow the breakpoints for S. aureus: MICs of 2 g/ml are considered susceptible and MICs 4 g/ml are classified resistant.[86] Reports of vancomycin (a glycopeptide antimicrobial agent) resistance have not been documented to date. In a recent in vitro study based on MIC50/90 values, the newest glycopeptide telavancin demonstrated potent activity against S. lugdunensis.[87] The successful eradication of S. lugdunensis prosthetic joint infection with linezolid after failure of ciprofloxacin and rifampin has been reported.[88] In their prospective study of ten patients with S. lugdunensis endocarditis, Anguera et al. observed no difference in mortality between monotherapy (-lactam or vancomycin) and combination therapy (-lactam with an aminoglycoside or rifampin or cephalosporin and vancomycin with an aminoglycoside or rifampin or cephalosporin or carbapenem).[20] There is a lack of randomized controlled data on the efficacy of antimicrobial agents for S. lugdunensis infections. The Infectious Diseases Society of America guidelines for endocarditis recommends treatment based on in vitro susceptibility profiles and follow-up monitoring of the development of periannular extension or extracardiac spread of infection.[89] Empiric treatment with a -lactam agent should be appropriate. For patients

with penicillin allergies, vancomycin is an alternative. Source control with drainage of abscesses, early surgical intervention for valvular compromise and removal of intravascular catheters and pacemaker leads should be pursued. In addition, transesophageal echocardiograms to assess valvular involvement and CT scans to evaluate for embolic phenomena should be strongly considered.

Prognosis
S. lugdunensis, unlike other CoNS, is associated with a high rate of complications.

Expert Commentary & Five-year View

S. lugdunensis is a Gram-positive CoNS species normally found as part of human skin flora. Owing to an increased effort to identify all staphylococcus isolates, the number of S. lugdunensis isolates has increased. Depending on methods used, the laboratory can incorrectly identify S. lugdunensis as S. aureus or more problematic, simply not further speciate a CoNS isolate, assuming contamination. Unlike other CoNS species, S. lugdunensis is unusually virulent and capable of the spectrum of infection as that of S. aureus. This includes skin and soft tissue, bone, joint, cardiovascular and CNS infections. The toxins typically associated with S. aureus have not been identified; however, various virulence factors are shared that may explain the similar pathogenic potential to S. aureus. S. lugdunensis is more aggressive than other CoNS and despite being sensitive to many antibiotics, carries a high mortality rate in patients with endocarditis compared with other CoNS.[16,20,25] If the clinical situation does not correlate with CoNS, prompt identification to the species level should be performed for identification of S. lugdunensis. Treatment with a -lactam and removal of any infected foreign material should be pursued. For penicillin-allergic patients, vancomycin is an alternative. Based on the virulence of this organism, if S. lugdunensis is isolated, a TEE to evaluate for infective endocarditis should be pursued.

Sidebar
Key Issues

Staphylococcus lugdunensisbehaves likes Staphylococcus aureusand should not be considered a typical coagulase-negative staphylococcus.

Infections may be underdiagnosed owing to identification methods. Cardiovascular infections including native and prosthetic valve endocarditis, pacemaker-related endocarditis and myocarditis have been described.

Endocarditis, secondary to other coagulase-negative staphylococci, tends to be indolent. However, the spectrum of infective endocarditis including valve dehiscence, abscess formation and vegetation with embolic phenomenon is seen with S. lugdunensis.

In the CNS, brain abscess, meningitis and ventriculoperitoneal shunt infections have been observed. Skin and soft-tissue infection, bacteremia, septic shock, toxic shock syndrome, peritonitis, osteomyelitis, prosthetic joint infections and ocular infections have been reported.

Infective endocarditis should be ruled out in patients with S. lugdunensisbacteremia. Obtaining a S. lugdunensisisolate from clinical specimens should prompt an approach similar to the approach considered for etiology, management and treatment of S. aureus.

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