The Lyon Heart – The Virulent Coagulase-Negative Staphylococcus

Coagulase negative staphylococcus are generally skin commensals we tend to ignore when they pop up in one set of blood cultures as they tend to represent contamination of the blood culture bottles rather than true bacteremia. The most commonly seen is Staphylococcus epidermidis. The reason they are called “coagulase negative staphylococcus” is these organisms, compared to Staphylococcus aureus, do not secrete free coagulase (1). Recall free coagulase leads to prothrombin activation and conversion of fibrinogen into fibrin (i.e. it creates a clot). Further, staphylococcus aureus also has 2 distinctive proteins, called clumping factor A and factor B, that directly converts fibrinogen into fibrin (1). These contribute to its virulence factor and, in general, this is not seen in standard microbiological studies of CoNS. 

While this generalization is reasonable to understand the difference between Staphylococcus aureus and other CoNS, one type of bacteria that everyone should be aware of is Staphylococcus lugdunensis. This is a gram positive, catalase-positive skin commensal that was named after Lyon, France, where it was discovered (2, Lyon, France was formerly known as Lugdunum, an important city in Gaul, part of the western part of the former Roman Empire). This organism, in many ways, behaves like Staphylococcus aureus. The micro lab tends to make the distinction between coagulase positive and coagulase negative based on its ability to coagulate rabbit plasma (3). Due to the low sensitivity of this method, it has largely been replaced by rapid agglutination kit, which detect clumping factor, protein A, and capsule types 5 and 8 (1). 

Microbiology:

The classification scheme for staphylococcus is not terribly important for clinical practice, as they have details that do not pop up in everyday rounding. Despite this, I think it is reasonable to look at a well-accepte scheme based on clinical and diagnostic aspects (4). Here, staphylococci are divided  into coagulase negative staphylococci (CoNS) and coagulase positive staphylococci (CoPS):

You will notice S. lugdunensis is in a category by itself under CoNS, however given it displays characteristics of both CoNS and CoPS, it occupies a spot in the middle (also, its half-way between blue and red). Indeed, this is due to the recognition that S. lugdunensis is actually quite pathogenic, more so than other CoNS. 

How is this organism typically distinguished from other staphylococci (2)?  While this is generally out of the scope of clinical practice, some interesting tidbits are worth mentioning:

• In general, it is a coagulase negative staphylococcus (tests negative for secreted coagulase in rabbit coagulase plasma), however a variable percentage of strains test positive for clumping factor (aka a bound coagulase). This ranges from 58%-100% depending on the case series. 
• Latex agglutination kits detect clumping reactions mediated by clumping factor. Newer agents incorporate monoclonal antibodies that detect protein A (which is not present in S. lugdunensis). Positivity for latex agglutination kits range from 7-60%, depending on the kit for S. lugdunensis
• These test positive for ornithine decarboxylase and pyrrolidonyl arylamidase (PYR), which is a way these isolates are differentiated from Staph aureus. 
• An interesting characteristic is its “hypochlorite bleach-like” odor that is similar to Eikenella corrodens. In one study (14) that isolated 60 specimens of S. lugdunensis, lab personnel performed a blindd odor test, with 93% of the isolates having that characteristic smell:
• 

The advent of molecular tests such as MALDI-TOF and 16S ribosomal sequencing may render the above methods obsolete in the next few years, but obviously this will depend on where you practice. 

The positivity for latex agglutination suggests that a differe clumping factor is partly responsible for its pathogenicity. Other studies have been undertaken to evaluate for other risk factors, though not one single one exotoxin has been identified. Resistance to lysozyme (enzymatic component of the innate immune system) and adherence proteins such as vWF- and fibrinogen-binding protein have been identified, which may aid in its pathogenicity. One study identified hemolysins, lipase, and esterase as candidate virulence factors (5), while another study of 38 strains isolated from SSTI found that 36 strains (94.7%) carried atlL gene, which encodes autolysin, while the slush gene, which encoded hemolytic peptides, was identified 15 isolates (39.5%; 6). Despite the lack of clear virulence factors, the thing to remember is that its virulence is similar to that of Staphylococcus aureus. 

Significance of its Isolation in Cultures

The recognition of the pathogenicity of this organism has lead to more microbiology labs to differentiate S. lugdunensis from other CoNS. How concerned should one be when you find it in culture? A retrospective study evaluated clinical specimens collected over a 63-month period (7). 155 specimens were isolated from 143 patients, with only 15.4% of these being classified as a contaminant. In this cohort, 39% of patients had only S. lugdunensis isolated while in 60%, it was isolated as part of mixed flora. Another retrospective study (8) evaluated 42 isolates over a 12-month period, which accounted for 7.3% of all CoNS isolates. 86% of patients were deemed to have a clinically significant isolate, with the vast majority being isolated from soft tissue/abscess (83%). Of the total isolates, 26/36 were from the outpatient setting. In another cohort of 63 patients who had S. lugdunensis isolated, 15 were deemed to have clinically significant isolates (23.8%), 4 with IE (9). Even isolation of the organism off only one set of blood cultures is significant in about half of cases, with a retrospective study finding that 45% of samples were clinically significant, though most were associated with cellulitis/foot ulcers or line-associated (10). 

To put the above together in a reader-friendly way, isolation of S. lugdunensis can be clinically relevant anywhere from about 25% to over a quarter of the time, especially when the clinical picture suggests a gram positive infection. 

Skin and Soft tissue infections:

S. lugdunensis tends to colonize areas with lots of apocrine (read: sweat) gland. A retrospective case-control study (11) collected cultures from left and right inguinal folds from 140 consecutive patients and found that 19 women (23%) and 12 men (19%) were S. lugdunensis isolated. Another study of 75 healthy volunteers found that S. lugdunensis tends to colonize axilla, perineum, groin and toe nails (12):

Indeed, abscesses have been isolated from the inguinal area, with one cohort study of 17 patits with S. lugdunensis abscess finding that 9 of these were isolated from the pelvic region (13). 

Skin and soft tissue infections tend to be the most common presentation of this organism, with it being indistinguishable from Staph aureus and representing anywhere from 25-80% of all these presentations (7, 8, 16). While it has a niche for the pelvic area, it can occur anywhere. For instance, case series reported 5 cases of cellulitis, with all patients presenting with either an inflamed cyst or abscess, mostly in the back (15). All patients had their abscess either surgically or spontaneously drained. A cohort of 491 cases of S. lugdunensis found that significant proportion of these were either abscesses or wound infections (61%, 14):

Bone and joint infections have also been reported, with one retrospective study (16) of 168 cases finding a high proportion  bone and joint infection (39.9%), followed by SSTI (262%), and then blood cultures(16.1%). Within the 67 cases of bone and joint,most of these (25/67, 64%) occurred in some sort of prosthetic material.

Infective Endocarditis

If there is something that makes S. lugdunensis unique, is its propensity to cause infective endocarditis, especially on native valves (17, 18). A prospective study (19) evaluated 10 patients who presented with infective endocarditis from Staphylococcus lugdunensis. None of the patients were IVDU, and 4 of the 10 were native valve endocarditis. All 3 patients in this cohort who had left sided native valve endocarditis had serious complications, including heart failure, periannular abscess, and shock. Furthermore, rates of surgery for S. lugdunensis was higher when compared to Staph aureus (OR 3.9, 95% CI 1.1-14.7) but not when compared to S. epidermidis (OR 1.5, 95% CI 0.3 to 10.0). Moreover, the mortality rate of S. lugdunensis was significantly higher (50%) when compared to that of Staph aureus (7.1%) or even staph epidermidis (20%). 

A literature review of an additional 59 cases of S. lugdunensis IE revealed the vast majority of cases were in native valve endocarditis (77%). 55% of these were in the mitral valve and 54% had an acute presentation of <30 days with 60% of these having complications:

Univariate analysis found that age >50 (OR 1), cases before 1995, and lack of surgery (2.9, 95% CI 1.0 to 8.7) were associated with increased mortality.This is likely due to lack of awareness of the disease at the time. Similar findings were reported in a literature review of 48 cases (17) where over 80% of cases were in native valve endocarditis:

A review of 61 cases of IE with S. lugdunensis found that 52 of these were in native valves (80.6%), with 87% of these cases being left-sided endocarditis (18). Multivariate analysis found that medical treatment alone was associated with increased mortality (OR 4.79, 95% CI 1.16-19.78). Notably, mortality remained significantly high despite surgical intervention. This is not surprising, as the mortality rate for all CoNS infective endocarditis was similar to that of staphylococcus aureus infective endocarditis (25% vs 27%, respectively) and higher than viridans streptococci infective endocarditis (7%) in one cohort study (20). 

Bacteremia:

Despite the high mortality rate of native valve endocarditis, the same cannot be said about S. lugdunensis bacteremia. Indeed, it seems that relative to IE, bacteremia does not have as many complications or seems to be as destructive. In a retrospective cohort (21) of 28 patients with staphylococcus lugdunensis bacteremia, 13 presented with infective endocarditis, all of which were community acquired 11/13 had surgical intervention with 3 of these dying from IE (23%). Notably, all patients with hospital acquired bacteremia did not have IE nor did they suffer from any complications. Another case series of 6 non-IE S. lugdunensis bacteremias, none of the patients died or suffered any complications (22). Finally, a retrospective study of 88 patients with S. lugdunensis isolated found that 48 of these had clinically significant infections, of which 41 had bacteremia (23). Multivariate analysis found that Pitt bacteremia score >2, infective endocarditis, and ESRD were associated with increased mortality. 

Notably, in this cohort, all isolates were susceptible to vancomycin and teicoplanin, while 20% were resistant to oxacillin. 69% of isolates were resistant to penicillin, while over 95% of isolates were susceptible to TMP-SMX. Why bacteremia is less aggressive than IE is unclear, however patients who present with community-acquired bacteremia have a higher incidence of infective endocarditis.

Conclusions:

A brief word on antibiotic therapy. By far, all isolates thus far reported tend to be susceptible to teicoplanin and vancomycin, so if you isolate the bacteria off blood, this is a good initial therapy. There are some reports of possible beta-lactam resistance (specifically, oxacillin/nafcillin), though this is fairly rare (8). Indeed one study of 569 isolates finding that over 99% were susceptible to cefoxitin (24):

One thing to note here is that EUCAST and CLSI have different breakpoints for S. lugdunensis when compared to other CoNS. For instance, the typical EUCAST zone diameter breakpoints for CoNS are >/= 25mm for susceptible isolates and 25mm for resistant organisms. Compare this to Staph lugdunensis, for which the breakpoint is 22mm, similar to Staph aureus (4). With all that said, you are fairly well off if you follow disease-specific guidelines (24-27) and treat this as Staph aureus i.e. if bacteremia without focus, treat for 2 weeks, if IE, treat for 6 weeks. Etc.

TL;DR

• Coagulase-negative staphylococcus are skin commensals and tend to be less pathogenic than Staph aureus
• Staph lugdunensis falls between CoNS and coagulase-positive staphylococcus, behaving like staphylococcus aureus
• It colonizes axilla and the pelvic girdle
• Do not ignore a blood culture with S. lugdunensis, as this can represent native valve endocarditis
• Most cases of S. lugdunensis are SSTI that look like Staph aureus, with abscesses being a common presentation
• The most common IE presentation is native valve IE, which has a high mortality despite surgical intervention. Watch for perivalvular abscesses and other complications
• Treat as in Staph aureus

References:

1. Argemi X, Hansmann Y, Riegel P, Prévost G. Is Staphylococcus lugdunensis Significant in Clinical Samples? J Clin Microbiol. 2017 Nov;55(11):3167-3174. doi: 10.1128/JCM.00846-17. Epub 2017 Aug 23. PMID: 28835477; PMCID: PMC5654899.
2. Frank KL, Del Pozo JL, Patel R. From clinical microbiology to infection pathogenesis: how daring to be different works for Staphylococcus lugdunensis. Clin Microbiol Rev. 2008 Jan;21(1):111-33. doi: 10.1128/CMR.00036-07. PMID: 18202439; PMCID: PMC2223846.
3. Bennett, Raphael Dolin, Martin J. Blaser. Mandell, Douglas, And Bennett’s Principles and Practice of Infectious Diseases. Philadelphia, PA :Elsevier/Saunders, 2015.
4. Becker K, Heilmann C, Peters G. Coagulase-negative staphylococci. Clin Microbiol Rev. 2014 Oct;27(4):870-926. doi: 10.1128/CMR.00109-13. PMID: 25278577; PMCID: PMC4187637.
5. D. W. Lambe Jr., K. P. Ferguson, J. L. Keplinger, C. G. Gemmell, and J. H. Kalbfleisch. Pathogenicity of Staphylococcus lugdunensis, Staphylococcus schleiferi, and three other coagulase-negative staphylococci in a mouse model and possible virulence factors. Canadian Journal of Microbiology. 36(7): 455-463. https://doi.org/10.1139/m90-080
6. Giormezis N, Kolonitsiou F, Makri A, Vogiatzi A, Christofidou M, Anastassiou ED, Spiliopoulou I. Virulence factors among Staphylococcus lugdunensis are associated with infection sites and clonal spread. Eur J Clin Microbiol Infect Dis. 2015 Apr;34(4):773-8. doi: 10.1007/s10096-014-2291-8. Epub 2014 Dec 4. PMID: 25471196.
7. Herchline TE, Ayers LW. Occurrence of Staphylococcus lugdunensis in consecutive clinical cultures and relationship of isolation to infection. J Clin Microbiol. 1991 Mar;29(3):419-21. doi: 10.1128/JCM.29.3.419-421.1991. PMID: 2037657; PMCID: PMC269791.
8. Kleiner E, Monk AB, Archer GL, Forbes BA. Clinical significance of Staphylococcus lugdunensis isolated from routine cultures. Clin Infect Dis. 2010 Oct 1;51(7):801-3. doi: 10.1086/656280. PMID: 20726772.
9. Choi SH, Chung JW, Lee EJ, Kim TH, Lee MS, Kang JM, Song EH, Jun JB, Kim MN, Kim YS, Woo JH, Choi SH. Incidence, characteristics, and outcomes of Staphylococcus lugdunensis bacteremia. J Clin Microbiol. 2010 Sep;48(9):3346-9. doi: 10.1128/JCM.00609-10. Epub 2010 Jun 30. PMID: 20592152; PMCID: PMC2937714.
10. Fadel HJ, Patel R, Vetter EA, Baddour LM. Clinical significance of a single Staphylococcus lugdunensis-positive blood culture. J Clin Microbiol. 2011 Apr;49(4):1697-9. doi: 10.1128/JCM.02058-10. Epub 2011 Jan 26. PMID: 21270222; PMCID: PMC3122868.
11. van der Mee-Marquet N, Achard A, Mereghetti L, Danton A, Minier M, Quentin R. Staphylococcus lugdunensis infections: high frequency of inguinal area carriage. J Clin Microbiol. 2003 Apr;41(4):1404-9. doi: 10.1128/jcm.41.4.1404-1409.2003. PMID: 12682121; PMCID: PMC153917.
12. Bieber L, Kahlmeter G. Staphylococcus lugdunensis in several niches of the normal skin flora. Clin Microbiol Infect. 2010 Apr;16(4):385-8. doi: 10.1111/j.1469-0691.2009.02813.x. Epub 2009 Jun 6. PMID: 19519842.
13. Bellamy R, Barkham T. Staphylococcus lugdunensis infection sites: predominance of abscesses in the pelvic girdle region. Clin Infect Dis. 2002 Aug 1;35(3):E32-4. doi: 10.1086/341304. Epub 2002 Jun 27. PMID: 12115114.
14. Böcher S, Tønning B, Skov RL, Prag J. Staphylococcus lugdunensis, a common cause of skin and soft tissue infections in the community. J Clin Microbiol. 2009 Apr;47(4):946-50. doi: 10.1128/JCM.01024-08. Epub 2009 Feb 25. PMID: 19244465; PMCID: PMC2668335.
15. Heldt Manica LA, Cohen PR. Staphylococcus lugdunensis Infections of the Skin and Soft Tissue: A Case Series and Review. Dermatol Ther (Heidelb). 2017 Dec;7(4):555-562. doi: 10.1007/s13555-017-0202-5. Epub 2017 Oct 11. PMID: 29022273; PMCID: PMC5698201.
16. Douiri N, Hansmann Y, Lefebvre N, Riegel P, Martin M, Baldeyrou M, Christmann D, Prevost G, Argemi X. Staphylococcus lugdunensis: a virulent pathogen causing bone and joint infections. Clin Microbiol Infect. 2016 Aug;22(8):747-8. doi: 10.1016/j.cmi.2016.05.031. Epub 2016 Jun 11. PMID: 27297318.
17. Seenivasan MH, Yu VL. Staphylococcus lugdunensis endocarditis–the hidden peril of coagulase-negative staphylococcus in blood cultures. Eur J Clin Microbiol Infect Dis. 2003 Aug;22(8):489-91. doi: 10.1007/s10096-003-0953-z. Epub 2003 Jul 4. PMID: 12845551.
18. Liu PY, Huang YF, Tang CW, Chen YY, Hsieh KS, Ger LP, Chen YS, Liu YC. Staphylococcus lugdunensis infective endocarditis: a literature review and analysis of risk factors. J Microbiol Immunol Infect. 2010 Dec;43(6):478-84. doi: 10.1016/S1684-1182(10)60074-6. PMID: 21195974.
19. Anguera I, Del Río A, Miró JM, Matínez-Lacasa X, Marco F, Gumá JR, Quaglio G, Claramonte X, Moreno A, Mestres CA, Mauri E, Azqueta M, Benito N, García-de la María C, Almela M, Jiménez-Expósito MJ, Sued O, De Lazzari E, Gatell JM; Hospital Clinic Endocarditis Study Group. Staphylococcus lugdunensis infective endocarditis: description of 10 cases and analysis of native valve, prosthetic valve, and pacemaker lead endocarditis clinical profiles. Heart. 2005 Feb;91(2):e10. doi: 10.1136/hrt.2004.040659. PMID: 15657200; PMCID: PMC1768720.
20. Chu VH, Woods CW, Miro JM, Hoen B, Cabell CH, Pappas PA, Federspiel J, Athan E, Stryjewski ME, Nacinovich F, Marco F, Levine DP, Elliott TS, Fortes CQ, Tornos P, Gordon DL, Utili R, Delahaye F, Corey GR, Fowler VG Jr; International Collaboration on Endocarditis-Prospective Cohort Study Group. Emergence of coagulase-negative staphylococci as a cause of native valve endocarditis. Clin Infect Dis. 2008 Jan 15;46(2):232-42. doi: 10.1086/524666. PMID: 18171255.
21. Zinkernagel AS, Zinkernagel MS, Elzi MV, Genoni M, Gubler J, Zbinden R, Mueller NJ. Significance of Staphylococcus lugdunensis bacteremia: report of 28 cases and review of the literature. Infection. 2008 Aug;36(4):314-21. doi: 10.1007/s15010-008-7287-9. Epub 2008 Jul 21. PMID: 18648747.
22. Ebright JR, Penugonda N, Brown W. Clinical experience with Staphylococcus lugdunensis bacteremia: a retrospective analysis. Diagn Microbiol Infect Dis. 2004 Jan;48(1):17-21. doi: 10.1016/j.diagmicrobio.2003.08.008. PMID: 14761717.
23. Lin JF, Cheng CW, Kuo AJ, Liu TP, Yang CC, Huang CT, Lee MH, Lu JJ. Clinical experience and microbiologic characteristics of invasive Staphylococcus lugdunensis infection in a tertiary center in northern Taiwan. J Microbiol Immunol Infect. 2015 Aug;48(4):406-12. doi: 10.1016/j.jmii.2013.12.010. Epub 2014 Feb 14. PMID: 24529852.
24. Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Tleyjeh IM, Rybak MJ, Barsic B, Lockhart PB, Gewitz MH, Levison ME, Bolger AF, Steckelberg JM, Baltimore RS, Fink AM, O’Gara P, Taubert KA; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015 Oct 13;132(15):1435-86. doi: 10.1161/CIR.0000000000000296. Epub 2015 Sep 15. Erratum in: Circulation. 2015 Oct 27;132(17):e215. Erratum in: Circulation. 2016 Aug 23;134(8):e113. Erratum in: Circulation. 2018 Jul 31;138(5):e78-e79. PMID: 26373316.
25. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF; Infectious Diseases Society of America. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011 Feb 1;52(3):e18-55. doi: 10.1093/cid/ciq146. Epub 2011 Jan 4. Erratum in: Clin Infect Dis. 2011 Aug 1;53(3):319. PMID: 21208910.
26. Berbari EF, Kanj SS, Kowalski TJ, Darouiche RO, Widmer AF, Schmitt SK, Hendershot EF, Holtom PD, Huddleston PM 3rd, Petermann GW, Osmon DR, Infectious Diseases Society of America. 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. Clin Infect Dis. 2015 Sep 15;61(6):e26-46. doi: 10.1093/cid/civ482. Epub 2015 Jul 29. PMID: 26229122.
27. Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, Rao N, Hanssen A, Wilson WR; Infectious Diseases Society of America. Executive summary: diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013 Jan;56(1):1-10. doi: 10.1093/cid/cis966. PMID: 23230301.