Staphylococcus lugdunensis

INTRODUCTION — Staphylococcus lugdunensis is a coagulase-negative staphylococcus (CoNS). Like other CoNS, S. lugdunensis in humans ranges from a harmless skin commensal to a life-threatening pathogen (as with infective endocarditis). Unlike other CoNS, however, S. lugdunensis can cause severe disease reminiscent of the virulent infections frequently attributable to Staphylococcus aureus [1]. In addition, most S. lugdunensis isolates remain susceptible to a large number of antimicrobial agents.

S. lugdunensis was first described in 1988 and was distinguished from other coagulase-negative staphylococcal species via DNA-relatedness studies based on 11 clinical strains. The new species was named after Lyon, the French city where the organism was first isolated (Lugdunum, the Latin name of Lyon) [2]. S. lugdunensis is unique among CoNS because of its propensity for causing aggressive native valve infective endocarditis and its susceptibility to a vast array of antimicrobial agents.

The microbiology, clinical features, and treatment of S. lugdunensis infections will be reviewed here. Other issues related to coagulase-negative staphylococci are discussed in detail separately.

EPIDEMIOLOGY — S. lugdunensis infections in humans range from harmless skin colonization to invasive infection. The majority of infections are related to skin and soft tissue, the bloodstream, and prosthetic devices.

The frequency of S. lugdunensis infection is probably underappreciated, since many clinical laboratories do not routinely speciate coagulase-negative staphylococci [3,4]. Among 494 coagulase-negative staphylococcal isolates from a clinical setting, S. lugdunensis accounted for 3 percent of isolates [3]. Unlike Staphylococcus epidermidis, in general, S. lugdunensis should be presumed to be a true pathogen. Among 229 S. lugdunensis clinical isolates in one series, only 15 percent were considered contaminants or colonizing organisms [5].

MICROBIOLOGY — S. lugdunensis is a gram-positive, catalase-positive, coagulase-negative coccus. It is a nonmotile, facultative anaerobe that may demonstrate hemolysis on blood agar [6]. Colonies of S. lugdunensis can appear unpigmented, cream-colored, or pale yellow to golden after five days of incubation [2,6].

Slide and rapid latex agglutination tests are used by many laboratories to distinguish coagulase-negative from coagulase-positive staphylococci (S. aureus). However, the performance characteristics of these tests for S. lugdunensis are variable, and the presence of clumping factor can lead to false identification of S. aureus [7-9]. For this reason, the tube coagulase test should be used to distinguish S. lugdunensis as a coagulase-negative Staphylococcus instead of a coagulase-positive Staphylococcus.

Biochemical testing for pyrrolidonyl arylamidase and ornithine decarboxylase activity can be used to distinguish S. lugdunensis from other coagulase-negative staphylococci (CoNS). Identification of S. lugdunensis can also be accomplished through commercially available phenotypic identification systems (commercial kits and automated systems) [8,10] and newer methods such as matrix-assisted desorption ionization–time of flight mass spectrometry [11]. In addition, S. lugdunensis can be identified by molecular methods using gene targets [12-15].

Antibiotic susceptibility — S. lugdunensis isolates are unique among the CoNS by virtue of their susceptibility to a wide range of antimicrobials. In vitro testing of clinical S. lugdunensis isolates has demonstrated antimicrobial susceptibility to cefazolin, daptomycin, linezolid, moxifloxacin, nafcillin, quinupristin-dalfopristin, rifampin, tetracycline, trimethoprim-sulfamethoxazole, and vancomycin [9]. S. lugdunensis resistance to beta-lactams, macrolides, and aminoglycosides is uncommon [6,16,17].

Penicillin resistance in S. lugdunensis was reported to be as low as <4 percent in the 1990s [18]; however, penicillin resistance appears to be increasing with estimates of 12 to 27 percent in the 2000s [7,8,19-21]. One study in 2010 noted a resistance rate of 45 percent [4].

Methicillin resistance in S. lugdunensis has been noted in a few case reports. Presence of mecA (the gene encoding methicillin resistance in S. aureus) in S. lugdunensis is uncommon; it has been reported in 0 to 5 percent of S. lugdunensis isolates; however, although a rate of 20 percent was reported from one hospital in Taiwan [4,7,22-24].

The oxacillin breakpoint for S. lugdunensis was modified in 2005 to more precisely reflect the presence of mecA. S. lugdunensis isolates with an oxacillin minimum inhibitory concentration (MIC) ≤2 mcg/mL are defined as susceptible; those with oxacillin MICs of ≥4 mcg/mL are defined as resistant [25]. This is in contrast with other CoNS for which the breakpoint for oxacillin susceptible is ≤0.5 mcg/mL and for oxacillin resistant is ≥1.0 mcg/mL [26].

Vancomycin tolerance has been described in S. lugdunensis, meaning that the bacteria are able to survive in the presence of an antibiotic to which it is considered susceptible by MIC. This was demonstrated in 93 percent of S. lugdunensis isolates tested using an minimal bactericidal concentration (MBC)/MIC ratio of ≥32 [9] and 46 percent (6 of 13) of isolates tested by the killing curve method [27]. The clinical significance of vancomycin tolerance is uncertain, although these findings raise important concerns regarding selection of antimicrobial therapy.

The presence of biofilm appears to influence the efficacy of antimicrobial agents in vitro [28-30]. A study of S. lugdunensis antimicrobial susceptibility demonstrated that planktonic S. lugdunensis isolates were susceptible to all 10 antistaphylococcal agents tested, while those in biofilms were highly resistant. Biofilm formation was increased in the presence of nafcillin by 93 percent of organisms, while biofilm formation was decreased in the presence of tetracycline and linezolid. Moxifloxacin was the only antibiotic with activity against the S. lugdunensis organisms in biofilm; 73 percent of the biofilm isolates were susceptible [9]. The clinical significance of biofilm and antimicrobial susceptibility is uncertain.

PATHOGENESIS — Adherence factors allowing S. lugdunensis to bind to host tissues and implantable materials are thought to play a major role in the pathogenesis of S. lugdunensis infections. Von Willebrand factor-binding protein allows interaction between the organism and clotting during vascular injury [31], and fibrinogen-binding protein allows S. lugdunensis to bind host matrix proteins.

Biofilm formation plays a major role in the pathogenesis of S. lugdunensis infections: it permits attachment of the organism on implantable devices and provides protection from antibiotics and host immunity [32]. The biofilm of S. lugdunensis is composed of proteins rather than polysaccharide (which is a major component of biofilm produced by other organisms) [33]. The clinical significance of a protein-based biofilm matrix is uncertain, although the presence of biofilm appears to modify the efficacy of antimicrobial agents in vitro. (See 'Antibiotic susceptibility' above.)

The role of biofilms in the pathogenesis of infection due to coagulase-negative staphylococci (CoNS) is discussed in further detail separately. (See "Infection due to coagulase-negative staphylococci: Epidemiology, microbiology, and pathogenesis", section on 'Biofilm'.)

S. lugdunensis can utilize host hemoglobin as an iron source through the Isd genes, unlike other CoNS [34]. Metalloproteases are involved in remodeling of bone and extracellular matrix. As such, a novel metalloprotease, lugdulysin, may play a role in S. lugdunensis bone and joint infections [35].

The pathogenesis of S. lugdunensis has not been associated with toxin production.

CLINICAL MANIFESTATIONS — The frequency of S. lugdunensis infection is probably underappreciated, since some clinical laboratories do not routinely speciate coagulase-negative staphylococci (CoNS); however, use of matrix-assisted desorption ionization–time of flight mass spectrometry in clinical laboratories may increase the detection and reporting of this species. Virulent infection due to CoNS should prompt speciation; unlike S. epidermidis, S. lugdunensis should generally be presumed to be a true pathogen.

Skin and soft tissue — Soft tissue infections make up 25 to 80 percent of clinical infections due to S. lugdunensis [4,5,36].

Several studies suggest that S. lugdunensis tends to colonize and cause infection below the waist [19,37-39]. There are reports of S. lugdunensis infective endocarditis (IE) occurring in the setting of prostate cancer [6], vasectomy [40], and perineal lesions [41-43], all suggesting that S. lugdunensis has a predilection for colonization and infection of the perineal area. Among 38 patients with S. lugdunensis infection in one series, 73 percent of infections (mostly soft tissue abscesses) occurred below the waist [19].

In a series of 140 patients, the prevalence of inguinal colonization with S. lugdunensis was about 20 percent [44]. Inguinal colonization of the inguinal area appears to predispose to infection after invasive procedures, and shaving this area prior to surgery has been associated with an increased rate of S. lugdunensis infections [44].

The breast is another important site of S. lugdunensis infection. Breast abscesses (both spontaneous and postoperative infections) have been reported in nonlactating women [45]. In one review, breast abscesses accounted for five of seven S. lugdunensis infections that occurred above the waist [19].

Endocarditis — S. lugdunensis endocarditis is an aggressive infection that affects native valves with greater frequency than prosthetic valves, in contrast to other CoNS [46-48].

S. lugdunensis native valve endocarditis is typically community acquired and associated with a high rate of complications and death, particularly as reported in early case series. In a review of 53 patients with native valve S. lugdunensis endocarditis from 1990 to 2003, the rate of heart failure was 45 percent, periannular abscess 19 percent, embolization 30 percent, and death 42 percent [49]. While high rates of heart failure and valvular complications are also seen in the setting of endocarditis due to other CoNS (mostly S. epidermidis), the mortality rate of S. lugdunensis endocarditis potentially rivals that of S. aureus [47,50-53]. (See "Native valve endocarditis: Epidemiology, risk factors, and microbiology".)

S. lugdunensis also causes prosthetic valve endocarditis. In a review of nine cases of S. lugdunensis prosthetic valve endocarditis, the rate of heart failure was 22 percent, periannular abscess 66 percent, embolization 11 percent, and death 78 percent [49]. The majority of these infections are late onset. Among six cases of S. lugdunensis prosthetic valve endocarditis, one infection occurred within six months of valve implantation; the rest occurred between 2 and 13 years after the original valve implantation [16].

S. lugdunensis pacemaker/implantable cardioverter defibrillator (ICD) lead endocarditis has also been described. Among seven patients managed with both hardware removal and antibiotic therapy, one patient died [49]. Small colony variants of S. lugdunensis (pathogenic forms that facilitate persistent and recurrent infection) have been reported in the setting of pacemaker retention and persistent infection [54].

Reasons for the high mortality observed in earlier studies of S. lugdunensis endocarditis are unclear. Nevertheless, evidence suggests that the prognosis for S. lugdunensis endocarditis has improved. Among 20 cases of S. lugdunensis endocarditis reported before 1993, the mortality was 70 percent; while among 28 cases reported after 1993, mortality was 18 percent [16,46]. In a more contemporary series from 2008 to 2018 including 30 episodes of IE (of which 70 percent of cases were native valve IE), the 30-day mortality was 20 percent [48]. This finding is more consistent with the mortality associated with native valve IE due to coagulase-negative staphylococci (mostly S. epidermidis) [48,50].

Potential explanations for the improved outcomes with S. lugdunensis IE in contemporary studies include a higher rate of surgery, earlier diagnosis of S. lugdunensis endocarditis due to more frequent speciation of CoNS, and a higher proportion of native valve (versus prosthetic valve) cases [46].

Bacteremia — S. lugdunensis nonendocarditis (non-IE) bacteremia is a less aggressive infection than S. lugdunensis endocarditis. Among 21 episodes of S. lugdunensis bacteremia in one series, six appeared to be clinically significant cases of non-IE bacteremia. Five of these patients had a hemodialysis or tunneled intravenous catheter; none experienced suppurative complications or death [55]. Similar outcomes were observed in another series of 15 cases of non-IE S. lugdunensis bacteremia; a catheter or foreign device was identified in 73 percent of patients, and there were no complications related to the bacteremia [56].

Thus, the data suggest that there is a dichotomy for S. lugdunensis bacteremia. Non-IE bacteremia tends to be healthcare associated (ie, nosocomial or associated with foreign devices) and has a relatively good prognosis; bacteremia with endocarditis is often community acquired and associated with an aggressive course [57]. However, the data are subject to selection bias, since CoNS is not speciated in all institutions.

Single positive blood cultures for S. lugdunensis should not be dismissed as culture contaminants; clinicians should carefully consider clinical presentation and risk factors for infection. In one study including 29 patients with a single positive blood culture for S. lugdunensis, the result was clinically significant in 45 percent of cases [58]. In the setting of two or more positive cultures, endocarditis should be considered. In one study including 74 patients with at least two positive blood cultures for S. lugdunensis, definite or positive IE was observed in 25 percent of patients; a systematic review noted that 6 to 27 percent of patients with ≥1 blood culture for S. lugdunensis had IE [59].

Bone and joint infections — Bone and joint infections account for up to one-third of S. lugdunensis infections; the majority of these are related to hardware [35]. In one study, prosthetic joint infections due to S. lugdunensis were more likely to present with fever and local signs of inflammation than prosthetic joint infections due to S. epidermidis or S. aureus [60].

S. lugdunensis tends to affect prosthetic knees more often than prosthetic hips [36,60-62]. In one study including 28 episodes of S. lugdunensis prosthetic joint infections, prosthetic knee infection was more common than prosthetic hip infection (89 versus 11 percent); in addition, an underlying urogenital abnormality was observed in nearly one-third of patients [62].

Cases of S. lugdunensis bone and joint infection have been described in detail [63-65]:

●S. lugdunensis infection was reported two years after a total hip arthroplasty in an otherwise healthy patient [63]. Treatment included abscess drainage, intraarticular teicoplanin injections, and oral clindamycin and rifampin for three months [63]. The patient remained asymptomatic up to six years of follow-up.

●Cases of S. lugdunensis knee arthroplasty infection have been reported, with clinical cure [64,65]. Emergence of antibiotic resistance and small colony variants after debridement and prosthesis retention for a S. lugdunensis late knee arthroplasty infection has been reported [66].

●Septic arthritis after arthroscopic anterior cruciate ligament revision has been described [67].

●Osteomyelitis of the cervical, thoracic, and lumbar spine have been reported [65,68-71].

●Native joint septic arthritis due to S. lugdunensis has been reported [72].

Other infections — A number of other infections due to S. lugdunensis have been described:

●S. lugdunensis has been reported in association with ventriculoperitoneal shunts and external ventriculostomy drains [73,74].

●Acute postoperative endophthalmitis (mean of 7.6 days after cataract surgery) was observed among five patients in one series. Treatment included intravenous, intravitreal, topical antibiotics, and pars plana vitrectomy (four patients). Despite aggressive treatment, outcomes were poor for three out of the five patients [75]. In addition to postoperative infection, endophthalmitis after globe injury has been reported [76]. (See "Bacterial endophthalmitis".)

●Osteomyelitis of the ear canal has been noted in a patient with noninsulin-dependent diabetes [77].

Cases of endometritis [78], acute suppurative lymphadenitis [79], psoas abscess [80], lung abscess [81], urinary tract infection [82,83], and peritonitis with exit site infection [84] have also been described.

TREATMENT — Treatment of infection due to S. lugdunensis should be guided by the results of antibiotic susceptibility testing. Most isolates are susceptible to penicillin, and this is the drug of choice for treatment of infection if susceptibility permits. Isolates possessing beta-lactamase (fewer than one-quarter) are resistant to penicillin [20]. The majority of S. lugdunensis isolates are susceptible to oxacillin, and the presence of mecA is uncommon [4,7,22,23].

Vancomycin is an appropriate alternative agent if resistance or sensitivity precludes use of beta-lactam agents.

Skin and soft tissue — The approach to antibiotic selection for treatment of S. lugdunensis skin and soft tissue infections is as outlined in the preceding section. Abscesses should be drained if possible. The duration of therapy depends on individual circumstances but, in general, consists of one to two weeks of therapy; the clinical response to therapy should guide antibiotic duration. Deep-seated infections may warrant parenteral therapy initially, though therapy may be completed with oral agents depending on individual circumstances.

Endocarditis — Treatment of native valve infectious endocarditis should consist of six weeks of parenteral beta-lactam therapy or vancomycin (depending on susceptibility testing and beta-lactam hypersensitivity). Limited data suggest comparable mortality outcomes with monotherapy and combination therapy for native valve infective endocarditis (IE) [49].

Treatment of prosthetic valve IE should consist of combination therapy including a beta-lactam (or vancomycin) with an aminoglycoside and rifampin. The gentamicin should be administered for the first two weeks of therapy; the beta-lactam (or vancomycin) and rifampin should be continued for six weeks. This approach is extrapolated from the S. aureus literature. (See "Antimicrobial therapy of prosthetic valve endocarditis".)

Surgery must be considered given the frequency of valvular compromise in the setting of S. lugdunensis IE. In a review of 10 patients with S. lugdunensis IE, all patients with left-sided IE had serious complications; surgery was required in more than half of cases [49]. Predictors of surgery included age <50, absence of significant comorbidity, aortic valve involvement, and periannular abscess. (See "Surgery for left-sided native valve infective endocarditis".)

The treatment of S. lugdunensis pacemaker endocarditis includes antibiotic therapy as well as removal of the pacer system. The mortality with this infection is low if the pacemaker and leads are removed [49]. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Bacteremia — Bacteremia without endocarditis (often related to an intravascular catheter) appears to have a good prognosis [56]. Nevertheless, given the potential for S. lugdunensis to be associated with aggressive IE, bacteremia due as S. lugdunensis should be treated similarly to S. aureus [85]. Therefore, for intravascular catheter-related S. lugdunensis bacteremia, the catheter should be removed, followed by 14 days of antibiotics, provided that all of the following are applicable: the patient is not diabetic or immunosuppressed; there is no prosthetic material, thrombophlebitis, IE, evidence of metastatic infection; and the patient's fever and bacteremia resolve within 72 hours after initiation of appropriate antibiotic therapy [85]. The approach to antibiotic selection is outlined above. (See 'Treatment' above.)

The outcome with retaining the intravascular catheter is uncertain but would likely require a longer course of antibiotics [85].

Bone and joint infections — Management of S. lugdunensis orthopedic infections with hardware generally consists of two-stage arthroplasty and at least six weeks of antibiotics. Antibiotic selection for treatment of infection due to S. lugdunensis is outlined in the preceding section. (See 'Treatment' above.)

The long-term outcome of S. lugdunensis prosthetic joint infection is unknown. Although some case reports describe definitive treatment of S. lugdunensis prosthetic joint infections without prosthesis removal, these data must be interpreted with caution since coagulase-negative staphylococcal infections can be indolent with delayed presentation.

Additional considerations for treatment of prosthetic joint infections are discussed in detail separately. (See "Prosthetic joint infection: Treatment".)

Other infections — Antibiotic selection for treatment of infection due to S. lugdunensis is outlined in the preceding section. (See 'Treatment' above.)

General approaches to septic arthritis, vertebral osteomyelitis, and other types of infection that can be caused by S. lugdunensis are discussed in detail separately. (See "Vertebral osteomyelitis and discitis in adults" and "Septic arthritis in adults".)

SUMMARY AND RECOMMENDATIONS

●In humans, the significance of Staphylococcus lugdunensis ranges from a harmless skin commensal to a life-threatening pathogen (such as in the case of infective endocarditis). Unlike other coagulase-negative staphylococci (CoNS), however, S. lugdunensis can cause severe disease reminiscent of the virulent infections frequently attributable to Staphylococcus aureus. (See 'Introduction' above.)

●The frequency of S. lugdunensis infection is probably underappreciated, since some clinical laboratories do not routinely speciate coagulase-negative staphylococci. Virulent infection due to CoNS should prompt speciation; unlike S. epidermidis, S. lugdunensis should generally be presumed to be a true pathogen. (See 'Epidemiology' above.)

●S. lugdunensis is a gram-positive, catalase-positive, coagulase-negative coccus. S. lugdunensis isolates are unique among the coagulase-negative staphylococci by virtue of their susceptibility to a wide range of antimicrobials. (See 'Microbiology' above.)

●Biofilm formation plays a major role in the pathogenesis of S. lugdunensis infection; it provides protection from antibiotics and host immunity and permits attachment of the organism on implantable devices. The presence of biofilm appears to modify the efficacy of antimicrobial agents in vitro. (See 'Pathogenesis' above.)

●Clinical infections due to S. lugdunensis include soft tissue infections, endocarditis, bacteremia, prosthetic device infections, osteomyelitis, and others. Several studies suggest that S. lugdunensis tends to colonize and cause infection below the waist. S. lugdunensis endocarditis is an aggressive infection that affects native valves with greater frequency than prosthetic valves. (See 'Clinical manifestations' above.)

●Treatment of infection due to S. lugdunensis should be guided by the results of antibiotic susceptibility testing. We suggest treatment of S. lugdunensis with penicillin (if susceptibility and individual circumstances permit) (Grade 2C). Appropriate alternative agents include other beta-lactam drugs and vancomycin. The duration of therapy depends on the site of infection. (See 'Treatment' above.)