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The aim of this study was to assess the characteristics of periprosthetic joint infection (PJI) due to Staphylococcus lugdunensis and to compare these to the characteristics of PJI due to Staphylococcus aureus and Staphylococcus epidermidis.
Methods
A retrospective multicentre study including all consecutive cases of S. lugdunensis PJI (2000–2014) was performed. Eighty-eight cases of staphylococcal PJI were recorded: 28 due to S. lugdunensis, 30 to S. aureus, and 30 to S. epidermidis, as identified by Vitek 2 or API Staph (bioMérieux).
Results
Clinical symptoms were more often reported in the S. lugdunensis group, and the median delay between surgery and infection was shorter for the S. lugdunensis group than for the S. aureus and S. epidermidis groups. Regarding antibiotic susceptibility, the S. lugdunensis strains were susceptible to antibiotics and 61% of the patients could be treated with levofloxacin + rifampicin. The outcome of the PJI was favourable for 89% of patients with S. lugdunensis, 83% with S. aureus, and 97% with S. epidermidis.
Conclusion
S. lugdunensis is an emerging pathogen with a pathogenicity quite similar to that of S. aureus. This coagulase-negative Staphylococcus must be identified precisely in PJI, in order to select the appropriate surgical treatment and antibiotics .
Periprosthetic joint infections (PJI) are the main complication of knee and hip prosthetic arthroplasty. Between 1% and 3% of patients undergoing prosthesis implantation are affected by these infections.
These common properties can lead to misidentification of S. lugdunensis: it may be positive for clumping factor and thus could show positive latex agglutination test results, like S. aureus. S. lugdunensis is also ornithine decarboxylase-positive, like other CoNS, and may therefore be mistaken for another CoNS. Recent developments in bacteriological techniques have led to considerable improvements in species identification. Automated systems and mass spectrometry have resolved the misidentification problems especially for CoNS.
The virulence factors of S. lugdunensis are shared with S. aureus, such as the ability to adhere to host proteins (fibronectin, fibrinogen), slime production, and the secretion of various toxins.
Pathogenicity of Staphylococcus lugdunensis, Staphylococcus schleiferi, and three other coagulase-negative staphylococci in a mouse model and possible virulence factors.
Moreover, the gene agr (accessory regulator), ica operon, fbl, atlL, vwbl, and slush factors involved in bacterial virulence have been identified in S. lugdunensis strains. All of these common properties show that S. lugdunensis is an aggressive pathogen and may be responsible for serious infections.
The major autolysin of Staphylococcus lugdunensis, AtlL, is involved in cell separation, stress-induced autolysis and contributes to bacterial pathogenesis.
S. lugdunensis is also described as a bacterium capable of biofilm production due to AtlL autolysin, particularly in prosthetic device-associated infections.
The pathogenic role of S. lugdunensis was emphasized in 1991 when a total of 155 S. lugdunensis specimens were isolated from different sites in 143 patients.
In that study, the patients included often presented necrotizing wounds, empyema, or abscesses. S. lugdunensis is well described as an aggressive pathogen involved in brain, thoracic, cutaneous, and soft tissue abscesses.
However, few studies have reported S. lugdunensis bone and joint infections.
S. lugdunensis shares several properties with S. aureus: in particular, S. lugdunensis may produce bound coagulase via a clumping factor. However, unlike S. aureus, it does not produce free coagulase. The rapid agglutination test (short coagulase test) may be positive for S. lugdunensis because of the same surface proteins shared with S. aureus. For these reasons it can be misidentified, and this could affect the management of PJI treatment. S. lugdunensis is more virulent and the clinical manifestations are more similar to S. aureus than CoNS.
Since its first description in 1988 by Freney et al.,
It appears that fewer than 30 cases of PJI due to S. lugdunensis have been reported in the literature.
The objective of this study was to assess the differences between S. lugdunensis and two other Staphylococcus species – S. aureus and S. epidermidis – in terms of clinical symptoms, delay between surgery and infection, antibiotic susceptibility, and clinical outcomes of PJI.
2. Materials and methods
2.1 Study population
A retrospective and descriptive study was conducted from 2000 to 2014, including patients from three orthopaedic centres in the same area. Eighty-eight consecutive cases of monomicrobial staphylococcal PJI due to S. lugdunensis (n = 28), S. aureus (n = 30), and S. epidermidis (n = 30) were analyzed.
2.2 Patients and samples
Data and information collected included age, sex, medical history, localization of the infection, clinical signs, surgical type, antibiotic therapy, duration of treatment, outcome post treatment, and delay between surgery and bacterial identification. These data are summarized in Table 1.
Table 1Patient characteristics and clinical information for cases of Staphylococcus lugdunensis periprosthetic joint infection
Patient
Sex
Age (years)
Medical history
Prosthesis site
Clinical signs
Surgery type
1
F
49
None
Knee
Pain
Irrigation and debridement
2
M
79
CVD
Knee
Pain
Irrigation and debridement
3
F
75
None
Hip
Pain
Irrigation and debridement
4
M
87
CVD
Knee
Fever, pain, SLI
One-stage surgery
5
F
63
None
Foot
Fever, pain, fistula
Irrigation and debridement
6
F
68
None
Shoulder
Fever, pain, SLI
Irrigation and debridement
7
M
63
None
Hip
Pain
Two-stage revision
8
F
67
CVD
Hip
Pain
Two-stage revision
9
M
37
None
Knee
Fever, pain
One-stage surgery
10
M
55
CVD
Knee
Fever, pain
Irrigation and debridement
11
F
83
None
Hip
Fever, pain, SLI
Irrigation and debridement
12
M
40
None
Knee
Fever, pain, SLI
Irrigation and debridement
13
F
70
None
Knee
Fever, SLI, pain
Two-stage revision
14
M
70
None
Knee
Fever, pain, SLI
Two-stage revision
15
M
40
None
Hip
Fever, pain, SLI
Irrigation and debridement
16
F
82
Diabetes mellitus
Hip
Fever, D, pain
Irrigation and debridement
17
M
48
Rheumatoid disease
Hip
SLI
Irrigation and debridement
18
F
78
None
Knee
Fistula
Two-stage revision
19
F
66
Cancer
Knee
Loosening
Two-stage revision
20
M
64
Cancer
Hip
Loosening
Two-stage revision
21
M
66
None
Knee
SLI, fever, pain
One-stage surgery
22
M
41
None
Hip
SLI, pain
Two-stage revision
23
F
87
None
Knee
Fistula
Two-stage revision
24
F
71
None
Knee
SLI, fever, pain
Two-stage revision
25
F
61
None
Knee
Fever, D, SLI
One-stage surgery
26
F
78
None
Knee
D
One-stage surgery
27
F
84
None
Knee
D
Two-stage revision
28
M
71
None
Hip
Fever, D, SLI
One-stage surgery
F, female; M, male; CVD, cardiovascular disease; D, dehiscence; SLI, signs of local inflammation.
All patients included in the study were suffering from a PJI. The diagnosis was based on multidisciplinary criteria and was assessed clinically, biologically, microbiologically, histopathologically, and radiologically.
The diagnosis of PJI was established in the presence of one major criterion or two minor criteria: (1) the major criteria were at least two positive periprosthetic cultures with phenotypically identical organisms, or a sinus tract communicating with the joint; (2) minor criteria were a C-reactive protein (CRP) value >10 mg/l and a histological analysis of periprosthetic tissue confirming a septic process .
Irrigation and debridement was the technique used for early PJI with less than 1 month between prosthesis implantation and clinical symptoms of infection. One-stage surgery was considered for patients with a chronic PJI but with an adequate state of bone and tissues. A gentamicin bone cement (Palacos-Genta; Zimmer 1800 West Center Street Warsaw, Poland) was used whenever possible. A two-stage revision procedure was indicated for patients who were not candidates for irrigation and debridement or one-stage surgery. These patients presented a chronic PJI, with bone and soft tissue defects. This strategy was used for patients who could undergo at least two surgeries. A local spacer impregnated with gentamicin was used until the placement of a new prosthesis.
Patient outcomes were based on at least 1 year of follow-up. This consisted of a multidisciplinary consultation (with a surgeon and an infectious diseases physician), including a clinical and radiological evaluation and a blood analysis for CRP. A favourable outcome was considered a good clinical recovery, satisfactory joint mobility, and no signs of inflammation.
Intraoperative bone tissue, synovial membranes, and articular fluid samples were obtained for the microbiological diagnosis. It was recommended that antibiotics be stopped 15 days prior to surgery in order to obtain growing bacteria in culture.
At least three intraoperative deep samples were collected per patient. After collection, the samples were transferred to the microbiology laboratory within less than 1 h.
2.3 Bacteriological culture
For each suspected site, hard and soft tissue specimens were collected in sterile glass vials. Articular fluid was inoculated into blood culture bottles. All samples were incubated under aerobic conditions with CO2 and an anaerobic atmosphere for 15 days. Gram staining was performed for each sample on day 1.
Hard and soft tissue specimens were crushed and vortexed in 1 ml of saline solution for 10 min. Standard cultures were performed on Columbia blood agar, PolyViteX chocolate agar, and thioglycolate solution (Oxoid, Dardilly, France). Articular fluids were inoculated into blood culture bottles and onto solid agar media.
Media were observed daily for microbial growth. Bacteriological criteria for a positive diagnosis of infection were the following: at least one positive sample for S. aureus-positive cultures; at least two positive samples for S. epidermidis- and S. lugdunensis-positive cultures.
Only monomicrobial cultures with S. aureus, S. lugdunensis, and S. epidermidis were selected. Seven polymicrobial infections including S. lugdunensis were excluded. In these cases, the PJI involved bacteria of the cutaneous flora: CoNS, corynebacteria, or Propionibacterium acnes. The exclusion of polymicrobial infections was necessary to be certain of the bacterium that caused the PJI . Thus all clinical, biological, and treatment-related results were specifically connected to a single bacterial species: S. aureus, S. lugdunensis, or S. epidermidis.
In the case of a positive culture, identification was performed by automated technique (Vitek 2; bioMérieux, Marcy l’Etoile, France) or manual technique (API Staph; bioMérieux). When identification results were conflicting, complementary tests were performed to confirm the species identification: (1) S. aureus: positive latex agglutination; (2) S. lugdunensis: typical salty smell, positive pyrrolidonyl arylamidase (L-PYR) test; (3) S. epidermidis: colistin resistance detected by disk diffusion test.
Antimicrobial susceptibilities were tested by Vitek 2 (bioMérieux) according to the recommendations of the Committee on Antibiotic Susceptibility of the French Society of Microbiology.
Methicillin resistance was interpreted from the oxacillin minimum inhibitory concentration (MIC). Staphylococcus strains were considered susceptible when the MIC was between 0.5 and 2 μg/ml. Conflicting results for methicillin susceptibility were verified by cefoxitin disk (Bio-Rad, Marnes-la-Coquette, France).
2.4 Statistical analysis
Continuous variables are presented as the median and interquartile range, while categorical variables are presented as the count and proportion. For the univariate analysis, continuous data were compared among the three groups of patients according to the type of Staphylococcus by Kruskal–Wallis test. Qualitative variables were compared by Chi-square test (or Fisher's exact test when necessary). The statistical analysis was performed using Stata 11.2 software (StataCorp, College Station, TX, USA).
3. Results
3.1 Population study
Twenty-eight cases of S. lugdunensis PJI were recorded between 2000 and 2014 at the three orthopaedic centres in the same area. Clinical and surgical data for these S. lugdunensis PJI are detailed in Table 1.
Age, sex, prosthesis site, clinical and biological signs, and the types of surgery performed in the three groups are summarized in Table 2.
Table 2Comparison of populations with Staphylococcus lugdunensis, Staphylococcus aureus, and Staphylococcus epidermidis periprosthetic joint infections
The populations of the three groups were comparable statistically for age (p = 0.34) and sex (p = 0.196).
With regard to S. lugdunensis patients, eight (29%) presented a comorbidity: four (14%) had cardiovascular disease, one (4%) had inflammatory rheumatism, one (4%) had diabetes mellitus, and two (7%) had a history of cancer. The median CRP value in this group was 42 mg/l.
Nine (30%) of the S. aureus patients had a comorbidity: five (17%) had cardiovascular disease, one (3%) had been treated for cancer, one (3%) had inflammatory rheumatism, one (3%) had diabetes mellitus, and one (3%) had hepatitis C. Thirteen (43%) of the S. epidermidis patients presented a comorbidity: five (17%) had cardiovascular disease, one (3%) had been treated for cancer, and five (17%) had diabetes mellitus. CRP data were available for only a few of the patients with S. aureus and S. epidermidis PJIs and so are not presented.
3.2 Surgical intervention
The median delay between surgery and infection and the type of surgery performed in the three groups are presented in Table 2. For S. lugdunensis PJI, the median delay was statistically shorter than in the other groups (p = 0.0449).
3.3 Bacteriological results
Bacteriological results for the deep intraoperative samples in the three groups are presented in Table 2; no significant difference was found between the three groups regarding the number of positive samples (p = 0.449) or the total number of samples (p = 0.413).
S. lugdunensis culture results and antibiotic resistance profiles are detailed in Table 3. A comparison of antibiotic resistance is presented in Table 4. S. lugdunensis was significantly the most susceptible species regarding penicillin G, methicillin, fluoroquinolones, clindamycin (p = 0.000), and rifampicin (0.038). Antibiotic resistance profiles in the three groups are compared in Figure 1.
Table 3Microbiological results and patient treatments and outcomes for cases of Staphylococcus lugdunensis periprosthetic joint infection
All patients received an empiric intravenous antibiotic regimen with vancomycin or daptomycin following surgery. After approximately 1 week of parenteral antibiotics, oral relay therapy was implemented for a mean duration of 7 weeks in all three groups. The main oral medical treatments are presented in Table 4. Antibiotics prescribed in S. lugdunensis and S. aureus PJI were mostly fluoroquinolones associated with rifampicin. Because S. epidermidis strains were more resistant than S. aureus and S. lugdunensis, second-line antibiotics like linezolid were more often used. A comparison of the oral medical treatment in the three groups is shown in Figure 2.
Figure 2Antibiotic treatment of Staphylococcus lugdunensis, Staphylococcus aureus, and Staphylococcus epidermidis periprosthetic joint infections.
The outcome was evaluated during a follow-up period starting at the end of treatment and continuing for at least 12 months for all patients. The outcome results are presented in Table 2 and were statistically comparable in the three groups (p = 0.233).
Nine unfavourable outcomes were reported in the total population. The overall success rate of the surgical technique applied, as defined by a lack of relapse, was 85% for irrigation and debridement, 97% for one-stage surgery, and 86% for two-stage revision.
4. Discussion
This study compared the clinical and bacteriological characteristics of 28 consecutive cases of S. lugdunensis PJI to those in PJI caused by other staphylococci.
S. lugdunensis colonization is described on the skin, especially in the inguinal and perineal areas.
This localization may play a role in the potential haematogenous or subcutaneous dissemination, which could lead to bone and joint infections. Several studies on S. lugdunensis bone and joint infections have reported osteomyelitis,
They have all described the invasive nature of these S. lugdunensis infections.
In this study, significantly more clinical symptoms such as pain, fever, and signs of local inflammation were observed in the S. lugdunensis and S. aureus series than in the S. epidermidis series. CRP at the time of diagnosis was not reported for all patients (especially for those with S. epidermidis PJI). Measurements were available for half of the patients with S. lugdunensis PJI and the mean value was 42 mg/l, which is much higher than the value usually reported for S. epidermidis PJI.
The delay between surgery and infection was significantly shorter in S. lugdunensis and S. aureus PJI compared to S. epidermidis PJI. Others studies have also reported a short delay in S. lugdunensis PJI. This result confirms the similar clinical course of S. lugdunensis PJI and S. aureus infections.
With regard to the type of surgical intervention, irrigation and debridement and two-stage revision were performed for S. lugdunensis and S. aureus PJI. In all other published studies, the most frequent type of surgery selected was two-stage revision with placement of an antibiotic spacer.
The treatment success rate for S. lugdunensis PJI was overall the same whatever the type of surgery. Three patients had an unfavourable outcome: one after irrigation and debridement and two after a two-stage revision.
In this study, S. lugdunensis was responsible for knee PJI more than hip PJI, as was S. aureus. In contrast, S. epidermidis was more involved in hip PJI. These data may confirm the suggestion of Shah et al., that S. lugdunensis could preferentially infect knees.
Although S. lugdunensis shares many properties with S. aureus, one of the main differences between the two species is the antimicrobial susceptibility. It was found that S. lugdunensis strains were all susceptible to methicillin, and half were resistant to penicillin G. These results are different to those of some previous studies, especially for penicillin G resistance.
No strain was resistant to linezolid or trimethoprim–sulfamethoxazole (SXT). S. aureus strains were quite susceptible to methicillin (87%), but it was found that 17% of strains were resistant to quinolones and 27% to clindamycin. In comparison, 77% of S. epidermidis strains were resistant to methicillin, 60% to quinolones, and 20% to rifampicin, the first-line antibiotics for the treatment of PJI. Thus S. aureus and S. lugdunensis strains in this study were much more susceptible than S. epidermidis strains, as reported in other publications on staphylococcal bone and joint infections.
Infectious prosthetic hip joint loosening: bacterial species involved in its aetiology and their antibiotic resistance profiles against antibiotics recommended for the therapy of implant-associated infections.
The treatment of S. lugdunensis PJI was a combination of fluoroquinolone + rifampicin for 61% of the patients. This is the reference treatment for methicillin-susceptible CoNS PJI recommended in French and international guidelines.
This combination was also chosen as the first-line treatment for S. aureus PJI, but only for 40% of patients with an S. epidermidis PJI. More second-line antibiotics, such as linezolid, SXT, cyclins, clindamycin, and fusidic acid, were used for the treatment of S. epidermidis PJI, due to the resistance of S. epidermidis.
The duration of treatment was on average 7 weeks in the three groups. It appears that the good outcomes achieved in these patients were more a result of early surgery (at <1 month) associated with an adapted antibiotic combination than the duration of treatment. Previous studies have reported a mean duration of treatment of 4 to 8 weeks.
Moreover 97% of patients with an S. epidermidis PJI had a favourable outcome, compared to 89% of patients with an S. lugdunensis PJI and 83% of patients with an S. aureus PJI (p = 0.233). These results were not significant in this population, but they nevertheless suggest the high pathogenicity of S. lugdunensis.
The total number of S. lugdunensis PJI cases collected in this study was only 28; this may not be statistically sufficient to confirm all of the observations. The present results warrant confirmation in prospective studies conducted on a larger number of S. lugdunensis PJI samples.
To conclude, S. lugdunensis is classified as a CoNS, but the clinical features of S. lugdunensis PJI, the early aspect of the infection, and the relapses observed are similar to those in S. aureus PJI. Regarding the microbiological diagnosis, the species of CoNS in PJI must be identified precisely and treatment adapted to the antibiotic susceptibility, even if only one deep sample is positive in culture.
Acknowledgements
We thank Dr Sébastien Hascoët for the statistical analysis and review of the manuscript.
Conflict of interest: We report no conflict of interest.
References
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Infection burden for hip and knee arthroplasty in the United States.
Pathogenicity of Staphylococcus lugdunensis, Staphylococcus schleiferi, and three other coagulase-negative staphylococci in a mouse model and possible virulence factors.
The major autolysin of Staphylococcus lugdunensis, AtlL, is involved in cell separation, stress-induced autolysis and contributes to bacterial pathogenesis.
Infectious prosthetic hip joint loosening: bacterial species involved in its aetiology and their antibiotic resistance profiles against antibiotics recommended for the therapy of implant-associated infections.
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