Staphylococcus aureus soft tissue infection may increase the risk of ...

International Journal of Infectious Diseases 60 (2017) 44–48

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Staphylococcus aureus soft tissue infection may increase the risk of subsequent staphylococcal soft tissue infections$ Cindy Bouveta , Shpresa Gjonib , Besa Zenelaja , Benjamin A. Lipskyc,d, Elif Hakkof , Ilker Uçkaya,c,e,* a

Orthopaedic Surgery Service, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Switzerland Division of General Medical Rehabilitation, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Switzerland Service of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Switzerland d Division of Medical Sciences, Green Templeton College, University of Oxford, Oxford, United Kingdom e Infection Control Program, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Switzerland f lık Hospital, Istanbul, Turkey Anadolu Sag b c

A R T I C L E I N F O

S U M M A R Y

Article history: Received 9 January 2017 Received in revised form 3 April 2017 Accepted 2 May 2017 Corresponding Editor: Eskild Petersen, Aarhus, Denmark

Background: Staphylococcus aureus is the most common cause of soft tissue infections. It is unknown, however, if a patient who has had such an infection is at greater risk for future soft tissue infections with S. aureus. Methods: We conducted an epidemiological survey of adult patients hospitalized in the only public hospital in Geneva for treatment (usually combined surgical and medical) of a soft tissue infection caused by S. aureus. By reviewing nursing and medical records from the emergency department and hospital wards, we assessed whether or not they developed any other soft tissue infections (excluding a recurrence) after or before the index one. Results: Among 1023 index episodes of soft tissue infections, 670 (65%) were caused by S. aureus, of which 47 were caused by methicillin-resistant strains (30 healthcare-associated and 17 community-acquired). The patients’ median age was 51 years and 334 (34%) were immune-compromised. The median time span between the patient’s first and last consultation (for any reason) in our hospital was 21.4 years (interquartile range, 10-30 years). In addition to their index infection, 124 patients (12%) developed a new nosocomial or community-acquired soft tissue infection. Among the index cases with an S. aureus infection, 92 (14%) had another soft tissue infection, compared to 32 (9%) who had a non-staphylococcal index infection (Pearson-x2-test; p = 0.03). Similarly, patients with an index S. aureus infection, compared to those with a non-S. aureus infection, had a higher rate of another soft tissue infection caused by S. aureus (x2-test; p < 0.01). In multivariate analysis, an index infection due to S. aureus shows a high association to further S. aureus soft tissue infections (logistic regression; odds ratio 2.5, 95% confidence interval 1.4-4.6). Conclusion: Among adult patients hospitalised for a soft tissue infection, those infected with S. aureus (compared with other pathogens) may be at higher risk of a subsequent soft tissue infection, particularly with S. aureus. © 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Keywords: Soft tissue infections epidemiology Staphylococcus aureus new episodes

Introduction $

All authors declare no financial support, grants, financial interests or consultancy that could lead to conflicts of interest. The information has been presented in part at the 6th Oxford Bone and Joint Infection Conference (OBIC), September 2016, Oxford, United Kingdom, and the Swiss Annual Meeting of Infectious Diseases, September 2016, Montreux, Switzerland. * Corresponding author at: Geneva University Hospitals and Faculty of Medicine 4, rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland. Tel: +41 22 372 9828, Fax: +41 22 372 3987. E-mail address: [email protected] (I. Uçkay).

Staphylococcus aureus is the most common cause of skin and soft tissue infections. Carriage of S. aureus in the anterior nares or elsewhere, which is found in 20% to 30% of all humans (Sollid et al., 2014; Brown et al., 2014), is an established risk factor for developing a surgical site infection with this organism (Bertrand et al., 2010; Uçkay et al., 2013; van Rijen et al., 2012). There are no published data on whether or not long-term S. aureus carriage increases the risk of subsequent infection S. aureus other than in

http://dx.doi.org/10.1016/j.ijid.2017.05.002 1201-9712/© 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

C. Bouvet et al. / International Journal of Infectious Diseases 60 (2017) 44–48

the perioperative setting or with the unusual entity of recurrent furunculosis (Sollid et al., 2014; Tzermpos et al., 2013). Specifically, it is unknown if a patient who has a soft tissue infection caused by S. aureus (as opposed to another pathogen) is at greater risk for another soft tissue infection (caused by S. aureus or another pathogen) during his or her lifetime. To address this issue, we conducted a single-center cohort study of all patients hopitalised for a soft tissue infection on our orthopaedic ward. Our main objective was to investigate how many developed another soft tissue infection that requires inpatient or outpatient treatment during their lifetime. In contrast, we did not investigate the outcome of these soft tissue infections, which we already published (Reber et al., 2012; Perez et al., 2010; Chargui et al., 2014; Müller et al., 2015; Uçkay et al., 2015). Methods Geneva University Hospitals are the only public hospital in Geneva Canton and some parts of neighboring France. The covered area has an estimated population of 600,000 habitants. The prevalence of community-acquired methicillin-resistant S. aureus (MRSA) is lower than 1% in our region (Longtin et al., 2009). Data sampling We performed a retrospective single-center, mixed cohort study of adult patients with healthcare and community-acquired soft tissue infections who were treated with surgery as part of their management. We noted the date, the microbiological results, patients’ sex and age, and the anatomic localisation of each of these infections. Additional variables were the origin of these infections, the antibiotic susceptibility pattern of the S. aureus isolates, the profession of the patients, and their immune status. The database stems from the hospital’s clinical pathway for diabetic foot infections, the Orthopedic Infectious Diseases consultations and different Orthopaedic Infection Cohorts (Uçkay et al., 2009a) as well as databases from several ongoing studies (septic bursitis, three studies regarding diabetic foot infections) or past investigations (soft tissue abscesses, phlegmonas of the hand) (Reber et al., 2012; Perez et al., 2010; Chargui et al., 2014; Müller et al., 2015; Uçkay et al., 2015). For roughly 40% of these studies, we consulted the hospital’s coding office, while approximately 60% of case findings originated from ongoing studies. For each patient with a soft tissue infection, we recorded when they were first seen in our hospital (which has been electronically recorded since 1990) and their last visit as of 29 February 2016. This time span during which the patient was followed up in our hospital served as a surrogate for the individual observation period. Study definitions and criteria We only enrolled patients in this study who had a soft tissue infection, which we defined as the presence of intraoperative pus, together with other symptoms (new onset of fever or local pain, warmth, redness or discharge). In seeking evidence of subsequent soft tissue infections after the index case, we excluded recurrent infection episodes, recurrent furunculosis (Sollid et al., 2014; Tzermpos et al., 2013), implant-related infections, and osteoarticular infections (Ferry et al., 2010; Post et al., 2014). A recurrence was defined has the clinical re-apparition of the same infection by the same pathogen at the same anatomical place due to failure of initial therapy. Subsequent soft tissue infections were new infections at any body site, any pathogen, at any time or reason and not due to failure of initial therapy. The reason for the exclusion of recurrent episodes was avoiding “recurrence biases”, because in our epidemiologic analysis, microbiological recurrences

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due to the same pathogens belonged to the same episode that was not healed, and were not considered as new episodes, which is a different situation. We defined a patient as being chronically immune-compromised if they had any one of the following conditions: diabetes mellitus, solid organ or bone marrow transplants, untreated HIV disease, chronic immune-suppressive medication, active cancer, cirrhosis of CHILD class C, renal dialysis, or splenectomy. Transient immune suppression such as polytrauma, sepsis, agranulocytosis without hematologic malignancy, limited steroid medication, cancer in remission, denutrition or advanced age were not counted as chronic immune suppression. A healthcare-associated infection was defined as due to an invasive medical or nursing procedure within the last 30 days prior to the onset of infection. Autoinjections or traumatic wounds within the hospital were not regarded as healthcare-associated. Microbiological analyses We processed all microbiologic specimens according to CLSI (Clinical and Laboratory Standard’s Institute) recommendations (Performance Standards for Antimicrobial Susceptibility Testing, 2007), before switching to EUCAST criteria (European Committee on Antimicrobial Susceptibility Testing) in 2014 (European Committee on Antimicrobial Susceptibility Testing, 2014). In our hospital, we keep only pathogens of bacteremia. Due to the retrospective and composite nature of our database, we lack typisation data comparing the S. aureus between subsequent and index episodes. As a surrogate we assessed differences in the antibiotic susceptibility testing of the different S. aureus isolates. Our laboratory routinely tested all clinical S. aureus isolates for penicillin, flucloxacillin, cefuroxime, ciprofloxacin, clindamycin, erythromycin, fusidic acid, co-trimoxazole, tetracycline, and rifampicin. Statistical analyses For group comparisons we used the Pearson x2 test, the Fisher exact test or the Wilcoxon rank sum test. An unmatched logistic regression analysis with the outcome “subsequent S. aureus soft tissue infection” adjusted for the case-mix. We included 8 to 10 predictor variables per outcome event and checked key variables for collinearity and for interaction (by Mantel-Haenszel estimates and interaction terms). We considered p values 0.05 as significant, and used STATATM software (9.0; College Station, Texas, USA). Results We found a total of 1023 index episodes of soft tissue infection without variation in the rate of index cases over the study period, or detected outbreak situations. The median age of enrolled patients was 51 years and 334 (34%) were chronically immunecompromised. Twenty-one patients were known intravenous drug abusers and nine indicated their profession as healthcare workers in close contact of somatic patients. Almost all infections were associated to abscesses of various diameters (948/1023; 93%), including 401 septic bursitis cases. There were 27 necrotizing fasciitis and 48 solely phlegmonous infections requiring surgical intervention. Only a minority of episodes (48/1023; 5%) were clearly healthcare-associated. Microbiology Among the index episodes of soft tissue infections, 670 (65%) were caused by S. aureus, of which 36 were due to healthcare-

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associated and 18 due to community-acquired MRSA. S. aureus was the biggest group of pathogens. Streptococcus sp. was the second group in terms of numbers (n = 176, of which 59 cases were caused by S. pyogenes), followed by gram-negative rods (n = 175, of which 64 episodes were due to non-fermenting rods). Pseudomonas sp. accounted for 35 cases. Less frequent isolated organisms were skin commensals such as coagulase-negative staphylococci or corynebacteria (n = 89), enterococci (n = 31), and obligate anaerobes (n = 27). Overall, we witnessed 69 different microbiological findings. Table 1 compares clinical variables in patients with a soft tissue infection caused by S. aureus versus other organisms.

Table 2 Univariate and multivariate logistic regression analysis assessing epidemiologic associations of an initial index case of S. aureus soft tissue infection with subsequent soft tissue infections due to S. aureus.

Subsequent soft tissue infections The median time span between the patient’s first medical encounter (for any reason) in our center and the last was 21.4 years (interquartile range, 10-30 years). Within this observation period, 124 patients (12%) of those with an index soft tissue infection yielded another nosocomial or community-acquired soft-tissue infection. Among the index cases, those who had an infection caused by S. aureus, 92 (of 670, 14%) had another soft tissue infection, compared to 32 (of 353, 9%) who had a nonstaphylococcal pathogen (Pearson-x2-test; p = 0.03). Similarly, patients whose index infection was caused by S. aureus, compared to a non-S. aureus pathogen, had a higher rate of other soft tissue infections due to S. aureus (70/86 vs. 16/86; Pearson-x2-test; p < 0.01). Among all 70 episodes with subsequent S. aureus infections, 37 (37/70; 53%) showed no difference in the antibiotic susceptibility patterns between the episodes. In contrast, subsequent isolates switched between MRSA and methicillin-susceptible S. aureus (MSSA) in 9 cases. Among subsequent episodes of MSSA, we witnessed susceptibility differences in three antibiotics (n = 4), in two antibiotics (n = 11), and in 1 antibiotic (n = 10). Adjusting for case-mix An unmatched logistic regression analysis with the outcome parameter “subsequent S. aureus soft tissue infection” adjusted for the case-mix. In the final model, an index infection due to S. aureus showed a high association to further S. aureus soft tissue infections (odds ratio 2.5, 95% confidence interval 1.4-4.6). S. aureus was not the only significant parameter. Many known clinical variables associated with infections in general, such as immune suppression, diabetes mellitus, septic bursitis, and especially known intravenous drug abuse, were prominent associations with subsequent staphylococcal infection (Table 2). Of note, the goodness-of-fit and the Receiver-Operating Curve (ROC) values were insignificant and

n = 1023

Univariate analysis

Multivariate analysis

Female sex Age (continuous variable) Septic bursitis Immune suppressiona – diabetes mellitus Polymicrobial infection Prior S. aureus infection – prior MRSA infection – prior CA-MRSA infection Healthcare-associated infections Known intravenous drug abuse

1.1, 0.7-1.7 1.0, 1.0-1.0 0.2, 0.1-0.3 5.2, 3.4-7.2 6.8, 4.2-10.8 1.6, 1.1-2.5 1.6, 1.1-2.4 4.1, 2.2-7.4 1.5, 0.4-5.1 8.9, 5.0-16.0 16.2, 6.4-41.0

n.d. n.d n.d. n.d. 7.2, 4.4-11.8 1.2, 0.7-2.2 2.5, 1.4-4.6 n.d. 1.3, 0.3-6.5 5.5, 2.6-11.5 7.2, 2.3-22.3

Results expressed as odds ratios with 95% confidence intervals. Significant results are displayed in bold and italic. n.d. = not done. MRSA = methicillin-resistant S. aureus; CA-MRSA = Community-acquired MRSA. a Renal dialysis, cirrhosis Child class C, diabetes mellitus, active malignancy, splenectomy.

0.81, respectively; highlighting a more than acceptable accuracy of our final model. Discussion In this retrospective, single-center mixed cohort study of 1023 adult patients with soft tissue infections without bone, joint or implant involvement, another soft tissue infection more often occurred in those who had had a soft tissue infection caused by S. aureus compared to a non-staphylococcal infection. Prior or subsequent soft tissue infections were highly likely to be again caused by S. aureus, which was equally confirmed in multivariate analysis adjusting for the case-mix. Even if there were also other well-known associations for general infection such as diabetes mellitus (Uçkay et al., 2015) or intravenous drug abuse, our findings suggest that carriage of S. aureus at any body site may not only be a risk factor for surgical site infection (Uçkay et al., 2013), but may also be an independent risk factor for future staphylococcal soft tissue infections. Previous studies of risk of infection in patients with staphylococcal colonization have mostly focused on immediate surgical site infections, not long-term risk. In one study, only a minority of patients with prior culture-proven S. aureus skin infection remained colonized with the same organism after treatment in the convalescent phase, and only a quarter of their household contacts were colonized with the index infecting strain (Brown et al., 2014; Miller et al., 2012). Small studies of patients with infections caused by methicillin-susceptible S. aureus, MRSA

Table 1 Clinical variables found in patients with soft tissue infection caused by Staphylococcus aureus compared to other pathogens.

n = 1023

S. aureus n = 670

p value*

Other pathogens n = 353

Female sex Median age ( 95% confidence intervals) Septic bursitis Healthcare-associated infection Bacteremia Intravenous drug abuse Professional healthcare workers Chronic immune suppressiona – Diabetes mellitus Another soft tissue infectionb

171 (26%) 51 years () 333 (50%) 34 (5%) 40 (6%) 14 (2%) 7 (1%) 227 (39%) 142 (22%) 92 (14%)

n.s. n.s. 0.01 n.s. n.s. n.s. n.s. n.s. n.s. 0.03

106 (30%) 52 years () 68 (19%) 18 (6%) 14 (4%) 7 (2%) 2 (1%) 117 (33%) 69 (20%) 32 (9%)

n.s. = not significant (p > 0.05). * Only statistically significant p values, i.e., 0.05 (two-tailed), are displayed. a Renal dialysis, cirrhosis Child class C, diabetes mellitus, active malignancy, splenectomy. b After and before the index case, at any body site.


(Zenelaj et al., 2014) or streptococci (Lebowitz et al., 2015) failed to show a difference in remission incidences on the long term. The duration of clinical follow-up in most publications regarding soft tissue or musculoskeletal infections has been no more than 2 years, except in some studies of arthroplasty infections. Thus, our two decades of follow-up provide an unusual view of the long-term outcome of soft tissue infections. S. aureus is the most frequently isolated pathogen in skin, soft tissue and musculoskeletal infections. Skin and mucosal carriage of S. aureus, which is found in 20-30% of people (Sollid et al., 2014; Brown et al., 2014), increases the risk of such infections. Skin carriage still may persist in 15% of patients despite treatment based on sophisticated algorithms (Tzermpos et al., 2013) using decolonisation protocols (Longtin et al., 2009). Interestingly, this S. aureus carriage is not necessarily monoclonal, as different strains can coexist (Zürcher-Pfund et al., 2013; Betz et al., 2015; Landelle et al., 2014) and can also be found with coagulase-negative staphylococci. We do not yet know how to predict which of these colonizing organisms may cause future infection. For example, in cases of trauma or surgery, evidence of healthcare-associated MRSA carriage does not predict the likelihood or nature of future skin and soft tissue (Chargui et al., 2014) or implant-related infections (Uçkay et al., 2009b). It is noteworthy that infections at various sites, such as arthroplasties, are more difficult to eradicate when they are caused by S. aureus compared even to other virulent gram-positive pathogens, such as streptococci (Zürcher-Pfund et al., 2013; Betz et al., 2015). There are several possible explanations for the tenacity of S. aureus as a colonizer and pathogen, even in absence of foreign material (Brown et al., 2014; Ferry et al., 2010). Mechanisms that help the organism evade the host’s acquired and innate defenses such as antimicrobial peptides (Sollid et al., 2014; Otto, 2010) certainly play a role. Microbiota considerations (Brown et al., 2014), including gene products that protect against reactive oxygen and desiccation (Sollid et al., 2014), are emerging as another explanation for long-term carriage. S. aureus’ arsenal of defenses against elimination includes modification of clumping factors, cathelicidin, defensins, carbohydrate modifications, mannose-binding lectins, and other products (Sollid et al., 2014). Transient or persistent S. aureus colonization induces specific host immune responses. Humoral responses have been the most studied, and little is known of cellular responses (Brown et al., 2014; Otto, 2010). However, even if human antibody response to S. aureus bacteraemia differs between known chronic carriers and non-carriers, these antibodies do not appear to be able to prevent future infections (Kolata et al., 2011). Despite years of effort, an effective vaccine against staphylococcal infections remains elusive (Brown et al., 2014). Our study has several limitations, the most important of which are that it is a retrospective single-center study, primarily targeting patients hospitalised for combined surgical and medical therapy of a soft tissue infection, which limits the generalizability of our findings. For example, we may not have had access to records of patients undergoing outpatient treatment of a small skin abscess by their general practitioner or those using private insurance. Furthermore, in this study we excluded implant-related, osteoarticular infections and recurrent infections, which may be associated with various concomitant soft tissue extension. We may also have missed patients who were treated elsewhere during their lifetime, especially for those only staying a few years in Geneva. However, because our center has been the largest in the area and the only public hospital for decades, we think this is likely to be only a small bias. We also lacked information on the specific type of our pathogenic strains, their genotypic typisation and could not investigate specific skin diseases known to be associated with staphylococcal infections, e.g., atopic dermatitis, psoriasis. Additionally, we have no data on the duration of individual S. aureus

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colonisation in the study group. A screening for the presence of methicillin-susceptible strains is usually performed only in the context of a prospective scientific study (Landelle et al., 2014). Finally, in our study, the composite database stems from different past and present retrospective and/or prospective studies (Reber et al., 2012; Perez et al., 2010; Chargui et al., 2014; Müller et al., 2015; Uçkay et al., 2015). The searching strategy for cases was thus different among the individual studies. On the other hand, we also asked the hospital’s coding office and/or kept prospective cohorts for every one of these studies. Moreover, our study principally concerns operated cases that are easy to be identified and our Orthopaedic Service employs Infectious Diseases physicians who note every important consultation. Therefore, we think that our case finding strategy was adequate. In conclusion, adult patients previously hospitalized and operated for a moderate to severe soft tissue infection caused by S. aureus, compared to non-staphylococcal infections, may be at higher risk of a future soft tissue infection, particularly one with S. aureus. In centers or services where there is no program for screening and decolonisation of S. aureus body carriage before elective orthopaedic surgery (Uçkay et al., 2013), it may be appropriate for patients with a history of a previous soft tissue infection to undergo screening for S. aureus, even if a prior a S. aureus infection is not the only variable associated with the risk of subsequent infections. Ethics statement This study is in line with several ongoing studies approved by local ethics Committee. Conflict of interest There was no funding for the preparation of this manuscript. BAL has served as a consultant to KCI/Acelity, Innocoll, Dipexium. IU has received research funding from Innocoll. However, the content of this paper has no relation with the consultancy of any of the authors. Funding There was no funding for this review. Acknowledgements We thank the teams of the Laboratory of Bacteriology and the Orthopaedic Service for their support. References Bertrand X, Slekovec C, Talon D. Use of mupirocin-chlorhexidine treatment to prevent Staphylococcus aureus surgical-site infections. Future Microbiol 2010;5:701–3. Betz M, Abrassart S, Vaudaux P, Gjika E, Schindler M, Billières J, et al. Increased risk of treatment failure in hip prostheses infected with Staphylococcus aureus treated with debridement, antibiotics and implant retention compared to Streptococcus. Int Orthop 2015;39:397–401. Brown AF, Leech JM, Rogers TR, McLoughlin RM. Staphylococcus aureus colonization: modulation of host immune response and impact on human vaccine design. Frontiers Immunol 2014;4:1–6. Chargui M, Uçkay I, Suvà D, Christofilopoulos P, Lomessy A, Pittet D. Deep soft tissue infections. Rev Med Suisse 2014;10:920–4. European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters, Version 4. 2014. Ferry T, Uçkay I, Vaudaux P, François P, Schrenzel J, Harbarth S, et al. Risk factors for treatment failure in orthopedic device-related methicillin-resistant Staphylococcus aureus infection. Eur J Clin Microbiol Infect Dis 2010;29:171–80.

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