Accepted Manuscript Skin and soft tissue infections in intercontinental travellers and the import of multiresistant Staphylococcus aureus to Europe Dennis Nurjadi, Barbara Friedrich-Jänicke, Johannes Schäfer, Perry JJ. Van Genderen, Abraham Goorhuis, Alice Perignon, Andreas Neumayr, Andreas Mueller, Anu Kantele, Mirjam Schunk, Joaquim Gascon, August Stich, Christoph Hatz, Eric Caumes, Martin P. Grobusch, Ralf Fleck, Frank P. Mockenhaupt, Philipp Zanger, MD MSc PII:
S1198-743X(15)00221-9
DOI:
10.1016/j.cmi.2015.01.016
Reference:
CMI 158
To appear in:
Clinical Microbiology and Infection
Received Date: 16 November 2014 Revised Date:
28 December 2014
Accepted Date: 16 January 2015
Please cite this article as: Nurjadi D, Friedrich-Jänicke B, Schäfer J, Van Genderen PJ, Goorhuis A, Perignon A, Neumayr A, Mueller A, Kantele A, Schunk M, Gascon J, Stich A, Hatz C, Caumes E, Grobusch MP, Fleck R, Mockenhaupt FP, Zanger P, Skin and soft tissue infections in intercontinental travellers and the import of multi-resistant Staphylococcus aureus to Europe, Clinical Microbiology and Infection (2015), doi: 10.1016/j.cmi.2015.01.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Skin and soft tissue infections in intercontinental travellers and the import of multi-
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resistant Staphylococcus aureus to Europe
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Dennis Nurjadi1, Barbara Friedrich-Jänicke2, Johannes Schäfer3, Perry JJ Van Genderen4,
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Abraham Goorhuis5, Alice Perignon6, Andreas Neumayr7,8, Andreas Mueller9, Anu Kantele10,
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Mirjam Schunk11, Joaquim Gascon12, August Stich9, Christoph Hatz7,8,13, Eric Caumes6,
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Martin P. Grobusch5, Ralf Fleck3, Frank P. Mockenhaupt2, Philipp Zanger14,15
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Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg
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University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
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Berlin, Spandauer Damm 130, 14050 Berlin, Germany
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Germany
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The Netherlands
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Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, The
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Netherlands
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boulevard de l'Hôpital, 75651 Paris cedex 13, France
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Switzerland
Institute of Tropical Medicine and International Health, Charité – Universitätsmedizin
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Tropenklinik, Paul-Lechler-Krankenhaus, Paul-Lechler-Straße 24, 72076 Tübingen,
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Instituut voor Tropische Ziekten, Havenziekenhuis, Haringvliet 72, 3011 TG Rotterdam,
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Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases,
Service de Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitié-Salpêtrière, 47-83
Swiss Tropical and Public Health Institute, Socinstraße 57, P.O. Box CH-4002, Basel,
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University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
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Missionsärztliche Klinik, Salvatorstraße 7, 97074 Würzburg, Germany
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Hospital, PO Box 348, 00029 HUS Helsinki, Finland
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Leopoldstraße 5, 80802 München, Germany
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Universitat de Barcelona, c/ Rosselló, 132, 08036 Barcelona, Spain
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84, CH-8001 Zürich, Switzerland
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Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
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Tübingen, Germany
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Division of Infectious Diseases, Department of Medicine, Helsinki University Central
Abteilung für Infektions- und Tropenmedizin der Ludwig-Maximilians-Universität,
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ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic –
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Epidemiology, Biostatistics and Prevention Institute, University of Zürich, Hirschengraben
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Institute of Public Health, Unit of Epidemiology and Biostatistics, Heidelberg University
Institute of Tropical Medicine, Eberhard Karls Universität, Wilhelmstraße 27, 72074
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Key words: travel medicine; sentinel surveillance; Panton-Valentine leukocidin; Methicillin-
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Resistant Staphylococcus aureus; staphylococcal skin infections; communicable diseases,
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emerging; trimethoprim-sulfamethoxazole combination; drug resistance, bacterial; risk
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factors; molecular epidemiology
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Running title: Travel & Import of S. aureus
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Corresponding author: Philipp Zanger, MD MSc, Institute of Public Health, University
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Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany, e-mail:
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[email protected], phone: +49 6221 56 8780, fax +49 6221 56 5948
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Part of this work has been presented on 12th May, 2014 at the 24th European Congress of
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Clinical Microbiology and Infectious Diseases in Barcelona, Spain.
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S.aureus is emerging globally. Treatment of infections is complicated by increasing antibiotic
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resistance. We collected clinical data and swabs of returnees with skin and soft tissue
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infections (SSTI) at thirteen travel-clinics in Europe (www.staphtrav.eu). Sixty-two percent
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(196/318) SSTI patients had S.aureus positive lesions of which almost two thirds (122/196)
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were Panton-Valentine leukocidin (PVL) positive. PVL was associated with disease severity,
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including hospitalization for SSTI (OR 5.2, 95% CI 1.5-18.2). In returnees with SSTI, longer
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travel and more intense population contact were risk factors for nasal colonization with PVL-
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positive S.aureus. Imported S.aureus frequently proved resistant to trimethoprim-
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sulfamethoxazole (21%), erythromycin (21%), tetracycline (20%), ciprofloxacin (13%),
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methicillin (12%), and clindamycin (8%). Place of exposure was significantly (P 30 days after return, n=8; non-traveling secondary cases, n=5) or clustering (SSTI
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in co-travellers, n=13), leaving 318 independent cases for the main analysis (table 1).
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Of these 318 submissions, 196 (62%) were positive for S.aureus, 122 of 196
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staphylococci contained PVL encoding genes, 23 of 196 staphylococci were MRSA, and 22
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of 23 MRSA were PVL-positive (PVL+). Cases had a median age of 31 years (inter quartile
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range 24 to 48) and were predominantly male (59%). Predominating travel destinations were
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Africa (n=102) and Southeast Asia (n=92). Median travel duration was 28 days (inter quartile
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range 17 to 91). Primary purpose of travel was leisure (60%), followed by voluntary aid work
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(21%); visiting friends and relatives (VFR) (10%); business (5%); and education (4%).
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Ninety-nine (31%) of 318 cases with complete information reported recurrent disease, 85 of
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317 (27%) surgical drainage, 50 of 316 (16%) SSTI in close contacts, 257 of 317 (81%) use
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of antibiotics for the treatment of SSTI, and 39 of 313 (12%) hospitalization due to travel-
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associated SSTI (table 1).
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Of 196 imported S.aureus, five were not spa typeable; one spa type was not done. The
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remaining 190 isolates belonged to 96 spa types and 16 spa clonal complexes: CC24/304,
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n=24; CC21/318, n=24; CC2, n=16; CC84, n=13; CC355, n=13; CC272, n=12; CC127, n=12;
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CC345, n=7; CC34, n=5; CC15, n=3; CC131, n=3; 5 clusters with no founder, n=11. Forty-
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two strains (27% of all spa types) were singletons and 5 isolates were excluded for short
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repeats. The genotypic characteristics of imported S.aureus by methicillin-resistance, PVL
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status, and travel destination are summarized in supplementary figure 1 and the tables 2 and 3.
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S.aureus positive SSTI Among all patients with travel-associated SSTI (table 1, left column), returnees with
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S.aureus positive lesions tended to be younger than patients with non-staphylococcal SSTI;
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also they were somewhat less likely to have visited South Asia, and were more often
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humanitarian mission travellers or VFRs. Clinically, S.aureus positive lesions were found to
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be more likely to present as deep lesions that require surgical drainage and to cause recurrent
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disease, yet less likely to present as ulcers, and to be preceded by insect bites or other minor
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trauma. The proportion of S.aureus positive among all lesions did not differ with sex, travel
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duration, antibiotic treatment, inpatient treatment, anatomic location of lesion, or report of
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contact persons being ill with SSTI.
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PVL-positive SSTI
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Among S.aureus positive SSTI, PVL was more often observed in isolates imported
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from Africa and Latin America and less often in those from the Pacific region and Southeast
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Asia (table 1, central column). PVL-positive (PVL+) compared to PVL-negative (PVL-)
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S.aureus was strongly associated with abscess formation, recurrent disease, surgical drainage,
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and lesions above the waistline. Patients with PVL+ lesions were more likely to require
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inpatient treatment when compared to travellers with SSTI caused by PVL- S.aureus.
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MRSA SSTI
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Methicillin-resistant S.aureus accounted for 7% (23/318) of all travel-associated SSTI and for
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12% (23/196) of all S.aureus positive cases. Travel to Latin America and for humanitarian
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purposes or VFR were independent risk factors for acquisition of MRSA (crude ORs, table 1,
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right column; adjusted ORLatin America 5.47, 2.09-24.33, P=0.001; adjusted ORVFR 2.84, 1.13-
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7.15, P=0.03). Compared to travellers with MSSA, cases with MRSA-related SSTI were more
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likely to report skin infections in contact persons (table 1, right column).
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Seven of 23 independent MRSA imports (30%) were PVL+ and spa type t008: 4 of 7
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were SCCmec type IVa, arcA positive and 3 of 7 were SCCmec IVc, arcA negative,
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consistent with the USA300-0114 and USA300-Latin American Variant lineages, respectively
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[18]. Five (71%) of these seven potential USA300 were imported from Latin America (table
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3). Other CA-MRSA imported from The Philippines and India revealed spa genotypes that
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are known to be associated with the Southwest Pacific (spa t019) [19] and the Bengal Bay
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(spa t657) [20] clones (table 3).
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Nasal carriage
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Nasal swabs were available for 310 of the 318 cases analysed. Of these, 39%
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(122/310) were nasal carriers of S.aureus, 17% (53/310) of PVL+ S.aureus, and 6% (18/310)
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of MRSA. Table 4 summarizes risk factors of various types of S.aureus nasal carriage and
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their association with clinical characteristics of SSTI in travellers.
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Antimicrobial (multi-)resistance
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Nearly half of all imported S.aureus (89/196) were resistant to at least one compound
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currently used for the empiric treatment of SSTI (i.e. isoxazolyl-penicillins, trimethoprim-
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sulfamethoxazole, tetracycline, clindamycin), 49% (96/196) to at least one non-beta-lactam,
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and 54% (106/196) to at least one of the compounds tested in this study. Frequency and
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patterns of antimicrobial resistance in imported S.aureus varied largely by place of exposure
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abroad (table 2, supplementary figure 2).
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Resistance to two, three, four, or seven of the tested compounds simultaneously was
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observed in 16% (32/196), 8% (15/196), 3% (6/196), and 0.5% (1/196) of imported isolate(s),
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respectively. Multi-resistance to two or more of any of the tested antibiotics was associated
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with travel to South Asia, various clinical characteristics of severe SSTI, PVL-positivity,
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to two, three, four, or seven non-beta-lactam antibiotics simultaneously was found in 13%
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(26/196), 8% (16/196), 1.5% (3/196), and 0.5% (1/196) of isolate(s) and was associated with
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travel to South Asia, various clinical characteristics of severe SSTI, PVL-positivity, and the
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spa types t355 and t021, but not with concomitant methicillin resistance or spa type t008
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(table 5, central column). To assess, whether clonality confounded the effect of exposure in
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South Asia was on multi-resistance to non-beta-lactams in S.aureus, we fitted a multivariable
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logistic regression model adjusting for those spa types that were associated with both, multi-
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resistance and South Asia. After adjusting for some positive confounding, exposure in South
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Asia remained a strong and independent predictor of multi-resistance to non-beta-lactams in
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imported S.aureus (table 5, right column).
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Choosing randomly from antibiotic compounds recommended for the empiric
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treatment of skin and soft tissue infections (i.e. isoxazolyl-penicillins, trimethoprim-
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sulfamethoxazole, tetracycline, clindamycin) [7-9], there was an overall 15% chance to treat
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any of the returnees included in this study ineffectively (table 2).
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Discussion In this European multi-centre study, we found that antimicrobial (multi-)resistance in
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imported S.aureus is common and its geographic distribution globally heterogeneous. We
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estimated that overall 12% of all S.aureus causing skin and soft tissue infections (SSTI) in
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intercontinental travellers is MRSA and observed that SSTI in returnees from Latin America
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promotes the spread of the highly virulent USA300 CA-MRSA lineage. This finding is in line
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with reports on the expansion of USA300 from the U.S. into Latin America [21, 22] and from
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there to Europe [23]. Besides, we provide evidence for a less prominent import of the
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pandemic South West Pacific and the emerging Bengal Bay CA-MRSA clones to Europe by
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travellers returning from the Philippines and India.
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We show that resistance to non-beta-lactam antibiotics in imported S.aureus is
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common, amounting to 50% of all isolates, depending on destination and antimicrobial class
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tested. Besides, we demonstrate that about one fourth of S.aureus causing SSTI abroad are
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multi-resistant and that travel to South Asia independently predicts multi-resistance to non-
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beta-lactams in these bacteria. Taken together, these findings challenge the unguided use of
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trimethoprim-sulfamethoxazole, tetracycline derivatives, and clindamycin against presumed
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methicillin-resistant S.aureus infections in returning travellers [7-9] and support the concept
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of regionally adapted treatment recommendations [24-26]. Furthermore, our observations
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allow assuming a regionally high prevalence of resistance to non-beta-lactam antibiotics in
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parts of Africa and Asia. This extrapolation is supported by our recent finding of similar
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resistance gene content in S.aureus collected from native Africans and travellers returning
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from that continent [27, 28]. Along this line, the presented data suggest that the use of
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tetracycline and trimethoprim-sulfamethoxazole as region-specific empiric antibiotic
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treatment of CA-MRSA SSTIs in Africa and Asia is limited considering that a substantial
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proportion of suspected cases will ultimately be caused by MSSA due to a lack of reliable
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predictors of methicillin resistance. Hence, future recommendations on the empiric antibiotic
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treatment of community-associated SSTI should incorporate resistance data gathered in
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MSSA and MRSA isolates alike. Following this rationale, we would like to challenge a recent
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review that looked at antibiotic resistance patterns in community MRSA globally and
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concluded that trimethoprim-sulfamethoxazole is an effective “region - specific empiric
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antibiotic treatment [in] Asia [if] community MRSA SSTI is considered likely” [24].
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Of note, we observed that those S.aureus lineages that were strongly associated with
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multi-resistance to non-beta-lactam antibiotics (spa t021 and t355, table 5) were also
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commonly PVL-positive (91% and 100%, supplementary figure 1). This is alarming since
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PVL+ MSSA is thought to represent the reservoir from which at least some of the successful
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epidemic CA-MRSA clones emerged through horizontal genetic exchange [29-33]. Hence,
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the relative abundance of multi-resistant PVL+ MSSA among imported staphylococci could
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herald the evolution of multi-resistant MRSA lineages in the community. This is in contrast to
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current practice in research, surveillance, and control of multi-resistant S.aureus that largely
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neglects antibiotic resistance in MSSA and tends to focus on methicillin resistant lineages
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instead. Better knowledge on the accumulation of multi-resistance in MSSA as presented here
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is needed to contain potential methicillin-sensitive precursors of multi-resistant community-
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associated MRSA.
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Nearly two thirds of S.aureus causing SSTI in intercontinental travellers were found to
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be PVL-positive and the lukS/lukF genes were strong predictors of SSTI associated morbidity.
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In addition to confirming its known associations with recurrent and deep-seated abscesses [6,
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23], we were able to demonstrate that SSTIs caused by PVL+ S.aureus more likely lead to
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hospitalization. According to a recent review [23], this has not been shown in an adult
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population before. Taking into account the diverse genetic backgrounds of S.aureus in our
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study, this finding supports the concept that PVL has indeed an effect on disease outcome
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rather than being merely linked with other virulence factors – a common shortcoming of
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research into infections from geographically confined populations and in clonally related
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S.aureus [23]. Nasal carriage of PVL+ S.aureus proved to be a risk factor for recurrent abscesses and
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was associated with SSTI lesions being located above the waistline. These observations
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suggest that PVL+ strains, compared to PVL- staphylococci, are more likely to cause manifest
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skin infections when spread from the nose to areas of the body that are within the direct reach
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of the hands. This emphasizes the role of colonized human nares in perpetuating PVL+ SSTI
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and supports empiric nasal decolonization therapy for secondary prevention of recurrent post-
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travel SSTI. Of note, we found longer duration of travel, humanitarian aid work, and visiting
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friends and relatives to be risk factors for nasal carriage of PVL+ S.aureus. This knowledge
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may prove useful when tailoring the content of pre-travel consultations and targeting infection
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prevention measures.
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In summary, the presented findings illustrate that sentinel surveillance of S.aureus
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infecting travellers is an efficient way of providing information on antimicrobial resistance in
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as yet understudied regions, call for the development of regionally stratified guidance on the
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antibiotic management of severe imported S.aureus disease, and put the infected and
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colonized traveller at the centre of interventions against the global spread of multi-resistant
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S.aureus. Our network will continue this surveillance with the aim to detect newly emerging
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clones and monitor trends of antimicrobial resistance in imported S.aureus over time.
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Funding: This work was supported by the Institute of Tropical Medicine, Tübingen, Germany;
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Institute of Public Health, Heidelberg University Hospital, Heidelberg, Germany; Department
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of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital,
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Heidelberg, Germany.
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Acknowledgements:
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(www.istm.org/eurotravnet/main.html) networks in tropical medicine and travel health for
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their support in identifying member sites for the StaphTrav network. Additional members of
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the StaphTrav network who contributed cases (in descending alphabetical order) are:
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Johannes Blum, Basel; Antonia Calvo, Barcelona; Jacob P. Cramer, Hamburg; Julian Gabor,
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Tübingen; Marika Gaile, Tübingen; Heimo Lagler, Wien; Hans-Dieter Nothdurft, München;
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Michael Ramharter, Wien; Thierry Rolling, Hamburg; Günther Slesak, Tübingen; Florian
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Steiner, Berlin, Uwe Ziegler, Würzburg.
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Conflicts: all authors, no conflicts
thank
the
TropNet
(www.tropnet.net)
and
EuroTravNet
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Nurjadi D, Olalekan AO, Layer F, et al. Emergence of trimethoprim resistance gene dfrG in Staphylococcus aureus causing human infection and colonization in sub-Saharan Africa and its import to Europe. J Antimicrob Chemother. 2014.
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Zanger P. Methicillin-Resistant Staphylococcus aureus and intercontinental travel-"bad bugs on the move!". J Travel Med. 2014; 21: 225-227.
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Olalekan AO, Schaumburg F, Nurjadi D, et al. Clonal expansion accounts for an excess of antimicrobial resistance in Staphylococcus aureus colonising HIV-positive individuals in Lagos, Nigeria. Int J Antimicrob Agents. 2012; 40: 268-272.
398 399 400
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Rasigade JP, Laurent F, Lina G, et al. Global distribution and evolution of Panton-Valentine leukocidin-positive methicillin-susceptible Staphylococcus aureus, 1981-2007. J Infect Dis. 2010; 201: 1589-1597.
401 402 403
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Orscheln RC, Hunstad DA, Fritz SA, et al. contribution of genetically restricted, methicillinsusceptible strains to the ongoing epidemic of community-acquired Staphylococcus aureus infections. Clin Infect Dis. 2009; 49: 536-542.
404 405
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Robinson DA, Kearns AM, Holmes A, et al. Re-emergence of early pandemic Staphylococcus aureus as a community-acquired meticillin-resistant clone. Lancet. 2005; 365: 1256-1258.
406 407 408 409
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Mönecke S, Slickers P, Ellington MJ, Kearns AM, Ehricht R. High diversity of PantonValentine leukocidin-positive, methicillin-susceptible isolates of Staphylococcus aureus and implications for the evolution of community-associated methicillin-resistant S. aureus. Clin Microbiol Infect. 2007; 13: 1157-1164.
410 411 412
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Nübel U, Roumagnac P, Feldkamp M, et al. Frequent emergence and limited geographic dispersal of methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci U S A. 2008; 105: 14130-14135.
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Table 1. Characteristics of returning travellers with skin and soft tissue infections All skin and soft tissue infections, n=318 PVL+ OR (95% CI) n=196 (%) Female Age in yearsa Travel characteristics Destinationb Latin America Africa South Asia Southeast Asia Australia/Pacific
77 (39) 31 (23-45)
32 64 32 57 8
(16) (33) (16) (29) (4)
n=122 (%) 52 (43) 35.5 (25-51)
15 38 29 35 3
PVL-
P
0.9 (0.5-1.4) 0.9 (0.8-1.0)
0.6 0.07
(12) (31) (24) (29) (2)
1.4 (0.7-2.7) 1.1 (0.7-1.7) 0.6 (0.4-1.1) 1.0 (0.6-1.7) 1.7 (0.4-6.5)
0.3 0.8 0.1 0.9 0.5
1.0 (0.99-1.02)
0.4
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other
OR (95% CI)
n=122 (%)
n=74 (%)
51 (42) 31 (23-46)
26 (35) 30 (24-44)
25 47 20 27 2
(21) (39) (16) (22) (2)
1.3 (0.7-2.4) 1.0 (0.9-1.2)
SC
S.aureus
S.aureus positive skin and soft tissue infections, n=196
7 17 12 30 6
MRSA
MSSA
n=23 (%)
n=173 (%)
0.4 0.7
11 (48) 28 (22-39)
66 (38) 31 (24-45)
P
OR (95% CI)
22 61 30 49 8
P
1.5 (0.6-3.6) 0.8 (0.6-1.1)
0.4 0.1
(13) (35) (17) (28) (5)
5.3 (2.1-13.5) 0.3 (0.1-1.0) 0.5 (0.1-2.0) 1.3 (0.5-3.4) -
0.001 0.04 0.3 0.5 0.3c
(10) (23) (16) (41) (8)
2.5 (1.0-6.0) 2.1 (1.1-4.0) 1.0 (0.5-2.2) 0.4 (0.2-0.8) 0.2 (0.04-1.0)
0.05 0.03 1.0 0.007 0.05
10 (44) 3 (13) 2 (9) 8 (35) 0 (0)
28.5 (17-116)
28 (19-88)
1.0 (0.99-1.01)
0.5
31 (20-194)
28 (17-100)
1.0 (0.99-1.01)
0.7
61 (50) 13 (11) 47 (39)
48 (65) 4 (5) 22 (30)
0.5 (0.3-1.0) 2.1 (0.7-6.7) 1.5 (0.8-2.7)
0.04 0.2 0.2
10 (43) 0 (0) 13 (57)
99 (57) 17 (10) 56 (32)
0.6 (0.2-1.4) 2.7 (1.1-6.6)
0.2 0.1c 0.03
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Characteristic
28 (17-109)
30 (17-90)
Purposee leisure business / education humanitarian / VFR
109 17 69
(56) (9) (35)
81 12 29
(66) (10) (24)
0.6 (0.4-1.0) 0.9 (0.4-1.9) 1.7 (1.0-2.9)
0.06 0.7 0.03
53 132 10
(27) (67) (5)
57 56 9
(47) (46) (7)
0.4 (0.3-0.7) 2.4 (1.5-3.9) 0.7 (0.3-1.7)
S1198-743X(15)00221-9
DOI:
10.1016/j.cmi.2015.01.016
Reference:
CMI 158
To appear in:
Clinical Microbiology and Infection
Received Date: 16 November 2014 Revised Date:
28 December 2014
Accepted Date: 16 January 2015
Please cite this article as: Nurjadi D, Friedrich-Jänicke B, Schäfer J, Van Genderen PJ, Goorhuis A, Perignon A, Neumayr A, Mueller A, Kantele A, Schunk M, Gascon J, Stich A, Hatz C, Caumes E, Grobusch MP, Fleck R, Mockenhaupt FP, Zanger P, Skin and soft tissue infections in intercontinental travellers and the import of multi-resistant Staphylococcus aureus to Europe, Clinical Microbiology and Infection (2015), doi: 10.1016/j.cmi.2015.01.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Skin and soft tissue infections in intercontinental travellers and the import of multi-
2
resistant Staphylococcus aureus to Europe
3
Dennis Nurjadi1, Barbara Friedrich-Jänicke2, Johannes Schäfer3, Perry JJ Van Genderen4,
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Abraham Goorhuis5, Alice Perignon6, Andreas Neumayr7,8, Andreas Mueller9, Anu Kantele10,
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Mirjam Schunk11, Joaquim Gascon12, August Stich9, Christoph Hatz7,8,13, Eric Caumes6,
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Martin P. Grobusch5, Ralf Fleck3, Frank P. Mockenhaupt2, Philipp Zanger14,15
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8 1
Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg
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University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
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2
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Berlin, Spandauer Damm 130, 14050 Berlin, Germany
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3
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Germany
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4
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The Netherlands
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5
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Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, The
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Netherlands
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6
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boulevard de l'Hôpital, 75651 Paris cedex 13, France
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7
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Switzerland
Institute of Tropical Medicine and International Health, Charité – Universitätsmedizin
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Tropenklinik, Paul-Lechler-Krankenhaus, Paul-Lechler-Straße 24, 72076 Tübingen,
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Instituut voor Tropische Ziekten, Havenziekenhuis, Haringvliet 72, 3011 TG Rotterdam,
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Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases,
Service de Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitié-Salpêtrière, 47-83
Swiss Tropical and Public Health Institute, Socinstraße 57, P.O. Box CH-4002, Basel,
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8
University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
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Missionsärztliche Klinik, Salvatorstraße 7, 97074 Würzburg, Germany
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10
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Hospital, PO Box 348, 00029 HUS Helsinki, Finland
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11
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Leopoldstraße 5, 80802 München, Germany
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12
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Universitat de Barcelona, c/ Rosselló, 132, 08036 Barcelona, Spain
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13
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84, CH-8001 Zürich, Switzerland
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14
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Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
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15
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Tübingen, Germany
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Division of Infectious Diseases, Department of Medicine, Helsinki University Central
Abteilung für Infektions- und Tropenmedizin der Ludwig-Maximilians-Universität,
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ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic –
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Epidemiology, Biostatistics and Prevention Institute, University of Zürich, Hirschengraben
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Institute of Public Health, Unit of Epidemiology and Biostatistics, Heidelberg University
Institute of Tropical Medicine, Eberhard Karls Universität, Wilhelmstraße 27, 72074
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Key words: travel medicine; sentinel surveillance; Panton-Valentine leukocidin; Methicillin-
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Resistant Staphylococcus aureus; staphylococcal skin infections; communicable diseases,
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emerging; trimethoprim-sulfamethoxazole combination; drug resistance, bacterial; risk
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factors; molecular epidemiology
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Running title: Travel & Import of S. aureus
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Word count: 2586 Page 2
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Corresponding author: Philipp Zanger, MD MSc, Institute of Public Health, University
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Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany, e-mail:
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[email protected], phone: +49 6221 56 8780, fax +49 6221 56 5948
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Part of this work has been presented on 12th May, 2014 at the 24th European Congress of
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Clinical Microbiology and Infectious Diseases in Barcelona, Spain.
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S.aureus is emerging globally. Treatment of infections is complicated by increasing antibiotic
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resistance. We collected clinical data and swabs of returnees with skin and soft tissue
57
infections (SSTI) at thirteen travel-clinics in Europe (www.staphtrav.eu). Sixty-two percent
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(196/318) SSTI patients had S.aureus positive lesions of which almost two thirds (122/196)
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were Panton-Valentine leukocidin (PVL) positive. PVL was associated with disease severity,
60
including hospitalization for SSTI (OR 5.2, 95% CI 1.5-18.2). In returnees with SSTI, longer
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travel and more intense population contact were risk factors for nasal colonization with PVL-
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positive S.aureus. Imported S.aureus frequently proved resistant to trimethoprim-
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sulfamethoxazole (21%), erythromycin (21%), tetracycline (20%), ciprofloxacin (13%),
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methicillin (12%), and clindamycin (8%). Place of exposure was significantly (P 30 days after return, n=8; non-traveling secondary cases, n=5) or clustering (SSTI
151
in co-travellers, n=13), leaving 318 independent cases for the main analysis (table 1).
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Of these 318 submissions, 196 (62%) were positive for S.aureus, 122 of 196
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staphylococci contained PVL encoding genes, 23 of 196 staphylococci were MRSA, and 22
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of 23 MRSA were PVL-positive (PVL+). Cases had a median age of 31 years (inter quartile
155
range 24 to 48) and were predominantly male (59%). Predominating travel destinations were
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Africa (n=102) and Southeast Asia (n=92). Median travel duration was 28 days (inter quartile
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range 17 to 91). Primary purpose of travel was leisure (60%), followed by voluntary aid work
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(21%); visiting friends and relatives (VFR) (10%); business (5%); and education (4%).
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Ninety-nine (31%) of 318 cases with complete information reported recurrent disease, 85 of
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317 (27%) surgical drainage, 50 of 316 (16%) SSTI in close contacts, 257 of 317 (81%) use
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of antibiotics for the treatment of SSTI, and 39 of 313 (12%) hospitalization due to travel-
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associated SSTI (table 1).
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Of 196 imported S.aureus, five were not spa typeable; one spa type was not done. The
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remaining 190 isolates belonged to 96 spa types and 16 spa clonal complexes: CC24/304,
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n=24; CC21/318, n=24; CC2, n=16; CC84, n=13; CC355, n=13; CC272, n=12; CC127, n=12;
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CC345, n=7; CC34, n=5; CC15, n=3; CC131, n=3; 5 clusters with no founder, n=11. Forty-
167
two strains (27% of all spa types) were singletons and 5 isolates were excluded for short
168
repeats. The genotypic characteristics of imported S.aureus by methicillin-resistance, PVL
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status, and travel destination are summarized in supplementary figure 1 and the tables 2 and 3.
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S.aureus positive SSTI Among all patients with travel-associated SSTI (table 1, left column), returnees with
172
S.aureus positive lesions tended to be younger than patients with non-staphylococcal SSTI;
173
also they were somewhat less likely to have visited South Asia, and were more often
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humanitarian mission travellers or VFRs. Clinically, S.aureus positive lesions were found to
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be more likely to present as deep lesions that require surgical drainage and to cause recurrent
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disease, yet less likely to present as ulcers, and to be preceded by insect bites or other minor
177
trauma. The proportion of S.aureus positive among all lesions did not differ with sex, travel
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duration, antibiotic treatment, inpatient treatment, anatomic location of lesion, or report of
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contact persons being ill with SSTI.
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PVL-positive SSTI
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Among S.aureus positive SSTI, PVL was more often observed in isolates imported
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from Africa and Latin America and less often in those from the Pacific region and Southeast
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Asia (table 1, central column). PVL-positive (PVL+) compared to PVL-negative (PVL-)
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S.aureus was strongly associated with abscess formation, recurrent disease, surgical drainage,
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and lesions above the waistline. Patients with PVL+ lesions were more likely to require
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inpatient treatment when compared to travellers with SSTI caused by PVL- S.aureus.
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MRSA SSTI
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Methicillin-resistant S.aureus accounted for 7% (23/318) of all travel-associated SSTI and for
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12% (23/196) of all S.aureus positive cases. Travel to Latin America and for humanitarian
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purposes or VFR were independent risk factors for acquisition of MRSA (crude ORs, table 1,
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right column; adjusted ORLatin America 5.47, 2.09-24.33, P=0.001; adjusted ORVFR 2.84, 1.13-
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7.15, P=0.03). Compared to travellers with MSSA, cases with MRSA-related SSTI were more
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likely to report skin infections in contact persons (table 1, right column).
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Seven of 23 independent MRSA imports (30%) were PVL+ and spa type t008: 4 of 7
195
were SCCmec type IVa, arcA positive and 3 of 7 were SCCmec IVc, arcA negative,
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consistent with the USA300-0114 and USA300-Latin American Variant lineages, respectively
197
[18]. Five (71%) of these seven potential USA300 were imported from Latin America (table
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3). Other CA-MRSA imported from The Philippines and India revealed spa genotypes that
199
are known to be associated with the Southwest Pacific (spa t019) [19] and the Bengal Bay
200
(spa t657) [20] clones (table 3).
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Nasal carriage
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Nasal swabs were available for 310 of the 318 cases analysed. Of these, 39%
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(122/310) were nasal carriers of S.aureus, 17% (53/310) of PVL+ S.aureus, and 6% (18/310)
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of MRSA. Table 4 summarizes risk factors of various types of S.aureus nasal carriage and
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their association with clinical characteristics of SSTI in travellers.
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Antimicrobial (multi-)resistance
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Nearly half of all imported S.aureus (89/196) were resistant to at least one compound
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currently used for the empiric treatment of SSTI (i.e. isoxazolyl-penicillins, trimethoprim-
209
sulfamethoxazole, tetracycline, clindamycin), 49% (96/196) to at least one non-beta-lactam,
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and 54% (106/196) to at least one of the compounds tested in this study. Frequency and
211
patterns of antimicrobial resistance in imported S.aureus varied largely by place of exposure
212
abroad (table 2, supplementary figure 2).
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Resistance to two, three, four, or seven of the tested compounds simultaneously was
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observed in 16% (32/196), 8% (15/196), 3% (6/196), and 0.5% (1/196) of imported isolate(s),
215
respectively. Multi-resistance to two or more of any of the tested antibiotics was associated
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with travel to South Asia, various clinical characteristics of severe SSTI, PVL-positivity,
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to two, three, four, or seven non-beta-lactam antibiotics simultaneously was found in 13%
219
(26/196), 8% (16/196), 1.5% (3/196), and 0.5% (1/196) of isolate(s) and was associated with
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travel to South Asia, various clinical characteristics of severe SSTI, PVL-positivity, and the
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spa types t355 and t021, but not with concomitant methicillin resistance or spa type t008
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(table 5, central column). To assess, whether clonality confounded the effect of exposure in
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South Asia was on multi-resistance to non-beta-lactams in S.aureus, we fitted a multivariable
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logistic regression model adjusting for those spa types that were associated with both, multi-
225
resistance and South Asia. After adjusting for some positive confounding, exposure in South
226
Asia remained a strong and independent predictor of multi-resistance to non-beta-lactams in
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imported S.aureus (table 5, right column).
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Choosing randomly from antibiotic compounds recommended for the empiric
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treatment of skin and soft tissue infections (i.e. isoxazolyl-penicillins, trimethoprim-
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sulfamethoxazole, tetracycline, clindamycin) [7-9], there was an overall 15% chance to treat
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any of the returnees included in this study ineffectively (table 2).
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Discussion In this European multi-centre study, we found that antimicrobial (multi-)resistance in
234
imported S.aureus is common and its geographic distribution globally heterogeneous. We
235
estimated that overall 12% of all S.aureus causing skin and soft tissue infections (SSTI) in
236
intercontinental travellers is MRSA and observed that SSTI in returnees from Latin America
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promotes the spread of the highly virulent USA300 CA-MRSA lineage. This finding is in line
238
with reports on the expansion of USA300 from the U.S. into Latin America [21, 22] and from
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there to Europe [23]. Besides, we provide evidence for a less prominent import of the
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pandemic South West Pacific and the emerging Bengal Bay CA-MRSA clones to Europe by
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travellers returning from the Philippines and India.
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We show that resistance to non-beta-lactam antibiotics in imported S.aureus is
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common, amounting to 50% of all isolates, depending on destination and antimicrobial class
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tested. Besides, we demonstrate that about one fourth of S.aureus causing SSTI abroad are
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multi-resistant and that travel to South Asia independently predicts multi-resistance to non-
246
beta-lactams in these bacteria. Taken together, these findings challenge the unguided use of
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trimethoprim-sulfamethoxazole, tetracycline derivatives, and clindamycin against presumed
248
methicillin-resistant S.aureus infections in returning travellers [7-9] and support the concept
249
of regionally adapted treatment recommendations [24-26]. Furthermore, our observations
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allow assuming a regionally high prevalence of resistance to non-beta-lactam antibiotics in
251
parts of Africa and Asia. This extrapolation is supported by our recent finding of similar
252
resistance gene content in S.aureus collected from native Africans and travellers returning
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from that continent [27, 28]. Along this line, the presented data suggest that the use of
254
tetracycline and trimethoprim-sulfamethoxazole as region-specific empiric antibiotic
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treatment of CA-MRSA SSTIs in Africa and Asia is limited considering that a substantial
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proportion of suspected cases will ultimately be caused by MSSA due to a lack of reliable
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predictors of methicillin resistance. Hence, future recommendations on the empiric antibiotic
258
treatment of community-associated SSTI should incorporate resistance data gathered in
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MSSA and MRSA isolates alike. Following this rationale, we would like to challenge a recent
260
review that looked at antibiotic resistance patterns in community MRSA globally and
261
concluded that trimethoprim-sulfamethoxazole is an effective “region - specific empiric
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antibiotic treatment [in] Asia [if] community MRSA SSTI is considered likely” [24].
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Of note, we observed that those S.aureus lineages that were strongly associated with
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multi-resistance to non-beta-lactam antibiotics (spa t021 and t355, table 5) were also
265
commonly PVL-positive (91% and 100%, supplementary figure 1). This is alarming since
266
PVL+ MSSA is thought to represent the reservoir from which at least some of the successful
267
epidemic CA-MRSA clones emerged through horizontal genetic exchange [29-33]. Hence,
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the relative abundance of multi-resistant PVL+ MSSA among imported staphylococci could
269
herald the evolution of multi-resistant MRSA lineages in the community. This is in contrast to
270
current practice in research, surveillance, and control of multi-resistant S.aureus that largely
271
neglects antibiotic resistance in MSSA and tends to focus on methicillin resistant lineages
272
instead. Better knowledge on the accumulation of multi-resistance in MSSA as presented here
273
is needed to contain potential methicillin-sensitive precursors of multi-resistant community-
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associated MRSA.
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Nearly two thirds of S.aureus causing SSTI in intercontinental travellers were found to
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be PVL-positive and the lukS/lukF genes were strong predictors of SSTI associated morbidity.
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In addition to confirming its known associations with recurrent and deep-seated abscesses [6,
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23], we were able to demonstrate that SSTIs caused by PVL+ S.aureus more likely lead to
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hospitalization. According to a recent review [23], this has not been shown in an adult
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population before. Taking into account the diverse genetic backgrounds of S.aureus in our
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study, this finding supports the concept that PVL has indeed an effect on disease outcome
282
rather than being merely linked with other virulence factors – a common shortcoming of
283
research into infections from geographically confined populations and in clonally related
284
S.aureus [23]. Nasal carriage of PVL+ S.aureus proved to be a risk factor for recurrent abscesses and
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was associated with SSTI lesions being located above the waistline. These observations
287
suggest that PVL+ strains, compared to PVL- staphylococci, are more likely to cause manifest
288
skin infections when spread from the nose to areas of the body that are within the direct reach
289
of the hands. This emphasizes the role of colonized human nares in perpetuating PVL+ SSTI
290
and supports empiric nasal decolonization therapy for secondary prevention of recurrent post-
291
travel SSTI. Of note, we found longer duration of travel, humanitarian aid work, and visiting
292
friends and relatives to be risk factors for nasal carriage of PVL+ S.aureus. This knowledge
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may prove useful when tailoring the content of pre-travel consultations and targeting infection
294
prevention measures.
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In summary, the presented findings illustrate that sentinel surveillance of S.aureus
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infecting travellers is an efficient way of providing information on antimicrobial resistance in
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as yet understudied regions, call for the development of regionally stratified guidance on the
298
antibiotic management of severe imported S.aureus disease, and put the infected and
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colonized traveller at the centre of interventions against the global spread of multi-resistant
300
S.aureus. Our network will continue this surveillance with the aim to detect newly emerging
301
clones and monitor trends of antimicrobial resistance in imported S.aureus over time.
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Funding: This work was supported by the Institute of Tropical Medicine, Tübingen, Germany;
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Institute of Public Health, Heidelberg University Hospital, Heidelberg, Germany; Department
305
of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital,
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Heidelberg, Germany.
307
Acknowledgements:
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(www.istm.org/eurotravnet/main.html) networks in tropical medicine and travel health for
309
their support in identifying member sites for the StaphTrav network. Additional members of
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the StaphTrav network who contributed cases (in descending alphabetical order) are:
311
Johannes Blum, Basel; Antonia Calvo, Barcelona; Jacob P. Cramer, Hamburg; Julian Gabor,
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Tübingen; Marika Gaile, Tübingen; Heimo Lagler, Wien; Hans-Dieter Nothdurft, München;
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Michael Ramharter, Wien; Thierry Rolling, Hamburg; Günther Slesak, Tübingen; Florian
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Steiner, Berlin, Uwe Ziegler, Würzburg.
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Conflicts: all authors, no conflicts
thank
the
TropNet
(www.tropnet.net)
and
EuroTravNet
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Artzi O, Sinai M, Solomon M, Schwartz E. Recurrent furunculosis in returning travelers: newly defined entity. J Travel Med. 2014.
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Table 1. Characteristics of returning travellers with skin and soft tissue infections All skin and soft tissue infections, n=318 PVL+ OR (95% CI) n=196 (%) Female Age in yearsa Travel characteristics Destinationb Latin America Africa South Asia Southeast Asia Australia/Pacific
77 (39) 31 (23-45)
32 64 32 57 8
(16) (33) (16) (29) (4)
n=122 (%) 52 (43) 35.5 (25-51)
15 38 29 35 3
PVL-
P
0.9 (0.5-1.4) 0.9 (0.8-1.0)
0.6 0.07
(12) (31) (24) (29) (2)
1.4 (0.7-2.7) 1.1 (0.7-1.7) 0.6 (0.4-1.1) 1.0 (0.6-1.7) 1.7 (0.4-6.5)
0.3 0.8 0.1 0.9 0.5
1.0 (0.99-1.02)
0.4
RI PT
other
OR (95% CI)
n=122 (%)
n=74 (%)
51 (42) 31 (23-46)
26 (35) 30 (24-44)
25 47 20 27 2
(21) (39) (16) (22) (2)
1.3 (0.7-2.4) 1.0 (0.9-1.2)
SC
S.aureus
S.aureus positive skin and soft tissue infections, n=196
7 17 12 30 6
MRSA
MSSA
n=23 (%)
n=173 (%)
0.4 0.7
11 (48) 28 (22-39)
66 (38) 31 (24-45)
P
OR (95% CI)
22 61 30 49 8
P
1.5 (0.6-3.6) 0.8 (0.6-1.1)
0.4 0.1
(13) (35) (17) (28) (5)
5.3 (2.1-13.5) 0.3 (0.1-1.0) 0.5 (0.1-2.0) 1.3 (0.5-3.4) -
0.001 0.04 0.3 0.5 0.3c
(10) (23) (16) (41) (8)
2.5 (1.0-6.0) 2.1 (1.1-4.0) 1.0 (0.5-2.2) 0.4 (0.2-0.8) 0.2 (0.04-1.0)
0.05 0.03 1.0 0.007 0.05
10 (44) 3 (13) 2 (9) 8 (35) 0 (0)
28.5 (17-116)
28 (19-88)
1.0 (0.99-1.01)
0.5
31 (20-194)
28 (17-100)
1.0 (0.99-1.01)
0.7
61 (50) 13 (11) 47 (39)
48 (65) 4 (5) 22 (30)
0.5 (0.3-1.0) 2.1 (0.7-6.7) 1.5 (0.8-2.7)
0.04 0.2 0.2
10 (43) 0 (0) 13 (57)
99 (57) 17 (10) 56 (32)
0.6 (0.2-1.4) 2.7 (1.1-6.6)
0.2 0.1c 0.03
M AN U
Characteristic
28 (17-109)
30 (17-90)
Purposee leisure business / education humanitarian / VFR
109 17 69
(56) (9) (35)
81 12 29
(66) (10) (24)
0.6 (0.4-1.0) 0.9 (0.4-1.9) 1.7 (1.0-2.9)
0.06 0.7 0.03
53 132 10
(27) (67) (5)
57 56 9
(47) (46) (7)
0.4 (0.3-0.7) 2.4 (1.5-3.9) 0.7 (0.3-1.7)
