Clinical and Molecular Characterization of Panton–Valentine Leukocidin-Positive Invasive Staphylococcus aureus Infections in Korea

Abstract

Aim:

Panton–Valentine leukocidin (PVL) is a virulent cytotoxin and an indicator of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection. In this study, we evaluated the prevalence and clinical and molecular characteristics of PVL-positive invasive S. aureus (ISA) infections in Korea.

Results:

A collection of 1,962 nonduplicate clinical isolates were screened for multilocus sequence typing, staphylococcal cassette chromosome mec (SCCmec), accessory gene regulator typing, major toxins, and antimicrobial susceptibility. Twenty-eight (1.4%) PVL-positive S. aureus samples were found; of them 19 (67.9%) were MRSA (8 CA and 11 healthcare-associated infections). Seventeen patients (60.7%) were men (median age: 63 years; range: 13–93 years) and 12 patients (42.9%) had no underlying comorbidities. The most common infections were skin and skin structure infection (SSSI) and pneumonia. The 30-day mortality rate was 37.0%. The most common PVL-positive MRSA clones were ST8-SCCmec IVa and ST30-SCCmec IVc along with their single-locus variants. Antimicrobial susceptibility and toxin-gene profile differed according to the clone.

Conclusions:

ISA infections caused by PVL-positive strains are rare in Korea, with the two most common infections being SSSI and pneumonia. Our findings indicated that several PVL-positive MRSA clones, predominantly ST8-SCCmecIVa and ST30-SCCmecIVc, were circulating and causing sporadic cases of ISA infections in the community and hospital settings.

Introduction

Staphylococcus aureus is a virulent microorganism that causes a diverse spectrum of illnesses, from toxin-mediated diseases, such as toxic shock syndrome, to fatal invasive infections, such as bacteremia or endocarditis, with high mortality.^1,2 Methicillin-resistant S. aureus (MRSA) has been isolated mainly from hospitalized patients; however, since the 1990s, new MRSA strains causing invasive infections, such as suppurative skin and skin structure infections (SSSIs) and severe necrotizing pneumonia, have emerged in individuals in the community with no healthcare-associated (HA) risk factors.³

In earlier studies from the United States, these community-associated MRSA (CA-MRSA) strains showed distinguishable microbiological and molecular epidemiological features, predominantly USA300 pulsed-field type, sequence type (ST) 8, and a staphylococcal cassette chromosome mec (SCCmec) type IV clone containing Panton–Valentine leukocidin (PVL) from traditional HA-MRSA strains.^4,5 The prevalence and molecular characteristics of CA-MRSA in Asian countries have not been thoroughly investigated, with several studies reporting substantial differences in CA-MRSA in Asian countries^6,7; CA-MRSA is not common in Korea, where MRSA is endemic in many hospitals and the most common CA-MRSA clone has been ST72-SCCmec IVa without PVL.⁸

PVL is a cytotoxin that causes tissue necrosis and leukocyte destruction. The presence of the PVL gene is a stable marker of CA-MRSA in the United States and in some European and Oceanic countries⁹; however, its prevalence and clinical meaning differ according to countries. For example, MRSA was isolated in emergency departments in the United States from 59% of patients with SSSI, with the PVL gene detected in 98% of MRSA isolates.⁵ By contrast, PVL-positive MRSA is uncommon in the United Kingdom, Germany, and Spain (0–4.4%).^10–12 Although cases of PVL-positive MRSA have occasionally been reported in Korea,^13,14 it is very rare in the community.⁸ In addition, although there was a recent report of HA-MRSA bacteremia cases caused by the USA300 strain in three Korean hospitals with diverse incidences,¹⁵ the epidemiology and clinical features of PVL-positive S. aureus infections in Korea had not been thoroughly evaluated on a large scale.

This study evaluated the prevalence of PVL-positive strains among clinical isolates from invasive S. aureus (ISA) infections in Korean hospitals. We also characterized the clinical features of the PVL-positive ISA infections and their molecular epidemiology.

Materials and Methods

Bacterial isolates and data collection

S. aureus isolates were obtained from two large, prospective, nationwide multicenter Korean surveillance studies for ISA infections. The study was conducted in 10 hospitals over 2 years (2009–2011)^2,16 and in 16 hospitals from May to December 2012.¹⁷ In brief, ISA infection was identified through regular screening of microbiological cultures in each hospital and diagnosed upon S. aureus isolation from normally sterile body fluid, as previously defined.¹⁸ All data, including demographic, clinical, and epidemiological characteristics, were collected prospectively by physicians specializing in infectious diseases or trained research nurses using a standardized protocol in each hospital. Data were subsequently screened again for errors by investigators in Seoul National University Bundang Hospital (SNUBH). All S. aureus isolates collected from the enrolled cases were transferred to the central laboratory in the SNUBH and stored at −70°C until experimental use. For the 2012 study,¹⁷ only S. aureus isolates collected from the clinical specimens of patients hospitalized for ≤72 h were stored because the study was designed to evaluate community-onset (CO) ISA infections.

Definitions

Infection was classified as CO or hospital-onset (HO) according to the timing of the S. aureus-isolated specimen (obtained within 72 h of or 72 h after hospitalization, respectively), as described previously.¹⁷ CA infection was determined when none of the established HA risk factors for MRSA acquisition or infections were present.¹⁹ Cases not fully meeting these criteria were classified as HA-ISA infections. The primary sites of ISA infections were established by physicians specializing in infectious diseases at each hospital.

Molecular-typing studies

All stored S. aureus isolates were screened for the presence of the lukS-PV and lukF-PV genes encoding PVL by polymerase chain reaction (PCR), as described previously.²⁰ For PVL-positive S. aureus strains, multilocus sequence typing (MLST) was performed, as described previously.²¹ Clonal complexes (CCs) were subsequently defined using the eBURSTv3 program (available on the MLST website; http://saureus.mlst.net/eburst). SCCmec typing,²² accessory gene regulator (agr) typing,²³ PCR for arginine catabolic mobile element (ACME),²⁴ and multiplex PCR for major staphylococcal toxin genes²⁵ were also performed.

Antimicrobial-susceptibility tests

An in vitro antimicrobial-susceptibility test for PVL-positive S. aureus strains was performed using Pos Combo 1A panels in the automated MicroScan WalkAway 96 system (Beckman Coulter, Brea, CA). The following 11 antibiotics were tested: penicillin, oxacillin, erythromycin, clindamycin, vancomycin, teicoplanin, ciprofloxacin, rifampicin, tetracycline, sulfamethoxazole–trimethoprim, and gentamicin. The resistance rate was calculated as the number of intermediate and resistant strains over the total number of strains.

Statistical analysis

Fisher's exact test was used to detect systematic differences between qualitative variables. Significance was determined at p < 0.05. The analysis was conducted using Epi Info version 7 for Windows, which was developed by the Centers for Disease Control and Prevention (Atlanta, GA). This study was approved by the Institutional Review Board of the SNUBH (IRB No: B-1205/153-104).

Results

A total of 1,962 nonduplicate S. aureus isolates were collected from two studies: 1,289 isolates from 1,717 ISA infections in the study from 2009 to 2011, of which 783 and 934 were CO- and HO-ISA infections, respectively; and 673 isolates from 816 CO-ISA infections from the 2012 study (Fig. 1). After screening for possession of PVL, only 28 (1.4%) S. aureus isolates showed PVL positivity: 1.7% (19/1,144) of all MRSA isolates and 1.1% (9/818) of all methicillin-susceptible S. aureus (MSSA) isolates. Most (27/28) of the cases were CO infections, whereas 57.1% (16/28) were CA infections. Of the 19 PVL-positive MRSA strains, 8 and 11 were from CA and HA infections, respectively, and possession of PVL was more common in CA-MRSA than HA-MRSA (5.0% vs. 1.1%; p = 0.003).

FIG. 1.

Schematics of invasive Staphylococcus aureus infections from two cohorts from 2009 to 2011 and in 2012, as well as the prevalence of PVL-positive S. aureus isolates in Korea. Total numbers of enrolled ISA cases, S. aureus isolates collected and screened for the PVL gene, and PVL-positive S. aureus isolates in each group are presented. CA, community associated; CO, community onset; HA, hospital associated; HO, hospital onset; ISAI, invasive S. aureus infection; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; PVL, Panton–Valentine leukocidin.

Clinical characteristics of 28 cases of PVL-positive ISA infection are given in Table 1. The cases were distributed in different hospitals at various times, indicating a low possibility of obtaining specific outbreak stains in the study, considering that most of these were CO strains. Seventeen (60.7%) of the 28 patients were men, with a median age of 63 years (range: 13–93 years). Of them, 44.4% (4/9) and 47.4% (9/19) were ≥65 years old with MSSA and MRSA infections, respectively. Twelve patients (42.9%) had no underlying comorbidities. The primary sites of infections were as follows: nine cases of SSSI, nine cases of pneumonia, four bone and joint infections (BJIs), four cardiovascular infections, and two unknown infections. Only SSSI and pneumonia were primary sites of infection in PVL-positive CA-MRSA infections. The 30-day mortality was 37.0% (10/27), with no significant difference observed between the MRSA and MSSA groups.

Table 1.

Clinical and Molecular Characteristics of Invasive Infections by Panton–Valentine Leukocidin-Positive Staphylococcus aureus in Korea (n = 28)

No.	Hospital	Isolation date (year/month)	Age (years)	Specimen	Sex	Primary site of infection	Acquisition site	Under-lying conditions	30-Day mortality	Oxacillin resistance	Multilocus sequence type	Clonal complex	SCCmec type	agr group	ACME	Toxin gene profile
1	A	2009/09	38	Pus	M	SSSI	CO-HA	None	Y	R	8	8	IVa	I	+	pvl
2	B	2009/09	70	Blood	M	Pneumonia	CA	None	Y	R	8	8	IVa	I	+	pvl
3	C	2009/11	49	Blood	F	Pneumonia	CA	None	N	S	282 SLV	Singleton		III		seg, sei, tst, pvl
4	C	2010/03	50	Blood	M	SSSI	CA		Y	S	2,696 SLV	Singleton		IV		seg, sei, pvl
5	C	2010/04	13	Pleural fluid	M	Pneumonia	CA	None	Y	R	938	30	IV	III	−	pvl
6	D	2010/08	50	Blood	M	SSSI	CA	None	N	S	1,232	398		I		pvl
7	E	2010/12	79	Blood	F	Pneumonia	CA		N	S	1	1		III		sec, seg, sei, tst, pvl
8	D	2010/12	44	Blood	M	Pneumonia	CA		Y	R	938	30	IVc	III	−	seb, pvl
9	F	2011/01	74	Blood	F	Pneumonia	HO		Y	R	8	8	IVc	I	+	pvl
10	G	2011/05	72	Blood	F	BJI	CA	None	N	S	938	30		III		seg, sei, pvl
11	H	2012/06	63	Blood	M	Unknown	CO-HA		N	R	1,232	398	V	I	−	pvl
12	I	2012/07	86	Blood	F	CVI	CO-HA		N	R	8 SLV	8	IVa	I	+	pvl
13	J	2012/07	53	Joint fluid	M	BJI	CA	None	N	S	30	30		III		sec, seg, sei, tst, pvl
14	K	2012/07	28	Pus	M	SSTI	CA	None	NA	R	8	8	IVb	I	−	sea, seh, pvl
15	L	2012/07	78	Blood	F	CVI	CO-HA		N	R	188	1	V	III	−	seg, sei, pvl
16	L	2012/07	25	Joint fluid	M	SSSI	CA	None	N	R	8	8	IVa	I	+	pvl
17	L	2012/08	47	Blood	F	Pneumonia	CO-HA		Y	R	8	8	IVa	I	+	sea, seg, sei, pvl
18	M	2012/08	56	Tissue	M	SSSI	CA	None	N	R	59	59	V	I	−	pvl
19	L	2012/08	77	Blood	F	Pneumonia	CO-HA	None	N	S	243 SVL	30		III		sec, seg, sei, tst, pvl
20	J	2012/08	69	Pus	F	SSSI	CA	None	N	R	8	8	IVa	I	−	pvl
21	M	2012/09	28	Pus	M	SSSI	CA	None	N	R	30	30	IVc	III	−	seg, sei, pvl
22	I	2012/10	62	Blood	M	CVI	CO-HA		N	R	8	8	IVa	I	+	pvl
23	L	2012/10	75	Blood	M	Pneumonia	CO-HA		N	R	243	30	IV	III	−	seg, sei, tst, pvl
24	N	2012/10	93	Blood	M	Unknown	CO-HA		Y	R	8	8	IVa	I	+	pvl
25	O	2012/10	71	Blood	F	SSSI	CO-HA		N	R	8 SLV	8	IVa	I	+	pvl
26	C	2012/11	69	Blood	M	CVI	CA	None	Y	S	1	1		III		sea, she, pvl
27	C	2012/11	70	Blood	F	BJI	CO-HA	None	N	R	30	30	IVc	III	−	seg, sei, pvl
28	J	2012/11	63	Blood	M	BJI	CA	None	Y	S	59	59		I		pvl

Grey background indicates the cases of methicillin-resistant S. aureus infection.

SCCmec, staphylococcal cassette chromosome mec; agr, accessory gene regulator; ACME, arginine catabolic mobile element; SSSI, skin and skin structure infection; BJI, bone and joint infection; CVI, cardiovascular infection; CO, community onset; HA, healthcare associated; CA, community associated; HO, hospital onset; NA, not available; R, resistant; S, susceptible; SLV, single-locus variant; sea to i, staphylococcal enterotoxins a to i; tst, toxic shock syndrome toxin.

MLST analysis revealed that CC8 (11 MRSA strains) and CC30 (five MRSA and three MSSA strains) were the most prevalent clones in PVL-positive S. aureus strains (Table 1). Although PVL-positive MSSA strains showed diverse genetic backgrounds, including four CCs and two singletons, most PVL-positive MRSA strains belonged to CC8 (11/19, 57.9%) and CC30 (5/19, 26.3%), with ST8-SCCmecIVa and ST30-SCCmecIVc predominant. All 11 CC8 MRSA strains were SCCmec type IV and agr group I, and 9 of them possessed ACME. By contrast, all CC30 MRSA strains were SCCmec type IV and agr group III without ACME. In addition, the toxin-gene profile was diverse, but MRSA tended to harbor fewer toxin genes relative to MSSA, especially in most of the CC8 MRSA strains that possessed PVL only.

Antimicrobial-susceptibility testing of PVL-positive MRSA strains showed their high susceptibility to clindamycin, rifampicin, tetracycline, sulfamethoxazole–trimethoprim, and gentamicin, but not to erythromycin and ciprofloxacin (Fig. 2). Analysis of the susceptibility profile according to CC showed that CC30-MRSA strains were highly susceptible (∼80–100%) to all non-β-lactam antibiotics, whereas CC8-MRSA strains showed low susceptibility to ciprofloxacin (0%) and erythromycin (18.2%). By contrast, PVL-positive MSSA strains were susceptible to most antibiotics, except for penicillin.

FIG. 2.

Antibiotic susceptibility profile of 28 PVL-positive Staphylococcus aureus isolates in invasive S. aureus infections in Korea. *GEN susceptibility of one MRSA strain was not available. CIP, ciprofloxacin; CLI, clindamycin; ERY, erythromycin; GEN, gentamicin; PEN, penicillin; RIF, rifampicin; SUL, sulfamethoxazole–trimethoprim; TEI, teicoplanin; TET, tetracycline; VAN, vancomycin.

Discussion

The PVL-positive ISA infections were rare in Korea according to this study. Although PVL positivity was higher in CA-MRSA (5.0%) relative to that in HA-MRSA (1.1%), possession of PVL was neither universal nor a unique characteristic of invasive CA-MRSA infections in Korea. When we calculated the prevalence of PVL-positive strains in SSSI and pneumonia caused by CA-MRSA only (data not shown), PVL positivity was still low (12.5% [5/40] and 20% [3/15], respectively). The prevalence of PVL positivity in MRSA infections is historically low in East Asian countries, although its epidemiology differs between countries. A multicenter prospective surveillance study for SSSI from CA-MRSA and performed during similar time periods in China showed low PVL positivity along with ST121-SCCmec IV predominance.²⁶ In addition, the prevalence of PVL-positive MRSA in the community was not high in Japan²⁷; however, a recent study suggested that a PVL-positive USA300 ST8-SCCmec IV MRSA clone is spreading in some hospitals and in the community.²⁸ Moreover, the prevalence of a predominantly PVL-positive ST59-SCCmec V CA-MRSA clone (the Taiwanese clone) has significantly increased in children, but not in adults, in the community in Taiwan.⁷

The most common primary sites of PVL-positive ISA infections were SSSI (seven cases) and pneumonia (six) in the MRSA group and BJI (three), pneumonia (three), and SSSI (two) in the MSSA group (Table 1). However, for PVL-positive CA-MRSA, only SSSI (five) and pneumonia (three) were primary sites of infection. In a previous surveillance study of CO-ISA infections in Korea,¹⁷ the most common sites of infection were SSSI in the MRSA group and BJI in the MSSA group, with pneumonia being uncommon, similar to PVL-positive CA-ISA infections in this study. Our data showing the relatively high prevalence of pneumonia in PVL-positive ISA infections, readdressed the association of PVL toxin and severe pneumonia, especially in cases of CA infections.²⁰ Given that almost 50% of the patients in this study had no comorbidities, the 30-day mortality rate associated with PVL-positive ISA infections was high. Although there was no difference in the 30-day mortality rate between the MRSA and MSSA groups, there were differences according to the primary sites of infection, with the highest mortality associated with pneumonia (5/9, 55.6%) (Table 1). Our data suggested that the presence of the PVL gene might play a potential role in poorer outcomes.

Recently, cases of HA-MRSA bacteremia caused by USA300 ST8-SCCmec IVa were reported in three Korean hospitals.¹⁵ Most of these strains were collected from 2014 to 2015, and the most common types of infection were bacteremia of unknown origin, followed by pneumonia. The prevalence of PVL-positive ST8-SCCmec IVa in MRSA bacteremia ranged from 0.4% to 12% according to hospital data, with all these cases being HO- or CO-HA infections and no CA cases. Although the results of that study could not be generalized because of the small number of participating hospitals, it is possible that the epidemiology of PVL-positive ISA infections has changed to being more frequently found in hospital settings rather than in the community in Korea. Considering the possible dissemination of PVL-positive USA300 ST8-SCCmec IV MRSA clones in some Japanese hospitals,²⁸ further studies evaluating the changing epidemiology of PVL-positive S. aureus over more extended periods of time are warranted.

Among a total of 19 PVL-positive MRSA strains, ST8-SCCmecIV and its single-locus variants (SLVs) (11) and ST30-SCCmecIV and its SLVs (5) were most common in this study (Table 1). The other clones included ST59-SCCmecV (one), ST188-SCCmecV (one), and ST1232-SCCmecV (one). USA300 ST8 MRSA, a representative clone of CA-MRSA in the United States and possessing SCCmec IVa, the PVL gene, and ACME,²⁹ was also the most common clone found in this study. Given that no ST8-MSSA strains harboring the PVL gene were found, the ST8-SCCmecIV MRSA strains might have been imported from foreign countries to cause sporadic ISA infections in Korea. The second most common PVL-positive MRSA clone was ST30-SCCmecIVc, which has been isolated worldwide, including Australia, the United States, Europe, and Japan.^7,9 In addition, ST59-SCCmecV has been an endemic CA-MRSA clone in Taiwan.³⁰ Although some ST30 or ST59 MRSA strains might have evolved from the same clone of PVL-positive MSSA found in this study, it is also likely that these clones were imported from other countries.

This study has potential limitations. First, the prevalence of PVL-positive S. aureus in Korea might have been underestimated by the estimation made in our study. Moreover, we collected the clinical isolates only from ISA that represent the most common sites of infection by PVL-positive CA-MRSA strains; however, the microbial confirmation is challenging in SSSIs. However, considering the high virulence of PVL toxin, cases of PVL-positive ISA infections were unlikely to be undiagnosed in this study. Second, we did not gather information concerning the patient history of recent international trips. Therefore, we were unable to infer whether the origin of these strains was domestic or international. Third, this study might not reflect a complete situation of PVL-positive ISA infections nationwide in Korea, because all the participating centers were secondary or tertiary hospitals. Moreover, we did not enroll recent cases in the study to investigate epidemiological changes over longer periods. Despite these limitations, the study strengths were its inclusion of a large number of clinical isolates from ISA infections nationwide and its prospective and multicenter design.

In conclusion, PVL-positive ISA infections were rare in Korea during the period investigated, with the most common types of infection being SSSI and pneumonia. The identified PVL-positive MRSA strains showed several genetic backgrounds, with a predominance of ST8-SCCmecIVa and ST30-SCCmecIVc clones, implying that multiple international clones were circulating and causing sporadic cases of ISA infections in the community and hospital settings in Korea. Vigilant surveillance for PVL-positive ISA infections and further studies to clarify the origin and changing epidemiology of these clones is warranted.

Footnotes

Acknowledgments

This work was supported by a grant No. 03-2012-005 from Seoul National University Bundang Hospital (to E.S.K.). This study was presented as a poster in ASM Microbe, Boston, MA, 2016 (abstract No. MONDAY-381).The authors thank the members of the Korea INfectious Diseases (KIND) study group and the associated staff for their cooperation in this study. The collaborators in the KIND study group were Hee-Chang Jang and Sook-In Jung, Department of Infectious Diseases, Chonnam National University Medical School, Gwangju, Republic Korea; Nara Yoon and Dong-Min Kim, Department of Internal Medicine, Chosun University Hospital, Gwangju, Republic of Korea; Chang Seop Lee, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; Jae Hoon Lee, Department of Internal Medicine, Wonkwang University Hospital, Iksan, Republic of Korea; Kkot Sil Lee, Department of Internal Medicine, Myongji Hospital, Goyang, Republic of Korea; Yee Gyung Kwak, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Republic of Korea; Seong Yeon Park, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea; Taek Soo Kim, Sue Shin, and Eui-Chong Kim, Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic Korea; Gayeon Kim, Shinhye Cheon, Nak-Hyun Kim, Wan Beom Park, and Nam-Joong Kim, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Sun Hee Lee, Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea; Ki Tae Kwon, Department of Internal Medicine, Daegu Fatima Hospital, Daegu, Republic of Korea; Chisook Moon, Department of Internal Medicine, Inje University College of Medicine, Busan, Republic of Korea; Sang Won Park, Division of Infectious Diseases, Seoul Metropolitan Government—Seoul National University Boramae Medical Center, Seoul, Republic of Korea; Jongyoun Yi, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea; Young Hwa Choi, Department of Infectious Diseases, Ajou University School of Medicine, Suwon, Republic of Korea.

Disclosure Statement

No competing financial interests exist.

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