Molecular Epidemiological Features of Methicillin-Resistant Staphylococcus aureus in Japan

Abstract

Recently, the epidemic types of methicillin-resistant Staphylococcus aureus (MRSA) in hospital and community settings in Japan have changed significantly. Before 2010, approximately 80% of the MRSA strains isolated from hospitals were typical healthcare-associated MRSA (HA-MRSA) with staphylococcal cassette chromosome (SCC) mec type II. However, USA400-like community-associated MRSA (CA-MRSA) with SCCmec type IV (defined as USA400/J) has become dominant in hospitals since 2014. By contrast, skin infections caused by the highly virulent CA-MRSA USA300 clone have increased. The USA300 clone is associated with intractable skin infections and necrotizing pneumonia because it carries a cytolytic pore-forming toxin, Panton–Valentine leukocidin (PVL), and an arginine catabolic mobile element that promotes skin colonization. In the past decade, the USA300 clone has shown limited prevalence and has not been considered a serious problem in Japan. However, the USA300 clone has recently spread in community and hospital settings. This review discusses the evolution and current status of the molecular epidemiological features of HA-MRSA and CA-MRSA strains in Japan.

1. INTRODUCTION

Staphylococcus aureus is a common bacterium in the human skin and nasal cavity that causes various infectious diseases. Methicillin-resistant S. aureus (MRSA) is one of the most important pathogens in the control of nosocomial infections. MRSA strains isolated from hospitalized patients are called healthcare-associated MRSA (HA-MRSA), and MRSA strains isolated from healthy individuals and outpatients in the community are called community-associated MRSA (CA-MRSA) (Table 1). CA-MRSA is defined as “MRSA isolated from patients with no risk factors for conventional HA-MRSA infection” and often includes MRSA isolated within 48 h of hospital admission.¹⁾

Table 1. Characteristics of Hospital- and Community-Associated MRSA in Japan before 2010

	HA-MRSA	CA-MRSA
Clinical definition	Isolated from inpatients (>48 h admission)	Isolated from healthy people and outpatients
SCCmec type	Type II	Type IV
Typical clone	New York/Japan	Wide variety
Virulence (toxin)	TSST-1	ET, PVL (rare)
Antimicrobial susceptibility	Multidrug and high-level resistance	Relatively high

SCCmec, staphylococcal cassette chromosome mec; TSST-1, toxic shock syndrome toxin-1; ET, exfoliative toxin; PVL, Panton–Valentine leukocidin; HA-MRSA, hospital-acquired methicillin-resistant Staphylococcus aureus; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus.

MRSA emerges by acquiring mecA, which encodes a penicillin-binding protein 2′ (PBP2′) with a low affinity for β-lactam antibiotics.²⁾ The mecA is located on the staphylococcal cassette chromosome (SCC), and this region is called SCCmec. Types I–III are mainly observed in HA-MRSA, and types IV and V are mainly observed in CA-MRSA³⁾ (Fig. 1). CA-MRSA is susceptible to many antimicrobial agents other than β-lactams, and some strains possess the arginine catabolic mobile element (ACME) and Panton–Valentine leukocidin (PVL), a leukocytolytic toxin encoded by lukS/F-PV.⁴⁾ Thus, CA-MRSA is more pathogenic than HA-MRSA. ACME, which enhances virulence and skin persistence, comprises an arginine deiminase gene cluster (arc) and an oligopeptide permease gene cluster (opp3).⁵⁾ PVL targets polymorphonuclear leukocytes and macrophages and induces cell death such as necrosis and apoptosis⁶⁾ (Fig. 2). PVL-positive MRSA is referred to as a highly virulent MRSA because it causes severe disease, including skin and soft tissue infections, necrotizing pneumonia, and sepsis, even in healthy individuals. The USA300 clone with molecular epidemiological features of SCCmec type IV, PVL-positive, ACME type I, and sequence type (ST) 8 is the most prevalent genotype of CA-MRSA in the USA.⁷⁾

Fig. 1. Schematic Structures of the Main Types of SCCmec³⁾

SCCmec, staphylococcal cassette chromosome mec.

Fig. 2. Mechanisms of Action of PVL Causing Severe Skin Infections⁶⁾

PVL, Panton–Valentine leukocidin.

PVL-positive MRSA was thought to be rare in Asian countries, including Japan.⁴⁾ Our surveillance has shown that the proportion of PVL-positive strains among CA-MRSA isolates in Japan has increased annually.⁸⁾ Furthermore, outbreaks of PVL-positive MRSA have occurred in hospitals, and the proportion of PVL-positive strains has increased.⁹⁾ To prevent outbreaks of PVL-positive MRSA, it is important to understand the prevalence and characteristics of MRSA in both hospital and community settings. This review discusses the evolution and current status of the molecular epidemiological features of HA-MRSA and CA-MRSA strains in Japan.

2. TRANSITION OF MOLECULAR EPIDEMIOLOGICAL FEATURES IN HA-MRSA

We investigated the trends of SCCmec types in MRSA isolated from several hospitals in Tokyo between 2009 and 2020^10,11) (Fig. 3). Until 2010, SCCmec type II strains, which predominate in HA-MRSA, accounted for approximately 80% of the cases; however, the proportion decreased each year; in 2014, SCCmec type IV strains, which predominate in CA-MRSA, reversed this trend. The proportion of SCCmec type IV strains has increased since 2015, exceeding 80% in 2019 (Yoshida et al., unpublished data). We performed multilocus sequence typing (MLST) to compare the genotypes of strains isolated before and after SCCmec type IV became the predominant strain^10,11) (Table 2). Before 2011, when SCCmec type II strains were predominant, the CA-MRSA/J clone with clonal complex (CC) 8 and PVL negative was the predominant genotype.¹²⁾ In 2014, when SCCmec type IV strains became predominant, the highest percentage of the PVL-negative CC1 clone (defined as USA400/J), closely related to the typical PVL-positive USA400 clone,¹³⁾ was observed. Other groups in Japan have reported that the major genotype of MRSA isolated in hospitals is CC1-SCCmec type IV (CC1-IV).^14,15) These data indicate that in just 10 years, the major genotype of MRSA isolated in Japanese hospitals has changed from the New York/Japan clone¹⁰⁾ of ST5-SCCmec type II (ST5-II), which was the predominant genotype, to CC1-IV.

Fig. 3.  Annual Transition of SCCmec Types in MRSA Isolated from Hospitals in Tokyo, Japan^10,11)

Unpublished data after 2015. SCCmec, staphylococcal cassette chromosome mec; MRSA, Methicillin-resistant Staphylococcus aureus.

Table 2. Clonal Types of SCCmec Type IV MRSA Strains Isolated from Hospitals^10,11)

Clonal complex	Clonal type	% of isolates
		2009–2011 (n = 94)	2014 (n = 104)
1	Community	8 (8.5)	64 (61.5)
5	Hospital	26 (27.7)	3 (2.9)
8	Community	32 (34.0)	21 (20.2)
30	Community	4 (4.3)	3 (2.9)
81	Unknown	15 (16.0)	11 (10.6)
89	Community	5 (5.3)	0
Other		4 (4.3)	2 (1.9)

SCCmec, staphylococcal cassette chromosome mec.

The predominance of CC1-IV strains in the hospital was attributed to (1) the spread of CA-MRSA from the community and (2) changes in antimicrobial use (selection pressure). To verify (1), we analyzed the genotypes of CA-MRSA isolated in the same area and at the same time as the hospital described above. However, no epidemic of the CC1-IV strain was observed¹⁶⁾ (Fig. 4). Then, to verify (2), we investigated the trends in antimicrobial susceptibility of strains isolated from hospitalized patients clinically identified as HA-MRSA¹⁷⁾ (Table 3). The results showed a significant decrease in the resistance rate of cefotaxime, a third-generation cephalosporin, and clindamycin, a lincomycin. When antimicrobial susceptibility was compared between MRSA genotypes, SCCmec type II strains had significantly higher resistance rates to cefotaxime and clindamycin than type IV strains (p < 0.05)¹⁷⁾ (Table 4). In addition, the hospital antimicrobial use density (AUD) showed an increase in narrow-spectrum penicillins and a decrease in cephems¹⁷⁾ (Fig. 5). CA-MRSA grows faster than HA-MRSA.¹⁸⁾ Furthermore, an action plan to combat antimicrobial resistance (AMR) has been implemented in Japan since 2016, and AUDs for broad-spectrum antimicrobial agents have decreased.¹⁹⁾ Therefore, the rapid-growth SCCmec type IV strain may have been replaced as the predominant strain in the hospital due to a significant change in antimicrobial selection pressure in recent years, and it is necessary to conduct further studies from different perspectives to elucidate the factors that lead to CC1 becoming the predominant SCCmec type IV strain.

Fig. 4. Genotypes of CA-MRSA Strains Isolated at the Same Time from the Same Region as the Strains in Table 2¹⁶⁾

CA-MRSA, Community-associated methicillin-resistant Staphylococcus aureus.

Table 3. Transition of Antimicrobial Susceptibility of MRSA Isolated from Hospitalized Patients¹⁷⁾

Antimicrobial agent	2010–2011 (n = 207)		2012–2013 (n = 211)		2014–2016 (n = 182)
	MIC50/MIC90(µg/mL)	R(%)	MIC50/MIC90(µg/mL)	R(%)	MIC50/MIC90(µg/mL)	R(%)
Ampicillin	32/32	100.0	32/64	100.0	32/64	100.0
Oxacillin	≥256/≥256	99.6	≥256/≥256	98.6	64/≥256	97.8
Cefotaxime	≥256/≥256	86.5	≥256/≥256	74.9	64/≥256	55.0
Levofloxacin	8/≥256	87.4	8/≥256	79.6	16/≥256	78.6
Clarithromycin	≥256/≥256	87.4	≥256/≥256	82.0	≥256/≥256	82.4
Clindamycin	≥256/≥256	75.4	≥256/≥256	69.2	0.13/≥256	46.2
Gentamicin	32/128	60.9	16/128	53.6	32/64	54.4
Minocycline	4/16	34.8	2/16	33.7	0.13/16	36.8
Arbekacin	0.5/1	0.0	0.25/1	0.0	0.5/1	0.0
Vancomycin	1/1	0.0	0.5/1	0.0	1/1	0.0
Linezolide	1/2	0.0	1/1	0.0	1/1	0.0

Table 4. Comparison of Antimicrobial Susceptibility between Genotypes of HA-MRSA and CA-MRSA¹⁷⁾

Antimicrobial agent	HA-MRSA		CA-MRSA
	CC5-II (n = 43)		CC8-IV (n = 20)		CC1-IV (n = 6)
	MIC50/MIC90(µg/mL)	R(%)	MIC50/MIC90(µg/mL)	R(%)	MIC50/MIC90(µg/mL)	R(%)
Ampicillin	32/64	100.0	16/32	100.0	32/32	100.0
Oxacillin	≥256/≥256	100.0	64/128	100.0	64/128	100.0
Cefotaxime	≥256/≥256	100.0	32/128	30.0	32/128	33.3
Levofloxacin	8/≥256	90.7	0.25/8	30.0	32/≥256	100.0
Clarithromycin	≥256/≥256	97.7	32/≥256	70.0	2/≥256	50.0
Clindamycin	≥256/≥256	97.7	≤0.06/≥256	25.0	≤0.06/0.13	0.0
Gentamicin	8/128	46.5	16/32	55.0	0.25/32	16.7
Minocycline	8/16	37.2	0.13/16	25.0	0.13/0.5	0.0

HA-MRSA, hospital-acquired methicillin-resistant Staphylococcus aureus; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus.

Fig. 5. Annual Change in Hospital AUD¹⁷⁾

AUD, Antimicrobial use density.

3. TRANSITION OF MOLECULAR EPIDEMIOLOGICAL FEATURES IN CA-MRSA

When S. aureus was isolated from specimens collected from patients with skin infections in various areas of Japan in 2013–2014, the proportion of MRSA was 25.6%²⁰⁾ (Fig. 6). The PVL-positive rate was 13.2% for MRSA and 0.9% for methicillin-susceptible S. aureus (MSSA), with a significantly higher rate for MRSA (p < 0.05). PVL-positive strains were associated with deep-seated skin infections, such as furuncles and carbuncles, and were more frequently isolated from more severe cases²⁰⁾ (Fig. 7). Genotyping of PVL-positive strains revealed that approximately half of them were USA300 clones, and the strain isolated on Ishigaki Island, Okinawa, was USA300-LV/J, which evolved independently in Japan.^20,21) These data indicate that PVL-positive MRSA, including the highly virulent USA300 clone, is observed in Japan and causes serious skin infections.

Fig. 6. Proportions of MRSA and PVL-Positive Strains in S. aureus Isolated from Patients with Skin Infections²⁰⁾

MRSA, Methicillin-resistant Staphylococcus aureus; PVL, Panton–Valentine leukocidin.

Fig. 7. Severity of Skin Infections Caused by PVL-Positive Strains²⁰⁾

PVL, Panton–Valentine leukocidin.

The proportion of PVL-positive strains among CA-MRSA isolates accounted for 44.8% in 2021, and PVL-positive MRSA strains were detected in all prefectures studied⁸⁾ (Fig. 8). Moreover, 90% were USA300 clones, and similar strains were associated with refractory skin infections. As a result, cases of severe and refractory skin infections caused by PVL-positive MRSA have become more common.^22–28) In one case, a septic pulmonary embolism caused by a wound infection in a collegiate rugby player was caused by a USA300 clone carried in the nasal cavity by asymptomatic teammates living in the same dormitory.^23,24) Currently, half of the MRSA isolates from patients with skin infections in the community are PVL-positive strains, and even healthy people can carry the USA300 clone in their nasal cavity. Therefore, to prevent an epidemic of the USA300 clone, routine nasal screening is recommended for contact athletes living in dormitories. In addition, there have been many cases of recurrent familial infection with the USA300 clone in the community.^26,28) In this case, we believe that asymptomatic family members living in the same home should be screened and actively decolonized.

Fig. 8. Annual Transition of MRSA (A) and PVL-Positive Strains in MRSA (B)⁸⁾

Gray prefectures were not subject to this surveillance. Unpublished data after 2018. MRSA, Methicillin-resistant Staphylococcus aureus; PVL, Panton–Valentine leukocidin.

Several PVL- and TSST-1-positive MRSA strains have been reported in Japan.^29–32) Among these strains, 8 (CC22) strains were identified from Japanese or Nepalese patients.^30–32) All of these strains were collected after 2017 and named ST22-PT in a recent report.³⁰⁾ Both PVL- and TSST-1-positive CC22 strains have been isolated sporadically in several countries.^30–37) We have recently identified ST22-PT strains in several healthcare facilities in Japan, and ST22-PT-like strains have been identified in several countries.³⁸⁾ Therefore, a PVL- and TSST-1-positive MRSA clone, ST22-PT, can potentially become epidemic.

4. SPREAD OF PVL-POSITIVE MRSA in HOSPITAL SETTINGS

The rapid spread of PVL-positive MRSA in the community was feared to spread to hospital settings. Therefore, we investigated the proportion of PVL-positive strains among MRSA isolates from several hospitals in Tokyo⁹⁾ (Fig. 9). Results include inpatients and outpatients; however, PVL-positive MRSA gradually increased from 2013 and exceeded 10% in 2019. The number of isolates from dermatological and pediatric skin specimens was particularly high among outpatients. In cases of skin infections caused by PVL-positive MRSA, community clinics are expected not to manage many and must be treated in hospitals. Sometimes, patients infected with PVL-positive MRSA may be hospitalized for a severe illness. Genotyping of the PVL-positive MRSA isolates in the hospital revealed that approximately 80% were USA300 and its related clones.

Fig. 9. Annual Transition of PVL-Positive Strains in MRSA Isolated from Hospitals⁹⁾

Unpublished data after 2016. MRSA, methicillin-resistant Staphylococcus aureus; PVL, Panton–Valentine leukocidin.

The nosocomial spread of PVL-positive MRSA caused an outbreak that included a healthy healthcare worker (a nurse) with no underlying disease.³⁹⁾ The risk of infection by nosocomial outbreak strains of traditional HA-MRSA is considered low in healthy healthcare workers. However, this report showed that the USA300 clone is easily transmitted to healthy healthcare workers and poses a high risk of causing serious infections. To prevent such outbreaks, we believe it is necessary to strengthen screening for USA300 clone carriages before hospital admission.

Genotypes of PVL-positive MRSA isolated and identified by us are shown in Table 5.^{9,21,22,25,40)} In addition to the USA300 clone, which is the most prevalent clone mainly in the USA, we detected USA300-related clones that may have evolved independently in Japan, such as the ΨUSA300 clone, which has a 12-bp deletion in ccrB2 of SCCmec,⁴⁰⁾ and the USA300-LV/J clone,²¹⁾ which is similar to the USA300-LV clone prevalent in South America. Furthermore, we identified several other PVL-positive MRSA strains, and for the first time, we observed a Japanese patient with ST1232 PVL-positive MRSA, which belongs to CC398, the same group as livestock-associated MRSA (LA-MRSA), which is a problem in Europe and other Asian countries.²⁵⁾ The patient had no history of overseas travel or direct contact with animals, suggesting that he was infected in the community in Japan. The PVL-positive CC398 strain (LA-MRSA human variant) has been reported to be more involved in human than animal infections.⁴¹⁾ Recently, the number ST1232 PVL-positive MRSA isolates from hospitalized patients has gradually increased; therefore, future trends should be closely monitored.

Table 5. Various PVL-Positive MRSA Isolated in Japan^{9,21,22,25,40)}

Clone	Typical ST (CC)	SCCmec type	Epidemic region
USA300	8 (8)	Iva	USA, Global
ΨUSA300	8 (8)	ΨIVa*	Japan
USA300-LV/J	8 (8)	IVc	Japan
ST22-PT	22 (22)	IV	Japan
South West Pacific	30 (30)	IV	Pacific
Taiwan	59 (59)	IV or V	Asia
ST80	80 (80)	II	Mediterranean
Bengal-Bay	772 (1)	V	India
LA-MRSA Human variant	1232 (398)	V	Asia

SCCmec, staphylococcal cassette chromosome mec. *12-bp deletion in ccrB2 of SCCmec; PVL, Panton–Valentine leukocidin.

The antimicrobial susceptibility of PVL-positive MRSA varies widely depending on their genotype^{9,21,22,25,40)} (Table 6). The USA300 clone and its related strains have similar susceptibility patterns. However, the gentamicin resistance rate of the ΨUSA300 clone is lower. The ST22-PT clone showed an antimicrobial susceptibility pattern similar to the ΨUSA300 clone. The South West Pacific and Taiwan clones were more susceptible than the other genotypes; however, the Taiwan clone had a high rate of clindamycin resistance. All LA-MRSA human variants were susceptible to levofloxacin and resistant to clindamycin. PVL-positive strains of all genotypes were highly susceptible to minocycline. Therefore, in addition to anti-MRSA agents, minocycline may be an option for treating patients with PVL-positive MRSA infections in Japan.

Table 6. Antimicrobial Susceptibility of PVL-Positive MRSA Isolated in Japan^{9,21,22,25,40)}

Clone (no. of strains)	% of resistance
	ABPC	MPIPC	LVFX	CAM	CLDM	GM	MINO	VCM	LZD
USA300 (238)	100	97.5	89.9	67.6	1.7	73.5	0.8	0	0
ΨUSA300 (62)	100	100	88.7	61.3	3.2	12.9	0	0	0
USA300-LV/J (39)	100	94.9	82.1	55.3	2.6	64.1	0	0	0
ST22-PT (30)	100	100	86.7	50.0	3.3	26.7	0	0	0
South West Pacific (20)	100	95.0	25.0	25.0	0	15.0	0	0	0
Taiwan (11)	100	45.5	9.1	81.8	81.8	9.1	0	0	0
LA-MRSA human variant (9)	100	100	0	88.9	100	33.3	0	0	0

ABPC, ampicillin; MPIPC, oxacillin; LVFX, levofloxacin; CAM, clarithromycin; CLDM, clindamycin; GM, gentamicin; MINO, minocycline; VCM, vancomycin; LZD, linezolid; PVL, Panton–Valentine leukocidin.

5. CONCLUSION

The prevalence of HA-MRSA isolates in Japan has changed significantly in just 10 years. One of the reasons for this change is that the AMR Action Plan has reduced the selection pressure of antimicrobial agents. Therefore, CA-MRSA, with its high antimicrobial susceptibility and low fitness costs, was able to colonize the hospital. Additionally, it is difficult to distinguish HA-MRSA from CA-MRSA based on clinical definitions (Table 1). The antimicrobial susceptibilities of SCCmec type II and IV strains correspond to those of HA-MRSA and CA-MRSA, respectively.⁵⁾ We believe that HA-MRSA and CA-MRSA can be distinguished based on their SCCmec type and antimicrobial susceptibility.

The prevalence of PVL-positive MRSA, primarily the USA300 clone and its related strains, has rapidly increased in community and hospital settings. The number of foreign visitors to Japan exceeded 10 million for the first time in 2013, 20 million in 2016, and 30 million in 2018 due to the opening of a new international terminal at Haneda Airport in 2010. The increase in the number of patients with skin infections caused by PVL-positive MRSA coincided with an increase in the number of foreign visitors to Japan. Therefore, one of the factors contributing to the prevalence of PVL-positive MRSA in Japan may be the influx of various MRSA genotypes due to an increase in the number of travelers from overseas.

Our surveillance showed that the molecular epidemiological features of MRSA changed drastically over a short period. Because these changes will not occur quickly, it is important to continue monitoring the latest epidemics and recognizing signs early. The virulence, colonization ability, and antimicrobial susceptibility of MRSA vary widely, depending on the epidemic type. Therefore, we believe that the treatment and prevention of MRSA infections should be updated based on the current molecular epidemiological features of MRSA.

Conflict of Interest

The author declares no conflict of interest.

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