Setting
Aomori prefecture has six major medical regions: Shimokita, Kamitosan, Hachinohe, Aomori city, Seihokugo, and Tsugaru. The Hachinohe, Aomori city, and Tsugaru regions each have a tertiary general hospital with more than 500 beds. There are several medium-sized general hospitals in these six medical regions. The prevalence rates of VRE-positive patients among patients tested for bacteriological cultures in 2017 in Aomori prefecture and in Japan were 0.003% and 0.024%, respectively 3). During the period from January 2018 to January 2021, interhospital transmission of VRE occurred in 14 hospitals in Aomori prefecture, indicated as A–N in chronological order according to the date of the first VRE-positive case identified at each hospital (Fig. 1), and included two tertiary general hospitals. Six hospitals had insidious intra-institutional spread of VRE, and required long-lasting strict countermeasures to end the outbreak.
Index case
Hospital A is a small-sized hospital with < 100 beds in the Hachinohe area. The first VRE-positive patient was detected there on January 26, 2018, followed by a second case three weeks later. The vanA gene was detected by PCR in the VRE isolates. Bacteriological screening of hospitalized patients, as instructed by the health center of Hachinohe city, revealed four additional cases in February. The health center shared information with AICON about the VRE outbreak at hospital A, which is not a member of AICON. On March 16, 2018, an emergent external inspection was carried out at hospital A by the health center of Hachinohe city. Genetic analysis and PFGE analysis suggested healthcare-associated transmission of vanA type VREf. A total of 15 cases were identified at this hospital during the eight-month period of the outbreak (Fig. 2).
Hospital B
Following the outbreak at hospital A, VRE outbreaks occurred in five general hospitals (B, C, D, E and G) from 2018 to 2020 (Fig. 2). Hospitals B, C, D and G belonged to AICON at the onset of the outbreaks. In hospital B, a general hospital with > 400 beds, five VRE-positive patients were identified in a medical ward in May 2018 following the identification of one patient in April 2018. VRE spread to five other wards in the next few months despite countermeasures that included patient cohorting, active surveillance, and education of medical staff. A second outbreak then occurred in December 2018, during which all inpatients were screened monthly and VRE-positive patients were cared for in a newly prepared isolation ward. Four external inspections were carried out during this long-standing outbreak (June 2018, January 2019, February 2019, and March 2019) by different teams of specialists sent from among the Japan Red Cross Society, Iwate University Hospital, and the National Institute of Infectious Diseases. Active surveillance of all patients at admission detected very few VRE-positive patients, indicating that there was no spread of VRE within the community. It took 33 months for hospital B to end the outbreak.
Hospital C
The first VRE-positive case appeared in August 2018 in the emergency department of hospital C, a tertiary general hospital in the same medical region as hospitals A and B. Despite countermeasures such as isolation and strict hand washing, active screening in the emergency department of hospital C revealed an abrupt increase in positive cases between December 2018 and January 2019, and a patient with severe burns was infected with VRE during this period. It was thought that meticulous wound care and handling of wet wound coverings contaminated with VRE would minimize the risk of spread; however, screening of all patients revealed additional VRE-positive cases in other wards. Scheduled hospitalizations and surgeries were postponed and the hospital accepted only emergent cases. External inspection was carried out by team of specialists sent by Hirosaki University Hospital, a member of AICON. An isolation ward was prepared as soon as the spread of VRE within the hospital was confirmed. Monthly screening of all inpatients was repeated between February 2019 and December 2019. The spread of VRE was brought under control after February 2019, and the number of VRE-positive patients decreased gradually thereafter.
Hospital D
One VRE-positive patient was found in September 2018, followed in November 2018 by two more patients in hospital D, a tertiary general hospital in Aomori city in the Tosei medical area. An additional six cases were found in screening of patients hospitalized on the same floor in December 2018. The first wave of the VRE outbreak was controlled by regular countermeasures such as strict hand washing, patient isolation, and active VRE screening of patients at hospitalization and at every month after hospitalization in the ward. After the curve of the epidemic showed a nadir in February 2018, a second outbreak occurred in May 2019, during which countermeasures for VRE-outbreak in the hospital were evaluated by specialists from the local government, Aomori City Health Center, AMR Clinical Reference Center in National Center for Global Health and Medicine, and AICON at an external inspection in December 2018. Monthly screening of all inpatients was repeated from May 2019. Active screening for VRE during the period from September 2019 to July 2020 revealed that 12/49 (24.5%) VRE-positive cases were already infected with VRE at the time of admission. VRE-positive patients at admission suggested the spread of VRE within the medical region. The number of VRE-positive patients gradually decreased after August 2019, and returned to zero in December 2019.
Hospital E
Hospital E is a medium-sized general hospital in the Hachinohe medical region. Patients are referred between hospitals B and E. Because of the VRE outbreak at hospital B, active VRE screening began at hospital E in May 2019. Six VRE-positive inpatients were found at the first screening. Monthly screening of all inpatients was introduced after the first external inspection by infection control specialists arranged through AICON. Follow-up external inspection was carried out in late November 2019. Infection control activities such as hand washing, zoning, environmental hygiene, and education were evaluated and encouraged. The number of VRE-positive patients returned to zero in January 2020.
Hospital G
Hospital G is a medium-sized general hospital in the Kamitosan medical region. VRE-positive patients were found sporadically at this hospital during periods of VRE outbreaks at other hospitals. The local health center of Kamitosan detected sporadic cases of VRE-positive patients in hospitals in their area of responsibility. Following the recommendation of the local health center, the first screening for VRE was carried out for hospitalized patients in December 2019, and found five VRE-positive patients. In addition to the reinforcement of routine infection control activities, VRE screening of patients at hospitalization was started immediately after the first screening. The outbreak ended within six months.
Other hospitals
From 2019, AICON recommended that participating hospitals should screen for VRE at hospitalization, which was conducted at 12 general hospitals and 1 special hospital. A small number of VRE-positive patients was detected by this screening and there was minimal intra-hospital transmission. No new VRE-positive cases were detected after May 2020 (Fig. 3).
Changes in VRE prevalence in 47 Japanese prefectures in 2015–2020
Figure 4 shows the VRE prevalence rate in the 47 prefectures of Japan, obtained from the JANIS surveillance data. VRE outbreaks at multiple hospitals in the same period caused a sharp peak in VRE prevalence. The remarkable size of the area under the curve representing Aomori prefecture suggests the epidemiological importance of the series of VRE outbreaks in this prefecture.
Change in the number of patients tested for bacteriological cultures in 2017–2020
The number of patients tested for bacteriological cultures in hospitals participating in AICON showed a remarkable increase during the VRE outbreak period. The total number in 2019 was 41.7% greater than that in 2017 (Figure 5).
Decrease in MRSA prevalence by countermeasures against VRE
Although the MRSA prevalence rate in hospitals B, C, and D had been consistently much lower than the average in Japanese hospitals participating in JANIS before the VRE outbreak, reinforced countermeasures against nosocomial infections resulted in a further decrease in the prevalence of MRSA during VRE outbreaks. In comparison between the data from MINA and JANIS, which represent Aomori prefecture and Japan, respectively, the MRSA prevalence rate decreased in MINA but not in JANIS (Figure 6).
Analysis of VRE strains using PFGE
Table 1 lists six source hospitals and sampling year for 20 isolates that were tested by PFGE analysis. VRE strains showed identical or very close patterns in PFGE analysis (Fig. 7). Lanes 1, 3, 6, 10, 11, 12, 15, 16, and 18 were judged as identical strains. Lanes 2, 4, and 19 were also identical. The former and the latter were judged as closely related with more than 85% similarity, which indicates interhospital clonal spread of VRE in this series of outbreaks.
SNPs phylogenetic tree analysis
Figure 8 shows the phylogenetic tree based on the core genome SNPs of the same 20 isolates. Whole genome sequencing analysis indicated vanA-type VREf ST1421 for most samples except samples 7 and 8 from hospital D. These were identified as other vanB-type strains, although sample 6, also from hospital D, was identified as vanA-type VREf ST1421.