What we can and cannot see from the surveillance for drug-resistant Pseudomonas aeruginosa - Findings from the evaluation of surveillance system for multidrug-resistant P. aeruginosa infections in Japan

doi:10.21203/rs.3.rs-4695483/v1

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What we can and cannot see from the surveillance for drug-resistant Pseudomonas aeruginosa - Findings from the evaluation of surveillance system for multidrug-resistant P. aeruginosa infections in Japan

https://doi.org/10.21203/rs.3.rs-4695483/v1

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Introduction Antimicrobial resistance of Pseudomonas aeruginosa is a global health concern, and some countries and regions have been monitoring drug resistance in P. aeruginosa with various surveillance systems. Japan has a national sentinel surveillance for multidrug-resistant P. aeruginosa (MDRP) infections, the sites of which are designated by prefectures, and we are seeing a decreasing trend in the number of MDRP reports in recent years. We evaluated the national surveillance system to verify whether this decreasing trend is true and discussed future directions of the surveillance.

Methods We conducted a cross-sectional study to evaluate the surveillance system for MDRP infections and discussed its usefulness in 2023. We used a quantitative method to analyze characteristics of reports on MDRP infections from designated sentinel sites (DSSs) between 2013–2022. Additionally, we sent a questionnaire to identifiable DSSs (target DSSs) requesting data on accurate numbers of MDRP infections between 2018–2022. We conducted face-to-face interviews with surveillance system stakeholders as a qualitative method.

Results In total, 1,666 cases of MDRP infections were reported by 463 target DSSs between 2013-2022. We obtained valid responses to the questionnaire survey from 229 target DSSs (49.5%). From 2018 to 2022, these sites reported 275 cases as MDRP infections, of which 182 were accurate cases of MDRP infection, with both numbers decreasing over time. False reporting or underreporting of MDRP infections was common, resulting in a positive predictive value of 0.44 and sensitivity of 0.65 for reports in the national sentinel surveillance. The interviews highlighted the difficulties this surveillance system has in timely detection, accurate reporting, and international comparison of surveillance data.

Conclusion Our evaluation indicated that current sentinel surveillance for MDRP infections fairly captured the true decreasing trend in Japan. As the epidemiology of drug-resistant P. aeruginosa is changing, the direction of the national policy may differ according to the public health needs. The surveillance system also needs to be modified based on the policy, the candidates of which may be a notifiable disease surveillance for MDRP infections to respond to outbreaks, or sentinel surveillance for carbapenem-resistant P. aeruginosa infections to facilitate antimicrobial stewardship and international comparison.

Antimicrobial resistance

Carbapenems

Infection control

Pseudomonas aeruginosa

Surveillance system

Pseudomonas aeruginosa is a Gram-negative bacterium responsible for opportunistic infections in immunocompromised hosts [1] that is frequently associated with healthcare-acquired infections [2]. Additionally, it is also a major public health concern, as evidenced by the outbreak linked to artificial tears in the United States (U.S.) in 2023 [3].

Antimicrobial resistance (AMR) of P. aeruginosa is recognized as a global health concern. P. aeruginosa has multiple mechanisms for acquiring antibiotic resistance [4] that can lead to a serious prognosis [5, 6]. In particular, carbapenem-resistant P. aeruginosa (CRPA) and multidrug-resistant P. aeruginosa (MDRP) have higher mortality rates compared to susceptible strains of P. aeruginosa [5–8]. Thus, the World Health Organization (WHO) listed CRPA as a pathogen of critical priority in 2017 [9]. Although CRPA has been moved from critical to high priority in the 2024 update, innovative research and development of antibiotics remain needed due to the significant burden in high-income countries and several regions [10]. The U.S. Centers for Disease Control and Prevention (CDC) has estimated 32,600 cases and 2,700 deaths due to MDRP infections annually and classified them as a serious public health threat, calling for the need for prompt and sustained action in 2019 [11].

Some countries and regions conduct surveillance for drug-resistant P. aeruginosa. The European Antimicrobial Resistance Surveillance Network (EARS-Net) collects AMR data from European Union and European Economic Area countries through the European Surveillance System and annually reports the proportions of MDRP within the WHO European Region and CRPA in each country [12]. In the U. S., the CDC tracks carbapenemase enzymes in CRPA by using data generated by the Antibiotic Resistance Laboratory Network (AR Lab Network) and CDC laboratories [13, 14].

Japan has two national surveillance system for drug-resistant P. aeruginosa [15]. First, the National Epidemiological Surveillance of Infectious Diseases (NESID) was launched in April 1999 based on the “Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases”. In this system, the sentinel sites report the MDRP infections with the information of age, sex, and detected specimen to the local public health center monthly to assess the nationwide trend in the number of MDRP infections. The central infectious disease surveillance center (National Institute of Infectious Diseases) integrates the data and shares it with the Ministry of Health, Labour and Welfare (Supplementary Fig. 1) [16, 17]. Second, the Japan Nosocomial Infections Surveillance (JANIS) was implemented in 2000 as a voluntary surveillance system designed to specifically monitor infection and colonization in healthcare settings. This system is a national statistical survey based on the “Statistics Act” and has collected all routine microbiological test results for more than eight million clinical samples annually from over 2,000 facilities as of 2022, the data format of which is uniform even though each hospital uses a different antimicrobial resistance testing system [15, 18, 19]. In both NESID and JANIS, MDRP is defined as P. aeruginosa resistant to three anti-pseudomonas antibiotics: carbapenems, amikacin, and fluoroquinolones [20]. To survey long-term trends in antimicrobial susceptibilities among relevant pathogenic bacteria, the susceptibility criteria used by NESID and JANIS for sentinel surveillances differ somewhat from the clinical breakpoints established by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (Supplementary Table 1) [21, 22].

The number of MDRP infections reported from sentinel sites to NESID peaked in 2003 at 759 cases (1.62 per sentinel site). Since then, the number has decreased, with 103 cases reported in 2022 (0.22 per sentinel site) [23]. It is thus necessary to evaluate whether this trend accurately represents the actual trend in MDRP infections nationwide. In 2023, the AMR national action plan (NAP) in Japan set a goal of achieving carbapenem resistance of P. aeruginosa of 3% or less by 2027 rather than focusing on the occurrence of MDRP [24]. Consequently, we also examined the current surveillance systems necessary at the national level for controlling drug-resistant P. aeruginosa.

Study design and aims

We conducted a cross-sectional study to evaluate the NESID for MDRP infections through quantitative and qualitative methods in 2023. Our study aimed to evaluate whether NESID accurately captures the nationwide trend in MDRP infections and to examine the surveillance systems necessary for controlling drug-resistant P. aeruginosa. We assessed the nine attributes of representativeness, positive predictive value (PPV), sensitivity, data quality, acceptability, timeliness, simplicity, flexibility, and stability, and discussed the usefulness of this surveillance (Table 1). This evaluation was mainly based on the Guidelines for Evaluating Public Health Surveillance Systems published by the U.S. CDC in 2001 [25].

NESID for MDRP infections in Japan

In Japan, each prefectural government selects at least one designated sentinel site (DSS) per secondary medical area, which is a medical administrative area under the Medical Care Law. The DSS generally is capable of hospitalizing at least 300 patients and has internal medicine and surgery departments [16, 17]. The DSSs can be changed according to the local governments’ needs. As details of the DSSs are not publicly available, we defined them as target DSSs (TDSSs) that remained open as of December 2022 and met either of the following two conditions:

(a) DSSs that reported MDRP infections to NESID from January 2013 to December 2022, or

(b) DSSs that reported methicillin-resistant Staphylococcus aureus (MRSA) infections to NESID from January to December 2021.

Condition (b) was required because MRSA infections are reported from most of the hospitals in Japan [19].

Data collection

Quantitative evaluation

We analyzed the characteristics of reports as MDRP infections to NESID from DSSs between January 2013 and December 2022. In February 2023, we sent a questionnaire to TDSSs, requesting the accurate number of MDRP infections occurring at each site between January 2018 and December 2022. If responses from the TDSS included the answer “unknown” for any year, we excluded all responses from the TDSS as invalid responses. We evaluated these results separately for hospitals with 300 or more beds and hospitals with fewer than 300 beds.

Qualitative evaluation

On the basis of the information flow (Supplementary Figure 1), we conducted face-to-face interviews with stakeholders of the surveillance system about its relevant attributes such as representativeness, acceptability, simplicity, and usefulness. In addition to three representatives from national academic authorities, our interviewees included two public health officers working at one local infectious disease surveillance center in a specific prefecture. We also selected six physicians, one infection control nurse, two pharmacists, and two bacteriology technologists working at five hospitals within the same prefecture (two TDSSs and three non-TDSSs), which were recommended by each local government. A well-trained interviewer conducted each interview by using a set of questionnaire items (Table 1) that was reviewed by experienced physicians and clinical microbiology technologists.

Analysis

We defined (i) as the number of reports of MDRP infections to NESID from TDSSs between January 2018 and December 2022 and (ii) as the number of MDRP infections reported as accurate MDRP infections on the questionnaire survey. We defined (iii) as the number of cases misreported as MDRP infections despite not meeting the criteria and (iv) as the number of underreported accurate MDRP infections computed as follows (Supplementary Figure 2):

(iii) = (i) – (ii) ((i) > (ii))

(iv) = (ii) – (i) ((ii) > (i))

We counted (i) through (iv) for each hospital, aggregated them annually, and evaluated the trend. In addition, we calculated the PPV and sensitivity of reports of MDRP infections by using pooled data in NESID from 2018 to 2022.

Ethics considerations

Because the information handled in this study does not lead to the identification of individuals, the National Institute of Infectious Diseases did not require informed consent or ethical review (receipt no. 1478).

In total, 1,670 cases were reported to NESID as MDRP infections from 347 DSSs between 2013 and 2022. One DSS reporting two cases closed in 2015, whereas the status of two others reporting one case each remained unknown. Although 119 DSSs did not report any cases as MDRP infections during the same period, they reported at least one case of MRSA infection in 2022. Thus, TDSSs in this study were defined as 463 facilities reporting 1,666 cases.

All 463 of the TDSSs offer both internal medicine and surgery. Among them, 347 (74.9%) have 300 or more beds and 116 (25.1%) have fewer than 300 beds, accounting for 24% and 2%, respectively, of all medical institutions with the same capacities in Japan. From 2013 to 2022, at least one case was reported as a MDRP infection by 262 (75.5%) of the 347 TDSSs with 300 or more beds and 82 (70.7%) of 116 TDSSs with fewer than 300 beds. The results of the quantitative and qualitative evaluation for each attribute are summarized in Table 1.

Quantitative evaluation

TDSSs accounted for 5–10% of all medical institutions in many prefectures, and TDSSs with 300 or more beds accounted for more than 80% of all TDSSs in most prefectures (Figure 1). In the questionnaire survey, we obtained valid responses from 229 TDSSs (49.5%) (Table 2). From 2018 to 2022, these TDSSs reported 275 cases as MDRP infections, of which 182 were accurate MDRP infections, with both numbers decreasing over time (Figure 2). There were 162 misreported as MDRP infections despite not meeting the criteria and 69 underreported as MDRP infections, with Figure 3 showing the distribution of TDSSs that misreported and underreported MDRP infections. Two TDSSs with fewer than 300 beds misreported 10 and 11 cases, respectively, and one TDSS with 300 or more beds underreported seven accurate MDRP infections. We excluded these cases as outliers when calculating PPV and sensitivity. Thus, the PPV and sensitivity for the reports of MDRP infections to NESID between 2018 and 2022 were 0.44 and 0.65, respectively (Table 3).

Qualitative evaluation

One public health officer working at a local infectious disease surveillance center said that DSSs were selected properly based on Japanese law. However, this same public health officer, some physicians, and one infection control nurse pointed out that it was insufficient for only DSSs to report MDRP infections because outbreaks occurring at long-term care facilities or small hospitals may be overlooked. Additionally, they questioned the appropriateness of reporting MDRP infections monthly because such outbreaks require prompt public health action. Some physicians found it easy to report the cases to NESID, but these physicians and clinical microbiology technologists mentioned that reporting errors may be caused by complicated criteria used to confirm resistance to three antibiotics using standards different from the breakpoints of CLSI and EUCAST, and colonized cases were excluded. These physicians and national academic authorities indicated that the reports of CRPA infections would enable comparison of the situation with other countries and could be utilized as an indicator for the appropriate usage of broad-spectrum antibiotics based on the Japanese NAP. For these reasons, most of the interviewees concluded that the current surveillance system for MDRP infections is difficult for the government and medical institutions to utilize for the control of drug-resistant P. aeruginosa.

We evaluated the Japanese surveillance system, NESID, for surveillance of MDRP infections quantitatively and qualitatively mainly based on the CDC guidelines [25]. Although current surveillance fairly captured the trend of MDRP infections in Japan, the surveillance should be designed based on actions and goals for the control of drug-resistant P. aeruginosa infections in the country.

The number of accurate MDRP infections occurring at TDSSs decreased over time, as did the number of cases reported as MDRP infections. Moreover, NESID showed good representativeness because TDSSs uniformly existed in each prefecture according to the population [16, 17], and there was no geographical bias was detected from our findings (Figure 1). Thus, we considered that the decreasing trend in surveillance data in TDSSs reflected the actual trend of MDRP infections across Japan. Additionally, data from JANIS, another national-level AMR surveillance system in Japan, also showed a decreasing trend of MDRP detection in inpatient settings from 0.05% in 2017 to 0.03% in 2022, which may also reflect the actual domestic situation due to its high coverage of hospitals (close to one-fourth of all hospitals participated in 2022) in Japan [15, 19]. Consequently, the original objective of NESID to assess the trend of MDRP infections has been achieved, and we confirmed from the surveillance data that the number of MDRP infections in Japan has been decreasing.

We learned through the interviews that some of the interviewees were of the opinion that the current surveillance system does not meet public health needs. Thus, the current situation should be reviewed to improve the surveillance system to meet new objectives in the control of drug-resistant P. aeruginosa infections nationwide. Drug-resistant P. aeruginosa was classified into CRPA, MDRP, extensively drug-resistant P. aeruginosa (XDRP), and pan drug-resistant P. aeruginosa (PDRP) according to the standardized international terminology published in 2012 [26]. Furthermore, difficult-to-treat resistance P. aeruginosa (DTRP) was defined in 2018, with a focus on the lack of effective first-line drugs [27-29]. As drug-resistant P. aeruginosa has been classified in several ways, each country focuses on different types [30]. In the AMR NAPs published in 132 countries [31], 51 countries (38.6%) mentioned P. aeruginosa, and 10 countries (7.6%) included it in their numerical benchmarks; eight countries targeted CRPA, while two countries targeted MDRP. No NAPs were targeting XDRP, PDRP, or DTRP at the end of 2023 (Supplementary Table 2).

The important points to be discussed in designing a surveillance system for drug-resistant P. aeruginosa are the definition of drug resistance including antimicrobial susceptibility testing and whether to conduct notifiable diseases surveillance or sentinel surveillance (Table 4).Regarding the definition of drug resistance, we focused on MDRP and CRPA, which were targeted by NAPs published in several countries.

Surveillance for drug-resistant P. aeruginosa to eliminate MDRP

MDRP is defined as P. aeruginosa non-susceptible to at least one agent in three and over antimicrobial categories such as carbapenems [26]. MDRP has quite limited treatment options and often leads to high inpatient mortality and prolonged hospital stays [32]. Thus, early detection is essential for an effective response to MDRP outbreaks. However, not all MDRP outbreaks can be identified through the sentinel surveillance unless the outbreak is epidemiologically or genetically unusual [33]. To eliminate MDRP outbreaks promptly, notifiable disease surveillance is preferable to sentinel surveillance because notifiable disease surveillance can detect MDRP infections from all hospitals. One challenge of the notifiable disease surveillance of MDRP is the difficulty in confirming drug resistance. Our results revealed an increase in the number of cases reported as MDRP infections despite not meeting the reporting criteria from 2018 to 2022. This issue would persist even if the surveillance system were changed to notifiable disease surveillance. Thus, quality assurance of antimicrobial susceptibility testing is the key to the successful implementation of the notification system. Another challenge is that we need to note whether the definition of MDRP is consistent when we compare the proportions of MDRP with other countries and regions.

Surveillance for drug-resistant P. aeruginosa to control carbapenem resistance

Carbapenems are essential broad-spectrum antibiotics that lead many developed countries to monitor CRPA infections. Such monitoring enables these countries to compare the carbapenem resistance rates of P. aeruginosa with each other [34]. For instance, EARS-Net determined the proportions of CRPA in each country within the WHO European Region and showed large differences [12]. A previous article indicated that appropriate use of carbapenems was inversely correlated with the prevalence of CRPA [35]; thus, the proportions of CRPA could serve as an indicator of the rational use of carbapenems. In addition, as carbapenemase-producing isolates of P. aeruginosa can cause severe outbreaks [3, 36], laboratory testing for carbapenemase is crucial. In the U. S., the AR Lab Network reported detecting carbapenemase genes in 2.2% of 68,712 CRPA isolates analyzed between 2017 and 2022, with 58.3% of them identified as VIM [14]. In contrast, only 4.2% of 382 meropenem-resistant CRPA isolates collected from 78 hospitals in Japan possessed acquired carbapenemases, with the IMP type being the most frequent, and no VIM-producing CRPA isolates were detected. Multilocus sequence typing of the 382 CRPA isolates revealed that ST274 was predominant. Notably, ST274 CRPA isolates rarely carried carbapenemase [37]. We consider it important to integrate the reporting system with laboratory-based surveillance to comprehensively evaluate the trend of CRPA infections, including the results of genomic sequencing. However, if CRPA infections are classified as notifiable diseases, excessive numbers of cases would be reported, potentially leading to economic costs and burdens for medical and laboratory institutions because P. aeruginosa has resistance to carbapenems through various mechanisms other than carbapenemase production [4]. Thus, sentinel surveillance integrated with laboratory-based surveillance would be indispensable to controlling carbapenem resistance by assessment of the trend of the number of CRPA infections and evaluation of whether CRPA isolates produce any of the carbapenemases.

Our study has some limitations. First, as we interviewed staff members working at hospitals and one local infectious disease surveillance center located in a specific prefecture, it is possible that the situation might differ somewhat from those in other regions. However, we endeavored to generalize the findings by conducting interviews with national academic authorities from various prefectures. Second, the interview results could be influenced both by social desirability bias that interviewees’ facilities have fewer underreported or misreported cases and by recall bias. Thus, we performed not only qualitative but also quantitative analysis for a comprehensive evaluation. Third, the reports of MDRP infections in NESID and our questionnaire survey were not confirmed by laboratory testing.

Our evaluation of the surveillance system for MDRP infections in Japan indicated that the reports of MDRP infections from DSSs represented the nationwide trend in MDRP infections, which has been decreasing over time. However, our study also showed that this system did not seem to meet current public health needs. Of concern were the difficulties in timely detection of and response to a cluster of MDRP infections due to reporting at monthly intervals, in accurate reporting due to complex diagnostic criteria, and in international comparison due to different definitions. As the epidemiology of drug-resistant P. aeruginosa is changing, the national policy may differ according to the public health needs, and the surveillance system also needs to be modified. Potential candidate systems may be a notifiable disease surveillance for MDRP infections or a sentinel surveillance integrated with laboratory-based surveillance for CRPA infections. Based on our findings, can contribute to develop the refined surveillance system to better manage drug resistance in P. aeruginosa.

AMR Antimicrobial resistance

AR Lab Network Antibiotic Resistance Laboratory Network

CDC Centers for Disease Control and Prevention

CLSI Clinical and Laboratory Standards Institute

CRPA Carbapenem-resistant Pseudomonas aeruginosa

DSS Designated sentinel site

DTRP Difficult-to-treat resistant Pseudomonas aeruginosa

EARS-Net European Antimicrobial Resistance Surveillance Network

EUCAST European Committee on Antimicrobial Susceptibility Testing

JANIS Japan Nosocomial Infections Surveillance

MDRP Multidrug-resistant Pseudomonas aeruginosa

MRSA Methicillin-resistant Staphylococcus aureus

NESID National Epidemiological Surveillance of Infectious Diseases

NAP National action plan

PDRP Pan drug-resistant Pseudomonas aeruginosa

PPV Positive predictive value

TDSS Taget designated sentinel site

U.S. United States

WHO World Health Organization

XDRP Extensively drug-resistant Pseudomonas aeruginosa

Ethical approval and consent to participate

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding

This research was supported by the Ministry of Health, Labour and Welfare, Japan [Grant number 23HA1004].

Authors’ contributions

SO and TY contributed to conception and design of the study. SO and TY collected the study data. SO, TY, T Shiomoto, MN, H Kurosu, CI, H Kato, MF, T Shimada, TT, M Suzuki, T Sunagawa, and M Sugai interpreted the data. SO and TY wrote the first draft of the manuscript, and T Shiomoto, TK, YA, and KN revised it. All authors reviewed the manuscript, made comments, and approved the final version.

Acknowledgements

We are grateful to public health officers, physicians, pharmacists, and clinical microbiology technologists who participated in the face-to-face interviews. We also thank the staff working at the designated sentinel sites, local public health centers, local infectious disease surveillance centers, and local public health institutes for cooperating with reporting to the national surveillance system and for responding to our questionnaire survey.

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Tables 1 to 4 are available in the Supplementary Files section

No competing interests reported.

SupplementaryFigure1.tif
Supplementary Fig. 1. Information flow of surveillance system for MDRP in Japan. The sentinel sites report the MDRP infections with the information of age, sex, and detected specimen to the local public health center monthly. The central infectious disease surveillance center integrates the data and shares it with the Ministry of Health, Labour and Welfare. MDRP multidrug-resistant Pseudomonas aeruginosa
SupplementaryFigure2.tif
Supplementary Fig. 2. Theoretical schema of cases misreported as MDRP infections and underreported as accurate infections. (i) The number of cases reported as MDRP infections. (ii) The accurate number of MDRP infections. (iii) The number of cases misreported as MDRP infections. (iv) The number of underreported accurate MDRP infections. MDRP multidrug-resistant Pseudomonas aeruginosa
Supplementarytable1.xlsx
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Editorial decision: Revision requested
09 Jul, 2024
Editor assigned by journal
08 Jul, 2024
Submission checks completed at journal
08 Jul, 2024
First submitted to journal
06 Jul, 2024

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What we can and cannot see from the surveillance for drug-resistant Pseudomonas aeruginosa - Findings from the evaluation of surveillance system for multidrug-resistant P. aeruginosa infections in Japan

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