. 2020 Oct 22;15(10):e0240655. doi:10.1371/journal.pone.0240655

Improved penicillin susceptibility ofStreptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18

Shinya Tsuzuki^1,^2,^*,Takayuki Akiyama¹,Nobuaki Matsunaga^1,^*,Koji Yahara³,Keigo Shibayama^3,⁴,Motoyuki Sugai³,Norio Ohmagari^1,⁵

Editor:Shampa Anupurba⁶

¹AMR Clinical Reference Center, National Center for Global Health and Medicine, Tokyo, Japan

²Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

³Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Tokyo, Japan

⁴Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo, Japan

⁵Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan

⁶Institute of Medical Sciences, Banaras Hindu University, INDIA

Competing Interests:The authors have declared that no competing interests exist.

^✉

* E-mail:stsuzuki@hosp.ncgm.go.jp(ST);nomatsunaga@hosp.ncgm.go.jp(NM)

Roles

Shinya Tsuzuki:Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing – original draft

Takayuki Akiyama:Methodology, Visualization, Writing – review & editing

Nobuaki Matsunaga:Conceptualization, Investigation, Project administration, Writing – review & editing

Koji Yahara:Data curation, Writing – review & editing

Keigo Shibayama:Data curation, Writing – review & editing

Motoyuki Sugai:Conceptualization, Writing – review & editing

Norio Ohmagari:Funding acquisition, Project administration, Supervision, Writing – review & editing

Shampa Anupurba:Editor

Received 2020 Jul 26; Accepted 2020 Oct 1; Collection date 2020.

This is an open access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PMC Copyright notice

PMCID: PMC7580930 PMID:33091045

Abstract

Objectives

To examine the association between penicillin susceptibility ofStreptococcus pneumoniae and penicillin consumption in Japan.

Methods

We used Japan Nosocomial Infection Surveillance data on the susceptibility ofS.pneumoniae and sales data obtained from IQVIA Services Japan K.K. for penicillin consumption. We analysed both sets of data by decomposing them into seasonality and chronological trend components. The cross-correlation function was checked using Spearman’s rank correlation coefficient to examine the correlation between susceptibility and consumption.

Results

After adjusting for seasonality, the susceptibility ofS.pneumoniae to penicillins gradually improved (55.7% in 2013 and 60.6% in 2018, respectively) and penicillin consumption increased during the same period (0.76 defined daily doses per 1,000 inhabitants per day [DID] in 2013, and 0.89 DID in 2018). The results showed positive cross-correlation (coefficient 0.801,p-value < 0.001). In contrast, cephalosporin consumption decreased (3.91 DID in 2013 and 3.19 DID in 2018) and showed negative cross-correlation with susceptibility ofS.pneumoniae to penicillins (coefficient −0.981,p-value < 0.001).

Conclusions

The rates of penicillin-susceptibleS.pneumoniae isolates did not negatively correlate with penicillin consumption at the population level. Increased penicillin consumption might not impair the penicillin susceptibility ofS.pneumoniae.

Introduction

Antimicrobial resistance (AMR) is currently one of the greatest threats to global health [1,2].Streptococcus pneumoniae is one of the major targets of AMR surveillance [3–7] because both morbidity and mortality due to severe infections are substantial [8–10].

After publication of the Global Action Plan on Antimicrobial Resistance in 2015 [1], the Japanese government established its National Action Plan on Antimicrobial Resistance the following year [11]. This plan includesS.pneumoniae as one of the major target organisms and aims to improve the microbe’s susceptibility to penicillin. In this plan, the susceptibility ofS.pneumoniae to penicillins is described in terms of the minimum inhibitory concentration (MIC) threshold for pneumococcal meningitis defined by the Clinical Laboratory Standards Institute (CLSI) in 2015 [12]. According to this criterion, 48% ofS.pneumoniae isolates in Japan were resistant to penicillins in 2014, and the Ministry of Health, Labour and Welfare (MHLW) of Japan set a goal to reduce the proportion of penicillin-resistantS.pneumoniae (PRSP) to below 15% by 2020 [11].

Because the guidelines published by the CLSI are now used in Japan, we used the interpretive MIC breakpoints for meningeal and non-meningeal isolates ofS.pneumoniae according to the 2008 revision of CLSI guidelines [13]. However, these figures change considerably when the non-meningitis MIC threshold is applied. In 2014, 99.6% ofS.pneumoniae isolates were susceptible to penicillins and in 2018, the number rose slightly to 99.7% [14]. Under these circumstances, it is difficult for us to find a substantial difference in the proportion of susceptible isolates before and after the action plan. If we used non-meningitis MIC, it would be difficult to find a time-series trend because mostS.pneumoniae would be classified as “sensitive”. However, the sample size would be too small if we used only cerebrospinal fluid specimens to monitor the penicillin susceptibility ofS.pneumoniae. Considering this, it might be reasonable to apply the meningitis MIC threshold to all types of specimens (sputum, cerebrospinal fluid, etc.) to follow the trend of AMR inS.pneumoniae.

Nevertheless, evaluation by meningitis MIC threshold is not an established method for surveying trends in the penicillin susceptibility ofS.pneumoniae. For instance, Torumkuney and colleagues evaluated the susceptibility ofS.pneumoniae from respiratory tract specimens via both non-meningitis and meningitis MICs [3,15]. Karlowsky and colleagues reported MIC₉₀ as an indicator of resistance [6]. However, because MIC₉₀ to penicillins was 0.12 mg/L in most years, it is not a good alternative for monitoring the trend. Although the European Committee on Antimicrobial Susceptibility Testing (EUCAST) uses 0.06 mg/L as the threshold for penicillin susceptibility, it defined the threshold for penicillin resistance as 2.0 mg/L and did not mention the classification of isolates whose MICs were between 0.06 mg/L and 2.0 mg/L [16]. Additionally, EUCAST redefined its susceptibility testing categories (i.e. S, I, and R) in 2019 [17]. Under the new definition,S.pneumoniae isolates, which have MICs of between 0.06 mg/L and 2.0 mg/L, are evaluated as “Susceptible, increased exposure”. Consequently, it is difficult to evaluate the penicillin susceptibility ofS.pneumoniae according to EUCAST criteria only.

The Survey of Antibiotic Resistance has provided findings about AMR in various countries and reported the distribution among MICs including MIC50 and MIC90 [3,15,18–25]. According to these previous studies,S.pneumoniae seldom showed MICs greater than 2 mg/L to penicillins in most countries, although the distribution of MIC values differed in each country. In other words, meningitis MIC might be a more appropriate threshold for monitoring the antibiotic susceptibility ofS.pneumoniae. However, non-meningitis MIC might be beneficial for clinical use because most community-acquired pneumococcal pneumonia can be treated with penicillin regardless of thein vitro MIC value [26,27].

Another concern is the recommendation of antibiotic prescriptions forS.pneumoniae. Needless to say, antibiotics should never be prescribed unless they are necessary, because the use of any type of antibiotic could exert selective pressure that could lead to AMR [28,29]. Many guidelines recommend the penicillin class of antibiotics as the first choice forS.pneumoniae infections due to its effectiveness and narrow spectrum [30–32]. However, it is unclear whether increased penicillin consumption at the population level could lead to reduced penicillin susceptibility ofS.pneumoniae.

This study had two main objectives. The first was to assess the appropriateness of meningitis MIC (0.06 mg/L) as an indicator for the penicillin susceptibility ofS.pneumoniae. The other was to evaluate the relationship between penicillin consumption at the population level and the penicillin susceptibility ofS.pneumoniae.

Materials and methods

Data source

We used data collected by Japan Nosocomial Infections Surveillance (JANIS), which was organized by the Ministry of Health, Labour and Welfare [33,34]. The JANIS Clinical Laboratory module comprehensively collects all routine microbiological test results, including culture-positive and -negative results from over 2000 hospitals voluntarily participating in the surveillance, which account for a quarter of the approximately 8000 hospitals across Japan.

We extracted the monthly data forS.pneumoniae (including isolates from blood, cerebrospinal fluid, and respiratory tract specimens) and its susceptibility to antibiotics from January 2013 to December 2018 from the database of the JANIS Clinical Laboratory module. Patients were de-identified by each hospital before the data were submitted to JANIS. We included 636 facilities that continuously submitted their data to JANIS between 2013 and 2018. Approval for the extraction and use of the data was granted by the Ministry of Health, Labour and Welfare (0214–3).

To assess antibiotic consumption, we used monthly sales data collected by IQVIA Services Japan, which covers more than 99% of drug distribution among wholesalers in Japan. We calculated the monthly AMU using defined daily doses per 1,000 inhabitants per day (DID) from January 2013 to December 2018. We defined antimicrobials as J01 according to the ATC classification [35].

Statistical analysis

We prepared monthly time-series data about the rate of penicillin-susceptibleS.pneumoniae isolates and sales volume of antibiotics by class (penicillins, cephalosporins, and sum of all classes). First, we decomposed both datasets into a trend component and a seasonality component to evaluate the chronological trend by using locally-weighted scatterplot smoother (LOWESS) method. Next, we used Spearman’s rank correlation test to examine the correlation between components. Additionally, we checked the correlation between susceptibility ofS.pneumoniae to penicillins and antibiotic consumption. Ap value < 0.05 was considered statistically significant. All analyses were conducted by R version 3.6.3 [36].

Results

Penicillin susceptibility ofS.pneumoniae isolates

By applying non-meningitis MICs, the rates of penicillin-susceptible isolates were 97.8% in 2013 and 98.3% in 2018 (Fig 1). However, when applying meningitis MICs, the rates were 55.7% for 2013 and 60.6% for 2018 (Fig 2). The difference in the rates of susceptible isolates between the two cases is shown inTable 1 andFig 3.

Fig 2 — The top row represents the raw data. The second row describes seasonality components. The third row describes trend components. The bottom row represents the remainder. Horizontal axes represent month and year. Vertical axes represent the rates of penicillin-susceptibleS.pneumoniae isolates.

Table 1. Rates of penicillin-susceptibleStreptococcus pneumoniae isolates in Japan, 2013–2018.

	Meningitis MICs (≤0.06 mg/L)	Non-meningitis MICs (≤2 mg/L)
2013	55.7%	97.8%
2014	57.6%	98.1%
2015	57.7%	98.0%
2016	59.0%	98.5%
2017	60.2%	98.5%
2018	60.6%	98.3%

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Fig 3 — The solid line with circles represents the results based on non-meningitis MICs and the dashed line with triangles represents the results based on meningitis MICs.

InFig 2, the rate of susceptible isolates increased as time elapsed, after adjusting for seasonality.Fig 4 represent the distribution of MICs ofS.pneumoniae isolates in each year.

Sales volume of antibiotics

While the sales volume of penicillins increased gradually (0.76 DID in 2013 to 0.89 DID in 2018), sales decreased for both cephalosporins (3.91 DID in 2013 to 3.19 DID in 2018) and total antibiotics (14.52 DID in 2013 to 12.91 DID in 2018) during the same period. The details are shown inTable 2 and Figs5–8.

Table 2. Annual sales volume of antibiotics in Japan, 2013–2018^*.

	Cephalosporins	Penicillins	Total
2013	3.91	0.76	14.52
2014	3.78	0.78	14.07
2015	3.82	0.85	14.23
2016	3.68	0.84	14.15
2017	3.43	0.83	13.36
2018	3.19	0.89	12.91

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*Unit = Number of defined daily doses per 1,000 inhabitants per day (DID).

Fig 5 — The solid line with circles represents the total antibiotics sales, the dashed line with triangles represent the sales of cephalosporin, and the dashed line with squares represent the sales of penicillin. The vertical axis represents the number of defined daily doses per 1,000 inhabitants per day (DID).

Fig 8 — The top row represents the raw data. The second row describes seasonality components. The third row describes trend components. The bottom row represents the remainder. Horizontal axes represent month and year. Vertical axes represent the number of defined daily doses per 1,000 inhabitants per day (DID).

Fig 6 — The top row represents the raw data. The second row describes seasonality components. The third row describes trend components. The bottom row represents the remainder. Horizontal axes represent month and year. Vertical axes represent the number of defined daily doses per 1,000 inhabitants per day (DID).

Fig 7 — The top row represents the raw data. The second row describes seasonality components. The third row describes trend components. The bottom row represents the remainder. Horizontal axes represent month and year. Vertical axes represent the number of defined daily doses per 1,000 inhabitants per day (DID).

Correlation between susceptibility and antibiotic consumption

The sales volume of penicillins positively correlated with the rate of penicillin-susceptible isolates (Spearman’s correlation coefficient: 0.801,p < 0.001). The sales volume of cephalosporins and total antibiotics negatively correlated with susceptibility (Spearman’s correlation coefficient: -0.981 and -0.888, bothp < 0.001). The details of the correlation tests are presented inTable 3.

Table 3. Correlation between antibiotic consumption and rate of susceptible isolates, 2013–2018.

	Coefficient^*	p-value
Cephalosporins	-0.981	< 0.001
Penicillins	0.801	< 0.001
All antibiotics	-0.888	< 0.001

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*Spearman’s rank correlation coefficient.

Susceptible isolates were defined as those MICs ≤0.06 mg/L.

Discussion

In this study, we evaluated CLSI meningitis MIC (or EUCAST criterion) as an indicator for the chronological trend of penicillin susceptibility ofS.pneumoniae. Our results showed that meningitis MIC can provide a more intelligible way of penicillin susceptibility follow-up than that of non-meningitis MIC. As mentioned above, JANIS uses MIC values defined by CLSI, and non-meningitis MICs do not reflect the present results because most of theS.pneumoniae isolates were penicillin susceptible according to non-meningitis MICs.

We have already recognized the utility of CLSI non-meningitis MICs as a threshold for the clinical choice of antibiotics for preventing antibiotic abuse because most bacterial pneumoniae cases caused byS.pneumoniae can be treated by penicillin, even if the MICs are above 0.06 mg/L [26,27,37–39]. Nevertheless, meningitis MICs are beneficial for AMR surveillance; therefore, the rate of penicillin susceptibility of allS.pneumoniae isolates should be assessed continuously by both non-meningitis and meningitis MICs. EUCAST criteria are useful if we regard 0.06 mg/L as the threshold for surveillance and 2.0 mg/L as the threshold for clinical use.

As for trend of antibiotic use, abuse of unnecessary antibiotics has been an important health issue in Japan, then various interventions have been implemented in Japanese healthcare system. For example, Ministry of Health, Labour and Welfare Japan became to provide incentives to healthcare facilities which implemented infection control team and other interventions in 2012 [40]. Although publication of National Action Plan was 2016, such interventions were considered to have influence on antimicrobial consumption at national level.

Increase of penicillin consumption can be considered as a result of promoting appropriate antibiotic use because cephalosporin and other classes of antibiotic consumption in Japan was higher than that in other countries [41]. When we reduced inappropriate cephalosporin and other classes of antibiotic consumption, a part of it should be replaced by penicillin.

Another novel finding is that the increase in penicillin consumption is not negatively associated with an increase in penicillin susceptibility inS.pneumoniae. On the contrary, our results showed that the sales volume of penicillins positively correlated with the rate of penicillin-susceptible isolates.

Of course, this should not be interpreted directly because the National Action Plan on Antimicrobial Resistance encouraged not only the use of narrow-spectrum antibiotics like penicillins but also the reduction of unnecessary prescriptions of any class of antibiotics [11]. As a result, the sales of cephalosporins and the sum of all classes of antibiotics decreased gradually during the study period. Similarly, antibiotic use decreased during the same period [42,43]. The improved penicillin susceptibility rate ofS.pneumoniae might be explained by this gradual decrease in total antibiotic consumption; hence, the positive correlation between the consumption of penicillins and susceptibility is not a causative relationship. Indeed, the negative correlation between total antibiotic consumption and penicillin susceptibility ofS.pneumoniae is compatible with the findings of previous studies [44,45].

Considering these findings, it seems that we do not need to change our current recommendation, which is the use of penicillin as the first choice for the treatment of pneumococcal pneumonias and bloodstream infections, because it will be unlikely to induce penicillin resistance, and the use of total antibiotics and cephalosporins is more strongly associated with a decrease of penicillin-susceptible isolates. It is possible that even in case the increase of penicillin consumption negatively influences the susceptibility ofS.pneumoniae, its influence might be cancelled by positive influence of consumption reduction of other classes. To encourage use “Access” drugs would be desirable in order to optimize antibiotic use at the population level [46–48].

Our data demonstrated obvious seasonality. Both sales data and penicillin resistance peaked in winter and were at their lowest levels in summer, similar to previous studies [44,45,49–51]. The correlation between the sales volume and susceptibility was strongest without lags, rather than with lags. Therefore, we are not sure about the length of time needed to observe the influence of changes in sales of antibiotics on susceptibility. It is easy to understand why antibiotic consumption peaks in winter, which is because acute respiratory tract infections are more commonly seen during this season; therefore, both appropriate and inappropriate use of antibiotics increases in winter. However, we are not sure why antibiotic resistance inS.pneumoniae peaks at the same time. This is another issue for further consideration.

This study had several limitations. First, our results showed correlation rather than causation. It is likely that increased penicillin consumption does not induce penicillin resistance inS.pneumoniae at the population level; however, it is also possible that improved penicillin susceptibility induces an increase in penicillin prescriptions. Second, we used only sales data and susceptibility data, and other factors (e.g. genetic mechanism) were not included in our analyses. Because various interventions, which include education for the general population, were implemented after (and even before) publishing the National Action Plan on Antimicrobial Resistance in Japan, social factors other than the decrease in antibiotic consumption might have had an influence on the susceptibility ofS.pneumoniae [52–55]. If we can take other societal factors into consideration, we may be able to evaluate the influence of change in antibiotic consumption on susceptibility more precisely.

Conclusions

Our findings suggest that meningitis MICs defined by CLSI might be useful indicators for the continuous monitoring of the susceptibility ofS.pneumoniae to penicillins. The increase in penicillin use is not positively associated with susceptibility ofS.pneumoniae isolates, which suggests that the current recommendations are reasonable. Further study including genetic mechanism of penicillin susceptibility ofS.pneumoniae would reveal additional details of the relationship between antibiotic consumption and antibiotic resistance inS.pneumoniae.

Supporting information

S1 Data

(ZIP)

Click here for additional data file.^{(25.2MB, zip)}

Acknowledgments

We would like to thank all the facilities that participated in JANIS.

Data Availability

Data are available within the Supporting Information file.

Funding Statement

Our study was supported by a grant from the Ministry of Health, Labour and Welfare (Grant number 20HA2003, changed from the previous one) and Research Program on Emerging and Re-emerging Infectious Diseases from the Japan Agency for Medical Research and Development (AMED) under grant number JP19fk0108061.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No author received a salary from the funders.

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PLoS One. doi:10.1371/journal.pone.0240655.r001

Decision Letter 0

Shampa Anupurba

Roles

Shampa Anupurba:Academic Editor

PMC Copyright notice

21 Aug 2020

PONE-D-20-23245

Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18

PLOS ONE

Dear Dr. Tsuzuki,

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Academic Editor

PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: The authors have carried out an important data analysis to reflect on the Penicillin susceptibility of Streptococcus pneumoniae and to show its relationship with consumption . They have collated data from JANIS , collected from 2000 healthcare setups. Appropriate statistical tools have been applied to show the changing outcomes . The diagrammatic representations would of the useful if appropriate legends as and explanatory statements had been placed for the table.

Few queries that and be addressed by the authors :

Whether the changes across the years were significantly different for Penicillin?

Why did the antibiotic consumption come down across the spectrum?

Was any regulatory mechanism influence the decrease?

It is interesting to note that as consumption went up the resistance came down, contrary to existing belief.

This calls for further look at genetic mechanism and factors influencing

Reviewer #2: The manuscript conveys an important message that, used appropriately, penicillin consumption may not be necessarily associated with increased resistance of Streptococcus pneumoniae to penicillin, by analyzing penicillin consumption data with penicillin susceptibility data over 5 years. They also addressed the relative suitability of various MIC breakpoints for such surveillance. It is well written. The figures have an orientation problem, particularly for the text, are difficult to interpret and needs attention. Though the study has been based on MIC, it only presents categorical interpretation (susceptible or resistant) of Streptococcus pneumoniae and doesn't mention the actual MICs of the isolates anywhere. A scatter diagram showing the exact MICs of isolates over time is desirable and will enhance understanding.

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Reviewer #1: Yes: Reba Kanungo

Reviewer #2: Yes: Dr Pallab Ray

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PLoS One. 2020 Oct 22;15(10):e0240655. doi:10.1371/journal.pone.0240655.r002

Author response to Decision Letter 0

Collection date 2020.

PMC Copyright notice

21 Sep 2020

18th September 2020

Shampa Anupurba,

Academic Editor, PLOS ONE

Dear Dr Anupurba,

Thank you very much for the comments regarding the manuscript we submitted, entitled “Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18” (ONE-D-20-23245), and for the opportunity to revise the paper. The reviewers’ and your feedback were great help in highlighting ways to improve our manuscript. Attached you will find a revised version of the manuscript with track changes, a cleaned version of the revision. Following this letter are reviewers’ comments with our responses in blue italics.

We believe that the paper improved significantly, and we hope that you agree. Once again, thank you for the helpful feedback.

Sincerely,

Shinya Tsuzuki, MD, MSc

AMR Clinical Reference Center,

National Center for Global Health and Medicine

stsuzuki@hosp.ncgm.go.jp

ONE-D-20-23245