Evaluation of the Influence of the National Action Plan on Antimicrobial Resistance and the COVID-19 Pandemic on the Consumption of Broad-Spectrum Antimicrobial and Anti-methicillin-resistant Staphylococcus aureus Agents

Ryota Goto; Ryo Inose; Ryuji Koizumi; Keisuke Sawada; Masahiro Ishikane; Norio Ohmagari; Yuichi Muraki

doi:10.1248/bpb.b24-00784

Abstract

Surveillance of antimicrobial consumption (AMC) is important for controlling antimicrobial resistance (AMR). In recent years, the landscape of infectious diseases has changed due to factors such as the introduction of the National Action Plan (NAP) on AMR and the coronavirus disease 2019 (COVID-19) pandemic. However, their impact on the consumption of broad-spectrum antimicrobial and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents remains unexplored. This study aimed to clarify trends in the consumption of these agents up to 2021, considering the spread of NAP and the COVID-19 pandemic. We used sales data from IQVIA Japan, which were analyzed using an interrupted time-series analysis, with April 2016 (introduction of NAP) and April 2020 (first declaration of a state of emergency) as key change points. The oral broad-spectrum antimicrobial agents consumption decreased, and the spread of the NAP (p-value: 8.15 * 10⁻³, 95% confidence intervals (95% CI): −7.70 * 10⁻³ to −2.06 * 10⁻³) and behavioral restrictions for the COVID-19 pandemic (p value: 1.60 * 10⁻⁸, 95% CI: −0.35 to −0.17) were significantly related to this change. Conversely, there was no notable change in the consumption of anti-MRSA agents from 2013 to 2021. Thus, the introduction of NAP and the COVID-19 pandemic may have been more effective in decreasing the consumption of oral broad-spectrum antimicrobial agents. Since antibiotics are used to treat infections across multiple anatomical therapeutic chemical classifications, continuous evaluation based on treatment purposes is important.

INTRODUCTION

Antimicrobial-resistant bacteria circumvent the mechanisms of action of drugs and pose a significant threat to public health.¹⁾ To tackle this societal issue, the WHO urged countries to develop a National Action Plan (NAP) to address antimicrobial resistance (AMR).²⁾ In response, the first NAP on AMR was introduced in Japan in 2016 and subsequently revised in 2023.^3,4) It is well known that the use of antimicrobial agents is related to the development of resistant bacteria,⁵⁾ and avoiding the excessive use of antimicrobial agents is a key measure to combat AMR. Therefore, implementing AMR countermeasures requires not only infection control and antimicrobial stewardship (AS) but also continuous monitoring of antimicrobial consumption.

The consumption of oral and parenteral antibiotics in Japan was first assessed in 2013, providing insights into the consumption of antibiotics by dosage form and drug class.⁶⁾ Since then, antimicrobial consumption (AMC) has been evaluated with a focus on specific settings, such as in nursing homes and among dentists.^7,8) However, even antimicrobial agents of the same class may be effective against different groups of bacteria, and conversely, antimicrobial agents of different classes may be effective against specific bacteria. Therefore, monitoring antimicrobial consumption solely by drug class makes proper evaluation challenging.

Data on the consumption of anti-methicillin resistant Staphylococcus aureus (MRSA) and broad-spectrum antimicrobial agents, which are effective against Pseudomonas aeruginosa and are associated with the emergence of multidrug-resistant bacteria, are crucial for evaluating AMR countermeasures. Previously, we investigated the usage trends of these drugs from 2006 to 2015^9,10) and found a statistically significant increase in the consumption of broad-spectrum antimicrobial and anti-MRSA agents between 2006 and 2015 in Japan.^9,10) Currently, trends in the consumption of antimicrobial agents in Japan are surveyed by the AMR Clinical Reference Center and are continually reported using sales data or national databases. However, these surveys are still limited to assessments by drug class, and recent trends in the consumption of these antibiotics remain unclear.

Since the introduction of the NAP in 2016, remarkable advancements have been made in AMR measures in Japan. For example, guidelines for implementing an AS program in Japan were issued in 2017,¹¹⁾ and in 2018, with the revision of the reimbursement system, an additional fee was incorporated to evaluate the facility implementing the AS.¹²⁾ Consequently, the number of publications related to AS increased.¹³⁾ In addition, the coronavirus disease 2019 (COVID-19) pandemic began in 2020.⁹⁾ In Japan, the first state of emergency was declared in April 2020, and people were forced to refrain from leaving their homes.⁹⁾ This resulted in a reduction in the effective reproduction number to below 1, which was reported to contribute to a temporary subsidence of the pandemic.¹⁴⁾ These environmental changes and their accompanying outcomes likely influenced the usage of broad-spectrum antimicrobial and anti-MRSA agents, but the actual condition remains unclear.

Therefore, in this study, we aimed to clarify the trends in the consumption of broad-spectrum antimicrobial and anti-MRSA agents up to 2021, considering the impact of the NAP or the COVID-19 pandemic.

MATERIALS AND METHODS

Data Collection

We used monthly pharmaceutical sales data from 2013 to 2021 in Japan owned by IQVIA Japan (https://www.iqvia.com/ja-jp/locations/japan) as the data source. Sales data is a reliable source for surveillance because AMC derived from sales data correlates with AMC derived from national databases based on insurance claims.¹⁵⁾ The broad-spectrum antimicrobial agents for this study were selected based on previous reports of usage trends⁹⁾ or AS evaluations¹⁶⁾ and indication for Pseudomonas aeruginosa in the package inserts of antimicrobial agents marketed in Japan from 2013 to 2021 (Table 1).

Table 1. List of Broad-Spectrum Antimicrobial Agents and Anti-MRSA Agents

(A) List of Broad-Spectrum Antimicrobial Agents
Antibiotic group	Route	Drug name	DDD (g)
Fluoroquinolones	Oral	Ciprofloxacin	1
		Levofloxacin	0.5
		Lomefloxacin	0.4
		Norfloxacin	0.8
		Ofloxacin	0.4
		Prulifloxacin	0.6
		Sitafloxacin	0.1
		Tosufloxacin	0.45
	Parenteral	Ciprofloxacin	0.8
		Levofloxacin	0.5
		Pazufloxacin	1
Carbapenems and monobactams	Parenteral	Aztreonam	4
		Biapenem	1.2
		Doripenem	1.5
		Imipenem/Cilastatin	2
		Imipenem/Cilastatin/Relebactam	5*
		Meropenem	3
		Panipenem/Betamipron	2
Aminoglycosides	Parenteral	Amikacin	1
		Dibekacin	0.14
		Gentamicin	0.24
		Isepamicin	0.4
		Kanamycin	1
		Tobramycin	0.24
Third- and fourth-generation cephalosporins	Parenteral	Cefepime	4
		Cefoperazone	4
		Cefoperazone/Sulbactam	8*
		Cefozopran	4
		Cefpirom	4
		Ceftazidime	4
Penicillins with extended-spectrum	Parenteral	Piperacillin	14
		Tazobactam/Piperacillin	15.75*
(B) List of Anti-MRSA Agents
Antibiotic group	Route	Drug name	DDD (g)
Glycopeptides	Parenteral	Vancomycin	2
		Teicoplanin	0.4
Aminoglycoside	Parenteral	Arbekacin	0.2
Oxazolidinones	Oral	Linezolid	1.2
		Tedizolid	0.2
	Parenteral	Linezolid	1.2
		Tedizolid	0.2
Cyclic lipopeptide	Parenteral	Daptomycin	0.28

*These DDD were defined based on the AMR Clinical Reference Center rules used for evaluation of AMC in Japan.¹¹⁾ MRSA, methicillin-resistant Staphylococcus aureus; DDD, defined daily dose.

Evaluation of Antimicrobial Consumption

The consumption of target drugs was evaluated by calculating the defined daily doses per 1,000 inhabitants per day. The defined daily dose (DDD) was based on the anatomical therapeutic chemical (ATC)/DDD Index 2024 (https://www.whocc.no/atc_ddd_index/) and the protocol suggested by the AMR Clinical Reference Center.¹⁷⁾ Population data were obtained from the Japanese Government Statistics (e-stat) portal, established by the Statistics Bureau of the Ministry of Internal Affairs and Communications (https://www.e-stat.go.jp/en).

Statistical Analysis

Trends in the consumption of target drugs were analyzed using an interrupted time-series analysis (ITSA) with adjustments for seasonal variations.^18,19) The point of change was set in April 2016, when the NAP was introduced,⁸⁾ and April 2020, when the first state of emergency was declared in Japan.⁹⁾ In addition, the spread of the NAP, the influence of behavioral restrictions for the COVID-19 pandemic, and the passage of time were evaluated. In the dataset, the spread of the NAP was assigned a value that increased by 1 each month starting in April 2016, and behavioral restrictions during the COVID-19 pandemic were represented by a dummy variable (0 for before the event, 1 for after the event). The passage of time was assigned a value that increased by 1 per month throughout the data period. Additionally, harmonic variables, which account for periodic variations, were included in the model to adjust for seasonality. These variables were included in a gamma model with the link function specified log, and the analyses were performed using R version 4.3.3.²⁰⁾ Within this analysis, the package “tsModel” was used to model the time series data, and the package “boot” was used to run 1000 bootstrap simulations and calculate 95% confidence intervals (95% CI). Statistical significance was considered with a p-value < 0.05.

Ethical approval was not required because the database does not contain patient information. Additionally, due to disclosure restrictions stipulated by IQVIA Japan, detailed usage data (ATC 5 level) for each drug cannot be directly expressed in numerical values and has been masked.

RESULTS

Evaluation of the Broad-Spectrum Antimicrobial Agent Consumption

Trends in the consumption of broad-spectrum antimicrobial agents are shown in Fig. 1 and Table 2. The consumption of oral broad-spectrum antimicrobial agents showed a decreasing trend compared with the counterfactual. In addition, the spread of NAP (p-value: 8.15 * 10⁻³, 95% CI: −7.70 * 10⁻³ to −2.06 * 10⁻³) and behavioral restrictions for the COVID-19 pandemic (p-value: 1.60 * 10⁻⁸, 95% CI: −0.35 to −0.17) were significantly associated with the consumption of oral broad-spectrum antimicrobial agents. By contrast, parenteral drug consumption showed a decreasing trend compared with counterfactuals, but the spread of the NAP and behavioral restrictions for the COVID-19 pandemic did not lead to significant changes. (Supplementary Table 1).

Fig. 1. (A) ITSA of the Trends in the Consumption of Oral Broad-Spectrum Antimicrobial Agents between 2013 and 2021; (B) ITSA of the Trends in the Consumption of Parenteral Broad-Spectrum Antimicrobial Agents between 2013 and 2021

ITSA, interrupted time-series analysis. The solid line represents the trend in the consumption of broad-spectrum antimicrobial agents, reflecting seasonal variations obtained through ITSA. The shaded area indicates the 95% confidence interval calculated using the bootstrap method. The dashed and dotted lines represent counterfactual predictions at the point of change.

Table 2. Model Estimates and Statistical Indicators from ITSA for the Oral and Parenteral Consumption of Broad-Spectrum Antimicrobial Agents

(A) Model Estimates and Statistical Indicators from ITSA for the Oral Consumption of Broad-Spectrum Antimicrobial Agents
	Estimate	p-Value	95% CI
(Intercept)	0.78	–	–
Spread of NAP	−4.80 * 10⁻³	8.15 * 10⁻³	−7.70 * 10⁻³−2.06 * 10⁻³
Behavioral restrictions for COVID-19 pandemic	−0.26	1.60 * 10⁻⁸	−0.35−0.17
Passage of time	−3.57 * 10⁻⁴	0.75	−1.88 * 10⁻³–1.20 * 10⁻³
(B) Model Estimates and Statistical Indicators from ITSA for the Parenteral Consumption of Broad-Spectrum Antimicrobial Agents
	Estimate	p-Value	95% CI
(Intercept)	−1.19	–	–
Spread of NAP	−1.44 * 10⁻³	0.58	−6.54 * 10⁻³–3.39 * 10⁻³
Behavioral restrictions for COVID-19 pandemic	−9.27 * 10⁻²	0.13	−0.24–5.74 * 10⁻²
Passage of time	6.16 * 10⁻⁴	0.71	−2.20 * 10⁻³–3.50 * 10⁻³

The results presented are derived from an analysis where the data follow a gamma model with link function specified log. COVID, coronavirus disease; NAP, National Action Plan; ITSA: interrupted time-series analysis; 95% CI, 95% confidence interval.

Downward trends were observed between 2013 and 2021 in the consumption of fluoroquinolones (2013: 2.2379 DID, 2021: 1.2356 DID), carbapenems and monobactams (2013: 0.0862 DID, 2021: 0.0707 DID), aminoglycosides (2013: 0.0458 DID, 2021: 0.0222 DID), and third- or fourth-generation cephalosporins (2013: 0.0697 DID, 2021: 0.0476 DID). In particular, fluoroquinolone consumption began to decline after 2016, and this change was noticeable for oral drugs. Additionally, the consumption of aminoglycosides and third- or fourth-generation cephalosporins continued to decline over the long term. Meanwhile, only penicillin with extended-spectrum consumption increased continually (2013: 0.0767 DID, 2021: 0.1046 DID) (Supplementary Table 2).

Evaluation of the Anti-MRSA Agent Consumption

Trends in the consumption of anti-MRSA agents are shown in Fig. 2 and Table 3. The anti-MRSA agent consumption remained stable and showed no notable change compared with the counterfactual. Also, neither the spread of NAP nor the behavioral restrictions for the COVID-19 pandemic had a significant influence on the consumption of anti-MRSA agents.

Fig. 2. ITSA of the Trends in the Consumption of Anti-MRSA Agents between 2013 and 2021

ITSA, interrupted time-series analysis; MRSA, methicillin-resistant Staphylococcus aureus The solid line represents the trend in the consumption of anti-MRSA agents, reflecting seasonal variations obtained through ITSA. The shaded area indicates the 95% confidence interval calculated using the bootstrap method. The dashed and dotted lines represent counterfactual predictions at the point of change.

Table 3. Model Estimates and Statistical Indicators Calculated from ITSA for the Consumption of Anti-MRSA Agents

	Estimate	p-Value	95% CI
(Intercept)	−3.07	–	–
Spread of NAP	−9.62 * 10⁻⁴	0.73	−6.16 * 10⁻³–3.75 * 10⁻³
Behavioral restrictions for COVID-19 pandemic	0.01	0.87	−0.12–0.16
Passage of time	1.04 * 10⁻³	0.57	−2.04 * 10⁻³–4.30 * 10⁻³

The results presented are derived from an analysis where the data follow a gamma model with link function specified log. COVID, coronavirus disease; MRSA, methicillin-resistant Staphylococcus aureus; NAP, National Action Plan; ITSA: interrupted time-series analysis; 95% CI, 95% confidence interval.

Vancomycin (VCM) was the most consumed anti-MRSA agent over the years (46.2–55.7%), but teicoplanin (TEIC) and arbekacin (ABK) were the least consumed anti-MRSA agents in 2020 (TEIC: 11.9%, ABK: 4.1%). Additionally, daptomycin (DAP) consumption has continued to increase, reaching a usage rate of 17.8% in 2021, making DAP the secondmost consumed anti-MRSA agent in recent years. Despite these changes, the percentage of each anti-MRSA agent consumed remained stable in recent years.

DISCUSSION

This study clarified the consumption of broad-spectrum antimicrobial and anti-MRSA agents in Japan based on the analyses of sales data from 2013 to 2021. In focusing on the 2016 and 2020 events, differences were observed in the trend changes in the consumption of broad-spectrum antimicrobial and anti-MRSA agents.

Total broad-spectrum antimicrobial agent consumption showed a decreasing trend and was significantly associated with the spread of NAP and behavioral restrictions for the COVID-19 pandemic. However, when evaluated by dosage form, oral drugs followed a similar trend, whereas no significant association was observed for parenteral drugs. The total anti-MRSA agent consumption remained stable, and no change was observed in the trends after the introduction of the NAP and COVID-19 pandemic. Therefore, it is possible that the spread of the NAP and the behavioral restrictions for the COVID-19 pandemic contributed to the decrease in the consumption of oral broad-spectrum antimicrobial agents. Additionally, this result is supported by multiple reports indicating a significant reduction in the use of outpatient medical services due to the prevention of infections from outpatient visits and requests for refraining from going out.^21,22) In each antibiotic group, the consumption of fluoroquinolones, carbapenems and monobactams, aminoglycosides, and third- or fourth-generation cephalosporins showed a decreasing trend after introducing the NAP. The consumption of many of these drugs has been reported to be reduced with the implementation of AS.^23,24) Furthermore, the rates of resistance of Pseudomonas aeruginosa to carbapenems are decreasing,²⁵⁾ suggesting the usefulness of AS. Therefore, it is essential to continue the implementation of AS in the future. By contrast, penicillins with extended-spectrum were the only broad-spectrum antimicrobial agents that continued to increase in consumption. The proportion of AS interventions for tazobactam/piperacillin (TAZ/PIPC), a representative extended-spectrum penicillin, had not been sufficiently promoted even in 2021,²⁶⁾ which may explain the increased consumption of penicillins with extended-spectrum. In the future, monitoring susceptibility to TAZ/PIPC may need closer attention.

The overall consumption of anti-MRSA agents remained stable, and no changes in the trends were observed after the adoption of the NAP or COVID-19 pandemic. This trend is different from that observed for broad-spectrum antimicrobial agents. The consumption of anti-MRSA agents, primarily used in hospitalized patients, seems to have been less affected by the reduction in the use of outpatient medical services with oral broad-spectrum antimicrobials. Therefore, it is suggested that the consumption of anti-MRSA agents was not related to the COVID-19 pandemic. Notably, the reported number of MRSA infections per observation point decreased from 42.4 in 2013 to 30.3 in 2021,²⁷⁾ which is inconsistent with the stable trend in the consumption of anti-MRSA agents. This discrepancy could be attributed to the recommendation of loading doses or empirical therapy and adherence to long-term administration. Additionally, the use of VCM for Gram-positive bacterial infections other than MRSA may have influenced this trend, and further research is needed to clarify these findings. Furthermore, while the total consumption of anti-MRSA agents remained stable, the consumption proportions of each anti-MRSA agent changed, with a decrease observed for TEIC and ABK, and a significant increase observed for DAP. According to the guidelines, TEIC and ABK are used as alternative drugs for the treatment of MRSA infections.²⁸⁾ Conversely, DAP is recommended as the first choice of drug, along with VCM.^28,29) Therefore, it is speculated that anti-MRSA agents are administered in accordance with these guidelines. Additionally, reports and partial recommendations in guidelines suggest that higher doses of DAP, exceeding the 6 mg/kg package insert dose, may be effective.^28,30) This could explain the increase in its consumption. Thus, the appropriate selection of anti-MRSA agent is supported by AS, and changes in the proportion of each drug are related to the clinical context and drug selection for individual patient.

This study has some limitations. With the use of sales data, the number of drugs sold without wholesalers was not included.³¹⁾ Therefore, the actual use may be underestimated. Also, the impact of the COVID-19 pandemic may not have been sufficiently evaluated with only an initial declaration of a state of emergency. Since the data available for this study are limited to 2021, continued evaluation of the impact of COVID-19 is needed in the future. Moreover, it is unclear whether the model created in this study is the best fit. However, several models were considered, and the decision was based on their fitness according to Akaike’s information criterion and real-world context. Despite these limitations, this study provided beneficial information for the evaluation of AMR countermeasures in Japan by evaluating changes in the trend of the consumption of broad-spectrum antimicrobial and anti-MRSA agents, considering events such as the spread of the NAP and behavioral restrictions for the COVID-19 pandemic.

In conclusion, this study evaluated the causal relationship between the consumption of broad-spectrum antimicrobial agents effective against Pseudomonas aeruginosa or anti-MRSA agents and the spread of the NAP or the COVID-19 pandemic using ITSA. The results suggest that the consumption of oral broad-spectrum antimicrobial agents may have decreased due to the influence of the spread of the NAP and behavioral restrictions for the COVID-19 pandemic. Conversely, these effects were not observed with the consumption of anti-MRSA agents, but the percentage of consumption of individual drugs changed. These results indicate the progress of AS as an AMR countermeasure. In the treatment of infections, antibiotics from multiple ATC classifications are often used. Therefore, as in this study, an evaluation based on treatment purposes is useful. Moving forward, it is necessary to continue monitoring various events and to strengthen measures to prevent the spread of AMR.

Acknowledgments

This work was supported by the Ministry of Health, Labour, and Welfare (Grant No: 23HA2002).

Conflict of Interest

YM has received funding for commissioned research from Kowa Company, Ltd. and a medical education Grant from Pfizer Japan, but this study is not directly related to that funding. RI has received funding for commissioned research from Kowa Company, Ltd., but this study is not directly related to that funding. The other authors declare no conflicts of interest.

Supplementary Materials

This article contains supplementary materials.

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