Trends in Antipseudomonal Agent Use Based on the 2006 to 2015 Sales Data in Japan

Abstract

Pseudomonas aeruginosa resistance is a major issue worldwide. Drug resistance is related to inappropriate antibiotic use. Because antipseudomonal agents have a wide spectrum, they must be used appropriately. The purpose of this study was to clarify the trends in antipseudomonal agent use in Japan based on sales data from 2006 to 2015. The total antipseudomonal agent use was increased significantly (r = 0.10, P_{for trend} = 0.00040). The proportion of fluoroquinolones use was the highest throughout the year, accounting for 88.6–91.4%. The use of piperacillin/tazobactam significantly increased. The increased use of these drugs may be due to the launch of higher doses and additional indications. On the other hand, for antipseudomonal agents, parenteral carbapenems use was 2.7–3.7%, but it has remained unchanged over the years. In Japan, permit and notification systems have been introduced to prevent the inappropriate use of parenteral carbapenems in medical institutions. It was speculated that these efforts suppressed the inappropriate use of parenteral carbapenems. This study clarified the trend of antipseudomonal agent use in Japan from 2006 to 2015. It is important to continue monitoring antipseudomonal agents use to conduct appropriate antimicrobial resistance measures.

INTRODUCTION

Drug-resistant bacteria are a major global health problem. The WHO announced the global trend of antimicrobial resistance (AMR) for the first time in 2014.¹⁾ The WHO also adopted a global action plan on AMR in 2015.²⁾ In Japan, a national action plan was formulated to promote AMR countermeasures in 2016.²⁾ The inappropriate use of antibiotics is one of the causes of drug-resistant bacteria. Thus, continuous surveys on antibiotic use, based on the internationally unified antimicrobial use index, is required as a strategy in the national action plan on AMR.³⁾

Pseudomonas aeruginosa is a ubiquitous bacterium that causes opportunistic infections. P. aeruginosa easily propagates in medical devices such as catheters and is one of the causes of serious nosocomial infections, including ventilator-associated pneumonia and sepsis.⁴⁾ The inherent resistance mechanism of P. aeruginosa includes low outer membrane permeability, expression of efflux pumps that drive antibiotics out of the cells, and the production of antibiotic-inactivating enzymes.⁵⁾ The resistance of P. aeruginosa was selected due to the improper use of antibiotics. Therefore, the national action plan for AMR especially aimed at reducing the resistance rate of P. aeruginosa to carbapenems to less than 10% by 2020.²⁾ However, these goals have not been achieved.⁶⁾ There is an urgent need to reduce the resistance rate of P. aeruginosa to carbapenems.

Broad-spectrum antibiotics, such as carbapenems, monobactams, broad-spectrum penicillins, third- and fourth-generation cephalosporins, aminoglycosides, and quinolones, have antipseudomonal action. Our previous study reported that broad-spectrum antibiotics are associated with resistance to P. aeruginosa.⁷⁾ Therefore, it is necessary to pay attention to inappropriate use. However, the previous study did not cover all medical institutions in Japan and was limited to intravenous antibiotics.⁷⁾ Therefore, it is necessary to evaluate the trend of broad-spectrum antibiotic use (including oral and intravenous antibiotics) in Japan.

We previously evaluated the trends of antibiotic use in each anatomical therapeutic chemical (ATC) classification system in Japan.⁸⁾ However, because antipseudomonal agents cross multiple ATC classification systems, it is necessary to evaluate not only them but also each drug. Therefore, the purpose of this study was to evaluate the trends of antipseudomonal agent use in Japan, based on sales data from 2006 to 2015 to clarify the findings before the national action plan was formulated.

MATERIALS AND METHODS

Data Collection

Information on the use of antipseudomonal agents from as far back as possible needed to be evaluated in order to clarify the findings before the national action plan was formulated. Given that the oldest available sales data were from 2006, we obtained sales data from 2006 to 2015 for 10 years within the funding. Sales data on antipseudomonal agents included in J01CA, J01CR, J01DD, J01DE, J01DF, J01DH, J01GB, and J01MA of the ATC classification (fourth level) by the WHO were consumed by the IQVIA Services Japan K.K. (Tokyo, Japan). By generation, fluoroquinolones are classified as first-generation fluoroquinolones (norfloxacin), second-generation fluoroquinolones (ofloxacin, ciprofloxacin, enoxacin, lomefloxacin, fleroxacin, sparfloxacin, levofloxacin (LVFX), and tosufloxacin), and third-generation fluoroquinolones (moxifloxacin, gatifloxacin, prulifloxacin, garenoxacin (GRNX), sitafloxacin (STFX), and pazufloxacin).⁹⁾ Although GRNX is not indicated for P. aeruginosa, it is a broad-spectrum antibiotic and was included in the analysis. Aminoglycosides included tobramycin as an inhalant.

Evaluation of Antipseudomonal Agent Use

The 2020 version of the ATC/defined daily dose (DDD) Index¹⁰⁾ was applied to all data. Table 1 shows the DDD of antipseudomonal agents. For drugs with no DDD in the ATC/DDD Index 2020, Japan DDD (JDDD),¹¹⁾ defined as the maximum dose in the Japanese package insert, was used. Population data were obtained from the Statistics Bureau of Japan.¹²⁾ In addition, each drug was tabulated in dosage form (oral/parenteral). The sales data were reported as DDDs per 1000 inhabitants per day (DID),⁹⁾ using the following equation:

  

Table 1. ATC Codes and DDD of Antipseudomonal Agents

Category	Route	Antipseudomonal agents	ATC	DDD (g)
First-fluoroquinolones	O	Norfloxacin	J01MA06	0.8
Second-fluoroquinolones	O	Ofloxacin	J01MA01	0.4
		Ciprofloxacin	J01MA02	1
		Enoxacin	J01MA04	0.8
		Lomefloxacin	J01MA07	0.4
		Fleroxacin	J01MA08	0.4
		Sparfloxacin	J01MA09	0.2
		Levofloxacin	J01MA12	0.5
		Tosufloxacin	J01MA22	0.45
	P	Ciprofloxacin	J01MA02	0.8
		Levofloxacin	J01MA12	0.5
Third-fluoroquinolones	O	Moxifloxacin	J01MA14	0.4
		Gatifloxacin	J01MA16	0.4
		Prulifloxacin	J01MA17	0.6
		Garenoxacin	J01MA19	0.4
		Sitafloxacin	J01MA21	0.1
	P	Pazufloxacin	J01MA18	1
Carbapenems	P	Meropenem	J01DH02	3
		Doripenem	J01DH04	1.5
		Biapenem	J01DH05	1.2
		Imipenem/Cilastatin	J01DH51	2
		Panipenem/Betamipron	J01DH55	2
Monobactums	P	Aztreonam	J01DF01	4
		Carumonam	J01DF02	2
Aminoglycosides	P	Tobramycin	J01GB01	0.24
		Gentamicin	J01GB03	0.24
		Kanamycin	J01GB04	1
		Amikacin	J01GB06	1
		Netilmicin	J01GB07	0.35
		Sisomicin	J01GB08	0.24
		Dibekacin	J01GB09	0.14
		Ribostamycin	J01GB10	1
		Isepamicin	J01GB11	0.4
		Arbekacin	J01GB12	0.2
		Bekanamycin	J01GB13	0.6
		Astromicin	J01GBXA*1	0.4*2
		Micronomicin	J01GBXB*1	0.24*2
	Inhal	Tobramycin	J01GB01	0.3
Third-cephalosporins	P	Ceftazidime	J01DD02	4
Forth-cephalosporins	P	Cefepime	J01DE01	4
		Cefpirome	J01DE02	4
		Cefozopran	J01DE03	4
Piperacillin and beta-lactamase inhibitor	P	Piperacillin/Tazobactam	J01CR05	*3
Penicillins with extended spectrum	P	Piperacillin	J01CA12	14

ATC, Anatomical Therapeutic Chemical; P, parenteral; O, oral; Inhal, inhalation; DDD, defined daily dose. *¹: Astromicin and micronomicin were classified as J01GBXA and J01GBXB, which have the same drug efficacy and action site, because there is no ATC classification with the same drug efficacy, action site, and components. *²: Japan DDD (JDDD) of astromicin and micronomicin was defined as the maximum dose in the Japanese package insert was used because DDD is not listed in the ATC/DDD Index 2019. *³: J01CR05 includes tazosin^® and zosyn^®. The combination ratio of piperacillin/tazobactam of zosyn^® was 8 : 1 and that of tazosin^® was 4 : 1. Because of the different mixing ratios, DDD used 17.5 for tazosin^® and 15.75 for zosyn^®.

Statistical Analysis

Evaluation of antibiotic use is generally performed using a time-series analysis. Time series analysis requires detailed information such as months and days as well as interventions, which are the starting points for change. However, this study used annual sales data and could not be used to set the starting point change. Thus, the trends of antipseudomonal agent use were evaluated using linear regression analyses.^13–15) The analyses were performed using JMP^® Pro 14 (SAS Institute Inc., Cary, NC, U.S.A.). A two-sided p value <0.05, was considered statistically significant for all analyses. The requirement for informed consent was waived because anonymized sales data were used.

RESULTS

Trends of Antipseudomonal Agent Use from 2006 to 2015

Figure 1 and Table 2 show the trends of antipseudomonal agent use from 2006 to 2015. The total antipseudomonal agent use increased significantly (r = 0.10, P_{for trend} = 0.00040). The use of fluoroquinolones and penicillins has increased significantly. Carbapenems and monobactams use remained unchanged. In contrast, the use of third- and fourth-generation cephalosporins and aminoglycosides decreased significantly. The highest proportions throughout the year were those of fluoroquinolones, at 88.6–91.4%.

Fig. 1. Trend of Antipseudomonal Agents Use from 2006 to 2015

Table 2. Trend of Antipseudomonal Agents Use from 2006 to 2015

	2006	2007	2008	2009	2010	2011	2012	2013	2014	2015	Change	Pfor trend	95%CI
Fluoroquinolones	2.1	2.1	2.1	2.3	2.5	2.7	2.9	2.9	2.9	2.7	0.10	0.00030	0.062 to 0.14
Carbapenems and monobactams	0.090	0.085	0.084	0.081	0.082	0.085	0.087	0.086	0.084	0.084	−0.00017	0.57	−0.00084 to 0.00050
Aminoglycosides	0.084	0.076	0.070	0.063	0.061	0.058	0.054	0.049	0.046	0.045	−0.0043	<0.0001	−0.0049 to −0.0037
Third- and fourth-cephalosporins	0.076	0.073	0.071	0.064	0.063	0.058	0.053	0.049	0.045	0.044	−0.0038	<0.0001	−0.0042 to −0.0035
Penicillins	0.024	0.025	0.028	0.044	0.054	0.060	0.068	0.077	0.080	0.086	0.0077	<0.0001	0.0068 to 0.0087
Total	2.4	2.4	2.4	2.5	2.8	3.0	3.2	3.1	3.1	3.0	0.10	0.00040	0.062 to 0.14

The values show DID (DDDs/1000 inhabitants/d). CI, confidence interval.

Trend of Oral Fluoroquinolones Use from 2006 to 2015

Oral fluoroquinolones accounted for more than 98% of the total fluoroquinolones use and increased significantly (r = 0.10, P_{for trend} = 0.00030) (Fig. 2). For each antibiotic, LVFX (second generation; r = 0.049, P_{for trend} = 0.015), STFX (third generation; r = 0.031, P_{for trend} < 0.0001), and GRNX (third generation; r = 0.064, P_{for trend} = 0.00010) increased significantly.

Fig. 2. Trend of Oral Fluoroquinolones Use from 2006 to 2015

Trend of Parenteral Antipseudomonal Agent Use from 2006 to 2015

Figure 3 shows the trend of parenteral antipseudomonal agent use from 2006 to 2015. Parenteral fluoroquinolones use increased significantly (r = 0.0012, P_{for trend} = 0.0041) (Fig. 3a).

Fig. 3. Trend of Parenteral Antipseudomonal Agents Use from 2006 to 2015

(a) Fluoroquinolones by generation. (b) Carbapenems. (c) Third- and fourth-generation cephalosporins. (d) Piperacillin and piperacillin-tazobactam. Monobactams were rarely used throughout 2006–2015—and are not shown in Fig. 3b. IPM/CS, imipenem/cilastatin; DRPM, doripenem; PAPM/BP, panipenem/betamipron; BIPM, biapenem; MEPM, meropenem; CFPM, cefepime; CZOP, cefozopran; CAZ, ceftazidime; CPR, cefpirome; PIPC, piperacillin; PIPC/TAZ, piperacillin/tazobactam.

Parenteral carbapenems use was 2.7–3.7% of the total antipseudomonal agents, and remained unchanged over the years (r = −0.00014, P_{for trend} = 0.65) (Fig. 3b). For each antibiotic, the trend for meropenem (MEPM) (r = 0.0025, P_{for trend} < 0.0001) and doripenem (DRPM) (r = 0.0014, P_{for trend} = 0.00020) increased significantly to 1.7 and 2.8 times, respectively, from 2006 to 2015. However, the trend for other parenteral carbapenems imipenem/cilastatin (r = −0.0020, P_{for trend} < 0.0001), panipenem/betamipron (r = −0.0014, P_{for trend} < 0.0001), and biapenem (r = −0.00067, P_{for trend} < 0.0001) decreased significantly. Monobactams were rarely used between 2006 and 2015, and their use decreased significantly (r = −0.000033, P_{for trend} < 0.0001) (data not shown).

The total use of third- and fourth-generation cephalosporins decreased significantly (r = −0.0038, P_{for trend} < 0.0001) (Fig. 3c). For each antibiotic, the use of cefepime (r = −0.00078, P_{for trend} < 0.0001), cefozopran (r = −0.00091, P_{for trend} < 0.0001), cefpirome (r = −0.0013, P_{for trend} < 0.0001), and ceftazidime (r = −0.00080, P_{for trend} < 0.0001) also decreased significantly.

The trend for piperacillin use decreased significantly (r = −0.0012, P_{for trend} < 0.0001) (Fig. 3d). In contrast, the trend for PIPC/TAZ use increased significantly (r = 0.0090, P_{for trend} < 0.0001).

DISCUSSION

In Japan, the trends of total antibiotic use and antibiotic use by ATC classification have been evaluated.¹⁶⁾ There are concerns about increased broad-spectrum antibiotic use in previous reports.¹⁶⁾ However, the trend of antipseudomonal agent use has not been clarified. This study clarified, for the first time, the trends of antipseudomonal agent use in Japan from 2006 to 2015. The total use of antipseudomonal agents significantly increased. The most commonly used antibiotics are oral fluoroquinolones. The proportion of parenteral carbapenems use for total antipseudomonal agent use was very low. In contrast, fluoroquinolones and penicillins use increased significantly, whereas the use of third- and fourth-generation cephalosporins and aminoglycosides decreased significantly. Carbapenems and monobactams use remained unchanged. In this study, the use of fluoroquinolones in 2015 was 2.74 DID, which was about five times higher than that in the U.K. (0.57 DID).¹⁷⁾ Fluoroquinolones have a broad spectrum and also affect many bacteria other than P. aeruginosa. The resistance rate of Escherichia coli to fluoroquinolones in Japan was 29.3%,⁶⁾ which is higher than that reported in the U.K. (15.6%).¹⁸⁾ These results suggest that the use of fluoroquinolones in Japan may have affected the resistance rate. This is because LVFX has been reported to be cross-resistant to other quinolones¹⁹⁾; thus, it is important to avoid unnecessary use of LVFX.

Among oral fluoroquinolones, the use of LVFX, GRNX, and STFX increased significantly. It is considered that one of the reasons for the increase in oral LVFX is that the high dose (500 mg) was launched in 2009 according to the spread of pharmacokinetics/pharmacodynamics theory.²⁰⁾ In addition, it was estimated that urinary tract infections and pneumonia are increasing as the number of elderly people is increasing in Japan.²¹⁾ LVFX, GRNX, and STFX are the first- and second-line drugs used in the treatment of pneumonia and urinary tract infections.^22,23) Thus, it is considered that the use of LVFX, GRNX, and STFX has increased. It is necessary to continuously evaluate the trends of quinolone use, including LVFX, and promote appropriate use.

Most of the carbapenems used parenterally were MEPM and DRPM, and their use increased significantly. It was speculated that increasing indications, the revision of insurance coverage on the maximum daily dose, and the sale of products containing a high dosage, accounted for this increase. However, the use of other parenteral carbapenems has significantly decreased.

Parenteral carbapenems use was 2.7–3.7% of all antipseudomonal agents used, and it has remained unchanged over the years. In Japan, the permit and notification systems were introduced to monitor the inappropriate use of parenteral carbapenems in medical institutions.²⁾ It was speculated that these efforts suppressed the inappropriate use of parenteral carbapenems. However, the selective pressure on parenteral carbapenems in patients should continue to be monitored.

On the other hand, the trend for PIPC/TAZ use increased significantly by approximately 43 times from 2006 to 2015. It is clear that the selective pressure on PIPC/TAZ increased in 2015 compared to 2006. PIPC/TAZ was approved in 2008 with the same mixture ratio (8 : 1) as in other countries, and acquired the indication for pneumonia. For these reasons, the trend for PIPC/TAZ use was considered to have increased significantly. Although the resistance rate of P. aeruginosa against PIPC/TAZ remains almost unchanged in Japan,⁶⁾ it has been reported that the promotion of PIPC/TAZ use induced drug-resistant P. aeruginosa in Romania.²⁴⁾ Thus, it is necessary to pay attention to the increase in resistance of P. aeruginosa to PIPC/TAZ.

This study has some limitations. First, because antibiotic use in our study was based on the sales volume, the actual volume administered may not have been accurately reflected. Detailed information such as patient background, purpose of use, and number of patients to which they were administered were unknown. However, the use of surveys based on sales data is a common method in other countries.²⁵⁾ Second, the findings may not reflect the volume sold directly to medical institutions.^14,15) However, the sales data used in this study accounted for approximately 98% of Japan’s total sales; therefore, it is considered to be highly comprehensive. Third, the most recent sales data were not included in this study. In the future, it will be necessary to conduct studies with more recent data and evaluate changes in the use of antipseudomonal agents. Despite these limitations, this study clarified, for the first time, the trends of antipseudomonal agent use in Japan and provided useful information on how to promote appropriate use.

CONCLUSION

This study clarified, for the first time, the trends of antipseudomonal agent use in Japan. The most commonly used antibiotics are oral fluoroquinolones. Although the proportion of parenteral carbapenems use was very low, the selective pressure on parenteral carbapenems in each patient needs to be monitored. It is important not only to monitor the total antibiotic use and antibiotic use by ATC classification, but also to continue monitoring the use of antipseudomonal agents to conduct appropriate AMR measures.

Acknowledgments

This work was supported by the Ministry of Health, Labour and Welfare (Grant No. H28-shinkougyousei-ippan-004, 20HA2003) and the Japan Society for the Promotion of Science KAKENHI (Grant No. JP18K09957).

Conflict of Interest

Yuichi Muraki received an honorarium from Pfizer Japan, Inc. for lecturing. The other authors declare no conflicts of interest.

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