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Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals
J Infect Chemother xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Original Article
Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals* Yoshiki Kusama a, b, *, Yuichi Muraki c, Takahiro Mochizuki d, Hanako Kurai e, Yoshiaki Gu a, Norio Ohmagari a, b a
AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, Japan Collaborative Chairs Emerging and Reemerging Infectious Diseases, National Center for Global Health and Medicine, Graduate School of Medicine, Tohoku University, 1-1, Seriryo-tyo, Aoba-ku, Sendai, Miyagi, Japan c Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University, 5, Nakauchi-machi, Misasagi, Yamashina-ku, Kyoto-shi, Kyoto, Japan d Department of Pharmacy, Shizuoka Cancer Center Hospital, Shizuoka, 1007, Shimonagakubo, Nagaizumi-cho, Sundo-gun, Shizuoka, Japan e Division of Infectious Diseases, Shizuoka Cancer Center Hospital, 1007, Shimonagakubo, Nagaizumi-cho, Sundo-gun, Shizuoka, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 September 2018 Received in revised form 10 June 2019 Accepted 20 August 2019 Available online xxx
In Japan, hospitals' pharmaceutical affairs committees freely select the drugs to be purchased depending on the regulations of each hospital. This system poses a risk of the absence of essential drugs or an excess of similar drugs, and may promote inappropriate use of third-generation cephalosporins (3GCs) and quinolones. Against this backdrop, we researched availability of antibacterial agents in Japanese hospitals. We conducted a questionnaire-based study in eastern Shizuoka Prefecture, Japan. Questionnaires were sent to 33 hospitals that had established an interactive regional partnership on infection control. We analyzed the number of available oral cephalosporins, macrolides, and quinolones in each hospital, and the correlation between the number of total available antibacterial agents and the hospital scale and cephalexin availability. Thirty-one hospitals participated in this study. First-generation cephalosporin (1 GC) was available in only 22.5% of them. In all participating hospitals, 3GCs were available, with more than one 3 GC available in 74.2%. Quinolones were available in all hospitals, and more than one quinolone in 67.7%. The numbers of hospital beds and total available antibacterial agents were positively correlated and hospitals that owned cephalexin available also significantly more often owned other available antibacterial agents. 1 GC were available in only a few hospitals, while multiple 3GCs and quinolones were available in most. This situation may lead to excess use of 3GCs or quinolones in Japan. A low number of available drugs was associated with cephalexin unavailability. Outpatient antimicrobial stewardship may focus not only on the quality of medicine, but also on the prescribing environment. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: First-generation cephalosporin Third-generation cephalosporin Quinolone Availability Japan
1. Introduction Judicious use of antimicrobials is important for impeding antimicrobial resistance, which is now major global public health issue [1,2]. In Japan, antimicrobial consumption has been estimated by sales data or claims data, which showed relatively low consumption compared with European countries, though the proportion of oral macrolides, cephalosporins, and quinolones to total antimicrobials is an evident problem. An additional issue is that oral * We declare that all authors complied with the ICMJE authorship criteria. * Corresponding author. 1-21-1, Toyama, Shinjuku-ku, Tokyo, Japan. E-mail address: [email protected] (Y. Kusama).
third-generation cephalosporins (3GCs) account for more than 90% of total oral cephalosporins [3e5]. In almost all Japanese hospitals, pharmaceutical affairs committeesdcomposed of a hospital director, pharmacy director, and/or director of each clinical departmentd freely select purchasing drugs depend on the regulation of each hospital. Hospital doctors must choose from the drugs on the respective lists when prescribing. While this system is effective in terms of ensuring hospitals' freedom from governmental restriction in selecting drugs, there is some risk of the absence of essential antimicrobials or excess supply of broadspectrum antibiotics. The present state of affairs may be associated with inappropriate 3 GC and quinolone use in Japan, and we
https://doi.org/10.1016/j.jiac.2019.08.013 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
2
Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx
therefore researched numbers of available antibacterial agents in a sample of Japanese hospitals.
3. Results 3.1. Currently available antibacterial agents in Japan
2. Materials and methods 2.1. Questionnaire We conducted a questionnaire-based study in eastern Shizuoka Prefecture, Japan. Of 82 total hospitals in eastern Shizuoka, we sent the questionnaire to 33 that had established an interactive regional partnership on infection control within the prefecture between September 20th to October 13th in 2017. The questionnaire inquired as to the hospital name, number of beds, presence of a department of infectious diseases, department of pediatrics, and/or department of hematology, and available drugs within the hospital. The available drugs were limited only for the inpatients because prescriptions for outpatients were not influenced by the hospital's pharmaceutical affairs committee's decisions or the hospital policies. The questionnaire was developed using Google Forms, with multiple-choice responses, rather than free entry, so as to avoid omissions. Before distributing the questionnaires, we explained the study to the participating hospital staff at the Shizuoka Cancer Center and Fuji City General Hospital, both leaders of a regional partnership. Then, we sent invitation letters to hospital directors. Research duration was 41 days and reminder letters were sent once at 14 days before the final deadline. 2.2. Analysis Although we included data on available antibiotics from all categories from the responses, we focused on analyzing the number of available oral cephalosporins, macrolides, and quinolones; which is a problematic issue, as noted above, in Japan. Antimicrobials were classified using the Anatomical Therapeutic Chemical (ATC) classification system developed by the World Health Organization (WHO) Collaboration Centre for Drug Statistics Methodology [6]. Macrolides and quinolones were placed in three categories based on acting time and spectrum. The classifications are detailed in a previous article [3]. We then stratified hospitals into four groups by number of beds (20e99, 100e199, 200e499, and 500 or more) and analyzed for correlation between the number of total available drugs and the hospital scale. And we also analyzed for correlation between the number of total available cephalosporins, macrolides, and quinolones and the hospital scale. We determined cephalexin availability as per those from the relevant drug list because the WHO categorizes cephalexin as an “access” drug, which means it is “…continuously available and affordable at public or private health facilities or medicine outlets that are within one hour's walk from the homes of the population” [7]. Thus, we analyzed the differences in the total numbers of available antibacterial agents between hospitals in which cephalexin was available and unavailable. The differences in the total numbers of cephalosporins, macrolides, and quinolones between cephalexin-available and unavailable hospitals were also analyzed. Spearman's rank correlation coefficients were calculated for correlation analysis and ManneWhitney U-tests were used to assess the differences in the numbers of antibacterial agents between cephalexin-available and unavailable hospitals. Significance was set at p < .05. All statistical analysis was performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA).
Table 1 lists all available antibacterial agents in Japan (as of September 20, 2017). For oral cephalosporins, two first-generation (1GCs), two second-generation (2GCs), and six 3GCs were available. For oral macrolides, one short-acting, two intermediate-acting, and one long-acting were available. For quinolones, two firstgeneration (1GQs), five second-generation (2GQs), and three third-generation (3GQs) were available. 3.2. Characteristics of participating hospitals Of the hospitals asked to participate, 31 of 33 completed the questionnaire (response rate: 93.9%). Table 2 shows these hospitals' characteristics. Six (19.4%) had 20e99 beds, 13 (41.9%) had 100e199 beds, 10 (32.3%) had 200e499 beds, and two (6.5%) had 500 or more beds. General hospitals accounted for 83.9% of the total participating. The others consisted of three (9.7%) rehabilitation hospitals, one (3.2%) neurosurgery hospital, and one orthopedic hospital (3.2%). Almost half (51.6%) of the participating hospitals had a pediatric department, two (6.5%) had a hematologic department, and one (3.2%) had a department of infectious diseases. 3.3. Numbers of available oral cephalosporins, macrolides, and quinolones Fig. 1 shows the numbers of available oral cephalosporins, macrolides, and quinolones. In seven (22.5%) hospitals 1GCs were available, 2GCs were available in 20 (64.5%), while 3GCs were available in all of them. Hospitals with availability of two 3GCs were the most common (38.7%), and those with more than two accounted for 35.5%. In two hospitals, five 3GCs were available. Although a short-acting macrolide was not available in 14 (45.2%)
Table 1 Available oral cephalosporins, macrolides, and quinolones in Japan (as of September 20, 2017). Cephalosporins
WHO ATC Code
Drug Name
First-generation
J01DB01 J01DB06 J01DC02 J01DC04 J01DC07 J01DD08 J01DD13 J01DD15 J01DD16 J01DD17 J01DD18 WHO ATC Code J01FA01 J01FA06 J01FA07 J01FA09 J01FA10 WHO ATC Code J01MA06 J01MB04 J01MA01 J01MA02 J01MA07 J01MA12 J01MA22 J01MA14 J01MA19 J01MA21
Cefalexin Cefroxadine Cefuroxime Cefaclor Cefotiam Cefixime Cefpodoxime Cefdinir Cefditoren Cefcapene Cefteram Drug Name Erythromycin Roxithromycin Josamycin Clarithromycin Azithromycin Drug Name Norfloxacin Pipemidic acid Ofloxacin Ciprofloxacin Lomefloxacin Levofloxacin Tosufloxacin Moxifloxacin Garenoxacin Sitafloxacin
Second-generation
Third-generation
Macrolides Short-acting Intermediate-acting
Long-acting Quinolones First-generation Second-generation
2.3. Ethics Third-generation
This study was approved by the Shizuoka Cancer Center ethics committee (Number T29-14-29-1-5).
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx Table 2 Characteristics of participating hospitals. Hospital beds (%) 20e100 100e200 200e500 >500 Hospital characteristics (%) General Rehabilitation Neurosurgery Orthopedic Having specific departments (%) Pediatrics (%) Hematology (%) Infectious Diseases (%)
6 (19.4) 13 (41.9) 10 (32.3) 2 (6.5) 26 (83.9) 3 (9.7) 1 (3.2) 1 (3.2) 16 (51.6) 2 (6.5) 1 (3.2)
hospitals, one intermediate-acting macrolide and one long-acting macrolide were available in most hospitals (77.4% and 80.6%, respectively). One hospital (3.2%) had availability of one 1GQ. For 2GQs, levofloxacin was available in all participating hospitals (data was not shown). Hospitals with availability of one 2GQ accounted for 54.8%, those with two accounted for 35.5%, and those with three accounted for 9.7%. No 3GQs were available in 12 (38.7%) hospitals, and more than one was available in seven (22.5%) hospitals. In terms of overall quinolone availability, in 21 (67.7%) hospitals more than one was available. 3.4. Correlation between the number of total available antibacterial agents and hospital scales and cephalexin availability The median number of available antibacterial agents was 13 (range: 9e16) in hospitals with 20e100 beds, 14 (range: 4e22) for 100e200 beds, 22.5 (range: 5e28) for 200e500 beds, and 22.5
3
(range: 18e27) those with more than 500 beds. Fig. 2A and B show the numbers of listed antibacterials according to hospital scales. There was a positive correlation between the number of hospital beds and the total number of available antibacterial agents and between the number of hospital beds and the total number of available cephalosporins, macrolides, and quinolones (coefficient: .55, p < .01 and .52, p < .01, respectively). Large variations were seen in the numbers of total available antibacterial agents among different hospital scales. Fig. 3A and B show the box-and-whisker plots of the total numbers of available antibacterial agents and the total numbers of cephalosporins, macrolides, and quinolones according to cephalexin-available and unavailable hospitals. More antibacterial agents were listed in cephalexin-available hospitals than were listed in cephalexin-unavailable hospitals. This tendency was seen both in the total number of available antibacterial agents (p < .01) and in that of cephalosporins, macrolides, and quinolones (p ¼ .11). 4. Discussion Bridging the pharmaceutical gap between Japan and Western countries is one of the issues in Japan's National Action Plan on Antimicrobial Resistance [8]. Available antibacterial agents largely affect doctors' prescription behaviors because doctors cannot prescribe drugs not purchased by their hospital's pharmaceutical affairs committee. As a first point of consideration, although oral 3GCs were available in all participating hospitals in the present study, 1GCs were available in only 22.5%. However, 1GCs have superior bioavailability and cost compared with 3GCs [9]. Additionally, there is less selection-related pressure for 1GCs because of the fewer choices than for 3GCs. The reason for the lack of 1 GC availability is unknown. We speculated that broader antibacterial agents are
Fig. 1. Number of available oral cephalosporins, macrolides, and quinolones in each hospital. Footnote: Bars show the number of hospitals in which each antibacterial was available.
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
4
Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx
Fig. 2. Numbers of listed antibacterial agents according to hospital scales. A. Total number of available antibacterial agents vs. number of beds. B. Total numbers of available cephalosporins, macrolides, and quinolones vs. number of beds. Footnote: Positive correlations were observed in both the total available antibacterial agents vs. number of beds and total available cephalosporins, macrolides, and quinolones vs. number of beds (coefficient: .55, p < .01 and .52, p < .01, respectively).
Fig. 3. Number of listed antibacterial agents according to cephalexin availability. A. Total numbers of available antibacterial agents vs. cephalexin availability. B. Total numbers of available cephalosporins, macrolides, and quinolones vs. cephalexin availability. Footnote: More antibacterial agents were listed in cephalexin-available hospitals than were listed in cephalexin-unavailable hospitals. This tendency was observed in both the total number of available antibacterial agents vs. cephalexin availability (p < .01) and the total number of available cephalosporins, macrolides, and quinolones vs. cephalexin availability (p ¼ .11).
better: a theory popularized in the 1980s and unchanged in present-day Japan. However, previous studies proved 1GCs are no less effective than 3GCs for skin and soft tissue infections [10e12], while a Japanese study suggested 3 GC use increases methicillinresistant Staphylococcus aureus infections [13]. Therefore, the current situation in which cephalexin is unavailable in most Japanese hospitals needs to be improved. Second, more than one 3GCs is available in 74.2% of the surveyed hospitals. This study did not assess how doctors use these drugs differently, preparing similar antibacterial agents usually does not make sense. Additionally, in terms of behavioral science, too many choices may impose a psychological strain on physicians, which could impede their decision-making abilities [14,15]. Multiple availability is also seen in quinolones; more than one quinolone
was available in about 70% of the hospitals. These results may partly explain why the proportions of 3 GC and quinolone use are higher in Japan than in European countries. Not only the pharmaceutical affairs committee but also an antimicrobial stewardship team (AST) should intervene available hospital antibacterial agents. Cooperation of the two, or including an AST in the pharmaceutical affairs committee, may be a necessary step for advancing such stewardship. The numbers of hospital beds and available antibacterial agents were positively correlated. This correlation is comprehensible because large hospitals have more opportunities to confront various infectious diseases. However, we revealed wide variation of the number of available antibacterial agents at each scale of hospital. This dispersion may owe to the presence/absence of
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx
infectious diseases specialists in pharmaceutical affairs committees, or committees' susceptibility to being persuaded by pharmaceutical companies' marketing. We demonstrated that hospitals which owned large numbers of antibacterial agents were more likely to own cephalexin. Given the limited number of cephalexin prescriptions in Shizuoka prefecture [16], cephalexin is rarely prescribed even in hospitals in which it is available. Although each hospital in Japan is required to have a dedicated pharmaceutical affairs committee, this finding suggests that if such committees strictly manage the available antibacterial agents, they do not select cephalexin, which the WHO considers an essential drug. Therefore, outpatient antimicrobial stewardship may focus not only on the quality of medicine but also on the prescribing environment. Establishing guidelines for minimum required antibacterial agents is one of the possible solutions, for example. From a different perspective, some Japanese hospitals have introduced “formularies”, that is lists of recommended drugs by pharmacies in terms of their effectiveness, safeness, and economy [17]. This approach was examined mainly among antihypertensive drugs, but it may be suitable for antibacterial agents [18]. This study has several limitations. First, we researched only the hospitals in one local region, not all hospitals in Japan. Various scales of hospital were included in this study and the response rate of over 90% may ensure strong representation. However, given that all participating hospitals are part of an interactive regional partnership on infection control, they may have more interest in infections than the average Japanese hospital. Second, questionnaire-based studies potentially have bias for data input errors, though we used multiple-choice responses in the questionnaires to help avoid such bias. Finally, the study's aim was only to research available antibacterial agents in hospitals in Japan; reasons or actual management for infectious diseases were not observed. Further study is needed to clarify individual prescription behaviors. 5. Conclusion Although 3GCs and quinolones were available in all participating hospitals in this study, 1GCs were available in only 22.5% of them. More than one 3 GC and quinolone were available in 74.2% and 67.7%, respectively. These results may partly explain why the proportions of 3 GC and quinolone use are higher in Japan than in European countries. Cephalexin availability was positively correlated with the total number of available antibacterial agents. This suggests that if pharmaceutical affairs committees strictly manage available antibacterial agents, they will not select cephalexin. Therefore, as mentioned, minimum required antibacterial agents guidelines may be needed in Japan in the future. Conflicts of interest None to declare.
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Acknowledgements We thank Adam Goulston, MS, ELS, from Edanz Group (www. edanzediting.com/ac) for editing a draft of this manuscript. This study was supported by a Ministry of Health, Labour and Welfare (MHLW) research grant of Japan (H29-shinkougyouseishitei-005). References € bele S, et al. Effect of [1] Baur D, Gladstone BP, Burkert F, Carrara E, Foschi F, Do antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect Dis 2017;17:990e1001. [2] Llor C, Bjerrum L. Antimicrobial resistance: risk associated with antibiotic overuse and initiatives to reduce the problem. Ther Adv Drug Saf 2014;5:229e41. [3] Muraki Y, Yagi T, Tsuji Y, Nishimura N, Tanabe M, Niwa T, et al. Japanese antimicrobial consumption surveillance: first report on oral and parenteral antimicrobial consumption in Japan (2009-2013). J Glob Antimicrob Resist 2016;7:19e23. [4] Tsutsui A, Yahara K, Shibayama K. Trends and patterns of national antimicrobial consumption in Japan from 2004 to 2016. J Infect Chemother 2018;24: 414e21. [5] Yamasaki D, Tanabe M, Muraki Y, Kato G, Ohmagari N, Yagi T. The first report of Japanese antimicrobial use measured by national database based on health insurance claims data (2011e2013): comparison with sales data, and trend analysis stratified by antimicrobial category and age group. Infection 2018;46: 207e14. [6] WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD index. 2018. http://www.whocc.no/atcddd/. [Accessed 30 June 2018]. [7] World Health Organization ý. The selection and use of essential medicines. 2017. http://www.who.int/medicines/publications/essentialmedicines/trs1006-2017/en/. [Accessed 25 July 2018]. [8] The Government of Japan. National action plan on antimicrobial resistance (AMR) 2016-2020. 2016. http://www.mhlw.go.jp/file/06-Seisakujouhou10900000-Kenkoukyoku/0000138942.pdf. [Accessed 26 June 2018]. [9] Spyker DA, Thomas BL, Sande MA, Bolton WK. Pharmacokinetics of cefaclor and cephalexin: dosage nomograms for impaired renal function. Antimicrob Agents Chemother 1978;14:172e7. [10] Giordano PA, Elston D, Akinlade BK, Weber K, Notario GF, Busman TA, et al. Cefdinir vs. cephalexin for mild to moderate uncomplicated skin and skin structure infections in adolescents and adults. Curr Med Res Opin 2006;22: 2419e28. [11] Tack KJ, Keyserling CH, McCarty J, Hedrick JA. Study of use of cefdinir versus cephalexin for treatment of skin infections in pediatric patients. The Cefdinir Pediatric Skin Infection Study Group. Antimicrob Agents Chemother 1997;41: 739e42. [12] Tack KJ, Littlejohn TW, Mailloux G, Wolf MM, Keyserling CH. Cefdinir versus cephalexin for the treatment of skin and skin-structure infections. The cefdinir adult skin infection study group. Clin Ther 1998;20:244e56. [13] Washio M, Mizoue T, Kajioka T, Yoshimitsu T, Okayama M, Hamada T, et al. Risk factors for methicillin-resistant staphylococcus aureus (MRSA) infection in a Japanese geriatric hospital. Public Health 1997;111:187e90. [14] Iyengar SS, Kamenica E. Choice proliferation, simplicity seeking, and asset allocation. J Public Econ 2010;94:530e9. [15] Mick DG, Broniarczyk SM, Haidt J. Choose, choose, choose, choose, choose, choose, choose: emerging and prospective research on the deleterious effects of living in consumer hyperchoice. J Bus Ethics 2004;52:207e11. [16] AMR Clinical Reference Center. Surveillance of antimicrobial use based on National Database. 2018. http://amrcrc.ncgm.go.jp/surveillance/010/ 20181128172333.html. [Accessed 6 March 2019]. [17] Hamashima Y, Hamashima C. Development of hospital formulary in Japan current trends and issues. Value Health 2016;19:A816. [18] Veve MP, Morin A, Kenney RM, Makowski CT, Davis SL. Formulary management and antimicrobial stewardship: a 7-year evaluation at an integrated health-system. Open Forum Infect Dis 2017;4(Suppl 1):S262e3.
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Original Article
Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals* Yoshiki Kusama a, b, *, Yuichi Muraki c, Takahiro Mochizuki d, Hanako Kurai e, Yoshiaki Gu a, Norio Ohmagari a, b a
AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, Japan Collaborative Chairs Emerging and Reemerging Infectious Diseases, National Center for Global Health and Medicine, Graduate School of Medicine, Tohoku University, 1-1, Seriryo-tyo, Aoba-ku, Sendai, Miyagi, Japan c Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University, 5, Nakauchi-machi, Misasagi, Yamashina-ku, Kyoto-shi, Kyoto, Japan d Department of Pharmacy, Shizuoka Cancer Center Hospital, Shizuoka, 1007, Shimonagakubo, Nagaizumi-cho, Sundo-gun, Shizuoka, Japan e Division of Infectious Diseases, Shizuoka Cancer Center Hospital, 1007, Shimonagakubo, Nagaizumi-cho, Sundo-gun, Shizuoka, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 September 2018 Received in revised form 10 June 2019 Accepted 20 August 2019 Available online xxx
In Japan, hospitals' pharmaceutical affairs committees freely select the drugs to be purchased depending on the regulations of each hospital. This system poses a risk of the absence of essential drugs or an excess of similar drugs, and may promote inappropriate use of third-generation cephalosporins (3GCs) and quinolones. Against this backdrop, we researched availability of antibacterial agents in Japanese hospitals. We conducted a questionnaire-based study in eastern Shizuoka Prefecture, Japan. Questionnaires were sent to 33 hospitals that had established an interactive regional partnership on infection control. We analyzed the number of available oral cephalosporins, macrolides, and quinolones in each hospital, and the correlation between the number of total available antibacterial agents and the hospital scale and cephalexin availability. Thirty-one hospitals participated in this study. First-generation cephalosporin (1 GC) was available in only 22.5% of them. In all participating hospitals, 3GCs were available, with more than one 3 GC available in 74.2%. Quinolones were available in all hospitals, and more than one quinolone in 67.7%. The numbers of hospital beds and total available antibacterial agents were positively correlated and hospitals that owned cephalexin available also significantly more often owned other available antibacterial agents. 1 GC were available in only a few hospitals, while multiple 3GCs and quinolones were available in most. This situation may lead to excess use of 3GCs or quinolones in Japan. A low number of available drugs was associated with cephalexin unavailability. Outpatient antimicrobial stewardship may focus not only on the quality of medicine, but also on the prescribing environment. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: First-generation cephalosporin Third-generation cephalosporin Quinolone Availability Japan
1. Introduction Judicious use of antimicrobials is important for impeding antimicrobial resistance, which is now major global public health issue [1,2]. In Japan, antimicrobial consumption has been estimated by sales data or claims data, which showed relatively low consumption compared with European countries, though the proportion of oral macrolides, cephalosporins, and quinolones to total antimicrobials is an evident problem. An additional issue is that oral * We declare that all authors complied with the ICMJE authorship criteria. * Corresponding author. 1-21-1, Toyama, Shinjuku-ku, Tokyo, Japan. E-mail address: [email protected] (Y. Kusama).
third-generation cephalosporins (3GCs) account for more than 90% of total oral cephalosporins [3e5]. In almost all Japanese hospitals, pharmaceutical affairs committeesdcomposed of a hospital director, pharmacy director, and/or director of each clinical departmentd freely select purchasing drugs depend on the regulation of each hospital. Hospital doctors must choose from the drugs on the respective lists when prescribing. While this system is effective in terms of ensuring hospitals' freedom from governmental restriction in selecting drugs, there is some risk of the absence of essential antimicrobials or excess supply of broadspectrum antibiotics. The present state of affairs may be associated with inappropriate 3 GC and quinolone use in Japan, and we
https://doi.org/10.1016/j.jiac.2019.08.013 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
2
Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx
therefore researched numbers of available antibacterial agents in a sample of Japanese hospitals.
3. Results 3.1. Currently available antibacterial agents in Japan
2. Materials and methods 2.1. Questionnaire We conducted a questionnaire-based study in eastern Shizuoka Prefecture, Japan. Of 82 total hospitals in eastern Shizuoka, we sent the questionnaire to 33 that had established an interactive regional partnership on infection control within the prefecture between September 20th to October 13th in 2017. The questionnaire inquired as to the hospital name, number of beds, presence of a department of infectious diseases, department of pediatrics, and/or department of hematology, and available drugs within the hospital. The available drugs were limited only for the inpatients because prescriptions for outpatients were not influenced by the hospital's pharmaceutical affairs committee's decisions or the hospital policies. The questionnaire was developed using Google Forms, with multiple-choice responses, rather than free entry, so as to avoid omissions. Before distributing the questionnaires, we explained the study to the participating hospital staff at the Shizuoka Cancer Center and Fuji City General Hospital, both leaders of a regional partnership. Then, we sent invitation letters to hospital directors. Research duration was 41 days and reminder letters were sent once at 14 days before the final deadline. 2.2. Analysis Although we included data on available antibiotics from all categories from the responses, we focused on analyzing the number of available oral cephalosporins, macrolides, and quinolones; which is a problematic issue, as noted above, in Japan. Antimicrobials were classified using the Anatomical Therapeutic Chemical (ATC) classification system developed by the World Health Organization (WHO) Collaboration Centre for Drug Statistics Methodology [6]. Macrolides and quinolones were placed in three categories based on acting time and spectrum. The classifications are detailed in a previous article [3]. We then stratified hospitals into four groups by number of beds (20e99, 100e199, 200e499, and 500 or more) and analyzed for correlation between the number of total available drugs and the hospital scale. And we also analyzed for correlation between the number of total available cephalosporins, macrolides, and quinolones and the hospital scale. We determined cephalexin availability as per those from the relevant drug list because the WHO categorizes cephalexin as an “access” drug, which means it is “…continuously available and affordable at public or private health facilities or medicine outlets that are within one hour's walk from the homes of the population” [7]. Thus, we analyzed the differences in the total numbers of available antibacterial agents between hospitals in which cephalexin was available and unavailable. The differences in the total numbers of cephalosporins, macrolides, and quinolones between cephalexin-available and unavailable hospitals were also analyzed. Spearman's rank correlation coefficients were calculated for correlation analysis and ManneWhitney U-tests were used to assess the differences in the numbers of antibacterial agents between cephalexin-available and unavailable hospitals. Significance was set at p < .05. All statistical analysis was performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA).
Table 1 lists all available antibacterial agents in Japan (as of September 20, 2017). For oral cephalosporins, two first-generation (1GCs), two second-generation (2GCs), and six 3GCs were available. For oral macrolides, one short-acting, two intermediate-acting, and one long-acting were available. For quinolones, two firstgeneration (1GQs), five second-generation (2GQs), and three third-generation (3GQs) were available. 3.2. Characteristics of participating hospitals Of the hospitals asked to participate, 31 of 33 completed the questionnaire (response rate: 93.9%). Table 2 shows these hospitals' characteristics. Six (19.4%) had 20e99 beds, 13 (41.9%) had 100e199 beds, 10 (32.3%) had 200e499 beds, and two (6.5%) had 500 or more beds. General hospitals accounted for 83.9% of the total participating. The others consisted of three (9.7%) rehabilitation hospitals, one (3.2%) neurosurgery hospital, and one orthopedic hospital (3.2%). Almost half (51.6%) of the participating hospitals had a pediatric department, two (6.5%) had a hematologic department, and one (3.2%) had a department of infectious diseases. 3.3. Numbers of available oral cephalosporins, macrolides, and quinolones Fig. 1 shows the numbers of available oral cephalosporins, macrolides, and quinolones. In seven (22.5%) hospitals 1GCs were available, 2GCs were available in 20 (64.5%), while 3GCs were available in all of them. Hospitals with availability of two 3GCs were the most common (38.7%), and those with more than two accounted for 35.5%. In two hospitals, five 3GCs were available. Although a short-acting macrolide was not available in 14 (45.2%)
Table 1 Available oral cephalosporins, macrolides, and quinolones in Japan (as of September 20, 2017). Cephalosporins
WHO ATC Code
Drug Name
First-generation
J01DB01 J01DB06 J01DC02 J01DC04 J01DC07 J01DD08 J01DD13 J01DD15 J01DD16 J01DD17 J01DD18 WHO ATC Code J01FA01 J01FA06 J01FA07 J01FA09 J01FA10 WHO ATC Code J01MA06 J01MB04 J01MA01 J01MA02 J01MA07 J01MA12 J01MA22 J01MA14 J01MA19 J01MA21
Cefalexin Cefroxadine Cefuroxime Cefaclor Cefotiam Cefixime Cefpodoxime Cefdinir Cefditoren Cefcapene Cefteram Drug Name Erythromycin Roxithromycin Josamycin Clarithromycin Azithromycin Drug Name Norfloxacin Pipemidic acid Ofloxacin Ciprofloxacin Lomefloxacin Levofloxacin Tosufloxacin Moxifloxacin Garenoxacin Sitafloxacin
Second-generation
Third-generation
Macrolides Short-acting Intermediate-acting
Long-acting Quinolones First-generation Second-generation
2.3. Ethics Third-generation
This study was approved by the Shizuoka Cancer Center ethics committee (Number T29-14-29-1-5).
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx Table 2 Characteristics of participating hospitals. Hospital beds (%) 20e100 100e200 200e500 >500 Hospital characteristics (%) General Rehabilitation Neurosurgery Orthopedic Having specific departments (%) Pediatrics (%) Hematology (%) Infectious Diseases (%)
6 (19.4) 13 (41.9) 10 (32.3) 2 (6.5) 26 (83.9) 3 (9.7) 1 (3.2) 1 (3.2) 16 (51.6) 2 (6.5) 1 (3.2)
hospitals, one intermediate-acting macrolide and one long-acting macrolide were available in most hospitals (77.4% and 80.6%, respectively). One hospital (3.2%) had availability of one 1GQ. For 2GQs, levofloxacin was available in all participating hospitals (data was not shown). Hospitals with availability of one 2GQ accounted for 54.8%, those with two accounted for 35.5%, and those with three accounted for 9.7%. No 3GQs were available in 12 (38.7%) hospitals, and more than one was available in seven (22.5%) hospitals. In terms of overall quinolone availability, in 21 (67.7%) hospitals more than one was available. 3.4. Correlation between the number of total available antibacterial agents and hospital scales and cephalexin availability The median number of available antibacterial agents was 13 (range: 9e16) in hospitals with 20e100 beds, 14 (range: 4e22) for 100e200 beds, 22.5 (range: 5e28) for 200e500 beds, and 22.5
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(range: 18e27) those with more than 500 beds. Fig. 2A and B show the numbers of listed antibacterials according to hospital scales. There was a positive correlation between the number of hospital beds and the total number of available antibacterial agents and between the number of hospital beds and the total number of available cephalosporins, macrolides, and quinolones (coefficient: .55, p < .01 and .52, p < .01, respectively). Large variations were seen in the numbers of total available antibacterial agents among different hospital scales. Fig. 3A and B show the box-and-whisker plots of the total numbers of available antibacterial agents and the total numbers of cephalosporins, macrolides, and quinolones according to cephalexin-available and unavailable hospitals. More antibacterial agents were listed in cephalexin-available hospitals than were listed in cephalexin-unavailable hospitals. This tendency was seen both in the total number of available antibacterial agents (p < .01) and in that of cephalosporins, macrolides, and quinolones (p ¼ .11). 4. Discussion Bridging the pharmaceutical gap between Japan and Western countries is one of the issues in Japan's National Action Plan on Antimicrobial Resistance [8]. Available antibacterial agents largely affect doctors' prescription behaviors because doctors cannot prescribe drugs not purchased by their hospital's pharmaceutical affairs committee. As a first point of consideration, although oral 3GCs were available in all participating hospitals in the present study, 1GCs were available in only 22.5%. However, 1GCs have superior bioavailability and cost compared with 3GCs [9]. Additionally, there is less selection-related pressure for 1GCs because of the fewer choices than for 3GCs. The reason for the lack of 1 GC availability is unknown. We speculated that broader antibacterial agents are
Fig. 1. Number of available oral cephalosporins, macrolides, and quinolones in each hospital. Footnote: Bars show the number of hospitals in which each antibacterial was available.
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
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Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx
Fig. 2. Numbers of listed antibacterial agents according to hospital scales. A. Total number of available antibacterial agents vs. number of beds. B. Total numbers of available cephalosporins, macrolides, and quinolones vs. number of beds. Footnote: Positive correlations were observed in both the total available antibacterial agents vs. number of beds and total available cephalosporins, macrolides, and quinolones vs. number of beds (coefficient: .55, p < .01 and .52, p < .01, respectively).
Fig. 3. Number of listed antibacterial agents according to cephalexin availability. A. Total numbers of available antibacterial agents vs. cephalexin availability. B. Total numbers of available cephalosporins, macrolides, and quinolones vs. cephalexin availability. Footnote: More antibacterial agents were listed in cephalexin-available hospitals than were listed in cephalexin-unavailable hospitals. This tendency was observed in both the total number of available antibacterial agents vs. cephalexin availability (p < .01) and the total number of available cephalosporins, macrolides, and quinolones vs. cephalexin availability (p ¼ .11).
better: a theory popularized in the 1980s and unchanged in present-day Japan. However, previous studies proved 1GCs are no less effective than 3GCs for skin and soft tissue infections [10e12], while a Japanese study suggested 3 GC use increases methicillinresistant Staphylococcus aureus infections [13]. Therefore, the current situation in which cephalexin is unavailable in most Japanese hospitals needs to be improved. Second, more than one 3GCs is available in 74.2% of the surveyed hospitals. This study did not assess how doctors use these drugs differently, preparing similar antibacterial agents usually does not make sense. Additionally, in terms of behavioral science, too many choices may impose a psychological strain on physicians, which could impede their decision-making abilities [14,15]. Multiple availability is also seen in quinolones; more than one quinolone
was available in about 70% of the hospitals. These results may partly explain why the proportions of 3 GC and quinolone use are higher in Japan than in European countries. Not only the pharmaceutical affairs committee but also an antimicrobial stewardship team (AST) should intervene available hospital antibacterial agents. Cooperation of the two, or including an AST in the pharmaceutical affairs committee, may be a necessary step for advancing such stewardship. The numbers of hospital beds and available antibacterial agents were positively correlated. This correlation is comprehensible because large hospitals have more opportunities to confront various infectious diseases. However, we revealed wide variation of the number of available antibacterial agents at each scale of hospital. This dispersion may owe to the presence/absence of
Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013
Y. Kusama et al. / J Infect Chemother xxx (xxxx) xxx
infectious diseases specialists in pharmaceutical affairs committees, or committees' susceptibility to being persuaded by pharmaceutical companies' marketing. We demonstrated that hospitals which owned large numbers of antibacterial agents were more likely to own cephalexin. Given the limited number of cephalexin prescriptions in Shizuoka prefecture [16], cephalexin is rarely prescribed even in hospitals in which it is available. Although each hospital in Japan is required to have a dedicated pharmaceutical affairs committee, this finding suggests that if such committees strictly manage the available antibacterial agents, they do not select cephalexin, which the WHO considers an essential drug. Therefore, outpatient antimicrobial stewardship may focus not only on the quality of medicine but also on the prescribing environment. Establishing guidelines for minimum required antibacterial agents is one of the possible solutions, for example. From a different perspective, some Japanese hospitals have introduced “formularies”, that is lists of recommended drugs by pharmacies in terms of their effectiveness, safeness, and economy [17]. This approach was examined mainly among antihypertensive drugs, but it may be suitable for antibacterial agents [18]. This study has several limitations. First, we researched only the hospitals in one local region, not all hospitals in Japan. Various scales of hospital were included in this study and the response rate of over 90% may ensure strong representation. However, given that all participating hospitals are part of an interactive regional partnership on infection control, they may have more interest in infections than the average Japanese hospital. Second, questionnaire-based studies potentially have bias for data input errors, though we used multiple-choice responses in the questionnaires to help avoid such bias. Finally, the study's aim was only to research available antibacterial agents in hospitals in Japan; reasons or actual management for infectious diseases were not observed. Further study is needed to clarify individual prescription behaviors. 5. Conclusion Although 3GCs and quinolones were available in all participating hospitals in this study, 1GCs were available in only 22.5% of them. More than one 3 GC and quinolone were available in 74.2% and 67.7%, respectively. These results may partly explain why the proportions of 3 GC and quinolone use are higher in Japan than in European countries. Cephalexin availability was positively correlated with the total number of available antibacterial agents. This suggests that if pharmaceutical affairs committees strictly manage available antibacterial agents, they will not select cephalexin. Therefore, as mentioned, minimum required antibacterial agents guidelines may be needed in Japan in the future. Conflicts of interest None to declare.
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Please cite this article as: Kusama Y et al., Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.013