Posted on Authorea 14 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161839221.10007524/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. tisapoa n osn opriiaewr o plcbet hssuybcuew sdpublicly used we because study this E- to applicable +81-59-256-2651, title not 2158- Running were Fax: participate Center; reports. to provided +81-59-259-1211, voluntarily consent Medical available and Chuo approval Tel: Ethics participate Mie Japan to consent Organization and 514-1101 approval Ethics Hospital Mie, National Tsu, Pharmacy, mail: Hisaimyojincho, Ph.D., 5 Asai, Mie, Yuki Tsu, Hisaimyojincho, 2158-5 Center; * Medical Chuo Mie Japan Organization 514-1101 Hospital National Pharmacy, Affiliation Abe Yasuharu Yamamoto, Takanori Asai*, Yuki Adverse Japanese Authors the Database Using Report Agranulocytosis Event Antibiotic-induced Drug of Analysis Comprehensive title Article Reports Short : type of Article characteristics Pharmacology the into Clinical insights of provided Journal findings British These type. 13 failure and out 18, wear 3, the were 12, agranulocytosis. parameter antibiotics 16, antibiotic-induced shape the 10, Weibull that the 6, of indicating 20, intervals cefmetazole, 1, were confidence ampicillin/sulbactam, vancomycin 95% for The and agranulocytosis respectively. teicoplanin, (1.31– of days, kanamycin, 2.05 times-to-onset (2.16–13.7), imipenem/cilastatin, median 6.05 The clindamycin, (2.11–3.60), respectively. cefozopran, 2.78 (1.40–2.82), (2.73–4.54), signals 2.01 3.54 ce- 2.49 (1.04–2.47), showed and cefmetazole, (1.79–3.80), 1.64 antibiotics 3.07), amikacin, 2.65 (1.88–3.95), were 60 ampicillin/sulbactam, 2.77 vancomycin (2.27–6.92), for of and intervals) 4.48 Ten teicoplanin, (1.91–4.34), confidence kanamycin, (95% imipenem/cilastatin, agranulocytosis. Adverse ciprofloxacin, ratios antibiotic-induced Japanese clindamycin, odds of the fozopran, reporting profiles analyzed the we identify Here, agranulocytosis; to for antibiotics. database by Report stimulated Event be Drug can agranulocytosis drug-induced infrequent, Although Abstract 2021 14, April 1 Database Asai Report Yuki Event Drug Adverse Japanese the Using Agranulocytosis Antibiotic-induced of Analysis Comprehensive ainlHsia raiainMeCu eia Center Medical Chuo Mie Organization Hospital National orsodn author Corresponding [email protected] 1 aaoiYamamoto Takanori , 1 n auauAbe Yasuharu and , 1 1 β o hs niitc eeoe n excluded and over were antibiotics these for Posted on Authorea 14 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161839221.10007524/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. rgEetRpr JDR aaae hc saalbeoln,wsetbihdi pi 04b h PMDA Adverse the by by Japanese collected 2004 April The are in (PMDA). AEs established was studies. Agency individual online, available clinical Japan, Devices is conduct which In Medical and database, AEs to and (JADER) surveillance. rare Report samples Pharmaceuticals postmarketing of Event of Drug the detection in for number at tools useful sufficient workers primary be a healthcare as to rare shown collect used a been to been have is difficult have (SRSs) agranulocytosis systems is because reporting However, it spontaneous antibodies, Recently, reaction. [6], antineutrophil hypersensitivity (AE) immune-mediated opsonizing event IgM by adverse [5] or caused Stossel agranulocytosis. IgG be and inducing an may Weitzman of i.e., agranulocytosis unknown, risk antibiotic-induced remain low agranulocytosis that a antibiotic-induced have speculated includ- of that with mechanisms antibiotics [4]. medications, patients identify the factor to of in to Although granulocyte-colony-stimulating necessary need range difficult with is urgent treatment wide particularly it an concomitant fever, is a becomes add a there and by have control Accordingly, antibiotic to caused infection continue another who be and to patients switch can [1], shows in Furthermore, and Agranulocytosis antibiotics (1000– diseases agranulocytosis. and infectious antibiotic-induced mild [2]. to [3] as susceptible 10–20% clozapine highly categorized of becomes ing count, patient rate the neutrophil mortality which absolute in a condition the life-threating in a is decrease a as 1500/ These characterized type. is failure Neutropenia out wear the agranulocytosis. were antibiotic-induced antibiotics of Introduction parameter the characteristics shape Weibull that the the into indicating of insights 1, intervals 16, provided confidence excluded 10, findings 95% and cefmetazole, 6, The over respectively. 20, ampicillin/sulbactam, were days, were antibiotics for 13 vancomycin and agranulocytosis and 18, (2.73– 3, teicoplanin, of 3.54 12, kanamycin, and times-to-onset imipenem/cilastatin, (1.31–3.07), median 2.05 clindamycin, (2.16–13.7), The cefozopran, 6.05 (2.11–3.60), (1.88– respectively. 2.77 2.78 (2.27–6.92), (1.40–2.82), 4.54), 4.48 2.01 for (1.91–4.34), (1.04–2.47), intervals) 2.49 1.64 imipenem/cilastatin, confidence (1.79–3.80), 3.95), 2.65 (95% ciprofloxacin, were ratios vancomycin clindamycin, and odds teicoplanin, cefozopran, reporting kanamycin, the cefmetazole, Ten agranulocytosis; amikacin, the agranulocytosis. for antibiotic-induced analyzed signals ampicillin/sulbactam, of we showed profiles antibiotics Here, identify to 60 antibiotics. database of by Report stimulated Event Drug be Adverse can Japanese agranulocytosis drug-induced infrequent, Although Abstract 1 count Figure 2 count Table clindamycin, amikacin words type. of 1,548/2,000 failure profiles count random the Word cefozopran, type, the failure with out consistent wear cefmetazole, were a ciprofloxacin were ciprofloxacin) and and amikacin, amikacin agranulocytosis. (excluding induce antibiotics may Eight ampicillin/sulbactam, vancomycin, and teicoplanin, including kanamycin, imipenem/cilastatin, ciprofloxacin, antibiotics, event. adverse Ten rare a adds is study it this but What antibiotics, by caused be can subject Agranulocytosis this analysis; about known time-to-onset already Report; is What Event Drug vancomycin Adverse system; Japanese reporting spontaneous agranulocytosis; drug-induced antibiotics; Keywords Agranulocytosis Antibiotic-induced of Investigation μ ) oeae(500–1000/ moderate L), μ ) rsvr ( severe or L), < 500/ 2 μ )[] h otsvr om aldagranulocytosis, called form, severe most The [1]. L) β o these for Posted on Authorea 14 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161839221.10007524/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ihmgaint oemro a aeahg iko nuigarnlctssbfr aamnn.How- mining. ceftriaxone data as such before transferability, agranulocytosis fluid with inducing cerebrospinal antibiotics high of with that risk antibiotics high speculated for a detected we for not have marrow, CIs) were may (2.73– bone signals marrow 3.54 (95% ever, in and bone RORs produced (1.31–3.07), to the 2.05 are migration (2.16–13.7), signals; high neutrophils 6.05 Because as (2.11–3.60), (1.88– agranulocyto- detected respectively. 2.77 2.78 of (2.27–6.92), (1.40–2.82), 4.54), were 4.48 2.01 reports antibiotics (1.91–4.34), (1.04–2.47), 2.49 of 60 1.64 imipenem/cilastatin, (1.79–3.80), number 3.95), of 2.65 ciprofloxacin, were The vancomycin 10 clindamycin, and 1, teicoplanin, reports cefozopran, 2021. kanamycin, Table 1,048,576 January cefmetazole, shown the and amikacin, As among 2004 ampicillin/sulbactam, treatment April 3,221. antibiotic between to was related database sis AEs JADER suspected the Time-to-onset of in reports decrease. 72,723 then extracted and USA). We NC, stage Cary, early Institute, an (SAS Discussion at software and increase 15 Results to version JMP considered using was performed hazard were the analyses 1, if than time; over less increase was to or considered administration was first hazard if of time; over WSP date constant of the from be combination date because The administration excluded available. when first were not follows: the was cases The subtracting agranulocytosis Fifty was [9]. by of patient population calculated onset date. each reference was for expression a administration administration require agranulocytosis first first not the the does of which from time was (WSP), time the parameter analysis elapsed from shape Statical onset Weibull the agranulocytosis using agranulocytosis. until evaluated Japan). of period Tokyo, calculated of reports Japan, not of median was of (IBM condition The ratio 27 number the version Conversely, odds small Statistics adjusted [8]. the of SPSS The 2 limit of with than association. a lower conducted because exposure-event greater from 1, no number analysis calculated than considered multivariate case were greater was and by CI) ROR 1 1, (95% than than follows: interval antibiotic-induced less greater as confidence ROR with CI defined 95% associated 95% was and signals corresponding detection ROR of the Signal the detection 1, table. the contingency for Fig. two-by-two (ROR) shown ratio As odds agranulocytosis. reporting the selected We the code 23.1J. agranulocytosis, (PT) version on term Activities Regulatory preferred focused analysis We for the Data Dictionary using 1. Medical Table defined the was in to Agranulocytosis shown according are neutropenia. (10001507) study of current type the AE life-threatening in most of analyzed latest antibiotics the 60 excluded. The only were extracted dates names inaccurate we the AE with in database, and Data identification relational reports Drugs patient file. the duplicate DEMO to from Because the according evaluation USA). on tables WA, the based data Redmond, reports affect four may (Microsoft, primary the history, database 2019 (medical from SRS Access HIST database PMDA 4) Microsoft relational and the using etc.); created 2) numbers from weight); outcomes, We and (AEs, searched age, REAC etc.). sex, was 3) including illness, etc.); information, 2021, causality, demographic (patients’ January name, DEMO (drug 1) to DRUG follows: 2004 of as consisted tables, April data database four from JADER The data (https://www.info.pmda.go.jp/fukusayoudb/CsvDownload.jsp). including website database, JADER The source JADER Data the using agranulocytosis antibiotic-induced used Methods of be profiles can expression database the JADER evaluated the database. we using study, mining this data agranulocytosis. In Thus, antibiotic-induced for [7]. tool practice screening clinical a of as realities the reflects and β a qa o1(admfiue n 5 Iof CI 95% and failure) (random 1 to equal was β a rae hn1(erotfiue n h 5 I(oe)of (lower) CI 95% the and failure) out (wear 1 than greater was β a esta eryfiue n h 5 I(pe)of (upper) CI 95% the and failure) (early 1 than less was 3 β nlddte1 h aadwsetmtdto estimated was hazard the 1, the included β n 5 Icudb nepee as interpreted be could CI 95% and β xedd1 the 1, exceeded β Posted on Authorea 14 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161839221.10007524/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h uhr aedcae htteei ocnito interest. of conflict no is there that declared have authors The editing. language statement English interest for of (www.editage.com) Conflict Editage thank to like would We clinical cefmetazole, further may amikacin, Acknowledgments Finally, in vancomycin ampicillin/sulbactam, counts and setting. which neutrophil teicoplanin, clinical through kanamycin, absolute agranulocytosis. the mechanisms induce imipenem/cilastatin, that in the ciprofloxacin, suggesting carefully verify clindamycin, agranulocytosis, monitored to cefozopran, antibiotics be of needed 10 should are identified risk we drugs studies high database, these with JADER taking the associated patients antibiotic-induced using be of of incidences may limitations the evaluating various that report the first Despite the administration was by agranulocytosis. be analysis caused comprehensive may be this agranulocytosis not conclusion, because In may Fourth, SRS by study. reported current agranulocytosis antibiotics. the the (gran- small of [21], was in 10018681 are infections and reports included severe there of (granulocytopenia) by not number 10018687 Second, induced were the codes Third, control PT decreased) antibiotics. the data. count for among because of information ulocyte compared lack underestimated contain and been and have under-reporting not quantified may as does and such be database biases, cannot JADER reporting JADER RORs the some the also because of useful considered because intensity be a First, the should be that patients, biases. limitations to several some likely has agranulocytosis. has is database for database JADER WSP period the using monitoring using mining safety with analysis Data consistent specific time-to-onset were the Accordingly, ciprofloxacin of and amikacin determination 2). of (Table for profiles needed. tool type the is type, failure research failure random out further the wear and The a unknown, indicating WSP are and 1, treatment. of antibiotic excluded details each first CIs of the the 95% pharmacokinetics however, in the of variations agranulocytosis; signal Although the week of to with mechanism 1 related antibiotics been onset within have 10 may the were the time kanamycin onset for treatment the data and cases following in time-to-onset onset difference 292 ciprofloxacin, agranulocytosis the extracted of cefmetazole, in evaluate ranges) we amikacin, to (interquartile aminoglycoside analysis, durations performed with the median time-to-onset been The the as has 2). For (Table gentamicin analysis detection WSP [9]. use mining, AEs to data target or SRS better for vancomycin of be with reports may recent treated it In be that kanamycin may speculate and amikacin MRSA we because therapy. study, by signals, combination current caused as the In detected endocarditis [20]. were infective aminoglycosides with Moreover, combination the in with teicoplanin with 19]. antibiotics administered use [18, often study. preferentially are effects this aminoglycosides to in setting, better clinical detected be the was In may signal it no which neutropenia, for febrile spectrum with same those as such targeting patients, carbapenems addition, anti- In with [16]. antibiotics et neutropenia Smith febrile contrast, of In aeruginosa treatment the anti-methicillin-resistant 15]. for [14, an effective 2–18% linezolid, and approximately that is vancomycin reported by of induced al. agranulocytosis development neutropenia antibiotic-induced of the investigated, incidence be that The toxicity. to administra- reported cumulative need or a study also concentration, by be antibiotics retrospective trough clarified not other A dosage, may be Although the not [13]. only. with could period marrow associated agranulocytosis tion not bone of was risk the transferability, neutropenia the fluid to vancomycin-induced that cerebrospinal migration suggested poor of with findings antibiotic these analysis an Therefore, [12], teicoplanin detected. whereas was [11], cefotaxime and [10] r miial sdfrteteteto erl etoei 1] niaigta hnusing when that indicating [17], neutropenia febrile of treatment the for used empirically are suooa aeruginosa Pseudomonas β o ih niitc ecuigaiai n irflxcn eeoe and over were ciprofloxacin) and amikacin (excluding antibiotics eight for rat-RAatvt nteeprclteteto high-risk of treatment empirical the in activity anti-MRSA or 4 tpyoocsaureus Staphylococcus β - atmatboist nuesynergistic induce to antibiotics lactam MS)aet a esafe be may agent, (MRSA) Pseudomonas Posted on Authorea 14 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161839221.10007524/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. References https://orcid.org/0000-0002-1933-8592 Asai: Yuki Abe Yamamoto, Asai, work: ORCID the of aspects all for Abe Accountable Yamamoto, Asai, manuscript: of approval Final Asai Abe writing: Yamamoto, Manuscript Asai, data: of interpretation and Assembly Abe Asai, design: study and Concept reasonable upon author corresponding the Authorship from available are study this of findings request. the support that data The statement availability Data Non information Funding Mri ,Wr .Hg niec fvnoyi-soitdluoei n etoei nacardio- a in neutropenia and leucopenia vancomycin-associated from of vancomycin incidence of High preparations C. of Ward toxicity A, the Morris of study 15. Retrospective Jr. RC Moellering BF, receiving patients Farber W. in 167-183. neutropenia 14. Zhao vancomycin-induced 39: of E, 2000; Epidemiology Jacqz-Aigrain Pharmacokinet. SA. Koster Y, Clin RC, Li teicoplanin. Mercier MP, of X, Pai pharmacokinetics Huang 13. Clinical Y, AP. Zheng Wilson Y, 12. Zhou HY, Xu S, Leroux HY, Shi XK, hu- Chen in concentration 11. ceftriaxone of Determination H. Hakamata J, Fujita Y, Hamada J, Hirai A, Kotani 10. Sue ,Craa ,Ecdr ,Mlki ,CreisV.Ilsrto ftewiulsaepara- shape weibull the of Illustration VR. Cornelius M, Molokhia A, Timing Escudero the A, Affecting Factors T, Carvajal M. Tachi O, Mochizuki Sauzet H, M, Shimizu Esaki 9. J, A, Maruyama K, Yoshida Uehara Y, S, Imai Kanematsu M, I, Hashiguchi Sugita 8. H, Katsuno hypersensitivity M, delayed Otsubo beta-lactam-induced A, of Ueno Incidence Y, K. Noguchi Alestig 1068-1072. 7. H, 1: Hogevik 1978; L, Lancet. Belin neutropenia. L, immunological Treatment Olaison Drug-induced Antimicrobial TP. Outpatient 6. Stossel from SA, Agranulocytosis Weitzman S. 2477-2482. 5. 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Life UV Biomed 995-1006. with Technol chromatography 36: Analyt liquid 2013; B high-performance Saf. by Drug fluid data. cerebrospinal man record healthcare electronic using e0144263. tool 10: detection 2015; signal One. meter PLoS Reactions. primary Drug different Adverse of with Detection 124. patients Signal 19: in of 2018; events Bioinformatics. drug BMC adverse system. exploring reporting for spontaneous 607-615. using method 159: diseases simple 1999; A Med. H. Intern Teramachi Arch endocarditis. infective of treatment during neutropenia and 18-190. 23: 2019; J. Perm Report. 324-328. Case 13: A 2002; Med. Ceftriaxone: Intern with J Eur a literature. the agranulocytosis: of drug-induced review non-chemotherapy and cases of 90 management of study Modern cohort P. monocentric Dufour JM, Brogard 174-182. 5 Posted on Authorea 14 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161839221.10007524/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. report-database analysis-of-antibiotic-induced-agranulocytosis-using-the-japanese-adverse-drug-event- Fig.1.pptx file Hosted report-database analysis-of-antibiotic-induced-agranulocytosis-using-the-japanese-adverse-drug-event- ratios. odds Table.pdf reporting of calculation the file for Hosted table contingency Two-by-two 1. Fig. Legends Figure SiR huQ agR in ,Wn .Svr ct acettswt lo neto yCandida by infection blood with pancreatitis acute Severe Q. Wang X, Xiong R, Fang Q, Zhou R, Shi 21. PB, Lockhart B, Barsic MJ, Rybak IM, Tleyjeh Jr, VG Fowler AS, Bayer syn- WR, by Wilson aeruginosa LM, Pseudomonas Baddour of 20. membrane outer the of new Penetration of M. activity Goldner synergistic Lim RA, vitro WJ, Scudamore in Chng 19. Comparative LP, WJ. Koh Martin SE, DA, Lim Bruckner LM, DJ, Poon Winston YL, TO, Chee Kurtz J, 18. Jin D, Ying M, Safety, Teng JJ. YJ, Schentag Zhao CR, AL, Rayner Khoo A, Forrest 17. AK, Meagher GA, Noskin MC, Birmingham PF, Smith 16. lbaacmlctdsvr gauoyoi:acs eot M netDs 08 8 706. 18: 2018; Dis. Infect BMC report. case a agranulocytosis: severe 1435-1486. complicated 132: glabrata 2015; Healthcare Circulation. for Statement Association. Scientific Heart on A American Council Diagno- Complications: Cardiology, the Adults: From of Clinical in Management Professionals on Endocarditis and Infective Council Taubert Therapy, Young, Council. P, Antimicrobial Stroke the O’Gara sis, and in Disea- Anesthesia, AM, Disease Kawasaki and Cardiovascular Fink and Surgery on Endocarditis, RS, Cardiovascular Fever, Council Baltimore Rheumatic the JM, on of Committee Steckelberg se Association AF, Heart Bolger American ME, KA; Levison MH, Gewitz Chemother. Agents Antimicrob antibiotics. aminoglycoside 1007-1010. and 21: 1982; beta-lactam of combinations ergistic marce- Serratia 139-243. and 20: 1981; aeruginosa Chemother. Pseudomonas Agents against febrile Antimicrob amikacin in scens. and use agents carbapenem antimicrobial empirical beta-lactam 350-357. for 52: strategy 2018; risk-guided Agents. a Antimicrob J of Int Evaluation LYA. neutropenia. Chai LY, Hsu cancer BP, 795-801. in 14: infections 2003; Gram-positive Oncol. resistant Ann of neutropenia. treatment for with linezolid patients of pharmacokinetics and efficacy vial at available vial at available https://authorea.com/users/407713/articles/517953-comprehensive- https://authorea.com/users/407713/articles/517953-comprehensive- 6