piv Pediatric Infection & Vaccine Pediatr Infect Vaccine 2384-1079 2384-1087 The Korean Society of Pediatric Infectious Diseases 10.14776/piv.2015.22.3.178 piv-22-178 Original Article The Impact of the Antibiotic Burden on the Selection of its Resistance among Gram Negative Bacteria Isolated from Children Kim Seohee Yoo Reenar Lee Jina Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 12015 2112015 223 178185 12072015 09092015 09092015 Copyright © 2015 The Korean Society of Pediatric Infectious Diseases 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Purpose

We investigated trends in antibiotic pressure and the antibiotic susceptibility of gram negative bacteria isolated from Korean children over 10 consecutive years.

 Methods

From January 2004 to December 2013, the antibiotic susceptibility of Kiebsiella pneumonlae, Escherichia cobi, Pseudomonas aeruginosa, and Acinetobacter baumanni blood isolates obtained from children <18 years of age was determined according to the 2009 Clinical and Laboratory Standards Institute guidelines. Antibiotic consumption data were also analyzed.

 Results

The prevalence 01K. pneumonae, E. coli', P aerugihosa, and A. baumannii bacteremia was 4.6, 3.5, 3.4, and 2.2 cases/1,000 blood culturesiyear, respectively. In K. pneumoniae, resistance to the third and fourth cephalosporin did not increase significantly. However, carbapenem-resistant K. pneumoniae first appeared in 2010, and the resistance rate increased to 9% between 2012 and 2013. Resistance to 3rd and 4th cephalosporin increased from 10% to 50% in E. co//, and resistance to carbapenem rose abruptly from 11% to 71% in A, baumanniI' (P for trend <0.01). However, such an increase of resistance was not observed in P. aeruginosa. There is a positive correlation between the resistance rate of cefepime in E. coli and the consumption of cefepime (r=0.900, P=0.037).

 Conclusion

The significant burden of antibiotic consumption and the high prevalence of antibiotic resistance to gram negative pathogen isolated from bacteremic children were observed. Empirical antibiotics should be wisely selected, and continued efforts to decrease the overall antibiotic pressure are mandatory, especially in highly resistant situations.

 Gram negative bacteria Antibiotic resistance Antibiotic consumption REFERENCES Kumar A Roberts D Wood KE Light B Parrillo IE Sharma S Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Crit Care Med 200634 158996 Hartman ME Linde—Zwirble WT Angus DC Watson RS Trends in the epidemiology of pediatric severe sepsis Pediatr Crit Care Med 201314 68693 Kang CI Kim SH Park WB Lee KD Kim HB Kim EC Bloodstream infections caused by antibiotic—resistant gram—negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome Antimicrob Agents Chemother 200549 7606 Dellinger RP Levy MM Rhodes A Annane D Gerlach H Opal SM, Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 Crit Care Med 201341 580637 Kim NH Hwang JH Song KH Choe PG Park WB Kim ES Changes in antimicrobial susceptibility of blood isolates in a university hospital in South Korea, 1998-2010 Infect Chemother 201244 27581 Kang SH Kim YR Characteristics of microorganisms isolated from blood cultures at a university hospital located in an island region during 2003—2007 Korean I Clin Mi—crobiol 200811 117 Kim SY, Lim G, Kim M], Suh IT, Lee H] Trends in five—year blood cultures of patients at a university hospital (2003—2007) Korean I Clin Microbiol 200912 1638 Ko EY Kang H} Kwon H] Choi UY Lee ]W Lee DG Clinical investigation of bacteremia in children with hemato-oncologic diseases Infect Chemother 201143 1917 Kang IE Seok IY Yun KW Kang H] Choi EH Park KD Etiological agents in bacteremia of children With hemato—oncologic diseases (2006—2010): A single center study Korean I Pediatr Infect Dis 201219 13140 Urbanek K Kolar M Loveckova Y Strojil I Santava L Influ—ence of third—generation cephalosporin utilization on the occurrence of ESBL—positive Klebsiella pneumoniae strains I Clin Pharm Ther 200732 4038 Chaouch C Hassairi A Riba M Boujaafar N Association between bacterial resistance and antimicrobial consumption Ann Biol Clin (Paris) 201472 55560 Sedlakova MH Urbanek K Vojtova V Suchankova H Im—wensi P Kolar M Antibiotic consumption and its influence on the resistance in Enterobacteriaceae BMC Res Notes 20147 454 Asensio A Alvarez—Espejo T Fernandez—Crehuet I Ramos A Vaque—Rafart I Bishopberger C, Trends in yearly prevalence of third—generation cephalosporin and fluoro—quinolone resistant Enterobacteriaceae infections and anti—microbial use in Spanish hospitals, Spain, 1999 to 2010 Euro Surveill 2011 16 Clinical and Laboratory Standards Institute Performance Standards for Antimicrobial Susceptibility Testing: Nineteenth Informational Supplement M100—Sl9 200929 3 Kim YK Pai H Lee H] Park SE Choi EH Kim I Blood—stream infections by extended—spectrum beta—lactamase—producing Escherichia 6011' and Klebsiella pneumoniae in children: epidemiology and clinical outcome Antimicrob Agents Chemother 200246 148191 Schwaber M] Navon—Venezia S Kaye KS Ben—Ami R Schwartz D Carmeli Y Clinical and economic impact of bacteremia with extended—spectrum beta—lactamase—pro-ducing Enterobacteriaceae Antimicrob Agents Chemother 200650 125762 Leibovici L Shraga I Drucker M Konigsberger H Samra Z Pitlik SD The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection J Intern Med 1998244 37986 Kim HT Iang HO Moon IS Nam SY ij DW Lee CG Etiology of community-acquired bacteremia in healthy children Korean I Pediatr 200548 71622 Kim H] Lee NY Kim S Shin IH Kim MN Kim EC, Characteristics of microorganisms isolated from blood cultures at nine university hospitals in Korea during 2009 Korean J Clin Microbiol 201114 4854 Rhee IY Park YK Shin IY Choi IY Lee MY Peck KR KPC—producing extreme drug—resistant Klebsiella pneumo— njae isolate from a patient with diabetes mellitus and chronic renal failure on hemodialysis in South Korea Antimicrob Agents Chemother 201054 22789 Yoo IS Kim HM Yoo 11 Yang IW Kim HS Chung GT, Detection of clonal KPC—Z-producing Hebsie/lapneumom'ae ST258 in Korea during nationwide surveillance in 2011 J Med Microbiol 201362 1338—42. Hong SK Yong D Kim K Hong SS Hong SG Khosbayar T, First outbreak of KPC—Z-producing Klebsiella pneu— moniae sequence type 258 in a hospital in South Korea J Clin Microbiol 201351 38779 Decousser IW Lamy B Pina P Allouch PY Trends in anti—biotic susceptibility ofbloodstream pathogens in hospitalized patients in France, 1996 to 2007 Diagn Microbiol Infect Dis 201066 292300 Lee 1, Oh CE, Choi EH, Lee H] The impact of the increased use of piperacillin/tazobactam 0n the selection of antibiotic resistance among invasive Escherichia coli and Klebsiella pneumoniae isolates Int I Infect Dis 2013 172e63843 Yong D Shin HB Kim YK Cho J Lee WG Ha GY Increase in the prevalence of carbapenem-resistant Acine—tobacter isolates and ampicfllin—resistant non—typhoidal Sal—monella species in Korea: a KONSAR study conducted in 2011 Infect Chemother 201446 8493 lung SI Park KH Kwon KT K0 KS Oh WS Chung DR Relationship between beta—lactam antmicrobial use and antimicrobial resistance in Klebsiella pneumoniae clinical isolates at 5 tertiary hospitals in Korea Infect Chemother 200739 18995 Hsueh PR Chen WH Luh KT Relationships between antimicrobial use and antimicrobial resistance in gram—negative bacteria causing nosocomial infections from 1991—2003 at a university hospital in Taiwan Int I Antimicrob Agents 200526 46372 Kim BN Overview of antibiotic use in Korea Infect Che—mother 201244 25062 Park S Chae SM Quality assessment of outpatient antibiotic consumptions in Korea compared with other countries Yakhak Hoeji 201458 2007 Lee I Pai H Kim YK Kim NH Eun BW Kang H] Control of extended—spectrum beta—lactamase-producing Escherichia coli and Klebsiella pneumoniae in a children's hospital by changing antimicrobial agent usage policy JAnti—microb Chemother 200760 62937 Du B Chen D Liu D Long Y Shi Y Wang H Restriction of third—generation cephalosporin use decreases infection— related mortality Crit Care Med 200331 108893 Meyer E Lapatschek M Bechtold A Schwarzkopf G Gastmeier P Schwab F Impact of restriction of third genera—tion cephalosporins on the burden of third generation cephalosporin resistant K. pneumoniae and E. coli in an ICU Intensive Care Med 200935 86270 Sistanizad M Kouchek M Miri M Goharani R Solouki M Ayazkhoo L Carbapenem restriction and its effect on bacterial resistance in an intensive care unit of a teaching hospital Iran I Pharm Res 201312 5039 Ntagiopoulos PG Paramythiotou E Antoniadou A Giama—rellou H Karabinis A Impact of an antibiotic restriction policy on the antibiotic resistance patterns of gram—negative microorganisms in an intensive care unit in Greece Int I Antimicrob Agents 200730 3605 de Araujo OR da Silva DC Diegues AR Arkader R Cabral EA Afonso MR Cefepime restriction improves gram—negative overall resistance patterns in neonatal intensive care unit Braz J Infect Dis 200711 27780 Figures and Tables

The prevalence of A. baumannii, E. coli, K. pneumoniae, and P. aeruginosa blood isolates obtained from hospitalized children during the study period, 2004-2013. P for trends evaluated by linear-by-linear association was as follows; 1.000 for A. baumannii, 0.826 for E. coli, 0.949 for K. pneumoniae, and 0.941 for R aeruginosa, respectively.

Changes in antibiotic use and antibiotic-resistance over 10 consecutive years (2004-2013). (A) K. pneumoniae, (B) E. coli, (C) P! aeruginosa, and (D) A. baumannii. The line graphs show the changes in the percentage of antibiotic resistances and bar graph represents antibiotic usage, presented as days on antibiotics per 1000 patient-days each year. Abbreviations: B/Bl, B-lactamlB-lactamase inhibitor; 3C5, 3rd generation cephalosporin; 4C5, 4th generation cephalosporin; AMP/SB, ampicillin/sulbactam; PlP/TZ piperacillin/tazobactam; ∗In P. aeruginosa, 3rd generation cephalosporin resistance rates were determined by the resistance to ceftazidime.

Changes in Parenteral Antibiotic Use∗ from 2004 to 2013

  2004-2005 2006-2007 2008-2009 2010-2011 2012-2013 P for trend
B/BI 63.6 61.9 49.4 45.6 61.3 0.34
  AMP/SB 53.3 50.2 41.6 38.8 37.0 0.039
  PIP/TZ 10.2 11.6 7.8 6.8 24.3 0.04
3CS 178.9 173.6 141.4 161.9 151.1 0.067
  CTX 81.4 83.0 83.4 111.0 103.4 0.013
  CRO 70.6 60.1 40.4 34.9 32.0 <0.001
  CAZ 26.9 30.5 17.6 16.0 15.7 0.014
4CS 33.2 37.4 41.8 38.3 46.8 0.143
  FEP 33.2 37.4 41.8 38.3 46.8 0.143
Carbapenem 73.5 80.7 68.0 67.1 72.9 0.603
  MER 56.5 60.3 49.1 59.3 65.2 0.48
  IM 16.9 20.4 18.9 7.7 7.7 0.013
Total 349.1 353.6 300.6 312.8 332.1 0.073

Antibiotic consumption was presented as days an antibiotic per 1,000 patien admission days per year. Abbreviations: AMP/SB, ampicillin/sulbactam; PIP/TZ piperacillin/tazobactam;) cefotaxime; CRO, ceftriaxone; CAZ, ceftazidime; FEP, cefepime; MER, meropn IM, imipenem; B/BI, B-Iactam/B-Iactamase inhibitor; 3CS, 3rd generation cephalo sporin- 4cs 4th generation cephalosporin.