akinohanayuki ブログ

学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

Clin Infect Dis (2017) 64 (7): 972-980.





















結論は同意です。 問題は重症度の見極めですね。


"Utilizing noncarbapenem β-lactams for the treatment of ESBL- producing organisms is an effective strategy to reduce carbapenem utilization and the associated downstream effects of carbapenem overuse. Available data suggest that cephamycins, cefepime, and βL-βLIs are potential alternatives for frequently encountered ESBL clinical scenarios such as patients with mild to moderate “low-inoculum” infections, with the most robust data available for βL-βLIs. On the other hand, carbapenems are still preferred, at least initially, for critically ill patients, infections with a high bacterial load, or elevated β-lactam MICs until more definitive data become available."


著者Pranita D. Tammaは、耐性菌治療の有名人


  1. Paterson DL, Hujer KM, Hujer AM, et al; International Klebsiella Study Group. Extended-spectrum beta-lactamases in Klebsiella pneumoniae bloodstream isolates from seven countries: dominance and widespread prevalence of SHV- and CTX-M-type beta-lactamases. Antimicrob Agents Chemother 2003; 47:3554–60.
  2. Villegas MV, Pallares CJ, Escandón-Vargas K, et al. Characterization and clinical impact of bloodstream infection caused by carbapenemase-producing Enterobacteriaceae in seven Latin American countries. PLoS One 2016; 11:e0154092.
  3. Jean SS, Coombs G, Ling T, et al. Epidemiology and antimicrobial susceptibility profiles of pathogens causing urinary tract infections in the Asia-Pacific region: results from the study for monitoring antimicrobial resistance trends (SMART), 2010–2013. Int J Antimicrob Agents 2016; 47:328–34.
  4. Lob SH, Kazmierczak KM, Badal RE, et al. Trends in susceptibility of Escherichia coli from intra abdominal infections to ertapenem and comparators in the United States according to data from the SMART program, 2009 to 2013. Antimicrob Agents Chemother 2015; 59:3606–10.
  5. Bush K. Proliferation and significance of clinically relevant β-lactamases. Ann N Y Acad Sci 2013; 1277:84–90.
  6. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alter- native antibiotics for the treatment of bacteraemia due to Enterobacteriaceae pro- ducing extended-spectrum β-lactamases: a systematic review and meta-analysis. J Antimicrob Chemother 2012; 67:2793–803.
  7. Paterson DL, Ko WC, Von Gottberg A, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases. Clin Infect Dis 2004; 39:31–7.
  8. Ofer-Friedman H, Shefler C, Sharma S, et al. Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extend- ed-spectrum beta-lactamase-producing Enterobacteriaceae. Infect Control Hosp Epidemiol 2015; 36:981–5.
  9. Paterson DL, Ko WC, Von Gottberg A, et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory. J Clin Microbiol 2001; 39:2206–12.
  10. Matsumura Y, Yamamoto M, Nagao M, Tanaka M, Takakura S, Ichiyama S. In vitro activities and detection performances of cefmetazole and flomoxef for extended-spectrum β-lactamase and plasmid-mediated AmpC β-lactamase-producing Enterobacteriaceae. Diagn Microbiol Infect Dis 2016; 84:322–7.
  11. Pangon B, Bizet C, Buré A, et al. In vivo selection of a cephamycin-resistant, por- indeficient mutant of Klebsiella pneumoniae producing a TEM-3 beta-lactamase. J Infect Dis 1989; 159:1005–6.
  12. Bradford PA, Urban C, Mariano N, Projan SJ, Rahal JJ, Bush K. Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC beta-lactamase, and the foss of an outer membrane protein. Antimicrob Agents Chemother 1997; 41:563–9.
  13. Lee CH, Chia JH, Chu C, Wu TL, Liu JW, Su LH. In vivo selection of OmpK35- deficient mutant after cefuroxime therapy for primary liver abscess caused by Klebsiella pneumoniae. J Antimicrob Chemother 2006; 58:857–60. 
  14. Lee CH, Chu C, Liu JW, Chen YS, Chiu CJ, Su LH. Collateral damage of flomoxef therapy: in vivo development of porin deficiency and acquisition of blaDHA-1 lead- ing to ertapenem resistance in a clinical isolate of Klebsiella pneumoniae producing CTX-M-3 and SHV-5 beta-lactamases. J Antimicrob Chemother 2007; 60:410–3.
  15. Lee CH, Su LH, Tang YF, Liu JW. Treatment of ESBL-producing Klebsiella pneu- moniae bacteraemia with carbapenems or flomoxef: a retrospective study and laboratory analysis of the isolates. J Antimicrob Chemother 2006; 58:1074–7.
  16. Kernéis S, Valade S, Geri G, et al. Cefoxitin as a carbapenem-sparing antibiotic for infections caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. Infect Dis (Lond) 2015; 47:789–95.
  17. Doi A, Shimada T, Harada S, Iwata K, Kamiya T. The efficacy of cefmetazole against pyelonephritis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae. Int J Infect Dis 2013; 17:e159–63.
  18. Yang CC, Li SH, Chuang FR, et al. Discrepancy between effects of carbapenems and flomoxef in treating nosocomial hemodialysis access-related bacteremia sec- ondary to extended spectrum beta-lactamase producing Klebsiella pneumoniae in patients on maintenance hemodialysis. BMC Infect Dis 2012; 12:206.
  19. Pilmis B, Parize P, Zahar JR, Lortholary O. Alternatives to carbapenems for infections caused by ESBL-producing Enterobacteriaceae. Eur J Clin Microbiol Infect Dis 2014; 33:1263–5.
  20. Matsumura Y, Yamamoto M, Nagao M, et al. Multicenter retrospective study of cefmetazole and flomoxef for treatment of extended-spectrum-β-lactamase-producing Escherichia coli bacteremia. Antimicrob Agents Chemother 2015; 59:5107–13.
  21. Guet-Revillet H, Emirian A, Groh M, et al. Pharmacological study of cefoxitin as an alternative antibiotic therapy to carbapenems in treatment of urinary tract infections due to extended-spectrum-β-lactamase-producing Escherichia coli. Antimicrob Agents Chemother 2014; 58:4899–901.
  22. Clinical and Laboratory Standards Institute. Performance standards for antimi- crobial susceptibility testing. 26th ed. CLSI supplement M100S. Wayne, PA: CLSI, 2016.
  23. European Union Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and sone diameters. Version 1.1. Available at: http://www.eucast.org/clinical_breakpoints/. Accessed February 15th, 2017.
  24. Kohner PC, Robberts FJ, Cockerill FR 3rd, Patel R. Cephalosporin MIC distribution of extended-spectrum-{beta}-lactamase- and pAmpC-producing Escherichia coli and Klebsiella species. J Clin Microbiol 2009; 47:2419–25.
  25. Jacoby GA, Carreras I. Activities of beta-lactam antibiotics against Escherichia coli strains producing extended-spectrum beta-lactamases. Antimicrob Agents Chemother 1990; 34:858–62.
  26. Thomson KS, Moland ES. Cefepime, piperacillin-tazobactam, and the inoculum effect in tests with extended-spectrum beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2001; 45:3548–54.
  27. Bedenić B, Beader N, Zagar Z. Effect of inoculum size on the antibacterial activity of cefpirome and cefepime against Klebsiella pneumoniae strains producing SHV extended-spectrum beta-lactamases. Clin Microbiol Infect 2001; 7:626–35.
  28. Szabó D, Máthé A, Filetóth Z, Anderlik P, Rókusz L, Rozgonyi F. In vitro and in vivo activities of amikacin, cefepime, amikacin plus cefepime, and imipenem against an SHV-5 extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strain. Antimicrob Agents Chemother 2001; 45:1287–91.  
  29. Rice LB, Yao JD, Klimm K, Eliopoulos GM, Moellering RC Jr. Efficacy of different beta-lactams against an extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strain in the rat intra-abdominal abscess model. Antimicrob Agents Chemother 1991; 35:1243–4.  
  30. Thauvin-Eliopoulos C, Tripodi MF, Moellering RC Jr, Eliopoulos GM. Efficacies of piperacillin-tazobactam and cefepime in rats with experimental intra-abdominal abscesses due to an extended-spectrum beta-lactamase-producing strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 1997; 41:1053–7.
  31. Jett BD, Ritchie DJ, Reichley R, Bailey TC, Sahm DF. In vitro activities of various beta-lactam antimicrobial agents against clinical isolates of Escherichia coli and Klebsiella spp. resistant to oxyimino cephalosporins. Antimicrob Agents Chemother 1995; 39:1187–90.
  32. Burgess DS, Hall RG 2nd. In vitro killing of parenteral beta-lactams against stand- ard and high inocula of extended-spectrum beta-lactamase and non-ESBL producing Klebsiella pneumoniae. Diagn Microbiol Infect Dis 2004; 49:41–6.
  33. Maglio D, Ong C, Banevicius MA, Geng Q, Nightingale CH, Nicolau DP. Determination of the in vivo pharmacodynamic profile of cefepime against extended-spectrum-beta-lactamase-producing Escherichia coli at various inocula. Antimicrob Agents Chemother 2004; 48:1941–7.
  34.  Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis 1995; 22:89–96.
  35. Reese AM, Frei CR, Burgess DS. Pharmacodynamics of intermittent and continuous infusion piperacillin/tazobactam and cefepime against extended-spectrum beta-lactamase-producing organisms. Int J Antimicrob Agents 2005; 26:114–9.
  36. Roos JF, Bulitta J, Lipman J, Kirkpatrick CM. Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units. J Antimicrob Chemother 2006; 58:987–93.
  37. Andes D, Craig A. Animal model pharmacokinetics and pharmacodynamics In: Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL 2001. Abstract A-1099.
  38. Wang R, Cosgrove SE, Tschudin-Sutter S, et al. Cefepime therapy for cefepime-susceptible extended-spectrum β-lactamase–producing Enterobacteriaceae bacter- emia. Open Forum Infect Dis 2016; 3:ofw132.
  39. Goethaert K, Van Looveren M, Lammens C, et al. High-dose cefepime as an alter- native treatment for infections caused by TEM-24 ESBL-producing Enterobacter aerogenes in severely-ill patients. Clin Microbiol Infect 2006; 12:56–62.
  40. Chopra T, Marchaim D, Veltman J, et al. Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother 2012; 56:3936–42.
  41. Zanetti G, Bally F, Greub G, et al; Cefepime Study Group. Cefepime versus imipenem-cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study. Antimicrob Agents Chemother 2003; 47:3442–7.
  42. Lee NY, Lee CC, Huang WH, Tsui KC, Hsueh PR, Ko WC. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis 2013; 56:488–95.
  43. Marchaim D, Sunkara B, Lephart PR, et al. Extended-spectrum β-lactamase pro- ducers reported as susceptible to piperacillin-tazobactam, cefepime, and cefuroxime in the era of lowered breakpoints and no confirmatory tests. Infect Control Hosp Epidemiol 2012; 33:853–5.
  44. Rice LB, Carias LL, Shlaes DM. In vivo efficacies of beta-lactam-beta-lactamase inhibitor combinations against a TEM-26-producing strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 1994; 38:2663–4.
  45. López-Cerero L, Picón E, Morillo C, et al. Comparative assessment of inoculum effects on the antimicrobial activity of amoxycillin-clavulanate and pip- eracillin-tazobactam with extended-spectrum beta-lactamase-producing and extended-spectrum beta-lactamase-non-producing Escherichia coli isolates. Clin Microbiol Infect 2010; 16:132–6.
  46. Zimhony O, Chmelnitsky I, Bardenstein R, et al. Endocarditis caused by extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae: emergence of resistance to ciprofloxacin and piperacillin-tazobactam during treatment despite initial susceptibility. Antimicrob Agents Chemother 2006; 50:3179–82.
  47. Rodriguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual Á; Extended- Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria. β-Lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis 2012; 54:167–74.
  48. Gavin PJ, Suseno MT, Thomson RB Jr, et al. Clinical correlation of the CLSI susceptibility breakpoint for piperacillin-tazobactam against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella species. Antimicrob Agents Chemother 2006; 50:2244–7.
  49. Kang CI, Park SY, Chung DR, Peck KR, Song JH. Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lacta- mase-producing Escherichia coli and Klebsiella pneumoniae. J Infect 2012; 64:533–4.
  50. 50. Harris PN, Yin M, Jureen R, et al. Comparable outcomes for β-lactam/β-lacta- mase inhibitor combinations and carbapenems in definitive treatment of bloodstream infections caused by cefotaxime-resistant Escherichia coli or Klebsiella pneumoniae. Antimicrob Resist Infect Control 2015; 4:14.
  51. Tamma PD, Han JH, Rock C, et al; Antibacterial Resistance Leadership Group. Carbapenem therapy is associated with improved survival compared with piper- acillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. Clin Infect Dis 2015; 60:1319–25.
  52. Gutiérrez-Gutiérrez B, Pérez-Galera S, Salamanca E, et al. A multinational, preregistered cohort study of β-lactam/β-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2016; 60:4159–69.
  53. Ng TM, Khong WX, Harris PN, et al. Empiric piperacillin-tazobactam versus car- bapenems in the treatment of bacteraemia due to extended-spectrum beta-lactamase-producing Enterobacteriaceae. PLoS One 2016; 11:e0153696.
  54. Harris PN, Peleg AY, Iredell J, et al. Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial. Trials 2015; 16:24.
  55. Kim A, Sutherland CA, Kuti JL, Nicolau DP. Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion? Pharmacotherapy 2007; 27:1490–7.
  56. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolo- zane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. hospitals (2011–2012). Antimicrob Agents Chemother 2013; 57:6305–10.
  57. Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against aerobic gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). J Infect 2014; 69:266–77.
  58. Lucasti C, Hershberger E, Miller B, et al. Multicenter, double-blind, ran- domized, phase II trial to assess the safety and efficacy of ceftolozane-tazo- bactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections. Antimicrob Agents Chemother 2014; 58:5350–7.
  59. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metroni- dazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 2015; 60:1462–71.
  60. Sader HS, Castanheira M, Flamm RK, Farrell DJ, Jones RN. Antimicrobial activity of ceftazidime-avibactam against gram-negative organisms collected from U.S. medical centers in 2012. Antimicrob Agents Chemother 2014; 58:1684–92.
  61. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, phase II trial. J Antimicrob Chemother 2013; 68:1183–92.
  62. Mazuski JE, Gasink LB, Armstrong J, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis 2016; 62:1380–9.
  63. Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis 2016; 63:754–62.