Double-carbapenem combination as salvage therapy for untreatable infections by KPC-2-producing Klebsiella pneumoniae

  • M. Souli
  • I. Karaiskos
  • A. Masgala
  • L. Galani
  • E. Barmpouti
  • H. Giamarellou
Original Article


We report our experience using the double-carbapenem combination as salvage therapy for patients with untreatable infections caused by KPC-2- producing Klebsiella pneumoniae. A total of 27 patients in two institutions in Athens, Greece suffering from complicated urinary tract infections (16) with or without secondary bacteraemia (four and 12 respectively), primary (six) or catheter-related bloodstream infections (two), HAP or VAP (two) and external ventricular drainage infection (one) were treated exclusively with ertapenem and high-dose prolonged infusion meropenem because in-vitro active antimicrobials were unavailable (19) or failed (four) or were contraindicated (six). Most patients presented with severe infections with median APACHE II score of 17 and 11 of those patients (40.7%) had severe sepsis (five) or septic shock (six). The clinical and microbiological success was 77.8 and 74.1% respectively. Crude mortality was 29.6% with attributable mortality of 11.1%. Adverse events, none of them severe, were reported in four patients (14.8%). The double-carbapenem combination as an exclusive regimen represents a safe and valid salvage therapy for untreatable infections by extensively- or pandrug-resistant KPC-producing K.pneumoniae.


Septic Shock Severe Sepsis Meropenem Colistin Tigecycline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with ethical standards


No funding was received for this study

Conflicts of interest

Maria Souli has received funding for research by Achaogen

Ilias Karaiskos: no conflict of interest to declare

Aikaterini Masgala: no conflict of interest to declare

Lamprini Galani: no conflict of interest to declare

Eleftheria Barmpouti: no conflict of interest to declare

Helen Giamarellou has received funding for research by Pfizer

Ethical approval

The study was approved by the Ethics Review Board of both hospitals.

Informed consent

Informed consent was obtained from all individual participants or their legal representatives


  1. 1.
    Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD et al (2001) Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 45:1151–1161CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL (2014) Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect 20:862–872CrossRefPubMedGoogle Scholar
  3. 3.
    Karaiskos I, Giamarellou H (2014) Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother 15:1351–1370CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A et al (2014) Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 58:2322–2328CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bulik CC, Nicolau DP (2011) Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother 55:3002–3004CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Horan TC, Andrus M, Dudeck MA (2008) CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 36:309–332CrossRefPubMedGoogle Scholar
  7. 7.
    Stevens V, Lodise TP, Tsuji B, Stringham M, Butterfield J, Dodds Ashley E et al (2012) The utility of acute physiology and chronic health evaluation II scores for prediction of mortality among intensive care unit (ICU) and non-ICU patients with methicillin-resistant Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol 33:558–564CrossRefPubMedGoogle Scholar
  8. 8.
    Charlson M, Szatrowski TP, Peterson J, Gold J (1994) Validation of a combined comorbidity index. J Clin Epidemiol 47(Suppl 11):1245–1251CrossRefPubMedGoogle Scholar
  9. 9.
    Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165–228CrossRefPubMedGoogle Scholar
  10. 10.
    Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H et al (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710CrossRefPubMedGoogle Scholar
  11. 11.
    Clinical and Laboratory Standards Institute (2012) Performance Standards for Antimicrobial Susceptibility Testing: Twenty Second Informational Supplement M100-S22. CLSI, Wayne, PA, USAGoogle Scholar
  12. 12.
    European Committee on Antimicrobial Susceptibility Testing (2012) Breakpoint tables for interpretation of MICs and zone diameters, Version 2.0.
  13. 13.
    Tsakris A, Poulou A, Themeli-Digalaki K, Voulgari E, Pittaras T, Sofianou D et al (2009) Use of boronic acid disk tests to detect extended-spectrum beta-lactamases in clinical isolates of KPC carbapenemase-possessing enterobacteriaceae. J Clin Microbiol 47:3420–3426Google Scholar
  14. 14.
    Souli M, Galani I, Antoniadou A, Papadomichelakis E, Poulakou G, Panagea T et al (2010) An outbreak of infection due to beta-lactamase Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae in a Greek University Hospital: molecular characterization, epidemiology, and outcomes. Clin Infect Dis 50:364–373CrossRefPubMedGoogle Scholar
  15. 15.
    Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG et al (2012) Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18:268–281CrossRefPubMedGoogle Scholar
  16. 16.
    Thomson KS (2012) Double-carbapenem therapy not proven to be more active than carbapenem monotherapy against KPC-positive Klebsiella pneumoniae. Antimicrob Agents Chemother 56:4037CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Oliva A, Gizzi F, Mascellino MT, Cipolla A, D’Abramo A, D’Agostino C et al (2016) Bactericidal and synergistic activity of double-carbapenem regimen for infections caused by carbapenemase-producing Klebsiella pneumoniae. Clin Microbiol Infect 22:147–153CrossRefPubMedGoogle Scholar
  18. 18.
    Ceccarelli G, Falcone M, Giordano A, Mezzatesta ML, Caio C, Stefani S et al (2013) Successful ertapenem-doripenem combination treatment of bacteremic ventilator-associated pneumonia due to colistin resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother 57:2900–2901CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Oliva A, D’Abramo A, D’Agostino C, Iannetta M, Mascellino MT, Gallinelli C et al (2014) Synergistic activity and effectiveness of a double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream Infections. J Antimicrob Chemother 69:1718–1720CrossRefPubMedGoogle Scholar
  20. 20.
    Poirel L, Kieffer N, Nordmann P (2016) In vitro evaluation of dual carbapenem combinations against carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother 71:156–161CrossRefPubMedGoogle Scholar
  21. 21.
    Wiskirchen DE, Crandon JL, Nicolau DP (2013) Impact of various conditions on the efficacy of dual carbapenem therapy against KPC-producing Klebsiella pneumoniae. Int J Antimicrob Agents 41:582–585CrossRefPubMedGoogle Scholar
  22. 22.
    Giamarellou H, Galani L, Baziaka F, Karaiskos I (2013) Effectiveness of a double-carbapenem regimen for infections in humans due to carbapenemase-producing pandrug-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother 57:2388–2390CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Nogid B, Venugopalan V, Bias T, Rahman, D. Nicolau. Double carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae: from test tube to clinical practice. In: Abstracts of the twenty-third European Congress of Clinical Microbiology and Infectious Diseases, 2013. Abstract 2110. European Society of Clinical Microbiology and Infectious DiseasesGoogle Scholar
  24. 24.
    Chua NG, Zhou YP, Tan TT, Lingegowda PB, Lee W, Lim TP et al (2015) Polymyxin B with dual carbapenem combination therapy against carbapenemase-producing Klebsiella pneumoniae. J Infect 70:309–311CrossRefPubMedGoogle Scholar
  25. 25.
    Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M et al (2015) Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 70:2133–2143CrossRefPubMedGoogle Scholar
  26. 26.
    Oliva A, Mascellino MT, Cipolla A, D’Abramo A, De Rosa A, Savinelli S et al (2015) Therapeutic strategy for pandrug-resistant Klebsiella pneumoniae severe infections: short-course treatment with colistin increases the in vivo and in vitro activity of double carbapenem regimen. Int J Infect Dis 33:132–134CrossRefPubMedGoogle Scholar
  27. 27.
    Camargo JF, Simkins J, Beduschi T, Tekin A, Aragon L, Pérez-Cardona A et al (2015) Successful treatment of carbapenemase-producing pandrug-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother 59:5903–5908CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cprek JB, Gallagher JC (2016) Ertapenem-containing double-carbapenem therapy for treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother 60:669–673CrossRefGoogle Scholar
  29. 29.
    Oliva A, Cipolla A, Gizzi F, D’Abramo A, Favaro M, De Angelis M et al (2016) Severe bloodstream infection due to KPC-producer E coli in a renal transplant recipient treated with the double-carbapenem regimen and analysis of in vitro synergy testing: A case report. Medicine 95:e2243CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Oliva A, Scorzolini L, Castaldi D, Gizzi F, De Angelis M, Storto M et al (2017) Double-carbapenem regimen, alone or in combination with colistin, in the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp). J Infect 74:103–106CrossRefPubMedGoogle Scholar
  31. 31.
    Karaiskos I, Souli M, Galani I, Giamarellou H (2017) Colistin: still a lifesaver for the 21st century? Expert Opin Drug Metab Toxicol 13:59–71CrossRefPubMedGoogle Scholar
  32. 32.
    Giacobbe DR, Del Bono V, Trecarichi EM, De Rosa FG, Giannella M, Bassetti M et al (2015) Risk factors for bloodstream infections due to colistin-resistant KPC-producing Klebsiella pneumoniae: results from a multicenter case–control–control study. Clin Microbiol Infect 21:1106.e1–1106.e8Google Scholar
  33. 33.
    Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:1589–1596CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • M. Souli
    • 1
  • I. Karaiskos
    • 2
  • A. Masgala
    • 3
  • L. Galani
    • 2
  • E. Barmpouti
    • 2
  • H. Giamarellou
    • 2
  1. 1.4th Department of Internal Medicine, National and Kapodistrian University of AthensUniversity General Hospital ATTIKONChaidariGreece
  2. 2.6th Department of Internal Medicine, Hygeia General HospitalAthensGreece
  3. 3.1st Department of Internal Medicine, Konstantopoulio General HospitalAthensGreece

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