Abstract
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.
Similar content being viewed by others
References
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 45:1151–1161
Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL (2014) Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect 20:862–872
Karaiskos I, Giamarellou H (2014) Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother 15:1351–1370
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 58:2322–2328
Bulik CC, Nicolau DP (2011) Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother 55:3002–3004
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 36:309–332
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 33:558–564
Charlson M, Szatrowski TP, Peterson J, Gold J (1994) Validation of a combined comorbidity index. J Clin Epidemiol 47(Suppl 11):1245–1251
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 39:165–228
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 22:707–710
Clinical and Laboratory Standards Institute (2012) Performance Standards for Antimicrobial Susceptibility Testing: Twenty Second Informational Supplement M100-S22. CLSI, Wayne, PA, USA
European Committee on Antimicrobial Susceptibility Testing (2012) Breakpoint tables for interpretation of MICs and zone diameters, Version 2.0. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Breakpoint_table_v_2.0_120221.pdf
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 47:3420–3426
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 50:364–373
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 18:268–281
Thomson KS (2012) Double-carbapenem therapy not proven to be more active than carbapenem monotherapy against KPC-positive Klebsiella pneumoniae. Antimicrob Agents Chemother 56:4037
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 22:147–153
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 57:2900–2901
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 69:1718–1720
Poirel L, Kieffer N, Nordmann P (2016) In vitro evaluation of dual carbapenem combinations against carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother 71:156–161
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 41:582–585
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 57:2388–2390
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 Diseases
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 70:309–311
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 70:2133–2143
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 33:132–134
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 59:5903–5908
Cprek JB, Gallagher JC (2016) Ertapenem-containing double-carbapenem therapy for treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother 60:669–673
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:e2243
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 74:103–106
Karaiskos I, Souli M, Galani I, Giamarellou H (2017) Colistin: still a lifesaver for the 21st century? Expert Opin Drug Metab Toxicol 13:59–71
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.e8
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 34:1589–1596
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
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
Rights and permissions
About this article
Cite this article
Souli, M., Karaiskos, I., Masgala, A. et al. Double-carbapenem combination as salvage therapy for untreatable infections by KPC-2-producing Klebsiella pneumoniae . Eur J Clin Microbiol Infect Dis 36, 1305–1315 (2017). https://doi.org/10.1007/s10096-017-2936-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10096-017-2936-5