Treatment outcome of non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae infections: a multicenter study in Taiwan
Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with high mortality, and experiences with its treatment are usually based on carbapenemase-producing strains. Non-carbapenemase-producing CRKP is of clinical significance, but relevant studies are lacking. This nationwide study aimed to evaluate the outcome of antimicrobial therapy in patients with non-carbapenemase-producing CRKP infections. Patients with non-carbapenemase-producing CRKP infections were enrolled from 16 hospitals during January 2013 to December 2014 in Taiwan. Carbapenem resistance was defined as reduced susceptibility with a minimum inhibitory concentration of ≥2 mg/L for imipenem or meropenem. The resistance mechanisms of CRKP isolates were analyzed, and the clinical data of these patients were collected retrospectively. Independent risk factors of 14-day morality were determined by Cox regression analysis. A total of 99 patients with non-carbapenemase-producing CRKP infections were enrolled, and 14-day mortality was 27.3%. Among 67 patients treated with appropriate antimicrobial therapy, most (n = 61) patients received monotherapy. The 14-day mortality was lower in patients treated with appropriate monotherapy (21.3%) than in those with inappropriate therapy (37.5%). The multivariate regression model identified monotherapy (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.13–0.71; P = 0.005) as protective factor, and APACHE II scores (HR, 1.09; 95% CI, 1.01–1.18; P = 0.022) as risk factor associated with 14-day mortality. Tigecycline, colistin, and carbapenem were the most commonly used drugs in monotherapy. This study provides evidence supporting the efficacy of monotherapy in the treatment of non-carbapenemase-producing CRKP infections, and provides a future target for antibiotics stewardship for CRKP infection.
The authors thank the Taiwan Carbapenem Resistance Study Group for the collection of isolates from Keelung Chang Gung Memorial Hospital, Tri-Service General Hospital, Taipei Veterans General Hospital, Linkou Chang Gung Memorial Hospital, China Medical University Hospital, Chiayi Chang Gung Memorial Hospital, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung Medical University Hospital, National Taiwan University Hospital, Taoyuan Armed Forces General Hospital, Buddhist Tzu Chi General Hospital, Hualien Armed Forces General Hospital, National Yang-Ming University Hospital, Taichung Armed Forces General Hospital, Chi Mei Medical Center, Kaohsiung Armed Forces General Hospital, and Kaohsiung Municipal Hsiao-Kang Hospital.
The authors thank Ms. Chiu-Mei Yeh for her endorsement and assistance in the statistical analyses. We also thank the Medical Science & Technology Building of Taipei Veterans General Hospital for providing experimental space and facilities.
Some of the results from this study were presented in oral section at ECCMID 2017 in Vienna, Austria.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this retrospective study, formal consent is not required.
- 3.Bradford PA, Urban C, Mariano N, Projan SJ, Rahal JJ, Bush K (1997) 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 41:563–569PubMedPubMedCentralGoogle Scholar
- 11.Zarkotou O, Pournaras S, Tselioti P, Dragoumanos V, Pitiriga V, Ranellou K et al (2011) Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect 17:1798–1803CrossRefPubMedGoogle Scholar
- 14.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
- 21.Correa L, Martino MD, Siqueira I, Pasternak J, Gales AC, Silva CV et al (2013) A hospital-based matched case-control study to identify clinical outcome and risk factors associated with carbapenem-resistant Klebsiella pneumoniae infection. BMC Infect Dis 13:80CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Clinical and Laboratory Standards Institute (2014) Performance standards for antimicrobial susceptibility testing. Twenty-Fourth informational supplement M100-S24 Clinical and Laboratory Standards Institute, Wayne, PAGoogle Scholar
- 25.The European Committee on Antimicrobial Susceptibility Testing (2015) Breakpoint tables for interpretation of MICs and zone diameters. Version 5.0. Available at: http://www.eucast.org. Accessed 18 Oct 2015
- 26.Food and Drug Administration. Highlights of prescribing information Tygacil. Food and Drug Administration, Silver Spring, MD. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021821s021lbl.pdf. Accessed 18 Oct 2015
- 34.Kontopidou F, Giamarellou H, Katerelos P, Maragos A, Kioumis I, Trikka-Graphakos E et al (2014) Infections caused by carbapenem-resistant Klebsiella pneumoniae among patients in intensive care units in Greece: a multi-centre study on clinical outcome and therapeutic options. Clin Microbiol Infect 20:O117–O123CrossRefPubMedGoogle Scholar
- 35.de Oliveira MS, de Assis DB, Freire MP, Boas do Prado GV, Machado AS, Abdala E, et al (2015) Treatment of KPC-producing Enterobacteriaceae: suboptimal efficacy of polymyxins. Clin Microbiol Infect 21:179e1–179e7Google Scholar
- 38.Gutierrez-Gutierrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Pano-Pardo JR et al (2017) Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis 17:726–734CrossRefPubMedGoogle Scholar