Klebsiella pneumoniae Bloodstream Infection

Multidrug resistance associated with extended-spectrum beta-lactamase (ESBL) and Klebsiella pneumoniae carbapenemase (KPC) among K. pneumoniae is endemic in southern Europe. We retrospectively analyzed the impact of resistance on the appropriateness of empirical therapy and treatment outcomes of K. pneumoniae bloodstream infections (BSIs) during a 2-year period at a 1420-bed tertiary-care teaching hospital in northern Italy. We identified 217 unique patient BSIs, including 92 (42%) KPCpositive, 49 (23%) ESBL-positive, and 1 (0.5%) metallo-betalactamase-positive isolates. Adequate empirical therapy was administered in 74% of infections caused by non-ESBL non-KPC strains, versus 33% of ESBL and 23% of KPC cases (p< 0.0001). To clarify the impact of resistance on BSI treatment outcomes, we compared several different models comprised of non-antibiotic treatment-related factors predictive of patients’ 30-day survival status. Acute Physiology and Chronic Health Evaluation (APACHE) II score determined at the time of positive blood culture was superior to other investigated models, correctly predicting survival status in 83% of the study cohort. In multivariate analysis accounting for APACHE II, receipt of inadequate empirical therapy was associated with nearly a twofold higher rate of death (adjusted hazard ratio 1.9, 95% confidence interval 1.1–3.4; p1⁄4 0.02). Multidrug-resistant K. pneumoniae accounted for two-thirds of all K. pneumoniae BSIs, high rates of inappropriate empirical therapy, and twofold higher rates of patient death irrespective of underlying illness. (Medicine 2014;93: 298–308) Abbreviations: AmpC = class C beta-lactamase, APACHE II = Acute Physiology and Chronic Health Evaluation II, aROC = area under receiver operator curves, BL/BLI = betalactam/beta-lactamase inhibitor, BSI = bloodstream infection, CDC = United States Centers for Disease Control and Prevention, CLSI = Clinical and Laboratory Standards Institute, CRE = carbapenem-resistant Enterobacteriaceae, CR-KP = carbapenem-resistant Klebsiella pneumoniae, ESBL = extended-spectrum beta-lactamase, EUCAST = European Committee on Antimicrobial Susceptibility Testing, HPA = United Kingdom Health Protection Agency, ICU = intensive care unit, KPC = Klebsiella pneumoniae carbapenemase, MALDI-TOF = Matrix-Assisted Laser Desorption Ionization Time-of-Flight, MBL = metallo-beta-lactamase, MDR = multidrug resistant, MIC = minimum inhibitory concentration, PCR = polymerase chain reaction, VIM = Verona integron-encoded metallo-betalactamase. INTRODUCTION Multidrug resistance among Enterobacteriaceae is a growing public health crisis that threatens to make many health care-associated infections untreatable with current antibiotics. The widespread use of broad-spectrum cephalosporin and fluoroquinolone antibiotics, in particular, has accelerated the emergence of fluoroquinoloneresistant and extended-spectrum beta-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae, which are now endemic in many communities and hospitals worldwide. Consequently, the diminishing activity of fluoroquinolones and third-generation cephalosporin has led to increasing use of carbapenem antibiotics for common health care-associated infections, creating pressure for the emergence of carbapenem-resistant Enterobacteriaceae (CRE). Indeed, outbreaks of K. pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae have been reported worldwide, and they are endemic in many hospitals and long-term care facilities in southern Europe, China, South America, and certain regions of North America. KPC enzymes efficiently hydrolyze all cephalosporins, monobactams, carbapenems, and even beta-lactamase inhibitors, leaving few effective treatment options. Triple drug concentrations consisting of meropenem, tigecycline, and colistin have been associated with improved survival in patients with KPC-K. pneumoniae bacteremia, but this combination is rarely administered empirically to patients. Moreover, the utility of continuing meropenem therapy as part of an active combination in the setting of extremely elevated carbapenem minimum inhibitory concentration (MICs) (>32mg/L) remains unclear. Most studies examining outcomes associated with KPC K. pneumoniae bacteremia have focused on unmodifiable risk factors such as older age, severity of underlying illness, dialysis, and solid-organ transplantation as predictors of poor outcome. Relatively few studies have examined the impact of modifiable risk factors (for example, empirical antimicrobial therapy, source control) in the outcome of multidrug-resistant (MDR) K. pneumoniae bloodstream infections (BSIs) while taking into account the severity of underlying patient illness. In Italy, approximately 25%–50% of all K. pneumoniae bloodstream isolates are positive for ESBL production, and From the Department of Medical Sciences and Surgery, Section of Infectious Diseases (NG, REL, MG, MB, ST, F. Tumietto, FC, F. Trapani, PV); Operative Unit of Microbiology (SA, PG); University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. Correspondence: Pierluigi Viale, MD, Infectious Diseases Unit, S. Orsola Malpighi Hospital, University of Bologna, via Massarenti 11, 40138 Bologna, Italy (e-mail: [email protected]). Financial support and conflicts of interest: The authors have no funding or conflicts of interest to disclose. Copyright © 2014 by Lippincott Williams & Wilkins. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000111 298 | www.md-journal.com Medicine • Volume 93, Number 17, October 2014 20%–30% of strains produce KPC-2 or KPC-3 carbapenemases. To understand the impact of these endemic resistance patterns on patient outcome, we performed a 2-year retrospective observational study of K. pneumoniae BSI in our hospital. Our specific objective was to determine if isolation of ESBL or KPC-producing-K. pneumoniae from the bloodstream was associated with higher rates of inadequate empirical antibiotic prescription, which we hypothesized to be an independent risk factor for patient death within 30 days of a positive blood culture. We also performed a literature review to provide a worldwide perspective on epidemiology, risk factors, and microbiologic and treatment issues of BSI due to MDR K. pneumoniae. PATIENTS AND METHODS Patient Population We performed a retrospective analysis of all K. pneumoniae BSIs at our institution from July 2010 to August 2012. The study site was S. Orsola-Malpighi Hospital, University of Bologna, a tertiary 1420-bed hospital with approximately 72,000 yearly inpatient admissions. Cases were eligible for analysis if they had a positive blood culture for K. pneumoniae and sufficient documentation in the medical record to assess treatment and outcomes within 30 days of the positive blood culture. Study Design Eligible patients were identified retrospectively from the institutional microbiology surveillance database and medical records. Data were extracted using standardized data collection tools, and the accuracy was confirmed by systematic reconciliation of case records using the original patient electronic medical record. Treatment outcomes associated with the BSI, including clinical response to antibacterial treatment, other intercurrent infections or medical complications, need for intensive care unit (ICU) admission, hospital discharge, or death were analyzed up to 30 days after the positive blood culture. Only the first positive culture (infection episode) per patient was included in the analysis. Definitions Bloodstream infections and systemic inflammatory response syndrome (SIRS) were defined according to the United States Centers for Disease Control and Prevention (CDC) criteria. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated for all case patients on the day of their initial blood culture positive for K. pneumoniae. Neutropenia was defined as a peripheral absolute neutrophil count of <500 cells/mL. Immunosuppressive corticosteroid therapy was defined as 3100mg of prednisone-equivalent therapy administered within 30 days of positive blood culture. Chemo-radiation therapy included receipt of cytotoxic antineoplastic drugs or ionizing radiation for cancer curative intent or palliation within 30 days before the blood culture. Acute renal failure was defined according to the RIFLE criteria. Cirrhosis was identified by patient history (with diagnostic liver biopsy) or a probable diagnosis (with clinical and analytical data suggesting chronic liver disease, hepatocellular dysfunction, and portal hypertension). Intercurrent complications were recorded in the 30-day period after a positive blood culture if the patient required blood transfusion for severe hemorrhage or anemia, developed other hospital-acquired infections or pressure ulcers, or required surgical treatment during the hospital stay. All-cause mortality was assessed in patients within 30 days of the positive blood culture. Empirical therapy consisted of all antibiotics administered to treat a suspected infection before final pathogen identification and availability of in vitro susceptibility results. Definitive therapy was defined as antimicrobial therapy given after the susceptibility testing results were available to the clinician. Antibiotic treatment was considered appropriate for susceptible, ESBL-producing, or KPC-producing K. pneumoniae BSI if at least 1 antibiotic was administered with documented sensitivity according to the breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). In the case of KPC-K. pneumoniae, appropriate therapy was defined as the administration of at least 1 agent proven sensitive (colistin [using as standard dosage a loading dose of 9 MU, then 4.5 MU every 12 h intravenously] or tigecycline or gentamicin) with either imipenem, meropenem, or tigecycline. For purposes of our analysis, tigecycline, doxycycline, or rifampin monotherapy was considered inappropriate therapy for KPCK. pneumoniae BSI. Only regimens continued for at least 48 hours were included in the analysis. Microbiology Blood cultures were incubated using the BACTEC FX Automated Blood Culture System (Becton Dickinson, Franklin Lakes, NJ). Identification and susceptibility testing of K. pneumoniae strains isolated from blood samples were performed with the Vitek 2 automated system (bioMerieux, Marcy l’Etoile, France). A positive ESBL test from the automated system was confirmed with disc diffusion tests according to United States Clinical and Laboratory Standards Institute (CLSI) guidelines. Enterobacteriaceae MICs were interpreted using EUCAST clinical breakpoints for all tested antimicrobials. Meropenem MICs were also confirmed by Etest using methods recommended by the manufacturer (bioMerieux). Phenotypic confirmation of carbapenemase production was performed for isolates with reduced susceptibility to carbapenems (MIC 3 0.5mg/L for ertapenem, imipenem, or meropenem) using the modified Hodge test, and a meropenem-based disc-diffusion synergy test (Rosco Diagnostica, Taastrup, Denmark). The presence of the blaKPC gene was confirmed by polymerase chain reaction (PCR) using previously described methods. Statistical Analysis Categorical variables were analyzed as absolute numbers and their relative frequencies. Continuous variables were analyzed as mean and standard deviation if normally distributed, or as median and interquartile range if nonnormally distributed. In the univariate analysis of risk factors for all-cause 30-day mortality, categorical variables were compared using the chi-square test, whereas continuous variables were compared using the Mann-Whitney U or 2tailed Student t-test, where appropriate. The primary study hypothesis was to determine if ESBL and KPC-producing Enterobacteriaceae would be associated with significantly higher rates of inadequate empirical antibiotic therapy, which would be an independent risk factor for 30-day crude mortality. To account for non-antibiotic therapy covariates impacting 30-day crude mortality, patient APACHE II scores calculated on the day of positive blood culture were entered in a ã 2014 Lippincott Williams & Wilkins www.md-journal.com | 299 Medicine • Volume 93, Number 17, October 2014 Klebsiella Pneumoniae Bloodstream Infection