Geographical variation in therapy for bloodstream infections due to multidrug-resistant enterobacteriaceae: a post hoc analysis of the INCREMENT study

We aimed to describe regional differences in therapy for bloodstream infection (BSI) caused by extended-spectrum ?-lactamase-producing Enterobacteriaceae (ESBL-E) or carbapenemase-producing Enterobacteriaceae (CPE). 1,482 patients in 12 countries were included from an observational study of BSI caused by ESBL-E or CPE. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs) for the influence of country of recruitment on empirical use of ?-lactam/?-lactamase inhibitors (BLBLI) or carbapenems, targeted use of BLBLI for ESBL-E and use of targeted combination therapy for CPE. The use of BLBLI for empirical therapy was least likely in sites from Israel (aOR 0.34, 95% CI 0.14-0.81), Greece (aOR 0.49, 95% CI 0.26-0.94) and Canada (aOR 0.31, 95% CI 0.11-0.88) but more likely in Italy (aOR 1.58, 95% CI 1.11-2.2) and Turkey (aOR 2.09, 95% CI 1.14-3.81), compared to Spain as a reference. Empirical carbapenems were more likely to be used in sites from Taiwan (aOR 1.73, 95% CI 1.03-2.92) and USA (aOR 1.89; 95% CI 1.05-3.39), and less likely in Italy (aOR 0.44, 95% CI 0.28-0.69) and Canada (aOR 0.10, 95% CI 0.01-0.74). Targeted BLBLI for ESBL-E was more likely in sites from Italy. Treatment at sites within Israel, Taiwan, Turkey and Brazil was associated with less combination therapy for CPE. Although this study does not provide precise data on the relative prevalence of ESBL-E or CPE, significant variation in therapy exists across countries even after adjustment for patient factors. A better understanding of what influences therapeutic choices for these infections will aid antimicrobial stewardship efforts.PH is supported by an Australian Postgraduate Award from the University of Queensland. The study was funded by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III - co-financed by European Development Regional Fund "A way to achieve Europe" ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). BGG, JRB, APH and YC also received funds from the COMBACTE-CARE project (grant agreement 115620), Innovative Medicines Initiative (IMI), the European Union's Seventh Framework Programme (FP7/2007-2013) and in-kind contributions from EFPIA companies

A Predictive Model of Mortality in Patients With Bloodstream Infections due to Carbapenemase-Producing Enterobacteriaceae

Objective To develop a score to predict mortality in patients with bloodstream infections (BSIs) due to carbapenemase-producing Enterobacteriaceae (CPE). Patients and Methods A multinational retrospective cohort study (INCREMENT project) was performed from January 1, 2004, through December 31, 2013. Patients with clinically relevant monomicrobial BSIs due to CPE were included and randomly assigned to either a derivation cohort (DC) or a validation cohort (VC). The variables were assessed on the day the susceptibility results were available, and the predictive score was developed using hierarchical logistic regression. The main outcome variable was 14-day all-cause mortality. The predictive ability of the model and scores were measured by calculating the area under the receiver operating characteristic curve. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for different cutoffs of the score. Results The DC and VC included 314 and 154 patients, respectively. The final logistic regression model of the DC included the following variables: severe sepsis or shock at presentation (5 points); Pitt score of 6 or more (4 points); Charlson comorbidity index of 2 or more (3 points); source of BSI other than urinary or biliary tract (3 points); inappropriate empirical therapy and inappropriate early targeted therapy (2 points). The score exhibited an area under the receiver operating characteristic curve of 0.80 (95% CI, 0.74-0.85) in the DC and 0.80 (95% CI, 0.73-0.88) in the VC. The results for 30-day all-cause mortality were similar. Conclusion A validated score predictive of early mortality in patients with BSIs due to CPE was developed. Trial Registration clinicaltrials.gov Identifier: NCT01 764490

Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli: an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals

107noneObjectives: To explore contemporary antibiotic management of infections caused by carbapenem-resistant Gram-negative bacteria in hospitals.Methods: Cross-sectional, internet-based questionnaire survey. We contacted representatives of all hospitals with more than 800 acute-care hospital beds in France, Greece, Israel, Italy, Kosovo, Slovenia, Spain and selected hospitals in the USA. We asked respondents to describe the most common actual practice at their hospital regarding management of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa through close-ended questions.Results: Between January and June 2017, 115 of 141 eligible hospitals participated (overall response rate 81.6%, country-specific rates 66.7%-100%). Most were tertiary-care (99/114, 86.8%), university-affiliated (110/115, 89.1%) hospitals and most representatives were infectious disease specialists (99/115, 86.1%). Combination therapy was prescribed in 114/115 (99.1%) hospitals at least occasionally. Respondents were more likely to consider combination therapy when treating bacteraemia, pneumonia and central nervous system infections and for Enterobacteriaceae, P. aeruginosa and A. baumannii similarly. Combination of a polymyxin with a carbapenem was used in most cases, whereas combinations of a polymyxin with tigecycline, an aminoglycoside, fosfomycin or rifampicin were also common. Monotherapy was used for treatment of complicated urinary tract infections, usually with an aminoglycoside or a polymyxin. The intended goal of combination therapy was to improve the effectiveness of the treatment and to prevent development of resistance. In general, respondents shared the misconception that combination therapy is supported by strong scientific evidence.Conclusions: Combination therapy was the preferred treatment strategy for infections caused by carbapenem-resistant Gram-negative bacteria among hospital representatives, even though high-quality evidence for carbapenem-based combination therapy is lacking. (c) 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.nonePapst, L.*; Beović, B.; Pulcini, C.; Durante-Mangoni, E.; Rodríguez-Baño, J.; Kaye, K.S.; Daikos, G.L.; Raka, L.; Paul, M.; Abbo, L.; Abgueguen, P.; Almirante, B.; Azzini, A.M.; Bani-Sadr, F.; Bassetti, M.; Ben-Ami, R.; Beović, B.; Béraud, G.; Botelho-Nevers, E.; Bou, G.; Boutoille, D.; Cabié, A.; Cacopardo, B.; Cascio, A.; Cassir, N.; Castelli, F.; Cecala, M.; Charmillon, A.; Chirouze, C.; Cisneros, J.M.; Colmenero, J.D.; Coppola, N.; Corcione, S.; Daikos, G.L.; Dalla Gasperina, D.; De la Calle Cabrera, C.; Delobel, P.; Di Caprio, D.; Durante Mangoni, E.; Dupon, M.; Ettahar, N.; Falagas, M.E.; Falcone, M.; Fariñas, M.C.; Faure, E.; Forestier, E.; Foti, G.; Gallagher, J.; Gattuso, G.; Gendrin, V.; Gentile, I.; Giacobbe, D.R.; Gogos, C.A.; Grandiere Perez, L.; Hansmann, Y.; Horcajada, J.P.; Iacobello, C.; Jacob, J.T.; Justo, J.A.; Kernéis, S.; Komnos, A.; Kotnik Kevorkijan, B.; Lebeaux, D.; Le Berre, R.; Lechiche, C.; Le Moxing, V.; Lescure, F.X.; Libanore, M.; Martinot, M.; Merino de Lucas, E.; Mondain, V.; Mondello, P.; Montejo, M.; Mootien, J.; Muñoz, P.; Nir-Paz, R.; Pan, A.; Paño-Pardo, J.R.; Patel, G.; Paul, M.; Pérez Rodríguez, M.T.; Piroth, L.; Pogue, J.; Potoski, B.A.; Pourcher, V.; Pyrpasopoulou, A.; Rahav, G.; Rizzi, M.; Rodríguez-Baño, J.; Salavert, M.; Scheetz, M.; Sims, M.; Spahija, G.; Stefani, S.; Stefos, A.; Tamma, P.D.; Tattevin, P.; Tedesco, A.; Torre-Cisneros, J.; Tripolitsioti, P.; Tsiodras, S.; Uomo, G.; Verdon, R.; Viale, P.; Vitrat, V.; Weinberger, M.; Wiener-Well, Y.Papst, L.; Beović, B.; Pulcini, C.; Durante-Mangoni, E.; Rodríguez-Baño, J.; Kaye, K. S.; Daikos, G. L.; Raka, L.; Paul, M.; Abbo, L.; Abgueguen, P.; Almirante, B.; Azzini, A. M.; Bani-Sadr, F.; Bassetti, M.; Ben-Ami, R.; Beović, B.; Béraud, G.; Botelho-Nevers, E.; Bou, G.; Boutoille, D.; Cabié, A.; Cacopardo, B.; Cascio, A.; Cassir, N.; Castelli, F.; Cecala, M.; Charmillon, A.; Chirouze, C.; Cisneros, J. M.; Colmenero, J. D.; Coppola, N.; Corcione, S.; Daikos, G. L.; Dalla Gasperina, D.; De la Calle Cabrera, C.; Delobel, P.; Di Caprio, D.; Durante Mangoni, E.; Dupon, M.; Ettahar, N.; Falagas, M. E.; Falcone, M.; Fariñas, M. C.; Faure, E.; Forestier, E.; Foti, G.; Gallagher, J.; Gattuso, G.; Gendrin, V.; Gentile, I.; Giacobbe, D. R.; Gogos, C. A.; Grandiere Perez, L.; Hansmann, Y.; Horcajada, J. P.; Iacobello, C.; Jacob, J. T.; Justo, J. A.; Kernéis, S.; Komnos, A.; Kotnik Kevorkijan, B.; Lebeaux, D.; Le Berre, R.; Lechiche, C.; Le Moxing, V.; Lescure, F. X.; Libanore, M.; Martinot, M.; Merino de Lucas, E.; Mondain, V.; Mondello, P.; Montejo, M.; Mootien, J.; Muñoz, P.; Nir-Paz, R.; Pan, A.; Paño-Pardo, J. R.; Patel, G.; Paul, M.; Pérez Rodríguez, M. T.; Piroth, L.; Pogue, J.; Potoski, B. A.; Pourcher, V.; Pyrpasopoulou, A.; Rahav, G.; Rizzi, M.; Rodríguez-Baño, J.; Salavert, M.; Scheetz, M.; Sims, M.; Spahija, G.; Stefani, S.; Stefos, A.; Tamma, P. D.; Tattevin, P.; Tedesco, A.; Torre-Cisneros, J.; Tripolitsioti, P.; Tsiodras, S.; Uomo, G.; Verdon, R.; Viale, P.; Vitrat, V.; Weinberger, M.; Wiener-Well, Y

Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study

Background The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. Methods In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0\ue2\u80\u937 [low mortality score] vs 8\ue2\u80\u9315 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. Findings Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38\uc2\ub75%] of 343 patients died vs 57 [60\uc2\ub76%] of 94; absolute difference 22\uc2\ub71% [95% CI 11\uc2\ub70\ue2\u80\u9333\uc2\ub73]; adjusted hazard ratio [HR] 0\uc2\ub745 [95% CI 0\uc2\ub733\ue2\u80\u930\uc2\ub762]; p<0\uc2\ub70001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1\uc2\ub763 [95% CI 0\uc2\ub767\ue2\u80\u933\uc2\ub791]; p=0\uc2\ub728). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0\uc2\ub756 [0\uc2\ub734\ue2\u80\u930\uc2\ub791]; p=0\uc2\ub702), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1\uc2\ub721 [0\uc2\ub756\ue2\u80\u932\uc2\ub756]; p=0\uc2\ub762). Interpretation Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. Funding Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative

A Multinational, Preregistered Cohort Study of beta-Lactam/beta-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-beta-Lactamase-Producing Enterobacteriaceae

The spread of extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether beta-lactam/beta-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.