80 results on '"Dickstein Y"'
Search Results
2. Duration of Treatment for Pseudomonas aeruginosa Bacteremia: a Retrospective Study
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Babich, T., Naucler, P., Valik, J.K., Giske, C.G., Benito, Natividad, Cardona, R., Rivera, Alba, Pulcini, C., Fattah, M.A., Haquin, J., Macgowan, A., Grier, S., Chazan, B., Yanovskay, A., Ami, R.B., Landes, M., Nesher, L., Zaidman-Shimshovitz, A., McCarthy, K., Paterson, D.L., Tacconelli, E., Buhl, M., Mauer, S., Rodríguez-Baño, J., de Cueto, M., Oliver, A., de Gopegui, E.R., Cano, A., Machuca, I., Gozalo-Marguello, M., Martinez-Martinez, L., Gonzalez-Barbera, E.M., Alfaro, I.G., Salavert, M., Beovic, B., Saje, A., Mueller-Premru, M., Pagani, L., Vitrat, V., Kofteridis, D., Zacharioudaki, M., Maraki, S., Weissman, Y., Paul, M., Dickstein, Y., Leibovici, L., Yahav, D., Universitat Autònoma de Barcelona, and Yahav, Dafna
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Microbiology (medical) ,Infectious Diseases ,Duration ,Antibiotics ,Pseudomonas aeruginosa ,Bacteremia ,Antimicrobial stewardship - Abstract
[Introduction] There is no consensus regarding optimal duration of antibiotic therapy for Pseudomonas aeruginosa bacteremia. We aimed to evaluate the impact of short antibiotic course., [Methods] We present a retrospective multicenter study including patients with P. aeruginosa bacteremia during 2009–2015. We evaluated outcomes of patients treated with short (6–10 days) versus long (11–15 days) antibiotic courses. The primary outcome was a composite of 30-day mortality or bacteremia recurrence and/or persistence. Univariate and inverse probability treatment-weighted (IPTW) adjusted multivariate analysis for the primary outcome was performed. To avoid immortal time bias, the landmark method was used., [Results] We included 657 patients; 273 received a short antibiotic course and 384 a long course. There was no significant difference in baseline characteristics of patients. The composite primary outcome occurred in 61/384 patients in the long-treatment group (16%) versus 32/273 in the short-treatment group (12%) (p = 0.131). Mortality accounted for 41/384 (11%) versus 25/273 (9%) of cases, respectively. Length of hospital stay was significantly shorter in the short group [median 13 days, interquartile range (IQR) 9–21 days, versus median 15 days, IQR 11–26 days, p = 0.002]. Ten patients in the long group discontinued antibiotic therapy owing to adverse events, compared with none in the short group. On univariate and multivariate analyses, duration of therapy was not associated with the primary outcome., [Conclusions] In this retrospective study, 6–10 days of antibiotic course for P. aeruginosa bacteremia were as effective as longer courses in terms of survival and recurrence. Shorter therapy was associated with reduced length of stay and less drug discontinuation.
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- 2022
3. Helicobacter pylori infection in patients with selective immunoglobulin a deficiency
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Magen, E., Waitman, D.-A., Goldstein, N., Schlesinger, M., Dickstein, Y., and Kahan, N. R.
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- 2016
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4. Colistin resistance development following colistin-meropenem combination therapy versus colistin monotherapy in patients with infections caused by carbapenem-resistant organisms
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Dickstein, Y. Lellouche, J. Schwartz, D. Nutman, A. Rakovitsky, N. Benattar, Y.D. Altunin, S. Bernardo, M. Iossa, D. Durante-Mangoni, E. Antoniadou, A. Skiada, A. Deliolanis, I. Daikos, G.L. Daitch, V. Yahav, D. Leibovici, L. Rognås, V. Friberg, L.E. Mouton, J.W. Paul, M. Carmeli, Y. Benattar, Y.D. Dickstein, Y. Bitterman, R. Zayyad, H. Koppel, F. Zak-Doron, Y. Altunin, S. Andria, N. Neuberger, A. Stern, A. Petersiel, N. Raines, M. Karban, A. Yahav, D. Eliakim-Raz, N. Zusman, O. Elbaz, M. Atamna, H. Daitch, V. Babich, T. Carmeli, Y. Nutman, A. Adler, A. Levi, I. Daikos, G.L. Skiada, A. Deliolanis, I. Pavleas, I. Antoniadou, A. Kotsaki, A. Andini, R. Iossa, D. Bernardo, M. Cavezza, G. Bertolino, L. Giuffre, G. Giurazza, R. Cuccurullo, S. Galdo, M. Murino, P. Cristinziano, A. Corcione, A. Zampino, R. Pafundi, P.C. Mouton, J. Friberg, L. Kristoffersson, A. Theuretzbacher, U. the AIDA Study Group
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polycyclic compounds ,bacteria ,lipids (amino acids, peptides, and proteins) ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses - Abstract
Background. We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms. Methods. This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E). Results. Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475–10.184; P = .006). Conclusions. Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention. © The Author(s) 2019.
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- 2020
5. Staffing for infectious diseases, clinical microbiology and infection control in hospitals in 2015: results of an ESCMID member survey
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Dickstein, Y., Nir-Paz, R., Pulcini, C., Cookson, B., Beović, B., Tacconelli, E., Nathwani, D., Vatcheva-Dobrevska, R., Rodríguez-Baño, J., Hell, M., Saenz, H., Leibovici, L., and Paul, M.
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- 2016
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6. Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity
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Daitch, V. Paul, M. Daikos, G.L. Durante-Mangoni, E. Yahav, D. Carmeli, Y. Benattar, Y.D. Skiada, A. Andini, R. Eliakim-Raz, N. Nutman, A. Zusman, O. Antoniadou, A. Cavezza, G. Adler, A. Dickstein, Y. Pavleas, I. Zampino, R. Bitterman, R. Zayyad, H. Koppel, F. Zak-Doron, Y. Levi, I. Babich, T. Turjeman, A. Ben-Zvi, H. Friberg, L.E. Mouton, J.W. Theuretzbacher, U. Leibovici, L.
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Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study’s population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial. Methods: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset. Results: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10–16) vs. 8.5 days (IQR 0–15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14. Conclusion: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice. Trial registration: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012. © 2021, The Author(s).
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- 2021
7. Clinical evaluation of new automated cytomegalovirus IgM and IgG assays for the Elecsys® analyser platform
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Revello, M. G., Vauloup-Fellous, C., Grangeot-Keros, L., van Helden, J., Dickstein, Y., Lipkin, I., Mühlbacher, A., and Lazzarotto, T.
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- 2012
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8. The rise of SARS-CoV-2 variant B.1.1.7 in Israel intensifies the role of surveillance and vaccination in elderly
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Munitz, A, primary, Yechezkel, M, additional, Dickstein, Y, additional, Yamin, D., additional, and Gerlic, M, additional
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- 2021
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9. Reply to wilson et al
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Dickstein, Y. Leibovici, L. Carmeli, Y. Daikos, G. Durante-Mangoni, E. Friberg, L.E. Paul, M.
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- 2020
10. Colistin plus meropenem for carbapenem-resistant Gram-negative infections: in vitro synergism is not associated with better clinical outcomes
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Nutman, A. Lellouche, J. Temkin, E. Daikos, G. Skiada, A. Durante-Mangoni, E. Dishon-Benattar, Y. Bitterman, R. Yahav, D. Daitch, V. Bernardo, M. Iossa, D. Zusman, O. Friberg, L.E. Mouton, J.W. Theuretzbacher, U. Leibovici, L. Paul, M. Carmeli, Y. Benattar, Y.D. Dickstein, Y. Zayyad, H. Koppel, F. Zak-Doron, Y. Altunin, S. Andria, N. Neuberger, A. Stern, A. Petersiel, N. Raines, M. Karban, A. Eliakim-Raz, N. Elbaz, M. Atamna, H. Babich, T. Adler, A. Levi, I. Daikos, G.L. Pavleas, I. Antoniadou, A. Kotsaki, A. Andini, R. Cavezza, G. Bertolino, L. Giuffre, G. Giurazza, R. Cuccurullo, S. Galdo, M. Murino, P. Cristinziano, A. Corcione, A. Zampino, R. Pafundi, P.C. Mouton, J. Friberg, L. Kristoffersson, A. AIDA Study Group
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polycyclic compounds ,bacteria ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses - Abstract
Objectives: In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. Methods: This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. Results: The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96). Discussion: In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit. © 2020 European Society of Clinical Microbiology and Infectious Diseases
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- 2020
11. Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial
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Dickstein, Y. Lellouche, J. Ben Dalak Amar, M. Schwartz, D. Nutman, A. Daitch, V. Yahav, D. Leibovici, L. Skiada, A. Antoniadou, A. Daikos, G.L. Andini, R. Zampino, R. Durante-Mangoni, E. Mouton, J.W. Friberg, L.E. Dishon Benattar, Y. Bitterman, R. Neuberger, A. Carmeli, Y. Paul, M. Zayyad, H. Koppel, F. Zak-Doron, Y. Altunin, S. Andria, N. Stern, A. Petersiel, N. Raines, M. Karban, A. Eliakim-Raz, N. Zusman, O. Elbaz, M. Atamna, H. Babich, T. Adler, A. Levi, I. Pavleas, I. Kotsaki, A. Iossa, D. Bernardo, M. Cavezza, G. Bertolino, L. Giuffre, G. Giurazza, R. Cuccurullo, S. Galdo, M. Murino, P. Cristinziano, A. Corcione, A. Clara Pafundi, P.
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polycyclic compounds ,bacteria ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses - Abstract
Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P =. 174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI},. 118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration: NCT01732250. © 2018 The Author(s) 2018.
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- 2019
12. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial
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Paul, M. Daikos, G.L. Durante-Mangoni, E. Yahav, D. Carmeli, Y. Benattar, Y.D. Skiada, A. Andini, R. Eliakim-Raz, N. Nutman, A. Zusman, O. Antoniadou, A. Pafundi, P.C. Adler, A. Dickstein, Y. Pavleas, I. Zampino, R. Daitch, V. Bitterman, R. Zayyad, H. Koppel, F. Levi, I. Babich, T. Friberg, L.E. Mouton, J.W. Theuretzbacher, U. Leibovici, L.
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Background: Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Methods: A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual. Findings: Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference −5·7%, 95% CI −13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury). Interpretation: Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria. Funding: EU AIDA grant Health-F3-2011-278348. © 2018 Elsevier Ltd
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- 2018
13. The Association Between Empirical Antibiotic Treatment and Mortality in Severe Infections Caused by Carbapenem-resistant Gram-negative Bacteria: A prospective study
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Zak-Doron, Y. Benattar, Y.D. Pfeffer, I. Daikos, G.L. Skiada, A. Antoniadou, A. Durante-Mangoni, E. Andini, R. Cavezza, G. Leibovici, L. Yahav, D. Eliakim-Raz, N. Carmeli, Y. Nutman, A. Paul, M. Dickstein, Y. Bitterman, R. Zayyad, H. Koppel, F. Altunin, S. Andria, N. Neuberger, A. Stern, A. Petersiel, N. Raines, M. Karban, A. Zusman, O. Elbaz, M. Atamna, H. Daitch, V. Babich, T. Adler, A. Levi, I. Daikos, G.L. Pavleas, I. Kotsaki, A. Iossa, D. Bernardo, M. Bertolino, L. Giuffrè, G. Giurazza, R. Cuccurullo, S. Galdo, M. Murino, P. Cristinziano, A. Corcione, A. Zampino, R. Pafundi, P.C. Mouton, J. Friberg, L. Kristoffersson, A. Theuretzbacher, U. AIDA Study Group
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Background. Empirical colistin should be avoided. We aimed to evaluate the association between covering empirical antibiotics (EAT) and mortality for infections caused by carbapenem-resistant gram-negative bacteria (CRGNB). Methods. This was a secondary analysis of a randomized controlled trial, including adults with bloodstream infections, pneumonia, or urosepsis caused by CRGNB. All patients received EAT followed by covering targeted therapy. The exposure variable was covering EAT in the first 48 hours. The outcome was 28-day mortality. We adjusted the analyses by multivariable regression analysis and propensity score matching. Results. The study included 406 inpatients with severe CRGNB infections, mostly Acinetobacter baumannii (312/406 [77%]). Covering EAT was given to 209 (51.5%) patients, mostly colistin (n = 200). Patients receiving noncovering EAT were older, more frequently unconscious and dependent, carrying catheters, and mechanically ventilated with pneumonia. Mortality was 84 of 197 (42.6%) with noncovering vs 96 of 209 (45.9%) with covering EAT (P = .504). Covering EAT was not associated with survival in the adjusted analysis; rather, there was a weak association with mortality (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.02-1.84). Results were similar for colistin monotherapy and colistin-carbapenem combination EAT. In the propensity score-matched cohort (n = 338) covering antibiotics were not significantly associated with mortality (OR, 1.42; 95% CI, .91-2.22). Similar results were obtained in an analysis of 14-day mortality. Conclusions. Empirical use of colistin before pathogen identification, with or without a carbapenem, was not associated with survival following severe infections caused by CRGNBs, mainly A. baumannii. © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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- 2018
14. Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant gram-negative infections (aida): A study protocol
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Dickstein, Y. Leibovici, L. Yahav, D. Eliakim-Raz, N. Daikos, G.L. Skiada, A. Antoniadou, A. Carmeli, Y. Nutman, A. Levi, I. Adler, A. Durante-Mangoni, E. Andini, R. Cavezza, G. Mouton, J.W. Awijma, R. Theuretzbacher, U. Friberg, L.E. Kristoffersson, A.N. Zusman, O. Koppel, F. Benattar, Y.D. Altunin, S. Paul, M.
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Mical Paul,1,14 Introduction: The emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem. A randomised controlled study is necessary for clarification. Methods and analysis: This is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin-meropenem combination therapy for infections caused by carbapenem-resistant Gramnegative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel). We include patients with hospital-associated and ventilatorassociated pneumonia, bloodstream infections and urosepsis. The primary outcome is treatment success at day 14, defined as survival, haemodynamic stability, stable or improved respiratory status for patients with pneumonia, microbiological cure for patients with bacteraemia and stability or improvement of the Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes include 14-day and 28-day mortality as well as other clinical end points and safety outcomes. A sample size of 360 patients was calculated on the basis of an absolute improvement in clinical success of 15% with combination therapy. Outcomes will be assessed by intention to treat. Serum colistin samples are obtained from all patients to obtain population pharmacokinetic models. Microbiological sampling includes weekly surveillance samples with analysis of resistance mechanisms and synergy. An observational trial is evaluating patientswho met eligibility requirements but were not randomised in order to assess generalisability of findings. Ethics and dissemination: The study was approved by ethics committees at each centre and informed consent will be obtained for all patients. The trial is being performed under the auspices of an independent data and safety monitoring committee and is included in a broad dissemination strategy regarding revival of old antibiotics.
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- 2016
15. Carbapenem-resistant Enterobacteriaceae colonization and infection in critically ill patients: a retrospective matched cohort comparison with non-carriers
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Dickstein, Y., primary, Edelman, R., additional, Dror, T., additional, Hussein, K., additional, Bar-Lavie, Y., additional, and Paul, M., additional
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- 2016
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16. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial
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Paul, M., primary, Bishara, J., additional, Yahav, D., additional, Goldberg, E., additional, Neuberger, A., additional, Ghanem-Zoubi, N., additional, Dickstein, Y., additional, Nseir, W., additional, Dan, M., additional, and Leibovici, L., additional
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- 2015
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17. THE DECREASED BASAL AND STIMULATED PROLACTIN LEVELS IN ISOLATED GONADOTROPHIN DEFICIENCY: A CONSEQUENCE OF THE LOW OESTROGEN STATE.
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SPITZ, I. M., ZYLBER-HARAN, E. A., TRESTIAN, S., DICKSTEIN, Y., PALTI, Z., and SCHENKER, J. G.
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- 1982
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18. The metabolism of T4 and T3 in cultured chick-embryo heart cells
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Dickstein, Y., primary, Schwartz, H., additional, Gross, J., additional, and Gordon, A., additional
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- 1980
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19. Stimulation of Sugar Transport in Cultured Heart Cells by Triiodothyronine (T3) Covalently Bound to Red Blood Cells and by T3in the Presence of Serum*
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DICKSTEIN, Y., primary, SCHWARTZ, H., additional, GROSS, J., additional, and GORDON, A., additional
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- 1983
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20. Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial
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Adriano Cristinziano, Pia Clara Pafundi, Sergey Altunin, Mariano Bernardo, Anders N. Kristoffersson, Ma’ayan Amar, Nizar Andria, Patrizia Murino, Giuseppe Giuffre, Mical Paul, David A. Schwartz, Antonio Corcione, Vered Daitch, Roberto Andini, Heyam Atamna, George L. Daikos, Fidi Koppel, Maria Galdo, Emanuele Durante-Mangoni, Hiba Zayyad, Roberto Giurazza, Yaakov Dickstein, Antigoni Kotsaki, Amos Adler, Yael Zak-Doron, Noa Eliakim-Raz, Amir Karban, Ami Neuberger, Giusi Cavezza, Domenico Iossa, Anat Stern, Oren Zusman, Johan W. Mouton, Neta Petersiel, Amir Nutman, Lena E. Friberg, Ursula Theuretzbacher, Jonathan Lellouche, Ioannis Pavleas, Roni Bitterman, Lorenzo Bertolino, Leonard Leibovici, Anna Skiada, Anastasia Antoniadou, Rosa Zampino, Marina Raines, Dafna Yahav, Michal Elbaz, Tanya Babich, Susanna Cuccurullo, Inbar Levi, Yehuda Carmeli, Yael Dishon Benattar, Johan Mouton, Dickstein, Y, Lellouche, J, Dalak Amar, Mb, Schwartz, D, Nutman, A, Daitch, V, Yahav, D, Leibovici, L, Skiada, A, Antoniadou, A, Daikos, Gl, Andini, R, Zampino, R, Durante-Mangoni, E, Mouton, Jw, Friberg, Le, Benattar, Yd, Bitterman, R, Neuberger, A, Carmeli, Y, Paul, M, AIDA study, Group., and Medical Microbiology & Infectious Diseases
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Acinetobacter baumannii ,Male ,0301 basic medicine ,Treatment outcome ,Infektionsmedicin ,law.invention ,Colistin resistance ,0302 clinical medicine ,Randomized controlled trial ,law ,Drug Resistance, Multiple, Bacterial ,polycyclic compounds ,colistin ,030212 general & internal medicine ,Acinetobacter ,biology ,Middle Aged ,gram-negative bacteria ,Anti-Bacterial Agents ,Treatment Outcome ,Infectious Diseases ,Data Interpretation, Statistical ,Drug Therapy, Combination ,Female ,Acinetobacter Infections ,medicine.drug ,Microbiology (medical) ,Infectious Medicine ,medicine.medical_specialty ,030106 microbiology ,Subgroup analysis ,Microbial Sensitivity Tests ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,XDR-TB ,Aged ,Retrospective Studies ,Colistin ,carbapenem-resistant ,business.industry ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,biology.organism_classification ,Carbapenems ,bacteria ,Carbapenem resistant Acinetobacter baumannii ,business - Abstract
Background We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118–.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021–9.202]). Conclusions Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration NCT01732250
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- 2018
21. Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity
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Roni Bitterman, Amir Nutman, Ursula Theuretzbacher, Emanuele Durante-Mangoni, Noa Eliakim-Raz, Adi Turjeman, Haim Ben-Zvi, Roberto Andini, Lena E. Friberg, Fidi Koppel, Anastasia Antoniadou, Yaakov Dickstein, Yael Zak-Doron, Mical Paul, Dafna Yahav, Ioannis Pavleas, Vered Daitch, Inbar Levi, Hiba Zayyad, Rosa Zampino, George L. Daikos, Yehuda Carmeli, Johan W. Mouton, Amos Adler, Yael Dishon Benattar, Oren Zusman, Giusi Cavezza, Tanya Babich, Leonard Leibovici, Anna Skiada, Daitch, V., Paul, M., Daikos, G. L., Durante-Mangoni, E., Yahav, D., Carmeli, Y., Benattar, Y. D., Skiada, A., Andini, R., Eliakim-Raz, N., Nutman, A., Zusman, O., Antoniadou, A., Cavezza, G., Adler, A., Dickstein, Y., Pavleas, I., Zampino, R., Bitterman, R., Zayyad, H., Koppel, F., Zak-Doron, Y., Levi, I., Babich, T., Turjeman, A., Ben-Zvi, H., Friberg, L. E., Mouton, J. W., Theuretzbacher, U., Leibovici, L., and Medical Microbiology & Infectious Diseases
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Acinetobacter baumannii ,Male ,Infektionsmedicin ,Antimicrobial resistance ,law.invention ,0302 clinical medicine ,Acinetobacter Infection ,Randomized controlled trial ,law ,Medicine ,030212 general & internal medicine ,Israel ,Carbapenem ,Randomized Controlled Trials as Topic ,education.field_of_study ,Univariate analysis ,Greece ,Middle Aged ,Anti-Bacterial Agents ,Infectious Diseases ,Treatment Outcome ,Italy ,Female ,Acinetobacter Infections ,Research Article ,medicine.drug ,Human ,medicine.medical_specialty ,Infectious Medicine ,Logistic Model ,Population ,lcsh:Infectious and parasitic diseases ,External validity ,03 medical and health sciences ,Population external validity ,SDG 3 - Good Health and Well-being ,Internal medicine ,Anti-Bacterial Agent ,Drug Resistance, Bacterial ,Humans ,lcsh:RC109-216 ,Risk factor ,education ,Aged ,business.industry ,Colistin ,030208 emergency & critical care medicine ,Meropenem ,Antibiotic treatment ,Logistic Models ,Carbapenems ,Concomitant ,Observational study ,business - Abstract
Background Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study’s population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial. Methods The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset. Results Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10–16) vs. 8.5 days (IQR 0–15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14. Conclusion The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice. Trial registration The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.
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- 2021
22. Colistin plus meropenem for carbapenem-resistant Gram-negative infections: in vitro synergism is not associated with better clinical outcomes
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Amir Nutman, Jonathan Lellouche, Elizabeth Temkin, George Daikos, Anna Skiada, Emanuele Durante-Mangoni, Yael Dishon-Benattar, Roni Bitterman, Dafna Yahav, Vered Daitch, Mariano Bernardo, Domenico Iossa, Oren Zusman, Lena E. Friberg, Johan W. Mouton, Ursula Theuretzbacher, Leonard Leibovici, Mical Paul, Yehuda Carmeli, Yael Dishon Benattar, Yaakov Dickstein, Hiba Zayyad, Fidi Koppel, Yael Zak-Doron, Sergey Altunin, Nizar Andria, Ami Neuberger, Anat Stern, Neta Petersiel, Marina Raines, Amir Karban, Noa Eliakim-Raz, Michal Elbaz, Heyam Atamna, Tanya Babich, Amos Adler, Inbar Levi, George L. Daikos, Ioannis Pavleas, Anastasia Antoniadou, Antigoni Kotsaki, Roberto Andini, Giusi Cavezza, Lorenzo Bertolino, Giuseppe Giuffre, Roberto Giurazza, Susanna Cuccurullo, Maria Galdo, Patrizia Murino, Adriano Cristinziano, Antonio Corcione, Rosa Zampino, Pia Clara Pafundi, Johan Mouton, Lena Friberg, Anders Kristoffersson, Medical Microbiology & Infectious Diseases, Nutman, A., Lellouche, J., Temkin, E., Daikos, G., Skiada, A., Durante Mangoni, E., Dishon-Benattar, Y., Bitterman, R., Yahav, D., Daitch, V., Bernardo, M., Iossa, D., Zusman, O., Friberg, L. E., Mouton, J. W., Theuretzbacher, U., Leibovici, L., Paul, M., Carmeli, Y., Benattar, Y. D., Dickstein, Y., Zayyad, H., Koppel, F., Zak-Doron, Y., Altunin, S., Andria, N., Neuberger, A., Stern, A., Petersiel, N., Raines, M., Karban, A., Eliakim-Raz, N., Elbaz, M., Atamna, H., Babich, T., Adler, A., Levi, I., Daikos, G. L., Pavleas, I., Antoniadou, A., Kotsaki, A., Andini, R., Cavezza, G., Bertolino, L., Giuffre, G., Giurazza, R., Cuccurullo, S., Galdo, M., Murino, P., Cristinziano, A., Corcione, A., Zampino, R., Pafundi, P. C., Mouton, J., Friberg, L., and Kristoffersson, A.
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0301 basic medicine ,Male ,Polymyxin ,Infektionsmedicin ,law.invention ,Checkerboard assay ,0302 clinical medicine ,Randomized controlled trial ,law ,polycyclic compounds ,030212 general & internal medicine ,Gram ,Aged, 80 and over ,Cross Infection ,biology ,Drug Synergism ,General Medicine ,Middle Aged ,Acinetobacter baumannii ,Gram-negative infections synergism ,Infectious Diseases ,Treatment Outcome ,Female ,medicine.drug ,Microbiology (medical) ,Infectious Medicine ,medicine.medical_specialty ,Carbapenem resistance ,medicine.drug_class ,030106 microbiology ,Microbial Sensitivity Tests ,Meropenem ,03 medical and health sciences ,Internal medicine ,Drug Resistance, Bacterial ,Gram-Negative Bacteria ,medicine ,Pneumonia, Bacterial ,Humans ,Aged ,business.industry ,Colistin ,Odds ratio ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,biology.organism_classification ,Carbapenems ,Combination treatment ,bacteria ,business ,Antagonism ,Gram-Negative Bacterial Infections - Abstract
Objectives In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. Methods This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. Results The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96). Discussion In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.
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- 2020
23. Prevalence and Clinical Consequences of Colistin Heteroresistance and Evolution into Full Resistance in Carbapenem-Resistant Acinetobacter baumannii.
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Kon H, Hameir A, Nutman A, Temkin E, Keren Paz A, Lellouche J, Schwartz D, Weiss DS, Kaye KS, Daikos GL, Skiada A, Durante-Mangoni E, Dishon Benattar Y, Yahav D, Daitch V, Bernardo M, Iossa D, Friberg LE, Theuretzbacher U, Leibovici L, Dickstein Y, Pollak D, Mendelsohn S, Paul M, and Carmeli Y
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- Humans, Colistin pharmacology, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Prevalence, Microbial Sensitivity Tests, Carbapenems pharmacology, Carbapenems therapeutic use, Drug Resistance, Multiple, Bacterial, Acinetobacter baumannii, Acinetobacter Infections drug therapy, Acinetobacter Infections epidemiology, Acinetobacter Infections microbiology
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Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings., Competing Interests: The authors declare a conflict of interest. E.D.M. reports grants and/or personal fees from Pfizer, M.S.D., Rosh, Anglini, Nordic Pharma, and Sanofi-Aventis. G.L.D. reports grants and/or personal fees from Pfizer, Menarini, and M.S.D. K.S.K. reports grants and/or personal fees from Spero Therapeutics, Q.P.E.X., and MicuRx. M.P. reports grants and/or personal fees from Shionogi and Pfizer. Y.C. reports grants and/or personal fees from Allecra Therapeutics, Genentech, Nabriva Therapeutics, Pfizer, PPD, Q.P.E.X. Biopharma, Roche Pharmaceuticals, Spero Therapeutics, VenatoRX Pharmaceuticals. All other authors have no interests to declare.
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- 2023
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24. Optimizing patient recruitment into clinical trials of antimicrobial-resistant pathogens.
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Paul M, Dishon-Benattar Y, Dickstein Y, and Yahav D
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Recruitment of patients with critical priority antimicrobial-resistant (AMR) bacteria into drug approval randomized controlled trials (RCTs) has not been successful to date. Approaching from the viewpoint of clinician-investigators and learning from the experience of AMR-focused investigator-initiated trials, we present suggestions to improve feasibility and efficiency of RCTs evaluating patients with severe infections caused by carbapenem-resistant Gram-negative or other AMR bacteria. Considerations address the trials' eligibility criteria, whether the focus of the trial is pathogen- or syndrome-targeted, trials' case report forms and monitoring, informed consent strategies for the recruitment of extremely ill patients, team dedication and incentives to run the trial and alternative trial designs. Evidence on the effects of new drugs against the AMR that these drugs target is weak and needs to be improved through better industry-academic collaboration, taking advantage of the different strengths of industry-led and investigator-initiated research., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
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- 2023
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25. External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia.
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Turjeman A, Koppel F, Franceschini E, Yahav D, Dolci G, Bacca E, Babich T, Khazem E, Baum E, Nassar R, Bitterman R, Dishon-Benatta Y, Hassoun-Kheir N, Santoro A, Eliakim-Raz N, Poran I, Pertzov B, Stern A, Dickstein Y, Maroun E, Raines M, Meschiari M, Bishara J, Goldberg E, Venturelli C, Sarti M, Mussini C, Paul M, and Leibovici L
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- Humans, Italy, Randomized Controlled Trials as Topic, Anti-Bacterial Agents therapeutic use, Bacteremia drug therapy
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Introduction: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial., Methods: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment., Results: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality., Conclusions: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking., (© 2022 S. Karger AG, Basel.)
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- 2023
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26. Duration of Treatment for Pseudomonas aeruginosa Bacteremia: a Retrospective Study.
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Babich T, Naucler P, Valik JK, Giske CG, Benito N, Cardona R, Rivera A, Pulcini C, Fattah MA, Haquin J, Macgowan A, Grier S, Chazan B, Yanovskay A, Ami RB, Landes M, Nesher L, Zaidman-Shimshovitz A, McCarthy K, Paterson DL, Tacconelli E, Buhl M, Mauer S, Rodríguez-Baño J, de Cueto M, Oliver A, de Gopegui ER, Cano A, Machuca I, Gozalo-Marguello M, Martinez-Martinez L, Gonzalez-Barbera EM, Alfaro IG, Salavert M, Beovic B, Saje A, Mueller-Premru M, Pagani L, Vitrat V, Kofteridis D, Zacharioudaki M, Maraki S, Weissman Y, Paul M, Dickstein Y, Leibovici L, and Yahav D
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Introduction: There is no consensus regarding optimal duration of antibiotic therapy for Pseudomonas aeruginosa bacteremia. We aimed to evaluate the impact of short antibiotic course., Methods: We present a retrospective multicenter study including patients with P. aeruginosa bacteremia during 2009-2015. We evaluated outcomes of patients treated with short (6-10 days) versus long (11-15 days) antibiotic courses. The primary outcome was a composite of 30-day mortality or bacteremia recurrence and/or persistence. Univariate and inverse probability treatment-weighted (IPTW) adjusted multivariate analysis for the primary outcome was performed. To avoid immortal time bias, the landmark method was used., Results: We included 657 patients; 273 received a short antibiotic course and 384 a long course. There was no significant difference in baseline characteristics of patients. The composite primary outcome occurred in 61/384 patients in the long-treatment group (16%) versus 32/273 in the short-treatment group (12%) (p = 0.131). Mortality accounted for 41/384 (11%) versus 25/273 (9%) of cases, respectively. Length of hospital stay was significantly shorter in the short group [median 13 days, interquartile range (IQR) 9-21 days, versus median 15 days, IQR 11-26 days, p = 0.002]. Ten patients in the long group discontinued antibiotic therapy owing to adverse events, compared with none in the short group. On univariate and multivariate analyses, duration of therapy was not associated with the primary outcome., Conclusions: In this retrospective study, 6-10 days of antibiotic course for P. aeruginosa bacteremia were as effective as longer courses in terms of survival and recurrence. Shorter therapy was associated with reduced length of stay and less drug discontinuation., (© 2022. The Author(s).)
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- 2022
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27. A systematic review of antimicrobial susceptibility testing as a tool in clinical trials assessing antimicrobials against infections due to gram-negative pathogens.
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Henderson A, Bursle E, Stewart A, Harris PNA, Paterson D, Chatfield MD, Paul M, Dickstein Y, Rodriguez-Baño J, Turnidge JD, and Kahlmeter G
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- Acinetobacter baumannii, Colistin, Humans, Randomized Controlled Trials as Topic, Anti-Bacterial Agents pharmacology, Gram-Negative Bacteria drug effects, Microbial Sensitivity Tests
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Background: Antimicrobial susceptibility testing (AST) is the standard of care for treating bacterial infections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time., Objectives: To determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorization on the trials' primary outcomes., Data Sources: We systematically searched PubMed, Embase, PsychINFO and Web of Science., Eligibility Criteria: We included registered randomized controlled trials published in journals between January 2015 and December 2019., Participants and Interventions: We included trials comparing different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria., Methods: Primary outcomes for different trial populations were extracted and differences between trial arms were compared for patients with infections caused by susceptible versus non-susceptible bacteria. Results are described narratively., Results: Of 32 randomized trials, 25 trials reported that local AST was performed, 1312 reported the local laboratory AST methods, no trial reported QC, but post-hoc referral for AST at a reference laboratory was common. Patients' outcomes were superior when patients with infections due to susceptible and non-susceptible pathogens were compared post hoc (median difference 14%, interquartile range 8%-24%) in trials allowing this comparison (seven antimicrobials), except for colistin, where 14-day mortality was 9% higher when patients were treated with colistin for colistin-susceptible versus colistin-resistant carbapenem-resistant Acinetobacter baumannii. When excluding patients with pathogens that were non-susceptible to either antimicrobial in the trials, the difference in the primary outcome between the trial arms was reduced in five out of six trials., Conclusions: Trials should perform AST to guide patient inclusion or exclusion from the study and consider the impact of the central laboratory susceptibility results on the study outcomes when using post-hoc reference testing., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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28. Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study.
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Turjeman A, Koppel F, Franceschini E, Yahav D, Dolci G, Babich T, Bitterman R, Neuberger A, Ghanem-Zoubi N, Santoro A, Eliakim-Raz N, Pertzov B, Stern A, Dickstein Y, Maroun E, Zayyad H, Meschiari M, Bishara J, Goldberg E, Venturelli C, Mussini C, Paul M, and Leibovici L
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- Aged, Aged, 80 and over, Anti-Bacterial Agents therapeutic use, Confidence Intervals, Female, Gram-Negative Bacteria drug effects, Humans, Lung Diseases drug therapy, Male, Middle Aged, Prospective Studies, Risk Factors, Gram-Negative Bacteria pathogenicity, Lung Diseases blood, Lung Diseases microbiology
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Objective: To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia., Patients and Methods: A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days., Results: Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60-80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01-1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5-8.6), low Norton score (OR, 0.87; 95% CI 0.79-0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14-3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12-4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04-1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21-0.78)., Conclusions: Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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29. The Israeli national policy for discontinuation of isolation of carbapenem-resistant Enterobacterales carriers by carbapenemase type: a retrospective cohort study.
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Dickstein Y, Solter E, Schwartz D, Nutman A, Harevrich I, Wulffhart L, Carmeli Y, and Schwaber MJ
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- Bacterial Proteins genetics, Enterobacteriaceae drug effects, Enterobacteriaceae isolation & purification, Humans, Israel, Policy, Retrospective Studies, beta-Lactamases genetics, Bacterial Proteins classification, Carrier State epidemiology, Drug Resistance, Bacterial, Enterobacteriaceae Infections drug therapy, Enterobacteriaceae Infections epidemiology, beta-Lactamases classification
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Objectives: The Israeli national policy for containing carbapenemase-producing Enterobacterales (CPE) includes a protocol allowing for discontinuation of carrier status following spontaneous decolonization. We examined the strategy's effectiveness based on carbapenemase type., Methods: We performed a retrospective cohort study comparing individuals colonized with KPC- or NDM-producing Enterobacterales who underwent the process of isolation discontinuation. The primary outcome was reversion of carrier status, i.e. re-identification of the same CPE species following isolation discontinuation. We used survival analysis to estimate overall hazard ratio and performed competing-risks analysis using a Fine-Gray subdistribution hazard model and cause-specific hazard ratios., Results: Between 1 January 2006 and 1 January 2019 we identified 1694 individuals who met inclusion criteria, including 1337 (78.9%) carriers of KPC-producing Enterobacterales, 305 (18.0%) carriers of NDM-producing Enterobacterales and 52 (3.1%) carriers of dual KPC-/NDM-producing Enterobacterales. A total of 134 individuals (7.9%) had reversion of carrier status: 9.1% (121/1337) and 4.3% (13/305) of individuals with KPC- and NDM-producing Enterobacterales, respectively. The subdistribution hazard ratio of status reversion was not increased among carriers of NDM producers compared with KPC producers (0.567, 95% CI 0.320-1.000], p 0.052). Cause-specific hazard ratios yielded similar results (0.522, 95% CI 0.291-0.937, p 0.029., Conclusions: Carriage of NDM-producing Enterobacterales was not associated with higher rates of reversion to carrier status following spontaneous decolonization than was carriage of KPC-producing Enterobacterales., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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30. Wall painting following terminal cleaning with a chlorine solution as part of an intervention to control an outbreak of carbapenem-resistant Acinetobacter baumannii in a neurosurgical intensive care unit in Israel.
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Dickstein Y, Eluk O, Warman S, Aboalheja W, Alon T, Firan I, Putler RKB, and Hussein K
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- Anti-Bacterial Agents therapeutic use, Carbapenems pharmacology, Carbapenems therapeutic use, Chlorine, Disease Outbreaks, Humans, Intensive Care Units, Israel epidemiology, Acinetobacter Infections drug therapy, Acinetobacter Infections epidemiology, Acinetobacter Infections prevention & control, Acinetobacter baumannii, Cross Infection drug therapy, Cross Infection epidemiology, Cross Infection prevention & control
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Background: To describe the use of wall painting as part of an intervention to control an outbreak of carbapenem-resistant Acinetobacter baumannii (CRAB)., Methods: An interrupted time-series analysis was performed analyzing an intervention in a neurosurgical intensive care unit (NSICU) and an inpatient hematology department in a tertiary level medical center in Israel. The intervention involved wall painting using a water based acrylic paint following patient discharge and terminal cleaning with sodium troclosene as part of an infection control bundle for an outbreak of CRAB in a NSICU and concurrent outbreaks of carbapenem-resistant Enterobacteriaceae (CRE) colonization/infection in the same NSICU and the hematology department., Results: Between January 2013 and December 2018, 122 patients hospitalized in the NSICU were identified with new CRAB colonization/infection. The median incidence in the periods prior to/post intervention were 2.24/1000 HD (interquartile range [IQR] 0.84-2.90/1000) vs. 0/1000 HD (IQR 0-0.49/1000), respectively. Poisson regression indicated a decrease of 92% in the CRAB incidence following the intervention onset (relative risk [RR] 0.080, 95% confidence interval [CI] 0.037-0.174, p < 0.001). Forty-seven patients in the NSICU and 110 in the hematology department were colonized/infected with CRE in the same time period; a significant change was not observed following the start of the intervention in either department (for NSICU RR 1.236, 95% CI 0.370-4.125, p = 0.731; for hematology RR 0.658, 95% CI 0.314-1.378, p = 0.267)., Conclusions: A. baumannii is able to survive on environmental surfaces despite decontamination efforts; wall-painting as part of a bundle may be a successful infection control measure., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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31. Combination versus monotherapy as definitive treatment for Pseudomonas aeruginosa bacteraemia: a multicentre retrospective observational cohort study.
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Babich T, Naucler P, Valik JK, Giske CG, Benito N, Cardona R, Rivera A, Pulcini C, Abdel Fattah M, Haquin J, MacGowan A, Grier S, Gibbs J, Chazan B, Yanovskay A, Ami RB, Landes M, Nesher L, Zaidman-Shimshovitz A, McCarthy K, Paterson DL, Tacconelli E, Buhl M, Mauer S, Rodriguez-Bano J, Morales I, Oliver A, Ruiz de Gopegui E, Cano A, Machuca I, Gozalo-Marguello M, Martinez LM, Gonzalez-Barbera EM, Alfaro IG, Salavert M, Beovic B, Saje A, Mueller-Premru M, Pagani L, Vitrat V, Kofteridis D, Zacharioudaki M, Maraki S, Weissman Y, Paul M, Dickstein Y, Leibovici L, and Yahav D
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- Anti-Bacterial Agents therapeutic use, Cohort Studies, Drug Therapy, Combination, Humans, Pseudomonas aeruginosa, Retrospective Studies, Treatment Outcome, Bacteremia drug therapy, Pseudomonas Infections drug therapy
- Abstract
Background: Pseudomonas aeruginosa bacteraemia is a common and serious infection. No consensus exists regarding whether definitive combination therapy is superior to monotherapy. We aimed to evaluate the impact of combination therapy on mortality., Methods: This was a multicentre retrospective study (nine countries, 25 centres), including 1277 patients with P. aeruginosa bacteraemia during 2009-15. We evaluated the association between β-lactam plus aminoglycoside or quinolone combination therapy versus β-lactam monotherapy and mortality. The primary outcome was 30 day all-cause mortality. Univariate and multivariate Cox regression analyses were conducted, introducing combination as a time-dependent variable. Propensity score was conducted to adjust for confounding for choosing combination therapy over monotherapy., Results: Of 1119 patients included, 843 received definitive monotherapy and 276 received combination therapy (59% aminoglycoside and 41% quinolone). Mortality at 30 days was 16.9% (189/1119) and was similar between combination (45/276; 16.3%) and monotherapy (144/843; 17.1%) groups (P = 0.765). In multivariate Cox regression, combination therapy was not associated with reduced mortality (HR 0.98, 95% CI 0.64-1.53). No advantage in terms of clinical failure, microbiological failure or recurrent/persistent bacteraemia was demonstrated using combination therapy. Likewise, adverse events and resistance development were similar for the two regimens., Conclusions: In this retrospective cohort, no mortality advantage was demonstrated using combination therapy over monotherapy for P. aeruginosa bacteraemia. Combination therapy did not improve clinical or microbiological failure rates, nor affect adverse events or resistance development. Our finding of no benefit with combination therapy needs confirmation in well-designed randomized controlled trials., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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32. BNT162b2 vaccination effectively prevents the rapid rise of SARS-CoV-2 variant B.1.1.7 in high-risk populations in Israel.
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Munitz A, Yechezkel M, Dickstein Y, Yamin D, and Gerlic M
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- Adolescent, Adult, Aged, BNT162 Vaccine immunology, COVID-19 epidemiology, COVID-19 virology, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Israel epidemiology, Male, Middle Aged, RNA, Viral metabolism, Risk Factors, SARS-CoV-2 genetics, Vaccination, Young Adult, BNT162 Vaccine administration & dosage, COVID-19 prevention & control, SARS-CoV-2 isolation & purification, Vaccine Efficacy statistics & numerical data
- Abstract
Since the emergence of the SARS-CoV-2 pandemic, various genetic variants have been described. The B.1.1.7 variant, which emerged in England during December 2020, is associated with increased infectivity. Therefore, its pattern of spread is of great importance. The Israeli government established three national programs: massive RT-PCR testing, focused surveillance in nursing homes, and robust prioritized vaccination with BNT162b2. To define the impact of the aforementioned programs, we analyze data from ∼300,000 RT-PCR samples collected from December 6, 2020, to February 10, 2021. We reveal that the B.1.1.7 is 45% (95% confidence interval [CI]: 20%-60%) more transmissible than the wild-type strain and has become the dominant strain in Israel within 3.5 weeks. Despite the rapid increase in viral spread, focused RT-PCR testing and prioritized vaccination programs are capable of preventing the spread of the B.1.1.7 variant in the elderly. Therefore, proactive surveillance programs, combined with prioritized vaccination, are achievable and can reduce severe illness and subsequent death., Competing Interests: A.M. and M.G. serve as scientific advisors for the Electra-TAU COVID-19 testing laboratory. Y.D. served as the Director of the Electra-TAU COVID-19 testing laboratory until March 31., (© 2021 The Author(s).)
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- 2021
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33. Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity.
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Daitch V, Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, Zusman O, Antoniadou A, Cavezza G, Adler A, Dickstein Y, Pavleas I, Zampino R, Bitterman R, Zayyad H, Koppel F, Zak-Doron Y, Levi I, Babich T, Turjeman A, Ben-Zvi H, Friberg LE, Mouton JW, Theuretzbacher U, and Leibovici L
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- Acinetobacter Infections microbiology, Acinetobacter baumannii isolation & purification, Aged, Carbapenems therapeutic use, Colistin therapeutic use, Female, Greece, Humans, Israel, Italy, Logistic Models, Male, Meropenem therapeutic use, Middle Aged, Randomized Controlled Trials as Topic, Treatment Outcome, Acinetobacter Infections drug therapy, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial
- Abstract
Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study's population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial., Methods: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset., Results: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10-16) vs. 8.5 days (IQR 0-15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14., Conclusion: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice., Trial Registration: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.
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- 2021
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34. Colistin Resistance Development Following Colistin-Meropenem Combination Therapy Versus Colistin Monotherapy in Patients With Infections Caused by Carbapenem-Resistant Organisms.
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Dickstein Y, Lellouche J, Schwartz D, Nutman A, Rakovitsky N, Dishon Benattar Y, Altunin S, Bernardo M, Iossa D, Durante-Mangoni E, Antoniadou A, Skiada A, Deliolanis I, Daikos GL, Daitch V, Yahav D, Leibovici L, Rognås V, Friberg LE, Mouton JW, Paul M, and Carmeli Y
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- Anti-Bacterial Agents therapeutic use, Gram-Negative Bacteria, Humans, Meropenem, Microbial Sensitivity Tests, Carbapenems therapeutic use, Colistin therapeutic use
- Abstract
Background: We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms., Methods: This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E)., Results: Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475-10.184; P = .006)., Conclusions: Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
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- 2020
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35. Reply to Wilson et al.
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Dickstein Y, Leibovici L, Carmeli Y, Daikos G, Durante-Mangoni E, Friberg LE, and Paul M
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- Carbapenems, Humans, Treatment Outcome, Acinetobacter baumannii, Colistin
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- 2020
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36. Utilising sigmoid models to predict the spread of antimicrobial resistance at the country level.
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Fallach N, Dickstein Y, Silberschein E, Turnidge J, Temkin E, Almagor J, and Carmeli Y
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- Datasets as Topic, Humans, Microbial Sensitivity Tests, Models, Theoretical, Predictive Value of Tests, Anti-Bacterial Agents therapeutic use, Bacterial Infections drug therapy, Drug Resistance, Bacterial
- Abstract
BackgroundThe spread of antimicrobial resistance (AMR) is of worldwide concern. Public health policymakers and pharmaceutical companies pursuing antibiotic development require accurate predictions about the future spread of AMR.AimWe aimed to identify and model temporal and geographical patterns of AMR spread and to predict future trends based on a slow, intermediate or rapid rise in resistance.MethodsWe obtained data from five antibiotic resistance surveillance projects spanning the years 1997 to 2015. We aggregated the isolate-level or country-level data by country and year to produce country-bacterium-antibiotic class triads. We fitted both linear and sigmoid models to these triads and chose the one with the better fit. For triads that conformed to a sigmoid model, we classified AMR progression into one of three characterising paces: slow, intermediate or fast, based on the sigmoid slope. Within each pace category, average sigmoid models were calculated and validated.ResultsWe constructed a database with 51,670 country-year-bacterium-antibiotic observations, grouped into 7,440 country-bacterium-antibiotic triads. A total of 1,037 triads (14%) met the inclusion criteria. Of these, 326 (31.4%) followed a sigmoid (logistic) pattern over time. Among 107 triads for which both sigmoid and linear models could be fit, the sigmoid model was a better fit in 84%. The sigmoid model deviated from observed data by a median of 6.5%; the degree of deviation was related to the pace of spread.ConclusionWe present a novel method of describing and predicting the spread of antibiotic-resistant organisms.
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- 2020
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37. Ceftazidime, Carbapenems, or Piperacillin-tazobactam as Single Definitive Therapy for Pseudomonas aeruginosa Bloodstream Infection: A Multisite Retrospective Study.
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Babich T, Naucler P, Valik JK, Giske CG, Benito N, Cardona R, Rivera A, Pulcini C, Abdel Fattah M, Haquin J, Macgowan A, Grier S, Gibbs J, Chazan B, Yanovskay A, Ben Ami R, Landes M, Nesher L, Zaidman-Shimshovitz A, McCarthy K, Paterson DL, Tacconelli E, Buhl M, Mauer S, Rodriguez-Bano J, Morales I, Oliver A, Ruiz De Gopegui E, Cano A, Machuca I, Gozalo-Marguello M, Martinez Martinez L, Gonzalez-Barbera EM, Alfaro IG, Salavert M, Beovic B, Saje A, Mueller-Premru M, Pagani L, Vitrat V, Kofteridis D, Zacharioudaki M, Maraki S, Weissman Y, Paul M, Dickstein Y, Leibovici L, and Yahav D
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- Anti-Bacterial Agents therapeutic use, Carbapenems therapeutic use, Ceftazidime therapeutic use, Humans, Microbial Sensitivity Tests, Penicillanic Acid therapeutic use, Piperacillin therapeutic use, Retrospective Studies, Pseudomonas Infections drug therapy, Pseudomonas aeruginosa
- Abstract
Background: The optimal antibiotic regimen for Pseudomonas aeruginosa bacteremia is controversial. Although β-lactam monotherapy is common, data to guide the choice between antibiotics are scarce. We aimed to compare ceftazidime, carbapenems, and piperacillin-tazobactam as definitive monotherapy., Methods: A multinational retrospective study (9 countries, 25 centers) including 767 hospitalized patients with P. aeruginosa bacteremia treated with β-lactam monotherapy during 2009-2015. The primary outcome was 30-day all-cause mortality. Univariate and multivariate, including propensity-adjusted, analyses were conducted introducing monotherapy type as an independent variable., Results: Thirty-day mortality was 37/213 (17.4%), 42/210 (20%), and 55/344 (16%) in the ceftazidime, carbapenem, and piperacillin-tazobactam groups, respectively. Type of monotherapy was not significantly associated with mortality in either univariate, multivariate, or propensity-adjusted analyses (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.52-2.46, for ceftazidime; OR, 1.3; 95% CI, 0.67-2.51, for piperacillin-tazobactam, with carbapenems as reference in propensity adjusted multivariate analysis; 542 patients). No significant difference between antibiotics was demonstrated for clinical failure, microbiological failure, or adverse events. Isolation of P. aeruginosa with new resistance to antipseudomonal drugs was significantly more frequent with carbapenems (36/206 [17.5%]) versus ceftazidime (25/201 [12.4%]) and piperacillin-tazobactam (28/332 [8.4%] (P = .007)., Conclusions: No significant difference in mortality, clinical, and microbiological outcomes or adverse events was demonstrated between ceftazidime, carbapenems, and piperacillin-tazobactam as definitive treatment of P. aeruginosa bacteremia. Higher rates of resistant P. aeruginosa after patients were treated with carbapenems, along with the general preference for carbapenem-sparing regimens, suggests using ceftazidime or piperacillin-tazobactam for treating susceptible infection., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
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- 2020
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38. Are all vaccines safe for the pregnant traveller? A systematic review and meta-analysis.
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Nasser R, Rakedzon S, Dickstein Y, Mousa A, Solt I, Peterisel N, Feldman T, and Neuberger A
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- Female, Humans, Pregnancy, Travel-Related Illness, Vaccination statistics & numerical data, Travel Medicine statistics & numerical data, Vaccines standards
- Abstract
Pregnant travellers and their offspring are vulnerable to severe outcomes following a wide range of infections. Vaccine-preventable diseases can have a particularly severe course in pregnant women, but little is known about the safety of travel vaccines in pregnant women. We performed a systematic review of all published literature concerning the safety of vaccines frequently given to travellers such as yellow fever, MMR (mumps, measles and rubella), influenza, Tdap (tetanus, diphtheria and pertussis), meningococcus, hepatitis A and B, rabies, polio, typhoid fever, tick-borne encephalitis and Japanese encephalitis vaccines. We included case series, cohort studies and randomized controlled trials (RCTs). For the meta-analysis, we included only RCTs that compared the administration of a vaccine to placebo or to no vaccine. Outcome measures included severe systemic adverse events, maternal outcomes related to the course of pregnancy, neonatal outcomes and local adverse events. We calculated the risk ratio and its 95% confidence interval as the summary measure. The safety of influenza vaccine is supported by high-quality evidence. For Tdap vaccine, no evidence of any harm was found in the meta-analysis of RCTs. A slight increase in chorioamnionitis rate was reported in 3 out of 12 observational studies. However, this small possible risk is far outweighed by a much larger benefit in terms of infant morbidity and mortality. Meningococcal vaccines are probably safe during pregnancy, as supported by RCTs comparing meningococcal vaccines to other vaccines. Data from observational studies support the safety of hepatitis A, hepatitis B and rabies vaccines, as well as that of the live attenuated yellow fever vaccine. We found little or no data about the safety of polio, typhoid, Japanese encephalitis, tick-borne encephalitis and MMR vaccines during pregnancy., (© International Society of Travel Medicine 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
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- 2020
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39. Risk factors for mortality among patients with Pseudomonas aeruginosa bacteraemia: a retrospective multicentre study.
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Babich T, Naucler P, Valik JK, Giske CG, Benito N, Cardona R, Rivera A, Pulcini C, Fattah MA, Haquin J, MacGowan A, Grier S, Chazan B, Yanovskay A, Ami RB, Landes M, Nesher L, Zaidman-Shimshovitz A, McCarthy K, Paterson DL, Tacconelli E, Buhl M, Maurer S, Rodriguez-Bano J, Morales I, Oliver A, de Gopegui ER, Cano A, Machuca I, Gozalo-Marguello M, Martinez-Martinez L, Gonzalez-Barbera EM, Alfaro IG, Salavert M, Beovic B, Saje A, Mueller-Premru M, Pagani L, Vitrat V, Kofteridis D, Zacharioudaki M, Maraki S, Weissman Y, Paul M, Dickstein Y, Leibovici L, and Yahav D
- Subjects
- Aged, Anti-Bacterial Agents therapeutic use, Bacteremia microbiology, Female, Humans, Male, Middle Aged, Pseudomonas Infections microbiology, Retrospective Studies, Risk Factors, Bacteremia mortality, Pseudomonas Infections mortality, Pseudomonas aeruginosa isolation & purification
- Abstract
This study aimed to evaluate risk factors for 30-day mortality among hospitalised patients with Pseudomonas aeruginosa bacteraemia, a highly fatal condition. A retrospective study was conducted between 1 January 2009 and 31 October 2015 in 25 centres (9 countries) including 2396 patients. Univariable and multivariable analyses of risk factors were conducted for the entire cohort and for patients surviving ≥48 h. A propensity score for predictors of appropriate empirical therapy was introduced into the analysis. Of the 2396 patients, 636 (26.5%) died within 30 days. Significant predictors (odds ratio and 95% confidence interval) of mortality in the multivariable analysis included patient-related factors: age (1.02, 1.01-1.03); female sex (1.34, 1.03-1.77); bedridden functional capacity (1.99, 1.24-3.21); recent hospitalisation (1.43, 1.07-1.92); concomitant corticosteroids (1.33, 1.02-1.73); and Charlson comorbidity index (1.05, 1.01-1.93). Infection-related factors were multidrug-resistant Pseudomonas (1.52, 1.15-2.1), non-urinary source (2.44, 1.54-3.85) and Sequential Organ Failure Assessment (SOFA) score (1.27, 1.18-1.36). Inappropriate empirical therapy was not associated with increased mortality (0.81, 0.49-1.33). Among 2135 patients surviving ≥48 h, hospital-acquired infection (1.59, 1.21-2.09), baseline endotracheal tube (1.63, 1.13-2.36) and ICU admission (1.53, 1.02-2.28) were additional risk factors. Risk factors for mortality among patients with P. aeruginosa were mostly irreversible. Early appropriate empirical therapy was not associated with reduced mortality. Further research should be conducted to explore subgroups that may not benefit from broad-spectrum antipseudomonal empirical therapy. Efforts should focus on prevention of infection, mainly hospital-acquired infection and multidrug-resistant pseudomonal infection., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2020
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40. Antibiotic treatment for invasive nonpregnancy-associated listeriosis and mortality: a retrospective cohort study.
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Dickstein Y, Oster Y, Shimon O, Nesher L, Yahav D, Wiener-Well Y, Cohen R, Ben-Ami R, Weinberger M, Rahav G, Maor Y, Chowers M, Nir-Paz R, and Paul M
- Subjects
- Aged, Aged, 80 and over, Drug Therapy, Combination, Female, Humans, Israel epidemiology, Listeria drug effects, Listeria isolation & purification, Listeriosis diagnosis, Listeriosis pathology, Male, Middle Aged, Mortality, Odds Ratio, Retrospective Studies, Ampicillin therapeutic use, Anti-Bacterial Agents therapeutic use, Gentamicins therapeutic use, Listeriosis drug therapy, Listeriosis mortality
- Abstract
Little evidence exists addressing the clinical value of adding gentamicin to ampicillin for invasive listeriosis. A multicenter retrospective observational study of nonpregnant adult patients with invasive listeriosis (primary bacteremia, central nervous system (CNS) disease, and others) in 11 hospitals in Israel between the years 2008 and 2014 was conducted. We evaluated the effect of penicillin-based monotherapy compared with early combination therapy with gentamicin, defined as treatment started within 48 h of culture results and continued for a minimum of 7 days. Patients who died within 48 h of the index culture were excluded. The primary outcome was 30-day all-cause mortality. A total of 190 patients with invasive listeriosis were included. Fifty-nine (30.6%) patients were treated with early combination therapy, 90 (46.6%) received monotherapy, and 44 (22.8%) received other treatments. Overall 30-day mortality was 20.5% (39/190). Factors associated with mortality included lower baseline functional status, congestive heart failure, and higher sequential organ failure assessment score. Source of infection, treatment type, and time from culture taken date to initiation of effective therapy were not associated with mortality. In multivariable analysis, monotherapy was not significantly associated with increased 30-day mortality compared with early combination therapy (OR 1.947, 95% CI 0.691-5.487). Results were similar in patients with CNS disease (OR 3.037, 95% CI 0.574-16.057) and primary bacteremia (OR 2.983, 95% CI 0.575-15.492). In our retrospective cohort, there was no statistically significant association between early combination therapy and 30-day mortality. A randomized controlled trial may be necessary to assess optimal treatment.
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- 2019
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41. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial.
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Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, Neuberger A, Ghanem-Zoubi N, Santoro A, Eliakim-Raz N, Pertzov B, Steinmetz T, Stern A, Dickstein Y, Maroun E, Zayyad H, Bishara J, Alon D, Edel Y, Goldberg E, Venturelli C, Mussini C, Leibovici L, and Paul M
- Subjects
- Aged, Aged, 80 and over, Anti-Bacterial Agents administration & dosage, Duration of Therapy, Female, Humans, Male, Middle Aged, Treatment Outcome, Anti-Bacterial Agents therapeutic use, Bacteremia drug therapy, Bacteremia microbiology, Gram-Negative Bacterial Infections drug therapy, Gram-Negative Bacterial Infections microbiology
- Abstract
Background: Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited., Methods: This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%., Results: We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, -2.6% [95% confidence interval, -10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm., Conclusions: In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention., Clinical Trials Registration: NCT01737320., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
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- 2019
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42. Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial.
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Dickstein Y, Lellouche J, Ben Dalak Amar M, Schwartz D, Nutman A, Daitch V, Yahav D, Leibovici L, Skiada A, Antoniadou A, Daikos GL, Andini R, Zampino R, Durante-Mangoni E, Mouton JW, Friberg LE, Dishon Benattar Y, Bitterman R, Neuberger A, Carmeli Y, and Paul M
- Subjects
- Acinetobacter Infections drug therapy, Acinetobacter baumannii drug effects, Aged, Anti-Bacterial Agents therapeutic use, Carbapenems therapeutic use, Colistin therapeutic use, Data Interpretation, Statistical, Drug Therapy, Combination, Female, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Retrospective Studies, Treatment Outcome, Acinetobacter Infections mortality, Anti-Bacterial Agents pharmacology, Carbapenems pharmacology, Colistin pharmacology, Drug Resistance, Multiple, Bacterial
- Abstract
Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy., Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality., Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202])., Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy., Clinical Trials Registration: NCT01732250., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2019
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43. Antimicrobial use trends, Israel, 2012 to 2017.
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Dickstein Y, Temkin E, Ben-David D, Carmeli Y, and Schwaber MJ
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- Antimicrobial Stewardship trends, Carbapenems, Drug Utilization trends, Humans, Infection Control, Intensive Care Units, Israel, Mandatory Reporting, Retrospective Studies, Anti-Bacterial Agents therapeutic use, Anti-Infective Agents administration & dosage, Antimicrobial Stewardship statistics & numerical data, Communicable Disease Control statistics & numerical data, Drug Utilization statistics & numerical data, Drug Utilization Review methods, Hospitals statistics & numerical data
- Abstract
BackgroundIn 2012, Israel's National Center for Infection Control initiated a national stewardship programme that included mandatory annual reporting of antimicrobial use. Here we present nationwide Israeli data for the period 2012 to 2017.AimThe goal of this study was to detect trends in antimicrobial use in Israel following the introduction of the stewardship programme, as part of an assessment of the programme's impact.MethodsIn this retrospective observational study, data were collected from Israel's health maintenance organisations (HMOs), acute care hospitals and post-acute care hospitals (PACHs). Acute care hospital data were collected for general medical and surgical wards, and medical/surgical intensive care units (ICUs). Data were converted into defined daily doses (DDD), with use rates presented as DDD per 1,000 insured/day in the community and DDD per 100 patient-days in hospitals and PACHs. Trends were analysed using linear regression.ResultsAntimicrobial use decreased across sectors between 2012 and 2017. In the community, the decrease was modest, from 22.8 to 21.8 DDD per 1,000 insured per day (4.4%, p = 0.004). In acute care hospitals, antibiotic DDDs per 100 patient-days decreased from 100.0 to 84.0 (16.0%, p = 0.002) in medical wards, from 112.8 to 94.2 (16.5%, p = 0.004) in surgical wards and from 154.4 to 137.2 (11.1%, p = 0.04) in ICUs. Antimicrobial use decreased most markedly in PACHs, from 29.1 to 18.1 DDD per 100 patient-days (37.8%, p = 0.005).ConclusionBetween 2012 and 2017, antimicrobial use decreased significantly in all types of healthcare institutions in Israel, following the introduction of the nationwide antimicrobial stewardship programme.
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- 2019
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44. Trends in antimicrobial resistance in Israel, 2014-2017.
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Dickstein Y, Temkin E, Ish Shalom M, Schwartz D, Carmeli Y, and Schwaber MJ
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- Anti-Bacterial Agents therapeutic use, Bacteremia drug therapy, Epidemiological Monitoring, Escherichia coli drug effects, Escherichia coli Infections drug therapy, Escherichia coli Infections epidemiology, Humans, Israel epidemiology, Klebsiella Infections drug therapy, Klebsiella Infections epidemiology, Klebsiella pneumoniae drug effects, Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests, Staphylococcal Infections drug therapy, Staphylococcal Infections epidemiology, Vancomycin-Resistant Enterococci drug effects, Anti-Bacterial Agents pharmacology, Bacteremia epidemiology, Bacteremia microbiology, Bacteria drug effects, Drug Resistance, Multiple, Bacterial
- Abstract
We analyzed Israeli national data on antimicrobial susceptibility from bloodstream isolates collected between 2014 and 2017 and compared resistance proportions with those of Europe. The incidence of bloodstream infection (BSI) caused by most antibiotic-resistant organisms remained unchanged or decreased. An exception was increased incidence of BSI caused by third-generation cephalosporin-resistant Escherichia coli . Overall, resistance proportions were similar to those observed in southern Europe, with the exception of a lower proportion of carbapenem-resistant Klebsiella pneumoniae in Israel., Competing Interests: Competing interestsThe authors declare that they have no competing interests.
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- 2019
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45. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial.
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Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, Zusman O, Antoniadou A, Pafundi PC, Adler A, Dickstein Y, Pavleas I, Zampino R, Daitch V, Bitterman R, Zayyad H, Koppel F, Levi I, Babich T, Friberg LE, Mouton JW, Theuretzbacher U, and Leibovici L
- Subjects
- Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents pharmacology, Drug Therapy, Combination methods, Female, Gram-Negative Bacteria classification, Gram-Negative Bacteria isolation & purification, Gram-Negative Bacterial Infections microbiology, Greece, Humans, Israel, Italy, Male, Middle Aged, Single-Blind Method, Treatment Outcome, Anti-Bacterial Agents administration & dosage, Colistin administration & dosage, Gram-Negative Bacteria drug effects, Gram-Negative Bacterial Infections drug therapy, Meropenem administration & dosage, beta-Lactam Resistance
- Abstract
Background: Colistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria., Methods: A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual., Findings: Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference -5·7%, 95% CI -13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83-1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87-1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury)., Interpretation: Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria., Funding: EU AIDA grant Health-F3-2011-278348., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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46. Anti-thyroid antibodies, parietal cell antibodies and tissue transglutaminase antibodies in patients with autoimmune thyroid disease.
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Twito O, Shapiro Y, Golan-Cohen A, Dickstein Y, Ness-Abramof R, and Shapiro M
- Abstract
Introduction: The co-existence of tissue-specific autoantibodies in autoimmune thyroid disease (ATD) is well established. The published prevalence of anti-parietal cell antibodies (PC-Ab) is 20-25%, and that of celiac antibodies is 2-5%. The goal of this study was to determine the prevalence of PC-Ab and anti-tissue transglutaminase antibodies (tTG-Ab) in patients with ATD and to evaluate the correlation between anti-thyroid antibodies and the other antibodies., Material and Methods: The files of 120 Israeli Jews and Arabs with ATD were evaluated for anti-thyroglobulin antibodies (Tg-Ab), anti-thyroid peroxidase antibodies (TPO-Ab), PC-Ab and tTG-Ab. For patients with positive PC-Ab and/or tTG-Ab, upper gastrointestinal (GI) endoscopy results were recorded. Gastrin levels were collected in patients with positive PC-Ab., Results: Twelve (10%) males and 108 (90%) females were evaluated, of whom 93.33% had Hashimoto's thyroiditis. Thirty-four (28.3%) subjects had positive PC-Ab. This rate was not affected by gender, ethnicity or thyroid disease. Abnormal gastroscopy findings were documented in 95.2% of the upper GI endoscopies. The mean gastrin level in this subgroup was 660.4 pg/ml. Five of 114 tTG-Ab tests were positive (4.4%). All were females with Hashimoto's thyroiditis. Rates were equal among Jews and Arabs. Higher TPO-Ab levels were associated with higher risk for PC-Ab positivity ( p = 0.027), but not tTG-positivity. Higher Tg-Ab levels were not associated with higher levels of other antibodies., Conclusions: Considering the frequency of PC-Ab and tTG-Ab positivity in ATD, checking for the presence of these two entities should be an integral part of the workup of this disease.
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- 2018
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47. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.
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Beyar-Katz O, Dickstein Y, Borok S, Vidal L, Leibovici L, and Paul M
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- Anti-Bacterial Agents adverse effects, Febrile Neutropenia mortality, Glycopeptides adverse effects, Glycopeptides therapeutic use, Gram-Positive Bacterial Infections mortality, Humans, Randomized Controlled Trials as Topic, Treatment Failure, Anti-Bacterial Agents therapeutic use, Febrile Neutropenia drug therapy, Gram-Positive Bacterial Infections drug therapy, Neoplasms complications
- Abstract
Background: The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram-positive infections. Some of these gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment., Objectives: To assess the effectiveness of empirical anti-gram-positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment., Search Methods: For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials., Selection Criteria: Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer., Data Collection and Analysis: Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I
2 > 50%). Outcomes were extracted by intention-to-treat and the analysis was patient-based whenever possible., Main Results: Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate-quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low-quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low-quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram-positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram-positive superinfections. Resistant colonisation was not documented in the studies., Authors' Conclusions: Based on very low- or low-quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.- Published
- 2017
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48. Microbiota manipulation for weight change.
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Dror T, Dickstein Y, Dubourg G, and Paul M
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- Adolescent, Adult, Anti-Bacterial Agents therapeutic use, Azithromycin administration & dosage, Azithromycin pharmacology, Bronchiectasis drug therapy, Child, Child, Preschool, Humans, Infant, Lactobacillus, Lung Diseases drug therapy, Meta-Analysis as Topic, Placebo Effect, Prebiotics, Probiotics therapeutic use, Randomized Controlled Trials as Topic, Synbiotics, Gastrointestinal Microbiome drug effects, Obesity microbiology, Weight Gain, Weight Loss
- Abstract
Manipulation of the intestinal microbiota has been linked to weight changes and obesity. To explore the influence of specific agents that alter the intestinal flora on weight in different patient groups we conducted a meta-analysis of randomized controlled trials (RCTs) reporting on the effects of probiotics, prebiotics, synbiotics, and antibiotics on weight. We searched the Pubmed and Cochrane Library databases for trials on adults, children, and infants evaluating the effects of these substances on weight. Our primary outcome was weight change from baseline. Standardized mean differences (SMDs) with 95% confidence intervals were calculated. We identified and included 13 adult, 17 children, and 23 infant RCTs. Effects were opposite among adults and children, showing weight loss among adults (SMD -0.54 [-0.83, -0.25)) and minor weight gains among children (SMD 0.20 [0.04, 0.36]) and infants (SMD 0.30 [-0.01, 0.62]) taking mainly Lactobacillus probiotic supplements. Heterogeneity was substantial in the adult and infant analyses and could not be explained by intervention or patient characteristics. Azithromycin administration in children with pulmonary disease was associated with weight gain (SMD 0.39 [0.24, 0.54]), without heterogeneity. A high risk of selective reporting and attrition bias was detected across the studies, making it difficult to draw firm conclusions. Overall, our meta-analysis suggests that there may be a role for probiotics in promoting weight loss in adults and weight gain in children, however additional studies are needed. Though we cannot recommend antibiotic administration for weight manipulation, its use provides advantageous weight gain in children with cystic fibrosis and bronchiectasis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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49. Predicting Antibiotic Resistance in Urinary Tract Infection Patients with Prior Urine Cultures.
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Dickstein Y, Geffen Y, Andreassen S, Leibovici L, and Paul M
- Subjects
- Aged, Carbapenems therapeutic use, Ciprofloxacin therapeutic use, Enterobacteriaceae drug effects, Enterobacteriaceae metabolism, Enterobacteriaceae Infections drug therapy, Enterobacteriaceae Infections microbiology, Female, Humans, Male, Retrospective Studies, beta-Lactamases metabolism, Anti-Bacterial Agents therapeutic use, Drug Resistance, Multiple, Bacterial drug effects, Urinary Tract Infections drug therapy, Urinary Tract Infections microbiology, Urine microbiology
- Abstract
To improve antibiotic prescribing, we sought to establish the probability of a resistant organism in urine culture given a previous resistant culture in a setting endemic for multidrug-resistant (MDR) organisms. We performed a retrospective analysis of inpatients with paired positive urine cultures. We focused on ciprofloxacin-resistant (cipro(r)) Gram-negative bacteria, extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and carbapenem-resistant nonfermenters (CRNF). Comparisons were made between the frequency of each resistance phenotype following a previous culture with the same phenotype and the overall frequency of that phenotype, and odds ratios (ORs) were calculated. We performed a regression to assess the effects of other variables on the likelihood of a repeat resistant culture. A total of 4,409 patients (52.5% women; median age, 70 years) with 19,546 paired positive urine cultures were analyzed. The frequencies of cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF among all cultures were 47.7%, 30.6%, 1.7%, and 2.6%, respectively. ORs for repeated resistance phenotypes were 1.87, 3.19, 48.25, and 19.02 for cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF, respectively (P < 0.001 for all). At 1 month, the frequencies of repeated resistance phenotypes were 77.4%, 66.4%, 57.1%, and 33.3% for cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF, respectively. Increasing time between cultures and the presence of an intervening nonresistant culture significantly reduced the chances of a repeat resistant culture. Associations were statistically significant over the duration of follow-up (60 months) for CRE and for up to 6 months for all other pathogens. Knowledge of microbiology results in the six preceding months may assist with antibiotic stewardship and improve the appropriateness of empirical treatment for urinary tract infections (UTIs)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
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50. Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol.
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Dickstein Y, Leibovici L, Yahav D, Eliakim-Raz N, Daikos GL, Skiada A, Antoniadou A, Carmeli Y, Nutman A, Levi I, Adler A, Durante-Mangoni E, Andini R, Cavezza G, Mouton JW, Wijma RA, Theuretzbacher U, Friberg LE, Kristoffersson AN, Zusman O, Koppel F, Dishon Benattar Y, Altunin S, and Paul M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents pharmacokinetics, Colistin pharmacokinetics, Drug Resistance, Multiple, Bacterial, Female, Gram-Negative Bacteria drug effects, Greece, Humans, Israel, Italy, Male, Meropenem, Microbial Sensitivity Tests, Middle Aged, Research Design, Thienamycins pharmacokinetics, Treatment Outcome, Young Adult, Anti-Bacterial Agents therapeutic use, Bacteremia drug therapy, Colistin therapeutic use, Pneumonia, Ventilator-Associated drug therapy, Thienamycins therapeutic use, Urinary Tract Infections drug therapy
- Abstract
Introduction: The emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem. A randomised controlled study is necessary for clarification., Methods and Analysis: This is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin-meropenem combination therapy for infections caused by carbapenem-resistant Gram-negative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel). We include patients with hospital-associated and ventilator-associated pneumonia, bloodstream infections and urosepsis. The primary outcome is treatment success at day 14, defined as survival, haemodynamic stability, stable or improved respiratory status for patients with pneumonia, microbiological cure for patients with bacteraemia and stability or improvement of the Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes include 14-day and 28-day mortality as well as other clinical end points and safety outcomes. A sample size of 360 patients was calculated on the basis of an absolute improvement in clinical success of 15% with combination therapy. Outcomes will be assessed by intention to treat. Serum colistin samples are obtained from all patients to obtain population pharmacokinetic models. Microbiological sampling includes weekly surveillance samples with analysis of resistance mechanisms and synergy. An observational trial is evaluating patients who met eligibility requirements but were not randomised in order to assess generalisability of findings., Ethics and Dissemination: The study was approved by ethics committees at each centre and informed consent will be obtained for all patients. The trial is being performed under the auspices of an independent data and safety monitoring committee and is included in a broad dissemination strategy regarding revival of old antibiotics., Trial Registration Number: NCT01732250 and 2012-004819-31; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
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