| 1. |
- Dickstein, Yaakov, et al.
(author)
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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
- 2016
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In: BMJ Open. - : BMJ. - 2044-6055. ; 6:4
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Journal article (peer-reviewed)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.
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| 2. |
- Dickstein, Yaakov, et al.
(author)
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Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections : An Exploratory Subgroup Analysis of a Randomized Clinical Trial
- 2019
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In: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 69:5, s. 769-776
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Journal article (peer-reviewed)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.
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| 3. |
- Nation, Roger L, et al.
(author)
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Framework for optimisation of the clinical use of colistin and polymyxin B : the Prato polymyxin consensus
- 2015
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In: The Lancet - Infectious diseases. - 1473-3099 .- 1474-4457. ; 15:2, s. 225-234
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Research review (peer-reviewed)abstract
- In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.
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| 4. |
- Paul, Mical, et al.
(author)
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Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria : an open-label, randomised controlled trial
- 2018
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In: The Lancet - Infectious diseases. - : ELSEVIER SCI LTD. - 1473-3099 .- 1474-4457. ; 18:4, s. 391-400
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Journal article (peer-reviewed)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 45 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.
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| 5. |
- Pulcini, Celine, et al.
(author)
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Forgotten antibiotics : a follow-up inventory study in Europe, the USA, Canada and Australia
- 2017
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In: International Journal of Antimicrobial Agents. - : ELSEVIER SCIENCE BV. - 0924-8579 .- 1872-7913. ; 49:1, s. 98-101
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Journal article (peer-reviewed)abstract
- The objective of this study was to update a 2011 survey, conducted on behalf of the ESCMID Study Group for Antibiotic Policies (ESGAP), studying the availability of old but clinically useful antibiotics in North America, Europe and Australia. This follow-up survey was performed in 2015 in 40 countries among specialists from the pharmaceutical, infectious diseases and microbiology sectors in North America, Europe and Australia in order to assess the availability through usual marketing processes of 36 systemic antibiotics (addition of 3 antibiotics compared with the 2011 survey) selected for their ability to treat infections caused by resistant bacteria and their unique value for specific criteria. The questionnaire was sent by e-mail to national contacts belonging to ESGAP and ReAct networks. In all, 39 of the 40 countries participated in this survey. The number of available antibiotics differed considerably from one drug to another as well as from one country to another (e.g. 7 antibiotics available in Estonia, 24 in France). Overall, 25/36 selected antibiotics were marketed in 20/39 countries or less. From 2011 to 2015 (data available for both periods in 37 countries for 33 antibiotics), the number of available selected antibiotics increased in 13 countries and decreased in 17. In conclusion, despite the ongoing bacterial resistance crisis, the situation regarding the availability of 'forgotten antibiotics' has worsened since 2011. Urgent measures are needed to ensure better availability of these antibiotics on a global scale as a conservation measure to ensure sustainable and responsible use of antibiotics. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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| 6. |
- Theuretzbacher, Ursula, et al.
(author)
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In Memoriam : William A. Craig
- 2015
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In: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 59:6, s. 2971-2971
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Journal article (other academic/artistic)
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| 7. |
- Theuretzbacher, Ursula, et al.
(author)
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Reviving old antibiotics
- 2015
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In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 70:8, s. 2177-2181
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Journal article (peer-reviewed)abstract
- In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to 're-develop' these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today's standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance. This paper describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.
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| 8. |
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| 9. |
- Årdal, Christine, et al.
(author)
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Insights into early stage of antibiotic development in small- and medium-sized enterprises : a survey of targets, costs, and durations
- 2018
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In: Journal of Pharmaceutical Policy and Practice. - : Springer Nature. - 2052-3211. ; 11:1
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Journal article (peer-reviewed)abstract
- Background Antibiotic innovation has dwindled to dangerously low levels in the past 30 years. Since resistance continues to evolve, this innovation deficit can have perilous consequences on patients. A number of new incentives have been suggested to stimulate greater antibacterial drug innovation. To design effective solutions, a greater understanding is needed of actual antibiotic discovery and development costs and timelines. Small and medium-sized enterprises (SMEs) undertake most discovery and early phase development for antibiotics and other drugs. This paper attempts to gather a better understanding of SMEs’ targets, costs, and durations related to discovery and early phase development of antibacterial therapies.Methods DRIVE-AB, a project focused on developing new economic incentives to stimulate antibacterial innovation, held a European stakeholder meeting in February 2015. All SMEs invited to this meeting (n = 44) were subsequently sent a survey to gather more data regarding their areas of activity, completed and expected development costs and timelines, and business models.Results Twenty-five companies responded to the survey. Respondents were primarily small companies each focusing on developing 1 to 3 new antibiotics, focused on pathogens of public health importance. Most have not yet completed any clinical trials. They have reported ranges of discovery and development out-of-pocket costs that appear to be less expensive than other studies of general pharmaceutical research and development (R&D) costs. The duration ranges reported for completing each phase of R&D are highly variable when compared to previously published general pharmaceutical innovation average durations. However, our sample population is small and may not be fully representative of all relevant antibiotic SMEs.Conclusions The data collected by this study provide important insights and estimates about R&D in European SMEs focusing on antibiotics, which can be combined with other data to design incentives to stimulate antibacterial innovation. The variation implies that costs and durations are difficult to generalize due to the unique characteristics of each antibiotic project and depend on individual business strategies and circumstances.
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