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New Treatment Options for XDR Acinetobacter

In my mind, multi drug resistant Acinetobacter is the greatest unmet need in antibiotic therapy today. The new β-lactam/β-lactamase inhibitor combinations such as ceftazidime/avibactam and meropenem/vaborbactam do not offer good options against MDR Acinetobacter . Plazomicin, the new aminoglycosides, also does not offer anything as a treatment for Acinetobacter . Here is a brief review of some of the options under development for carbapenem resistant Acinetobacter . Cefiderocol The one new drug close to availability which does have anti- Acinetobacter activity is cefiderocol. Cefiderocol, a siderophore cephalosporin, has been used successfully for UTI but we have no reports yet of its clinical use against Acinetobacter. However, in vitro, it appears to be highly active. In a poster at ID Week 2017, cefiderocol was active against 89% of a set of well characterised strains from the CDC. Not perfect, but certainly an advance on our current armamentarium. It is currently in phase
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The death of colistin for KPC producers - part 4

This week there are 2 pieces of news on treatment of KPC producers. Taken together with a previous single-center observational study and two RCTs, all of which showed inferiority of colistin based regimens, I feel we can safely sound the death knell for polymyxins as treatment of KPC producers. Clinical Infectious Diseases has just released advance access on a multicenter evaluation of outcomes for KPC producers treated with either ceftazidime-avibactam or colistin . The article can be found here: https://academic.oup.com/cid/article-abstract/doi/10.1093/cid/cix783/4103289/Colistin-vs-Ceftazidime-avibactam-in-the-Treatment?redirectedFrom=fulltext This study evaluated outcomes of 137 patients in the CRACKLE study, sponsored by the NIH via the Antibiotic Resistance Leadership Group. The execution of this study required a huge amount of effort and lead author, David van Duin, deserves credit for getting this study done. Of the 137 patients with KPC producers, 63 (46%) had bloodst
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The death of polymyxins for KPC producers - parts 2 and 3

I recently posted news from Pittsburgh in which outcomes for patients with KPC producers treated with ceftazidime-avibactam were superior to those in which polymyxins were used. This data was observational, not from an RCT, and so requires confirmation from larger, better designed studies. This week, results from the TANGO-2 study, were released in which a randomized trial comparing meropenem-vaborbactam with "best available therapy" (BAT) was stopped early by its DSMB because of the risk to patients in the BAT arm. The press release describing these results can be found here: http://www.themedicinescompany.com/investors/news/medicines-company-announces-tango-2-trial-meropenem-vaborbactam-formerly-carbavance Only 72 patients were enrolled, of which 43 had CRE infections. Clinical cure was significantly higher in patients treated with meropenem-vaborbactam. These patients also had lower mortality and lower rates of renal adverse events. This data has not yet been pu
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Ceftazidime-avibactam combined with aztreonam successful for NDM producers

NDM is a metallo-beta-lactamase and provides a bigger treatment challenge than KPC. This is because avibactam (and vaborbactam and relebactam) does not inhibit it. Therefore, NDM producers are resistant to ceftazidime-avibactam. However, avibactam may still play a role in the treatment of infections with NDM producers. This is when it is combined with aztreonam. Aztreonam is a curious antibiotic because it is not inactivated by NDM. However, most NDM producing bacteria produce other beta-lactamases as well, some of which will inactivate aztreonam. So aztreonam alone will rarely be a useful option for NDM producers. Several years ago, David Livermore from the UK, hypothesized that combining avibactam with aztreonam would provide a useful treatment option for NDM producers. This is because the avibactam will inactivate all of the "other" beta-lactamases, allowing aztreonam to kill the bacteria because it is not destroyed by NDM. Development of the aztreonam-avibactam com
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Vancomycin plus a beta-lactam for MRSA - what a weird idea!

MRSA is a killer but luckily we are seeing less of it in hospitals than we used to. Treatment of MRSA has been turned on its head with the advent of antibiotics like daptomycin and linezolid. But my guess is that we still turn to vancomycin in many situations, including MRSA bloodstream infections. Counterintuitively, adding an antistaphylococcal beta-lactam (eg, flucloxacillin or nafcillin) to vancomycin is synergistic in both in vitro and animal models. Could this add to vancomycin's effectiveness in patients? A pilot study ("CAMERA"), published in CID, showed that the mean duration of MRSA bacteremia was 3.0 days in patients assigned to vancomycin monotherapy and 1.94 days in those given vancomycin plus flucloxacillin. These findings can be found here: Combination of Vancomycin and β-Lactam Therapy for  Methicillin-Resistant Staphylococcus aureus  Bacteremia: A Pilot Multicenter Randomized Controlled Trial. Davis JS, Sud A, O'Sullivan MVN, Robinson JO,
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The death of polymyxins for KPC - part 1

Is there still a role for colistin or polymyxin B in the treatment of KPC producers? There is a plethora of articles examining treatment of KPC producers. Most now conclude that a combination of a polymyxin with other antibiotics is more effective than use of a polymyxin alone. Based on a single center experience, recently made available online by Antimicrobial Agents and Chemotherapy , the place of polymyxins as firstline therapy for KPC producers is looking very doubtful . This article looked at treatment of bloodstream infection due to carbapenem resistant Klebsiella pneumoniae at the University of Pittsburgh Medical Center. Importantly, it was observational, not a RCT. Clinical success was defined at 30 days as survival, resolution of signs and symptoms of infection, sterilization of blood cultures within 7 days of treatment initiation, and absence of recurrent infections. A good choice of endpoints. 85% (11/13) patients treated with ceftazidime-avibactam had clinical succes
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Reflections on speeches by Nobel Prize winners - Bob Dylan to Alexander Fleming to BLING-3

The Nobel Prize website is full of absolute gems. In addition to a searchable list of "who won" and "what for", it also has bios of the winners, a listing of who nominated them and PDFs of both their Nobel lecture and their banquet speech. Bob Dylan's fabulous speech is found here: https://www.nobelprize.org/nobel_prizes/literature/laureates/2016/dylan-lecture.html Moving back to ID, Sir Alexander Fleming's Nobel lecture can be found here: https://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.pdf For those of you who are microbiologists, it is interesting to learn that Fleming used his newly discovered penicillin as a selective agent in culture medium to isolate Bordetella pertussis and "Pfeiffer's influenza bacillus" (presumably H. influenzae ) from respiratory samples. Famously Fleming delivered an important message to those of us who are antibiotic stewards or interested in antibiotic dosing: "I
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