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Highlights from the 27th ECCMID
Newsdesk
Highlights from the 27th ECCMID The European Congress of Clinical Microbiology and Infectious Diseases was held this year in Vienna, Austria. John McConnell and Onisillos Sekkides report on the meeting highlights. Adjunctive rifampicin
ECCMID 2017 was held on April 22–25. Abstracts and presentations are available at http://www.eccmidlive.org/
586
A late-breaker session on findings from clinical trials included a presentation by Guy Thwaites (Oxford University, UK) on the results of the just-completed ARREST trial. This randomised, blinded trial was designed to test whether addition of rifampicin to standard antibiotic therapy would reduce mortality from Staphylococcus aureus bacteraemia. From December 2012 to October 2016, 770 adult patients with S aureus bacteraemia in 29 UK hospitals were randomised one to one to receive 2 weeks of rifampicin or placebo, plus standard antibiotic therapy in all patients. The primary endpoint was bacteriological failure or recurrence of infection or death from all causes up to 12 weeks from randomisation. 758 patients were included in the analysis, 388 allocated to placebo and 370 to rifampicin. The background antibiotics most often given included flucloxacillin and a glycopeptide. Almost two-thirds of bacteraemias were community acquired and about 7% were caused by meticillin-resistant S aureus. Detailed results of the randomised comparison are still being analysed. However, there was no overall significant effect of the intervention on the primary endpoint (62 events in rifampicin group vs 71 in placebo group; difference –1·4% [95% CI –7·1% to 4·2%]; HR 0·96 [95% CI 0·68 to 1·34], p=0·80) or on any of the prespecified secondary endpoints, although in post-hoc analysis there was a small but significant reduction in disease recurrence. There were significantly more antibiotic-modifying adverse events and more drug interactions reported with rifampicin than with placebo, although only two patients developed rifampicinresistant S aureus bacteraemia. The
preliminary findings of this trial appear to settle the debate over whether rifampicin is a useful adjunctive treatment in S aureus bacteraemia.
Oral vs intravenous antibiotics for bone and joint infections
Matthew Scarborough (Oxford University Hospitals, UK) presented the results of another trial that challenged established dogma. The OVIVA randomised, open-label, non-inferiority trial tested whether intravenous antibiotics have an advantage over oral for treatment of bone and joint infections. Adults presenting with bone, joint, or orthopaedic metalware-associated infections were randomised to either oral or intravenous antibiotics for the first 6 weeks of treatment. An infection specialist made the choice of antibiotic. The primary endpoint was treatment failure within 1 year of randomisation. 527 patients were randomised to each intervention across 26 UK sites. In the modified intention-to-treat analysis, oral therapy was non-inferior to intravenous for the primary endpoint. An associated cost analysis showed that oral treatment was £2740 per patient cheaper than intravenous. For early treatment of bone and joint infections, oral antibiotics are the equal of intravenous, and much cheaper.
Preventing and treating Clostridium difficile
Clostridium difficile infection (CDI) occurs during antibiotic treatment because antibiotics excreted into the gut disrupt the microbiome, allowing C difficile to proliferate. John KokaiKun (Synthetic Biologics, Bethesda, MD, USA) reported a phase 2 trial with the drug ribaxamase (SYN-004),
which is an oral β-lactamase that remains localised in the gut and is designed to degrade β-lactam antibiotics before they can reach the colon. The primary endpoint of the double-blind, placebo controlled trial was prevention of CDI (defined as diarrhoea plus presence of C difficile toxin), monitored for 6 weeks. Changes in the gut microbiome were also monitored. Patients were eligible if admitted to hospital for treatment of lower respiratory tract infection and expected to receive 5 or more days of intravenous ceftriaxone (a β-lactam antibiotic). Eligible patients were randomised one to one to receive either ribaxamase or placebo during ceftriaxone treatment and for 72 h after. The modified intention to treat population included 412 patients. Compared with the placebo group, ribaxamase-treated patients had a significant 71% relative risk reduction in CDI (p=0·045), plus a 44% relative risk reduction in new colonisation by vancomycin-resistant enterococci. Ribaxamase was also protective against dysbiosis of the gut microbiome. Synthetic Biologics is preparing a protocol for a phase 3 trial of ribaxamase. Michael Trucksis (Seres Therapeutics, Cambridge, MA, USA) presented a double-blind phase 2 trial of SER-109, which is a collection of bacterial spores purified from donor stool and intended to restore the gut microbiome after antibiotic treatment. The 89 enrolled patients with a history of recurrent CDI were randomised two to one to SER-109 or placebo, and recurrent CDI up to 8 weeks after treatment was recorded. There was no significant difference between groups for the primary endpoint of recurrence. Posthoc analysis suggested that an increase in dose of SER-109 may be necessary. www.thelancet.com/infection Vol 16 June 2017
Newsdesk
Plasmid-borne resistance
Roberto Melano (University of Toronto, Toronto, ON, Canada) explored the evidence for conjugative plasmids in the nosocomial spread of antimicrobial resistance in Gramnegatives organisms. The spread of resistant organisms is well documented; however, Melano pointed out that it is now evident that there is an added complication. For example, MCR1-carrying organisms identified in hospitals across the Americas were found to be unrelated. Therefore, the resistance plasmid seemed readily transmissible, raising the potential of so-called plasmid outbreaks with indistinguishable (or highly related) plasmids present in unrelated bacterial strains and species in the same patient. Amy Mathers (University of Virginia, Charlottesville, VA, USA) went on to detail horizontal transfer of antimicrobial resistance in patients and the environment. She described the finding that high plasmid diversity had been observed despite the initial impression of a conserved plasmid being transferred. This implied that plasmid transfer involved multiple mechanisms, complicating the identification of the environmental reservoirs harbouring the plasmid-carrying organisms. Ultimately, the source of the contamination was traced to sinks and tackled through conventional infection control measures. However, this investigation revealed that plasmid exchange in the environment is much more complicated than commonly thought, particularly because the resistant organism in question seemed strangely receptive to gene transfer.
Heater–cooler units
Daniel Diekema (University of Iowa, Iowa City, IA, USA) outlined the epidemiology of heater–cooler linked outbreaks. He began by highlighting that unless sterile these units pose a significant contamination risk to theatres. One complication is www.thelancet.com/infection Vol 16 June 2017
that manufacturer guidelines are insufficient for dealing with some contaminants. The issue is further compounded by the finding that the units of one particular manufacturer were contaminated with mycobacteria over the past 8–10 years. Which seems to have resulted in disseminated infection in patients in receipt of implants. The contaminating mycobacteria proved to be very resistant to disinfectants and their biofilms made them more so. Diekema advised that in surgical patients with unexplained symptoms, mycobacterial infection should be suspected if the relevant brand of unit was used. He added that the best way to accommodate these units is to direct their exhaust outside the theatre.
Vaccine research late-breakers
Several studies were outlined at the news in vaccine research late-breakers session. The first presentation was given by Germaine Hanquet (EpiConcept, Paris, France) on the indirect effect of childhood pneumococcal vaccination on invasive disease in elderly Europeans. She explained that although the herd effects of 5 years of infant vaccination seems to have led to decline in disease in elderly people due to vaccine serotypes, there also seems to be a correlation with increases in nonvaccine serotype disease in this same population. Therefore, there is little benefit in extending the use of the current vaccines to elderly people. Next Morven Wilkie (University of Oxford, Oxford, UK) described a study exploring if the non-specific effects of BCG vaccination in healthy UK adults had the potential to promote innate immunity against four common bacterial pathogens. Assessment was by growth inhibition assay; however, no effect was evident. Daniel Silman (University of Oxford, Oxford, UK) presented the initial assessment of a novel malaria vaccine candidate: R21 adjuvanted with Matrix-M. He explained that R21 is an improved
RTS,S like vaccine consisting of the pre-erythrocytic circumsporozoite protein. Matrix-M is a new saponinbased adjuvant. The findings were sufficiently promising to justify progress to a phase 2a challenge study to assess vaccine efficacy.
MDR tuberculosis
Christoph Lange (University of Lübeck, Lübeck, Germany) provided an overview of advances in the clinical management of multidrug-resistant (MDR) tuberculosis. He began with the somewhat arresting statement that despite the aim of the endTB strategy to eliminate tuberculosis by 2035, recent increases in cases make this is very unlikely. Similarly, he pointed out that there are more people living with tuberculosis today than at any time in history. On the topic of management, Lange stressed that whole-genome sequencing was a preferable diagnostic method over Xpert MTB/ RIF because it gave a clearer picture and accounted for resistance beyond rifampicin. And the more detailed view provided by whole-genome sequencing meant rifampicin could still be a viable treatment option for some cases of MDR tuberculosis. The crucial factor was the type of resistance mutation. Lange recommended the diagnostic and treatment approach outlined by Horsburgh and colleagues (N Engl J Med 2015; 373: 2149–60). He then moved to more general issues with regard to the management of tuberculosis, explaining that the significant problems raised by the prolonged treatment of tuberculosis (ie, compliance etc) were largely because there was a lack of biomarkers and thus uncertainty about when treatment could be discontinued. The relevance of prolonged treatment to MDR tuberculosis is the high cost of the regimen, so shortening treatment would allow for cost savings that could make newer drugs such as bedaquiline more viable options.
John McConnell, Onisillos Sekkides 587
Highlights from the 27th ECCMID The European Congress of Clinical Microbiology and Infectious Diseases was held this year in Vienna, Austria. John McConnell and Onisillos Sekkides report on the meeting highlights. Adjunctive rifampicin
ECCMID 2017 was held on April 22–25. Abstracts and presentations are available at http://www.eccmidlive.org/
586
A late-breaker session on findings from clinical trials included a presentation by Guy Thwaites (Oxford University, UK) on the results of the just-completed ARREST trial. This randomised, blinded trial was designed to test whether addition of rifampicin to standard antibiotic therapy would reduce mortality from Staphylococcus aureus bacteraemia. From December 2012 to October 2016, 770 adult patients with S aureus bacteraemia in 29 UK hospitals were randomised one to one to receive 2 weeks of rifampicin or placebo, plus standard antibiotic therapy in all patients. The primary endpoint was bacteriological failure or recurrence of infection or death from all causes up to 12 weeks from randomisation. 758 patients were included in the analysis, 388 allocated to placebo and 370 to rifampicin. The background antibiotics most often given included flucloxacillin and a glycopeptide. Almost two-thirds of bacteraemias were community acquired and about 7% were caused by meticillin-resistant S aureus. Detailed results of the randomised comparison are still being analysed. However, there was no overall significant effect of the intervention on the primary endpoint (62 events in rifampicin group vs 71 in placebo group; difference –1·4% [95% CI –7·1% to 4·2%]; HR 0·96 [95% CI 0·68 to 1·34], p=0·80) or on any of the prespecified secondary endpoints, although in post-hoc analysis there was a small but significant reduction in disease recurrence. There were significantly more antibiotic-modifying adverse events and more drug interactions reported with rifampicin than with placebo, although only two patients developed rifampicinresistant S aureus bacteraemia. The
preliminary findings of this trial appear to settle the debate over whether rifampicin is a useful adjunctive treatment in S aureus bacteraemia.
Oral vs intravenous antibiotics for bone and joint infections
Matthew Scarborough (Oxford University Hospitals, UK) presented the results of another trial that challenged established dogma. The OVIVA randomised, open-label, non-inferiority trial tested whether intravenous antibiotics have an advantage over oral for treatment of bone and joint infections. Adults presenting with bone, joint, or orthopaedic metalware-associated infections were randomised to either oral or intravenous antibiotics for the first 6 weeks of treatment. An infection specialist made the choice of antibiotic. The primary endpoint was treatment failure within 1 year of randomisation. 527 patients were randomised to each intervention across 26 UK sites. In the modified intention-to-treat analysis, oral therapy was non-inferior to intravenous for the primary endpoint. An associated cost analysis showed that oral treatment was £2740 per patient cheaper than intravenous. For early treatment of bone and joint infections, oral antibiotics are the equal of intravenous, and much cheaper.
Preventing and treating Clostridium difficile
Clostridium difficile infection (CDI) occurs during antibiotic treatment because antibiotics excreted into the gut disrupt the microbiome, allowing C difficile to proliferate. John KokaiKun (Synthetic Biologics, Bethesda, MD, USA) reported a phase 2 trial with the drug ribaxamase (SYN-004),
which is an oral β-lactamase that remains localised in the gut and is designed to degrade β-lactam antibiotics before they can reach the colon. The primary endpoint of the double-blind, placebo controlled trial was prevention of CDI (defined as diarrhoea plus presence of C difficile toxin), monitored for 6 weeks. Changes in the gut microbiome were also monitored. Patients were eligible if admitted to hospital for treatment of lower respiratory tract infection and expected to receive 5 or more days of intravenous ceftriaxone (a β-lactam antibiotic). Eligible patients were randomised one to one to receive either ribaxamase or placebo during ceftriaxone treatment and for 72 h after. The modified intention to treat population included 412 patients. Compared with the placebo group, ribaxamase-treated patients had a significant 71% relative risk reduction in CDI (p=0·045), plus a 44% relative risk reduction in new colonisation by vancomycin-resistant enterococci. Ribaxamase was also protective against dysbiosis of the gut microbiome. Synthetic Biologics is preparing a protocol for a phase 3 trial of ribaxamase. Michael Trucksis (Seres Therapeutics, Cambridge, MA, USA) presented a double-blind phase 2 trial of SER-109, which is a collection of bacterial spores purified from donor stool and intended to restore the gut microbiome after antibiotic treatment. The 89 enrolled patients with a history of recurrent CDI were randomised two to one to SER-109 or placebo, and recurrent CDI up to 8 weeks after treatment was recorded. There was no significant difference between groups for the primary endpoint of recurrence. Posthoc analysis suggested that an increase in dose of SER-109 may be necessary. www.thelancet.com/infection Vol 16 June 2017
Newsdesk
Plasmid-borne resistance
Roberto Melano (University of Toronto, Toronto, ON, Canada) explored the evidence for conjugative plasmids in the nosocomial spread of antimicrobial resistance in Gramnegatives organisms. The spread of resistant organisms is well documented; however, Melano pointed out that it is now evident that there is an added complication. For example, MCR1-carrying organisms identified in hospitals across the Americas were found to be unrelated. Therefore, the resistance plasmid seemed readily transmissible, raising the potential of so-called plasmid outbreaks with indistinguishable (or highly related) plasmids present in unrelated bacterial strains and species in the same patient. Amy Mathers (University of Virginia, Charlottesville, VA, USA) went on to detail horizontal transfer of antimicrobial resistance in patients and the environment. She described the finding that high plasmid diversity had been observed despite the initial impression of a conserved plasmid being transferred. This implied that plasmid transfer involved multiple mechanisms, complicating the identification of the environmental reservoirs harbouring the plasmid-carrying organisms. Ultimately, the source of the contamination was traced to sinks and tackled through conventional infection control measures. However, this investigation revealed that plasmid exchange in the environment is much more complicated than commonly thought, particularly because the resistant organism in question seemed strangely receptive to gene transfer.
Heater–cooler units
Daniel Diekema (University of Iowa, Iowa City, IA, USA) outlined the epidemiology of heater–cooler linked outbreaks. He began by highlighting that unless sterile these units pose a significant contamination risk to theatres. One complication is www.thelancet.com/infection Vol 16 June 2017
that manufacturer guidelines are insufficient for dealing with some contaminants. The issue is further compounded by the finding that the units of one particular manufacturer were contaminated with mycobacteria over the past 8–10 years. Which seems to have resulted in disseminated infection in patients in receipt of implants. The contaminating mycobacteria proved to be very resistant to disinfectants and their biofilms made them more so. Diekema advised that in surgical patients with unexplained symptoms, mycobacterial infection should be suspected if the relevant brand of unit was used. He added that the best way to accommodate these units is to direct their exhaust outside the theatre.
Vaccine research late-breakers
Several studies were outlined at the news in vaccine research late-breakers session. The first presentation was given by Germaine Hanquet (EpiConcept, Paris, France) on the indirect effect of childhood pneumococcal vaccination on invasive disease in elderly Europeans. She explained that although the herd effects of 5 years of infant vaccination seems to have led to decline in disease in elderly people due to vaccine serotypes, there also seems to be a correlation with increases in nonvaccine serotype disease in this same population. Therefore, there is little benefit in extending the use of the current vaccines to elderly people. Next Morven Wilkie (University of Oxford, Oxford, UK) described a study exploring if the non-specific effects of BCG vaccination in healthy UK adults had the potential to promote innate immunity against four common bacterial pathogens. Assessment was by growth inhibition assay; however, no effect was evident. Daniel Silman (University of Oxford, Oxford, UK) presented the initial assessment of a novel malaria vaccine candidate: R21 adjuvanted with Matrix-M. He explained that R21 is an improved
RTS,S like vaccine consisting of the pre-erythrocytic circumsporozoite protein. Matrix-M is a new saponinbased adjuvant. The findings were sufficiently promising to justify progress to a phase 2a challenge study to assess vaccine efficacy.
MDR tuberculosis
Christoph Lange (University of Lübeck, Lübeck, Germany) provided an overview of advances in the clinical management of multidrug-resistant (MDR) tuberculosis. He began with the somewhat arresting statement that despite the aim of the endTB strategy to eliminate tuberculosis by 2035, recent increases in cases make this is very unlikely. Similarly, he pointed out that there are more people living with tuberculosis today than at any time in history. On the topic of management, Lange stressed that whole-genome sequencing was a preferable diagnostic method over Xpert MTB/ RIF because it gave a clearer picture and accounted for resistance beyond rifampicin. And the more detailed view provided by whole-genome sequencing meant rifampicin could still be a viable treatment option for some cases of MDR tuberculosis. The crucial factor was the type of resistance mutation. Lange recommended the diagnostic and treatment approach outlined by Horsburgh and colleagues (N Engl J Med 2015; 373: 2149–60). He then moved to more general issues with regard to the management of tuberculosis, explaining that the significant problems raised by the prolonged treatment of tuberculosis (ie, compliance etc) were largely because there was a lack of biomarkers and thus uncertainty about when treatment could be discontinued. The relevance of prolonged treatment to MDR tuberculosis is the high cost of the regimen, so shortening treatment would allow for cost savings that could make newer drugs such as bedaquiline more viable options.
John McConnell, Onisillos Sekkides 587