Authors: Martha Powell, Future Science Group
2019 has seen lots of great research in the field of infectious disease and to try and highlight some of the best we’ve given our Expert Panel the difficult task of choosing their favorite paper from the year! Discover more below.
These are my picks in 2019: three great papers on detection of minority resistance variants using next-generation sequencing (NGS) and a novel methodology for quantifying the latent HIV reservoir. First is an innovative paper on the quantitative measurement of the latent HIV reservoir. This method allows a precise quantification of intact and defective proviruses.
Second is a recent experience of the application of NGS within a treatment-as-prevention trial in KwaZulu Natal, South Africa. This methodology had been very useful in detecting pre-treatment drug resistance mutations at low level.
Finally, we have a very interesting article, which proposes a novel methodology combining MiSeq and HyDRA advantages for the precise quantification of low abundant drug resistant variants.
Calcineurin is a major signaling and transcription factor. In humans, blockade of calcineurin is used as an immunosuppressive drug for a series of immune disorders (cyclosporin) or to prevent graft rejection in transplant patients (tacrolimus or FK506). These drugs work since blockade of calcineurin blocks critical aspects of the human immune response, namely T-cell proliferation. Critically, calcineurin is also critical for fungal biology and the calcineurin pathway is required for virulence in pathogenic fungi, i.e., the calcineurin pathway is required for fungi to be able to infect mammalian hosts. Blockade of calcineurin pathway in fungi would then be a very effective way of treating fungal disease. This article is the last in the series of articles trying to achieve a fine balance into maximizing the antifungal effects and minimizing the effects on humans.
The authors obtained crystal structures of calcineurin for three of the major fungal pathogens and then compared it to the already known structure of human calcineurin to perform rational drug design in order to design a calcineurin inhibitor with preference for fungal calcineurin versus human calcineurin. They obtained one compound that had comparable efficacy to fluconazole (a commonly used antifungal) in a mouse model of cryptococcal disease.
I hope that this article leads to further development of this class of drugs and ultimately an effective antifungal treatment.
Cécile van Els
My favorite paper from 2019 was the study by Hagan et al in Cell, highlighted by Bordon in Nature Reviews Immunology. To underpin a role of microbiome composition in human immunity Hagan et al conducted two clinical studies in which healthy volunteers were vaccinated with seasonal influenza vaccine and half of the subjects underwent a 5-day broad-spectrum antibiotic regimen that induced alterations to the gut microbiome.
It was shown that in subjects having lower pre-existing influenza-specific antibody titers, antibiotic treatment impaired H1N1-specific neutralizing antibody responses. Multi-omics integration of data indicated an effect of the microbiome on immune function through diverse mechanisms: directly by affecting immune cells such as dendritic cells and indirectly by regulating critical metabolites including bile acid and tryptophan metabolism. Whether these mechanisms also relate to the generally weaker immune response and altered microbiome of elderly remains unknown. As antibiotics and vaccines represent two of the most widely used medical interventions, their mutual relation to the microbiome has important implication for clinical practice and public health.
The emergence and rapid dissemination of multidrug-resistant organisms (MDROs) as well as the therapeutic challenges faced in treating patients with infections caused by these MDROs remain a serious cause for concern. When I first read this report, I know it would be a strong contender as my selection for 2019 panellist’s choice because it represents hope in the war against antibiotic resistance.
The authors present a 15-year-old cystic fibrosis patient with significant co-morbidities who against all odds successfully underwent bilateral lung transplantation only to develop disseminated Mycobacterium abscessus infection. She was successfully treated with three-phage cocktail of lytic phages that had been genetically engineered to effectively kill the causative M. abscessus strain. This is the first report of therapeutic use of phage therapy for human mycobacterial infection. However, it is also significant as it is the first description of the use of genetically engineered phages.
Bacteriophages are viruses that invade bacteria and were discovered about a century ago. As natural predators of bacteria, their therapeutic potential makes sense although this had not been widely exploited. However, as in recent years with the increasing challenge of antibiotic resistance, we have witnessed an upward surge in research on utilization of phage therapy as part of our arsenal against MDROs. Phage therapy and use of genome engineering to produce phages targeting specific bacterial strains as shown in this report hold a great deal of promise and hope in the war against MDROs.
In 2018 Paul et al reported their findings from a large multicenter study (AIDA) that compared colistin monotherapy with colistin plus meropenem. The premise for the study was the colistin–carbapenem combination is synergistic in vitro against carbapenem-resistant Gram-negative bacteria. The aim was to examine whether this combination improved clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. This 406-patient study showed that the combination of colistin-meropenem was not therapeutically superior to colistin monotherapy.
Another reason for using combination therapy is to reduce resistance development. Dickstein et al used the data from this large study to explore this hypothesis that colistin resistance would emerge less frequently on combination therapy.
This was a pre-planned analysis of a secondary outcome. The investigators evaluated rectal swabs taken on day seven from enrollment or later for the presence of new colistin-resistant isolates. They evaluated the emergence of any colistin-resistant isolate and the emergence of colistin-resistant Enterobacteriaceae.
214 patients were included in the analysis; emergent colistin resistant organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) vs. patients randomized to colistin-meropenem combination therapy (12/108, 11.1%), p=0.669. Colistin-resistant Enterobacteriaceae were reported in 18/249 (7.2%) patients available for analysis.
No difference was observed between the two treatment arms (colistin monotherapy 6/128 [4.7%] vs. combination therapy 12/121 [9.9%], p=0.111).
Thus, in a further paradoxical finding it was shown that meropenem–colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms in addition to being therapeutically non-inferior.
The AIDA study was designed to test different hypotheses pertaining to the management of carbapenem resistant infections but failed to support either hypothesis. Why is this important?
In 2017 the WHO reported that carbapenem-resistant pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii are of critical importance in the battle against antibiotic resistance and they should be the focus of research efforts. Until new agents are developed and approved, clinicians are turning to a variety of regimen to combat these significant infections. Combination therapy is one approach. Current monotherapies either lack the spectrum of activity or have toxicity issues. The specific combination of meropenem–colistin has been proposed as a better regimen in carbapenem-resistant infections. Moreover, the combination could positively impact resistance development.
This study established that neither proposition was supported by a large multicenter study and further highlights the critical need for new agents to treat carbapenem-resistant infections. We still await new therapies that are effective against all carbapenem-resistant pathogens.
Bruner KM, Wang Z, Simonetti FR et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature 566, 120–125 (2019).
Derache A, Iwuji CC, Baisley K et al. Impact of next-generation sequencing defined human immunodeficiency virus pretreatment drug resistance on virological outcomes in the ANRS 12249 treatment-as-prevention trial. Clin. Infect. Dis. 69(2), 207–214 (2019)
Taylor T, Lee ER, Nykoluk M et al. A MiSeq-HyDRA platform for enhanced HIV drug resistance genotyping and surveillance. Sci. Rep. 9, 8970 (2019).
Juvvadi PR, Fox III DM, Bobay BG et al. Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nat Commun. 10(1), 4275 (2019)
Hagan T, Cortese M, Rouphael N et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell 178(6), 1313–1328.e13 (2019).
Bordon Y. Antibiotics can impede flu vaccines. Nat. Rev. Immunol. 19(11), 663 (2019).
Dedrick RM, Guerrero-Bustamante CA, Garlena RA et al. Engineered bacteriophages for treatment of a patient with a disseminated drug resistant Mycobacterium abscessus. Nat Med. 25(5), 730–733 (2019).
Paul M, Daikos GL, Durante-Mangoni E et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect. Dis. 18(4), 391–400 (2019).
Dickstein Y, Lellouche J, Schwartz D et al. Colistin resistance development following colistin–meropenem combination therapy vs. colistin monotherapy in patients with infections caused by carbapenem-resistant organisms. Clin. Infect. Dis. ciz1146. doi:10.1093/cid/ciz1146 (2019).