Inhibiting host-protein deposition on urinary catheters reduces associated urinary tract infections
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Curated by eLife
Evaluation Summary:
In a set of in vitro and in vivo experiments the investigators demonstrated that coating of urinary tract catheters with fibrinogen-degrading substances reduced adhesion and colonization with a broad range of bacteria relevant in the pathogenesis of CAUTI. This approach might, therefore, be interesting for prevention of CAUTI as an alternative to catheters coated with antibiotics.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Microbial adhesion to medical devices is common for hospital-acquired infections, particularly for urinary catheters. If not properly treated these infections cause complications and exacerbate antimicrobial resistance. Catheter use elicits bladder inflammation, releasing host serum proteins, including fibrinogen (Fg), into the bladder, which deposit on the urinary catheter. Enterococcus faecalis uses Fg as a scaffold to bind and persist in the bladder despite antibiotic treatments. Inhibition of Fg–pathogen interaction significantly reduces infection. Here, we show deposited Fg is advantageous for uropathogens E. faecalis , Escherichia coli , Pseudomonas aeruginosa , K. pneumoniae , A. baumannii , and C. albicans , suggesting that targeting catheter protein deposition may reduce colonization creating an effective intervention for catheter-associated urinary tract infections (CAUTIs). In a mouse model of CAUTI, host-protein deposition was reduced, using liquid-infused silicone catheters, resulting in decreased colonization on catheters, in bladders, and dissemination in vivo. Furthermore, proteomics revealed a significant decrease in deposition of host-secreted proteins on liquid-infused catheter surfaces. Our findings suggest targeting microbial-binding scaffolds may be an effective antibiotic-sparing intervention for use against CAUTIs and other medical device infections.
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Author Response:
Evaluation Summary:
In a set of in vitro and in vivo experiments the investigators demonstrated that coating of urinary tract catheters with fibrinogen-degrading substances reduced adhesion and colonization with a broad range of bacteria relevant in the pathogenesis of CAUTI. This approach might, therefore, be interesting for prevention of CAUTI as an alternative to catheters coated with antibiotics.
We appreciate the summary done. However, this coating doesn’t aim to degrade fibrinogen, it simply reduces fibrinogen’s ability to adhere to the catheter. “Fibrinogen anti-fouling” would be a more accurate description. Additionally, this study not only focused on bacteria but also fungi and thus “microbial” would be a more accurate description of the scope of this study.
Reviewer #1 (Public Review):
The major …
Author Response:
Evaluation Summary:
In a set of in vitro and in vivo experiments the investigators demonstrated that coating of urinary tract catheters with fibrinogen-degrading substances reduced adhesion and colonization with a broad range of bacteria relevant in the pathogenesis of CAUTI. This approach might, therefore, be interesting for prevention of CAUTI as an alternative to catheters coated with antibiotics.
We appreciate the summary done. However, this coating doesn’t aim to degrade fibrinogen, it simply reduces fibrinogen’s ability to adhere to the catheter. “Fibrinogen anti-fouling” would be a more accurate description. Additionally, this study not only focused on bacteria but also fungi and thus “microbial” would be a more accurate description of the scope of this study.
Reviewer #1 (Public Review):
The major strengths are a clear hypothesis and the consecutive description of a set of experiments, each time demonstrating the next step in the pathogenetic pathway.
We thank the Reviewer for their supportive and enthusiastic response.
The weakness is that the experiments stop where the clinical relevance would start. Are the in vitro and in vivo animal experiments representative of the in-human situation?
We appreciate the insightful comments provided by the Reviewer. This works has a clinical potential based on our data that shows that our use of urine as a media to grow our pathogens for in vitro testing as well as our mouse model of infection recapitulates human CAUTI. Some of our findings are shown in Flores-Mireles, Mbio 2016; Flores-Mireles, J Urol 2016; Flores-Mireles, Nat Rev Microbio 2015; and Flores-Mireles, STM 2014. To emphasize the clinical relevance of this study, we have changed the introduction and discussion.
Moreover, it does not become clear from the discussion whether this approach of coating is technically feasible. This step towards in-human testing will determine the impact and significance of the work.
We thank the Reviewer for this feedback. To improve the clarity of the technical feasibility of this coating, we have addressed it in the introduction, results, discussion, and methods.
Reviewer #2 (Public Review):
This article provides a detailed account of both in vitro and in vivo experiments that: • Establish the role of fibrinogen (Fg) in the etiology of catheter-associated urinary tract infections (CA-UTI) • Investigate the prevention of CA-UTI with the use of LIS catheters, containing anti-fouling modifications (liquid infused silicone) to prevent the interaction between Fg and common uropathogens.
The study follows up on previous (by the investigators) research on the role of Fg on the attachment of uropathogens and the formation of biofilms. It is a comprehensive article that contains a detailed description of the following experiments:
- In vivo experiments demonstrate the interaction between Fg and uropathogens in the bladder and the catheter lumen.
- The manuscript provides in vitro evidence that Fg-coated silicone catheters enhances the binding of uropathogens, compared to uncoated or bovine serum albumin coated catheters.
- The manuscript describes the development of the LIS catheter, in which a catheter is drained in silicone gel. It demonstrates the effects of this process on the catheter weight, length and inner and outer membrane diameter.
- The manuscript provides in vitro evidence that the use of a LIS-catheter reduces Fg deposition and uropathogens binding.
- Using in vivo mouse experiments, the study provides evidence that when introducing a variety of uropathogens and thereby inducing CA-UTI, the use of LIS-catheters reduces o Fg deposition and uropathogens binding on the catheter o uropathogens colonization of the kidneys, spleen and heart
- Finally, the manuscript demonstrates in mice that the LIS catheter reduces protein deposition on catheters in case of CA-UTI
The study has a clear structure and there is little to criticize about the study methods. For steps 4 to 6, they used a control group of uncoated catheters, which they compared with a Mann-Whitney U test. The results, although not all statistical significant, provide convincing evidence for the efficacy of LIS catheters within this study. Another strength of the study is the simplicity of the development and (probably) the limited costs of a LIS catheter, so that it can also be applied in the future in less wealthy countries.
I identified two potential weaknesses of this study. Addressing these would improve the replication of these findings, the set-up of follow-up studies, also outside your study group, and it would help in the translation and implementation of the LIS catheter in humans.
First, it is insufficiently clear from the methods how the LIS catheter was developed exactly, and specifically the LIS-catheter that was used for the mice experiments. This complicates the understanding and replication of these study findings. It is not exactly clear for me if these catheters were drained in liquid infused silicone or whether liquid infused silicone was infused into the catheter tuber before insertion? For how long were the LIS-catheters that were finally used for the mice experiments incubated in silicone oil?
We thank the Reviewer for pointing out where our explanation was lacking. This liquid infused modification was made by submerging the silicone tubing into silicone oil for at least 5 days (for in vitro assay catheter materials) or 30 min (for catheters used in in vivo assays). This information has been added to the results section as well as materials and methods section.
Second, the article demonstrates that the drainage of a catheter in silicone gel increases the weight, length, inner and outer diameter of the mouse catheter. These results seem to stand alone and are not addressed in the discussion.
We thank the Reviewer for pointing out this deficiency. These results now are discussed.
What influence this could have on the urinary flow and the introduction/ascent of uropathogens?
Currently, we are performing an in-depth characterization of the LIScatheter and their effect in urine flow. This evaluation is out of the scope of this study. This in-depth study will be part of a follow publication. Regarding, the introduction/ascending of uropathogens, our colonization studies have showed a decrease of colonization in the kidneys, suggesting that ascending of the pathogen to the upper urinary tract is affected. Our data shows (Fig. 4) that this modification reduces initial binding of both pathogens and deposition of Fg.
Could it be that the effect of the silicone gel diminishes over time, which necessitates a catheter change? Do you have evidence on the stability of this polymer?
We are so excited that the reviewer is thinking about the follow up steps to this study. Currently, we are investigating the long-term stability in urine conditions in vitro, in the bladder in vivo, and in prolonged CAUTI. However, these analyses are out of the scope of this study and will be part of further publications. A study done by Sotiri et al (2018) has shown that this modification has long-term stability in vitro.
Would it be possible to infuse silicone oil when the catheter is in situ?
We appreciate the Reviewer’s comments. Based on the time that is needed to fully infuse the catheter, it will be difficult to do it in situ. This will need further investigation under urine conditions.
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Evaluation Summary:
In a set of in vitro and in vivo experiments the investigators demonstrated that coating of urinary tract catheters with fibrinogen-degrading substances reduced adhesion and colonization with a broad range of bacteria relevant in the pathogenesis of CAUTI. This approach might, therefore, be interesting for prevention of CAUTI as an alternative to catheters coated with antibiotics.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In a set of in vitro and in vivo experiments the investigators demonstrated that coating of urinary tract catheters with fibrinogen-degrading substances reduced adhesion and colonization with a broad range of bacteria relevant in the pathogenesis of CAUTI. This approach might, therefore, be interesting for prevention of CAUTI as an alternative to catheters coated with antibiotics.
The major strengths are a clear hypothesis and the consecutive description of a set of experiments, each time demonstrating the next step in the pathogenetic pathway.
The weakness is that the experiments stop where the clinical relevance would start. Are the in vitro and in vivo animal experiments representative of the in-human situation? Moreover, it does not become clear from the discussion whether this approach of coating is …
Reviewer #1 (Public Review):
In a set of in vitro and in vivo experiments the investigators demonstrated that coating of urinary tract catheters with fibrinogen-degrading substances reduced adhesion and colonization with a broad range of bacteria relevant in the pathogenesis of CAUTI. This approach might, therefore, be interesting for prevention of CAUTI as an alternative to catheters coated with antibiotics.
The major strengths are a clear hypothesis and the consecutive description of a set of experiments, each time demonstrating the next step in the pathogenetic pathway.
The weakness is that the experiments stop where the clinical relevance would start. Are the in vitro and in vivo animal experiments representative of the in-human situation? Moreover, it does not become clear from the discussion whether this approach of coating is technically feasible. This step towards in-human testing will determine the impact and significance of the work.
-
Reviewer #2 (Public Review):
This article provides a detailed account of both in vitro and in vivo experiments that:
• Establish the role of fibrinogen (Fg) in the etiology of catheter-associated urinary tract infections (CA-UTI)
• Investigate the prevention of CA-UTI with the use of LIS catheters, containing anti-fouling modifications (liquid infused silicone) to prevent the interaction between Fg and common uropathogens.
The study follows up on previous (by the investigators) research on the role of Fg on the attachment of uropathogens and the formation of biofilms. It is a comprehensive article that contains a detailed description of the following experiments:
1. In vivo experiments demonstrate the interaction between Fg and uropathogens in the bladder and the catheter lumen.
2. The manuscript provides in vitro evidence that …Reviewer #2 (Public Review):
This article provides a detailed account of both in vitro and in vivo experiments that:
• Establish the role of fibrinogen (Fg) in the etiology of catheter-associated urinary tract infections (CA-UTI)
• Investigate the prevention of CA-UTI with the use of LIS catheters, containing anti-fouling modifications (liquid infused silicone) to prevent the interaction between Fg and common uropathogens.
The study follows up on previous (by the investigators) research on the role of Fg on the attachment of uropathogens and the formation of biofilms. It is a comprehensive article that contains a detailed description of the following experiments:
1. In vivo experiments demonstrate the interaction between Fg and uropathogens in the bladder and the catheter lumen.
2. The manuscript provides in vitro evidence that Fg-coated silicone catheters enhances the binding of uropathogens, compared to uncoated or bovine serum albumin coated catheters.
3. The manuscript describes the development of the LIS catheter, in which a catheter is drained in silicone gel. It demonstrates the effects of this process on the catheter weight, length and inner and outer membrane diameter.
4. The manuscript provides in vitro evidence that the use of a LIS-catheter reduces Fg deposition and uropathogens binding.
5. Using in vivo mouse experiments, the study provides evidence that when introducing a variety of uropathogens and thereby inducing CA-UTI, the use of LIS-catheters reduces
o Fg deposition and uropathogens binding on the catheter
o uropathogens colonization of the kidneys, spleen and heart
6. Finally, the manuscript demonstrates in mice that the LIS catheter reduces protein deposition on catheters in case of CA-UTIThe study has a clear structure and there is little to criticize about the study methods. For steps 4 to 6, they used a control group of uncoated catheters, which they compared with a Mann-Whitney U test. The results, although not all statistical significant, provide convincing evidence for the efficacy of LIS catheters within this study. Another strength of the study is the simplicity of the development and (probably) the limited costs of a LIS catheter, so that it can also be applied in the future in less wealthy countries.
I identified two potential weaknesses of this study. Addressing these would improve the replication of these findings, the set-up of follow-up studies, also outside your study group, and it would help in the translation and implementation of the LIS catheter in humans.
First, it is insufficiently clear from the methods how the LIS catheter was developed exactly, and specifically the LIS-catheter that was used for the mice experiments. This complicates the understanding and replication of these study findings. It is not exactly clear for me if these catheters were drained in liquid infused silicone or whether liquid infused silicone was infused into the catheter tuber before insertion? For how long were the LIS-catheters that were finally used for the mice experiments incubated in silicone oil?
Second, the article demonstrates that the drainage of a catheter in silicone gel increases the weight, length, inner and outer diameter of the mouse catheter. These results seem to stand alone and are not addressed in the discussion. What influence this could have on the urinary flow and the introduction/ascent of uropathogens? Could it be that the effect of the silicone gel diminishes over time, which necessitates a catheter change? Do you have evidence on the stability of this polymer? Would it be possible to infuse silicone oil when the catheter is in situ?
Overall the study is of excellent quality. While there are still barriers to overcome before the LIS catheter can be applied in humans, as also acknowledged in the discussion, it offers a hopeful new strategy in preventing CA-UTIs.
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