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 Could Short-course antibiotics for UTIs, which appear to promote resistant bacteria and bacterial reservoirs, possibly lead to the development of IC/PBS.

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Join date : 2016-01-30

PostSubject: Could Short-course antibiotics for UTIs, which appear to promote resistant bacteria and bacterial reservoirs, possibly lead to the development of IC/PBS.   Thu Jun 23, 2016 5:44 am

Could short-course antibiotics for UTIs, which appear to promote resistant bacteria and bacterial reservoirs, possibly lead to the development of IC/PBS?

The following is one scenario that appears common for someone who has developed IC/PBS:

1. A woman develops an acute UTI.  Her GP sees evidence of infection from dipstick examination and may send the sample off to the labs for verification.  If she’s in the UK, the typical first line treatment will be a 3 day course of Trimethoprim.  If she’s in Australia, first line treatment will usually be a 5 day course of Trimethoprim. The lab report confirms an e-coli  infection, which is said to be responsible for more than 85 percent of all UTIs, according to a 2012 report in the journal Emerging Infectious Diseases. Her symptoms resolve as expected.

2. Some months later she returns to her GP with another acute UTI.  She is again prescribed a short course of Trimethoprim and her symptoms appear to resolve. In some cases however, the appearance of resolution is illusory.

3. Thereafter, infections start to recur more frequently. Different antibiotics may be tried. Mainstream physicians follow the prescribing guidelines that advocate 3, 5, max 7 days, depending on the antibiotic. (Generally doctors consider these episodes new infections, possibly stemming from the gut or vagina).  Occasionally a nightly low dose antibiotic will be advised for a period of 3-6 months as a prophylactic to keep the urine ‘sterile’ to prevent re-infection. Even with this longer regime she has breakthrough infections.  

Note: Important new research led by Scott Hultgren, Prof of Molecular Biology, Washington University St Louis, has found this common pattern of recurrent UTIs to be caused by uropathogenic e coli (UPEC).  He has demonstrated that very early on during the initial acute UTI, a UPEC forms bacterial reservoirs inside the bladder, which then go on to re-infect the host:

UPEC utilizes complex mechanisms to subvert innate defenses to persist and cause disease. The ability of UPEC to invade into superficial cells of the bladder has been shown to be a critical mechanism in the ability of UPEC to establish a persistent infection” (1)  

 Hultgren’s research suggests that the typical short-course Trimethoprim that women receive is ineffective in resolving these infections:  

Ten days of trimethoprim-sulfamethoxazole (SXT) therapy reduces urinary recurrences and eradicates fecal colonization, whereas 3 days of SXT treatment has no effect over a twenty-eight-day observation period despite clearing fecal colonization acutely. Interestingly, SXT is unable to eradicate bacteria from the bladder reservoir even after a 10-day treatment regimen, thus demonstrating that the bladder reservoir can persist even in the face of long-term antibiotic therapy.” (2)

 His research has also implicated prophylactic antibiotics in the development of antibiotic-resistant strains of UPEC, which women with recurrent UTIs are so often prescribed:  

Patients with chronic urinary tract infections are commonly treated with long-term prophylactic antibiotics that promote the development of antibiotic-resistant forms of uropathogenic Escherichia coli (UPEC), further complicating treatment.” (3)  

Other researchers are finding that for some infectious diseases, much higher antibiotic doses are required to eradicate bacteria completely. For example: Professor Sun Nyunt Wai, Umeå University speaking of cholera says:  

Antibiotics are no problem if the dosage is right. But if it isn’t high enough, bacteria counterattack with an alternative strategy,” (4)    

From a Research Gate publication:  

Sub-lethal concentrations of antibiotics increase mutation frequency in the cystic fibrosis pathogen Pseudomonas aeruginosa” (5)      

4.  At some point in the course of the patient’s recurrent infections, it is not unusual for both dipstick and laboratory analysis to start demonstrating no evidence of infection.  Guided by these tests, doctors assume the infection has been successfully treated, in spite of her on-going symptoms.  In the prevailing acceptance of the belief that absence of evidence is evidence of absence a GP has to make assumptions to try and establish a diagnosis.  Perhaps she has developed a sensitive bladder?  Could the lining of her bladder have been compromised?  Maybe she’s under stress and her problem is psychological?  

On the face of it this is inadequate.  Knowing her history and her symptoms, would it perhaps be fair for the practitioner also to question the accuracy of these age-old tests? The following study from the Research Department of Clinical Physiology, University College London Medical School has refuted the accuracy of dipstick and standard urinalysis:

"Despite official guidelines and widespread use these tests cannot be considered appropriate for diagnosing urinary tract infection in patients with lower urinary tract symptoms, and should be abandoned in this context." (6)  

Another study from the Loyola University Chicago, which has recently disproved the common belief that urine is sterile:

"Traditional tools for urinary bacterial assessment, including urinary dipsticks and standard urine cultures, have significant limitations that restrict the information available to clinicians" (7)

4. At this point in the scenario, antibiotic treatment for her recurrent UTIs has ceased. Her symptoms often intensify, with chronic pain, frequency, nocturia etc., and pain may involve areas seemingly unrelated to the bladder, eg.inner thighs, supra-pubic, legs etc.  Any further testing offered continues to indicate that an infectious cause is not involved.  The patient may then be referred to a specialist, who may conduct standard urological investigations (which can worsen symptoms). If nothing significant is found , which is often the case, a diagnosis of IC/PBS is made as a default. (Hunner’s ulcers, considered a hallmark for IC, are rare, typically in less than 7% of patients)  

5. She has now been labeled with a chronic, painful condition that is little acknowledged and poorly understood.  She is offered treatments for symptoms management, which are riddled with unpleasant side effects and unacceptably high failure rates.  She may even be referred to a psychologist and will sometimes be offered pain management. After years of unrelenting pain, bladder removal is an option.  It is a sad story and one that is being experienced by far too many to be ignored.

After considering the information above, I would be glad if you could please give your views on a couple of questions I have:

Q.  Would you give any credence to the notion that if acute UTIs are only partially treated with short-course and prophylactic antibiotics, there is risk of:

 a) the development of resistant strains?

 b) the development of bacterial reservoirs?

Q.  Is it a possibility that undertreated UTIs may lead to complications such as resistant strains and bacterial reservoirs, which then lead to the development of IC/PBS?

Q.  Based on the above information, could it be argued that UTIs should always be treated much more aggressively, as opposed to popular 3 day courses?

Q.  Do you think current testing is adequate in identifying UPECs and bacterial reservoirs, which are now implicated in recurrent and chronic UTIs?

Q.  Since IC is a rare consequence of the above scenario, will you be investigating other factors that might predispose someone to develop IC/PBS?  

1. http://www.pnas.org/content/101/5/1333.full.pdf
2. http://www.ncbi.nlm.nih.gov/pubmed/12438384/
3. http://www.ncbi.nlm.nih.gov/pubmed/22089451
4. http://sciencenordic.com/weak-antibiotic-doses-undermine-our-body%E2%80%99s-defences



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PostSubject: Re: Could Short-course antibiotics for UTIs, which appear to promote resistant bacteria and bacterial reservoirs, possibly lead to the development of IC/PBS.   Fri Jun 24, 2016 9:16 am

Jill1947 - great info and great questions!

I know not everyone starts out with a history of recurrent UTIs, but my story is very similar to what you describe here. For me, treatment for UTIs has usually been a 5-day course, and sometimes with a repeat prescription if needed (maybe because I am rural). But some years back I was definitely put on a prophylactic course of low-dose antibiotics for 3 months. I've always wondered if the low dose antibiotics is somehow linked to what I have now. My daughter was put on a prophylactic course of antibiotics for vesico-ureteric reflux when she was a pre-schooler and now in her 20s she has recurrent UTIs.

I was doing some research and I came across information from the Royal Children's Hospital in Melbourne stating they no longer recommend routine prophylaxis for children because they say it's associated with future infections with resistant organisms. And they especially don't recommend it for vesico-ureteric reflux. http://www.rch.org.au/clinicalguide/guideline_index/urinary_tract_infection_guideline/#prophylactic

I also came across this 2015 study: 'Subinhibitory Antibiotic Therapy Alters Recurrent Urinary Tract Infection Pathogenesis through Modulation of Bacterial Virulence and Host Immunity' (Goneau, Hannan, MacPhee, Schwartz, Macklaim, Gloor, Razvi, Reid, Hultgren and Burton)

This study raises concerns about low-dose antibiotic therapies, including prophylaxis for recurrent UTIs, as they have found some agents may have 'off target' effects if sub-lethal concentrations are present, creating risk factors for severe, complicated infections. This is exactly what you're saying in your post.

In this study, some antibiotics looked at were found to "induce the expression of adhesins critical to urothelial colonization, resulting in biofilm formation, colonization of murine bladders and kidneys and promotion of intracellular niche formation" - promoting the establishment of chronic infection.

Their mouse studies show that sub-inhibitory antibiotics prime uropathogens for adherence and invasion of murine urothelial tissues. "A part of these changes was thought to be due to suppression of mucosal immunity, as demonstrated through reduction in cytokine secretion and migration of leukocytes into the urinary tract".

When comparing bladder titers, they found prophylaxis significantly increased the presence of low-level bladder CFU (colony forming units), which was likely to indicate more QIRs (quiescent intracellular reservoirs). This is what I talked about in my post on testing - these low-level bacterial CFUs are ignored by standard lab testing and your report comes back 'negative'.

It's estimated that 1 in 2 women will get a UTI in their lifetime, and with that, this study states upwards of 44 percent will experience a recurrence. That's a huge. Surely it's not a coincidence that IC/PBS and UTIs both affect far more women than men.

Like you, I can't help thinking that short-course and/or low-dose antibiotics could be linked to promoting intracellular bacterial/biofilm infections in those suffering with a diagnosis of IC/PBS.

I hope someone Prof Marshall's team will join this conversation.

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PostSubject: Re: Could Short-course antibiotics for UTIs, which appear to promote resistant bacteria and bacterial reservoirs, possibly lead to the development of IC/PBS.   Tue Jun 28, 2016 7:02 am

I was reading further about why bacteria can survive past a course of antibiotics and this led me to 'persistent bacteria'. These are bacteria that, despite being sensitive to antibiotics, have a special mechanism that enables them to go dormant for periods of time to survive antibiotic attack. Researchers believe these persistent bacteria are significant in chronic and recurrent infections.

These bacteria were first described as ‘persistent bacteria’ by Joseph Bigger in the early 1940s, but his discovery didn’t gain much interest or attention.

In 2010, research by Kim Lewis from the Northwestern University, Boston, noted persistent bacteria in cystic fibrosis patients and describes them as dormant variants of regular cells that form randomly in microbial populations. This research found all bacteria tested (including e coli) have the ability to switch back and forth between active and dormant states to avoid antibiotic attack. http://www.ncbi.nlm.nih.gov/pubmed/20528688

In 2013, research by Professor Nathalie Balaban and Professor Gadi Glaser at the Hebrew University of Jerusalem, first demonstrated how persistent bacteria avoid antibiotic attack. “…when antibiotics attack these bacteria, the HipA toxin disrupts the chemical ‘messaging’ process necessary for nutrients to build proteins. This is interpreted by the bacteria as a ‘hunger signal’ and sends them into an inactive state, (dormancy) in which they are able to survive until the antibacterial treatment is over and they can resume their harmful activity”. http://bio-site.phys.huji.ac.il/Publications

In 2014, research by Etienne Maisonneuve and Kenn Gerdes commented that “persister formation is an evolved and deterministic bet-hedging strategy used by bacteria to survive rapid and potentially lethal environmental changes”. They say all bacteria can form persisters that are able to survive antibiotic attack. However, it’s been a challenging area of study because of the “complex underlying molecular mechanisms” and the “low frequencies of persisters in growing bacterial cultures”. This research raises the possibility that persisters contribute to, or maybe even enable, relapsing and chronic infections. It also suggests persisters could sustain the development of antibiotic resistance. http://www.ncbi.nlm.nih.gov/pubmed/24766804

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