UroPharma

06/06/2024

The new UK anti- plan

Colleagues
I’ve been wading through the UK second 5-year anti-AMR action plan, “Confronting 2024-2029, that was launched last week. It is rich in rhetoric and packed with policy plans and ambition. but unfortunately lacks operational details for clinicians needing to treat patients with infections.

It warns continues to be dangerously on the rise, that we should reduce use and prescribe them appropriately, e.g by avoiding them with viral and fungal infections and preventing their disposal from polluting the environment. Such important information and guidance have been espoused since I was a medical student in the 1970s - hardly new thinking.

Responsible are highly sensitive to AMR risks when prescribing and would welcome any pragmatic initiatives for minimising them at the clinical “coal face.” The document’s lack of operational details for confronting bacteria reinforces that we are left to find such solutions ourselves.

, in his 1945 Nobel Lecture warned presciently that, “it is not difficult to make resistant to in the laboratory by exposing them to concentrations not sufficient to kill them,” …. yet we do precisely that with every oral antibiotic treatment for . We drip-feed the over many hours through ureters into infected pools while the bugs multiply within minutes. The inevitable delays offer them opportunities to secrete biofilms and . Pharmacology has long advocated direct targeting as the best approach for drug treatments. Implementing these preachings in treating cystitis and is a long overdue and very practical way to help meet the goals set by the governments strategy.

09/05/2024

Combatting catheter associated ( ) - Tomorrow’s .

On the day of the UK’s launch of its new 5-year plan, I offer this account as it is closely linked in attempting to reduce the incidences of CAUTI, and thus, incident AMR risks. Here’s some food for thought

Patients and health services suffer the scourge of CAUTI in both hospitals and communities. No approved strategy has made a substantial difference. Various alternatives exist but need unblocking by officialdom. Here’s a selection:

1 - cleaning:
To prevent perineal bacteria migrating along an indwelling catheter, antiseptically cleaning it makes sense, although alcohol wipes are of no use. because following evaporation, more perineal bacteria immediately can climb on and march along. Long-acting-antiseptic wipes exist, but the NHS doesn’t procure them, which ignores this basic hygiene need.

2 - urethral gel:
Evidence to date indicates antimicrobial catheter coatings don’t work, presumably because intra- inoculated with catheter insertion can jump off into the before the coating’s toxin can be absorbed by them. Prevention might be achieved through bacterial attachment-entrapment. Such non-antibiotic, anti-infective compounds exist in nature and could be incorporated into a urethral gel aiming to reduce bacterial migration into bladders. They require investment for regulatory approvals

3 - Intravesical prophylaxis:
CAUTI bacteria are least in number when entering the bladder during catheter insertion. They could immediately encounter high concentrations of antimicrobials thereafter following urine drainage and intravesical delivery via the same device. A drug-delivery catheter for sterile intravesical instillation of prophylactics is going through regulatory processes for future availability.

None of these tactics yet have product approval, but UroPharma is working to change the landscape. Wouldn’t it be great to smash the iatrogenic scourge of CAUTI? Follow UroPharma and me, CAUTI’s nemeses.

07/05/2024

Doctors with commercial interests.

I offer this “case report” and cautionary note to dedicated doctors with inventive minds.



For many years in UK medicine, the most publicly trusted profession, I investigated intravesical treatments, initially with for LUTS, finding it safe, effective, systemic free, valuable to patients and desired by them. Trial subjects preferred it to popping side-effect rich pills for their (UU). But without a delivery device, prescribing for self-administration in the community today is challenging and professionally risky.



Clearly, the quality of through oral/systemic delivery generally fall below standards we want and often are detrimental to patients and healthcare widely, e.g with progressing via oral for treating . Additionally, oral for treating UU (OAB and neurogenic urgency) predispose to , especially amongst the elderly and people with . Well established in the medical research literature and appreciated in urology is that bladders do better when targeted directly (N.b. adjuvant cancer chemotherapy and botulinum toxin).



This set me inventing and then on a mission to provide a drug-delivery catheter to enable direct bladder targeting under licence for self-administration, community-based treatments and surgery.



I’ve also sat on many healthcare-improvement panels and committees and was a founding trustee of healthcare charities, now long-established. However, having co-founded UroPharma, a med-tech company, backed by doctors wanting the new technology to better treat the commonest bladder conditions and diseases, I’m now disqualified from offering my specialist knowledge in certain official quarters, indicating a lack of trust after over 43 years in this profession. Nevertheless, I’m trusted to be with patients!



The government relies on and encourages commercial healthcare enterprise, as it’s the most efficient way to bring new treatments to the masses, so I remain undaunted as an innovator, but question the irony.

01/05/2024

tablets and patient safety

syndrome, (OAB), describing of unknown cause, was so named because investigations of complainants revealed at volumes below expected norms.

overactivity was blamed. For about a decade, tricyclic tablets, having antimuscarinic properties, were unofficially repurposed to antagonise detrusor receptors before being overtaken by oxybutynin’s approval by the FDA in 1976. It spawned a -dollar market with a plethora of “me-too” tablets and captured in the net neuropaths with urgency and disinhibited detrusors, e.g people with ( ).

The simplest thought analysis at the time would have raised doubts about the science, because contractions/relaxations do not correlate with continuous urgency sensations, whereas progressive bladder distension does.

Some years ago, uro-neurophysiologists and latterly pharmacologists debunked the dogma. Detrusor contractions merely are epiphenomena. Far more likely the source of such urgency lies somewhere in the sensory arc of the micturition neural circuitry, starting in bladder urothelium and ascending to the brain, with detrusor simply responding to abnormal instructions from the urothelium or brain in the only way it can.

Many years later, still without a shred of evidence that is causative, the label OAB remains and such prescribed treatments float through patients’ systems producing side effects, while barely influencing urgency, but they endure while new ones entered the markets and are sold to suffering patients at taxpayer expense, while driving some patients into nursing care because of treatment failures, drug-induced or other of the ubiquitous adverse side effects such systemic drugs readily produce, all with official approval.

What do patient safety regulators think about that?

What’s the value proposition to the NHS or Medicare?

I propose patient safety regulators and clinical governance stewards update drug review mechanisms.

Patients and prescribers need safe, .

29/04/2024

A path to safer : Botanical compounds, that we call cPACs exist in nature and having been patented by UroPharma for use, are being investigated by the company.

They are for incorporation into a urethral gel for safer urinary catheterisation, because the first line of defence against CAUTI is to prevent the bacteria getting into the bladder in the first place!

are such essential clinical tools that over a billion units are used annually with numbers increasing year on year.

Unfortunately, catheter acquired ( ) is common, risky and inordinately costly to healthcare, especially through post-op UTI and its sequelae, .

The problem with catheter coatings appears to be that, to produce their effect, must have time to absorb the toxin before they jump off the catheter to enter the bladder, but their exposure times to the coatings are too short for effect.

A substance within a urethral gel that could receive the catheter and entrap bacteria on it to prevent their transit into the bladder should reduce the microbial risking .

24/04/2024

Cystitis and AMR. A critical analysis in

Nearly 150 million cases of urinary tract infections (UTIs) are reported each year, of which uncomplicated cystitis triggers > 25% of outpatient prescriptions of oral antimicrobial treatment (OAT). OAT aids immune cells infiltrating the urothelium in eliminating uropathogens capable of invading the....

22/04/2024

Psychology in

Unconscious bias is a systematic cognitive error in decision-making, about which the decision-maker is unaware.

Unconscious bias against is common, especially infected ones. Compared to other organs, progress in management has barely changed for ~ ¾ of a century, despite incidences increasing, recurrences abounding, and AMR becoming more pervasive, because of antiquated, flawed and haphazard treatments. We challenge “haphazard” through but blithely accept “antiquated and flawed.” Other common non-surgical bladder problems fare similarly badly (e.g, urgency, inflammation, pain).

Cystitis is one of the most common human and the most common hospital acquired one. (don’t mention “the bladder”) are heavily implicated. Cystitis gums up hospital services, causing both direct, and widespread complications, so you might expect it would receive a lot of attention. No such luck.

Healthcare is failing far too many people through disdain of bladders. It seems men’s much lower incidences of cystitis, primeval aversions to intrusion into beloved pen*ses or “incontinence disgust” may be the reasons.

The long-overdue, recently accepted diagnostic category, “chronic UTI,” doesn’t even indicate they overwhelmingly are bladder infections.

We’ve made almost no progress in reducing the burden of cystitis other than with implementing hygiene for CAUTI prophylaxis, a 19th century idea, and through expeditious catheter removal, just common sense.

Urologic surgeons are deemed the experts in bladder healthcare, but surgery actually has no role to play in most cystitis management. Urologist attendees at Bladder Health UK’s latest conference were sparse. Nurses dominated.

Last summer’s British Society of Antimicrobial Chemotherapy’s June conference opened with, “we know almost nothing about managing UTI.” That statement really applies only to cystitis.

Unconscious bias against bladders actually belies its profound effects on healthcare from primary, through intensive care. Will raising awareness campaigns, like NHS England’s last October, make a difference? If so, thanks for reading.

15/04/2024

When will the penny drop about ?

For some reason, we long assumed that in the extra-systemic, cavity are subject to the same conditions as in other tissue infections, but they aren’t. get to other tissue infections via blood whereas encounter antibiotics in . That’s a big difference,

First of all, blood pH range is narrow, so an antibiotic’s MIC (minimum inhibitory concentration) is predictable there. The urinary pH range is very wide. Antibiotic MIC in urine varies with pH because pH influences its solubility and ionisation.

Secondly, the urine pool, especially if it is big, can dilute the entering antibiotic’s concentration enormously. can be big urine reservoirs.

Thirdly, the antibiotic drip-feed into that pool is rate limited, so build up to urinary MIC can take many hours into days.

All those factors delaying the antibiotic reaching its urinary MIC enable the pathogens to build their defences. Sometimes they do, with results varying from treatment failure to infection recurrence and even AMR.

Intravesical instillation of a high concentration of a quick acting drug makes more therapeutic sense. That’s why continues to gain traction in urology services, even though it remains off-label. Since treatments give bacteria time to build their defences, be they biofilms or AMR, we should not be surprised by the deleterious outcomes we’re seeing.

09/04/2024

Urinary , existential threats and :

The dominant goal of life for every species is its preservation. All individual lives, spanning from humans to bacteria are finite, but reproduction provides the means.

Uropathogens are so called, when friendly colonic commensals and symbionts become “dislocated” finding way into bladders where they become our enemies in pursuit of their essential goal. Our intravesical environment sometimes just can’t overcome the invaders.

That’s unsurprising. have been adapting to hostile environments for 3.8 billion years, during which time they have developed a plethora of robust features for the purpose. Some can survive famine with intracellular stores of reserve materials or can differentiate into “resting forms” in nutrient deficient environments. They collaborate, look after their “relatives,” sometimes even suicidally self-sacrificially. They can mutate to adapt and build biofilm fortresses to survive environmental threats. They also can be very aggressive invaders and, although microscopic, can pack a very macroscopic “punch.”

derive strength in numbers. To win against them our best chances are to rid them entirely from the battlefield, when least in number. Antibiotics may be fatal to them before they can muster their defences, but time is on their side through growth, fortress building and mutation. Drip-feeding antibiotics into pool diluents delays therapeutic effects and so facilitates AMR.

People who need catheters are especially at risk from uropathogens because the pave the way for invasion. Nevertheless, are necessary clinical tools.

With all this in mind, UroPharma has developed a to timely high concentration, immediate post-drainage, sterile, direct intended to help overcome the challenges of cystitis and fundamental flaws of catheters that yield catheter associated ( ). Hopefully, it will soon be to open the door to a range of , under licence, to hit the invaders hard before they can wreak their havoc in our patients’ .

UroPharma seeks to help bring this about.

04/04/2024

Starvation amidst plenty with anti-infectives.

line tissue surfaces that the outside world can directly access, such as skin, sclera, mouth, gut, va**na, and . The natural world produces a vast array of , antifungal and antiviral compounds, especially as flavonoids, alkaloids and phenols. Attacks on most of those tissues and breaches of their integrity are amenable to natural topical treatments and are well treated by many. However, regarding the lower tract, we impose heavy constraints on our healthcare through our medicines regulatory agencies treating and systemic treatments as equivalents, thus with as exceptional regarding topical pharmacological treatments.



Treating skin infections effectively with honey, the gut with foods and nutraceuticals, and even va**nal epithelium with “live yoghurt” legitimately avoids onerous regulatory constraints, but neither bladder nor urethral urothelium have such drug-regulation “get-outs,” although there are similar, sound physiological and pharmacological grounds for considering them equivalently.



and associated have become scourges, with associated from their treatments with antibiotics causing serious problems for patients and healthcare more widely. Wouldn’t it be better if we didn’t have to rely on Big Pharma that has been reticent to expend the requisite hundreds of millions of dollars to produce a new systemic antibiotic for the lower urinary tract, if we could extract therapeutics from nature and safely apply them as topical treatments with regulatory agency approval? We’re starved of treatments in the midst of plenty.

30/03/2024

Success, dependence and demise or innovation
When we find a solution to a problem, naturally we look to the same approach for the next similar challenge. changed the landscape of human very quickly, so obviously we turn to them to lead the way with each new challenge to our health in this interminable war, because it’s easy to think that way. Daniel , the Nobel Laureate of 2002 describes WYSIATI (What you see is all there is) as a cognitive bias that, by supporting our mindset, risks closing our minds to other evidence or better ideas.

Bacteria have successfully deployed mutation and adaptation for about 3.8 billion years to protect themselves, multiply and spread themselves throughout the planet, so won’t just “roll over” forever to our . is a natural bacterial response.

Our follow-on response to AMR with , although necessary, is relatively mild and so isn’t the solution to our relentlessly evolving plight. Although we caught them off-guard, without doubt, over the long-term bacterial tactics have greater potential than our current strategy. We need to challenge our dependencies on antibiotics and seek new approaches for our protection from bacterial infections. The suggested as much in its 5-year antimicrobial resistance national action plan, but little has transpired to that effect.

Nature offers many opportunities, but we need a mindset that will allow us to exploit them optimally. , defined as having the right at the right at the right place and at the right time doesn’t mention or reproduction blockers. Antibiotics are not all there is. We should broaden our thinking.

If we do, we can better exploit, through repurposing, more of nature’s solutions. More on that in a future posting. First, let’s open our minds to seeking better.

20/03/2024

Recurrent reportedly occurs in about 25% of women within months after a first episode, which far exceeds recurrences from other infections. Cystitis investigations reveal a worryingly high rate of associated antimicrobial resistance ( ) compared with other common , suggesting survive our treatments, adapt and reinfect. Dead bacteria don’t do either, so despite clinical recovery, evidently many cystitis treatments, even uncomplicated ones, fail to eradicate the pathogens.

Evidence from mouse experiments indicates bacteria can find sanctuary intracellularly, but researchers report they haven’t found intracellular bacterial colonies in pig or human urothelium, despite looking for many years.

We can reliably test for resolution of other infections but not for cystitis. A post-treatment mid-stream test wouldn’t pick up bacteria adherent to urothelial cell membranes.

Symptom relief following treatment requires no special confirmatory test, but the ultimate test of efficacy must be infection resolution through annihilation. Should we be satisfied that current treatments could cause these “downstream” complications, without investigating efficacy further? Should we be resigned to accepting it is beyond our ability to produce such a test and instead provide for increases in the number of recurrent and chronic cystitis clinics as patients return in misery in increasing numbers and progresses relentlessly, demonstrating our failure with those patients and as guardians of the future of healthcare?

28/02/2024

Following on from revelations that we have a complex symbiotic relationship with our microbiome, the discovery that we also have a has attracted much attention. There’s no going back to believing the urinary is sterile. Thank you, Alan .



Studies showing differences between normal and diseased bladder urobiomes raise questions about their influences on bladder health and disease aetiology, especially regarding and syndromes, about which we know so little. The idea that we should protect a urobiome’s integrity in developing treatments for bladder pain syndromes and even bladder is worthy of investigation but not unreserved acceptance.

Correlation being interpreted as causative is a common flaw in deductive analysis and can misdirect clinical management as it did with urgency being attributed to uninhibited contractions, encouraging oral treatments to suppress detrusor at the cost of cognitive impairments and a raft of symptomatic side effects with little positive to offer beyond placebo.

As yet, I can find no information indicating we need to protect the urobiome, other than from known uropathogens, to protect human health or treat bladder diseases. The notion of bacterial imbalances reflects a Galenic view of health and disease. Furthermore, distinguishing intravesical commensals from symbionts appears yet to be established.

What I have found in 2024 is a probiotic industry capitalising on both our ignorance of bladder disease aetiologies and recurrent challenges by blatantly exploiting not only patients but also gullible specialist -clinicians. It seems having a bladder disease is not only unhealthy but can be unjustifiably expensive for patients. At this time, such professional involvement appears to blur boundaries between placebo treatments and disreputable practices.

Ptof. Scott Glickman

19/02/2024

“We know almost nothing about managing UTI.” This assertion went unchallenged at the British Society of Chemotherapy multidisciplinary conference of experts last year. Increasingly, we struggle because following , recurrences and antimicrobial too often occur, compromising patients’ health and efficient service provision.

PubMed UK searches reveal over 81,000 articles are available on “UTI” and more than 16,000 on “cystitis,” so are not mysterious diseases. Our treatments methods are long established and straightforward. In 43 years as a practising doctor my wide exposures to clinical services indicates most prescribers are responsible professionals and cystitis treatments are well documented. Something must be eluding us.

Albert Szent-Gyorgi, the Nobel prize winner in Physiology or Medicine (1937), is quoted as saying, “research is to see what everybody else has seen, and to think what nobody else has thought.” From a root cause analysis (RCA) of standard oral antibiotic treatments, I learned that they all have a set of flaws in common that are evident, but circumstantial. I wish to share the RCA where I can also field challenges, as proper scientific scrutiny warrants.

Critical review of our current oral cystitis treatment methodologies, to which we are so habituated, was long overdue. Please let me know if your services would be interested in a presentation. It is titled: Science and Art in UTI Treatment: Misconceptions, Mysteries and Mistakes in Cystitis Management.