Up until this point, Dr. Crandall (my dad) had been working on modulating his drug protocols with a fair amount of success.  But the steroids were becoming less and less effective.  And increasing his dose was out of the question. 

Dad was never a complainer.  So when he was experiencing issues with what would ultimately be bladder stones, he never said anything until he could not void. This, of course, necessitated a run to the ER where they immediately catheterized him.  This then necessitated his admission with the pending diagnosis of UTI.  And for the first time in forever, he received antibiotics.  

I came into Dad’s room after he was admitted and saw a lifeless guy on the gurney-like bed whose white board communicated was “mute” “unable to feed self”.  And he definitely looked the part. This once happy, smiley guy wouldn’t even open his eyes as I walked in.  I grabbed his limp hand and squeezed it to let him know I was there. I covered him up with another blanket and put a call into the hospitalist who would be making big decisions that I felt would be best served knowing my Dad’s back-story.  As I sat there in the quiet room with only beeping equipment, I honestly thought it might be over. The fight we’d been battling together – had it come to a close? Did we just loose? Is this Dad giving up? 

I stayed for as long as it took to orient every provider overseeing Dad’s care that above all else, the steroid dose he was presently on could not be interrupted or changed. Though the hospitalist and the resident fought me on that, saying the UTI was directly related to his being on steroids. In the end, they both agreed to reserve making more than one change – and for now the change was adding an IV antibiotic while they cultured the bug.  Relieved for the time being, I went home to tend to my own family.  

When I returned the following day, to my astonishment, Dad was sitting up eating a hearty meal of soup, sandwich and salad – and drinking a glass of milk.  He waved as I walked through the door and motioned me to sit down in the recliner next to him.  “What a difference a day makes!” is all I could think as his nurse walked in, erased the white board to put her name over the gloom and doom notation from the day before.  She then turned to me and said “your dad is doing so much better. They said he couldn’t feed himself yesterday, and now look at him!” 

Between mouthfuls of food, Dad turned to me and said the fated words that would change his approach to his drug protocols: “I thought steroids were the answer, but now I am certain it’s antibiotics. I was right in supposing my issue is an infection in my brain.”  When we ran the idea by the hospitalist, he said the idea was impossible – that bacteria in the brain kills people. “No” he told us, “UTI’s do this to older people.  You’re just experiencing a strange side-effect of an infection in your urinary tract.”

So when the culture came back negative, you can imagine how surprised that doctor was. But instead of explaining himself further, all he did was discharge Dad – off antibiotics.

Within a few days outpatient, Dad became feverish and asked to be taken back to the hospital. There he was re-cultured, and this time was positive for a UTI. But the bacteria he had in his urinary tract was determined to have been introduced when Dad was catheterized during the last hospitalization. This relatively rare bacterium required a specific antibiotic which was different from the first one. Nervous he’d not see the cognitive improvements he experienced with the other drug, Dad was relieved to report that he was definitely thinking considerably clearer even with this new medication.  

Out of the hospital on on a dwindling prescription of this new antibiotic, Dad went on-line to see if there were any instances where a bacterial brain infection didn’t kill the host quickly. Especially since he’d now experienced improvements to his thinking twice now, and as a direct result of antibiotic therapy. Almost immediately he began seeing references to scientists finding the oral bacteria P. Gingivalis in the brains of Alzheimer’s patients. Interestingly, this bacteria was one that Dad was very familiar with: because as a dentist – he’d been exposed to this this periodontal pathogen day-in and day-out for his 50 years of practice. What was even better, is that the two antibiotics Dad had been taking are known to kill P. Gingivalis. Even more interesting!

But when your doctors tell you something so convincingly, you can’t help but think their way too. So when the antibiotic prescription ran out, and Dad said he could feel himself returning to his previous level of MCI, we both thought he’d not successfully eradicated his UTI and needed to be re-cultured. He also shot out a few emails to the scientists that were reporting oral bacteria in the brains of Alzheimer’s patients. One PhD from the UK supported the notion and said that his team had even contemplated starting prophylactic antibiotics (daily use without a positive culture) to protect themselves from Alzheimer’s Dementia. He agreed with Dad’s earlier dose and recommended he give his studies to his medical doctors in support of continuing the prior antibiotics.

At his Urologist’s office, Dad’s initial culture came back negative. While we waited for the culture to grow out, the doctor read the Bristol University Study and agreed to place Dad back on antibiotics because he was very convinced Dad was in the early stage of a new UTI.  And just as with before, within 36 hours on antibiotics Dad started to return to his old self.  You can imagine then how shocked we all were when the culture came back negative again!

At first I reasoned that they were just testing for the wrong bacteria.  And interestingly enough, learned that in the process of culturing for bad bacteria, the solute used actually kills off good bacteria so it doesn’t get in the way of the result. “What happens if you have too much good bacteria?” I wondered.  “Could that cause cognitive issues? And because we are killing them off in the process of culturing, we end up missing this potentially harmful imbalance?  Interestingly, I could find no literature on this.  And when I brought this novel idea up to the Urologist, he pondered for a moment. “It’s possible. What I can say, is I see a fair amount of older folks that don’t test positive on culture, yet show every sign of a UTI.  So many folks, in fact, that our clinic has started a study to follow this unexplainable trend. I’d like to add your dad into the study – which will assure he gets the antibiotics he demonstrates he needs.” And at that point, Dad’s drug regimen pivoted.  And life was again good.  For the time being.

But as this article implies, not all antibiotics worked.  Some worked well (as in these last three) in allowing Dad’s brain to work well. And some worked not so well, and in a few cases some didn’t work at all…which is what happened next.

Several months later Dad was hospitalized to rule out a spinal infection. The Infectious Disease Doc decided to discontinue Dad’s current antibiotic and replace it with a new one – Zosyn, which is a hybrid of Piperacillin and tazobactam.  The doc touted this antimicrobial alternative as “the best broad-spectrum anti-microbial money can buy.” But discontinuation of the RIGHT antibiotic and initiation of Zosyn ended up being catastrophic to Dad. It was as if he wasn’t getting antibiotics at all. Dad went from talking and walking to literally comatose in the fetal position in his hospital bed. He couldn’t wake and absolutely would not eat or drink. If it hadn’t been for his IV, we would have never had been able to give him any of his meds. This went on for two full days. 

That second night, I was awakened by a very unsettling dream. It was the ginormous Pillsbury Doughboy from the movie Ghost Busters trying to get through my bedroom door. I was awake long enough to write down the words “too big – size” next to my bed stand and went back to sleep. In the morning, I’d forgotten all about the dream until I went to make my bed. And there they were, the words written sideways on that sheet of paper. After a second or so, it hit me – the door, “was that the Blood Brain Barrier? Is it possible the BBB is a door that can allow just certain things through?” I thought this was a false clue as my limited understanding of the BBB was that it let NOTHING through. But I’ve become one to wonder lately. And to pay attention to signs. And so I followed that clue and questioned: Is it the size of the antibiotic that mattered? 

In the following 2009 paper, molecular weight of a substance most definitely factors in to its ability to permeate the BBB. As this paper is an overview on the literature surrounding the topic, though experts vary slightly in this number, the general rule, is anything smaller than 400 g/mol WILL cross the BBB. Weights above this show unpredictable results, often with no measurable brain uptake (2):

The molecular weight of Zosyn is 839.8 g/mol

The molecular weight of the RIGHT antibiotic (the drug that so far has worked) is 381 g/mol

After learning why this new antibiotic wasn’t working, I went to the hospital and paged the infectious diseases doctor. When he called back I shared that I believed the reason Dad was tanking so fast (regardless of what we’d find with his spine) is that Dad had an underlying infection in his brain and the antibiotic the ID doctor had just prescribed was too big to get through the blood brain barrier. I don’t know why I was so surprised when, instead of being open-minded, the ID doc told me: “It’s impossible to have a bacterial infection in his brain as it would kill him instantly.”  And no matter what I said, this doc was completely steadfast with his position. As I could see Dad’s nurse was getting concerned at how heated this conversation was getting, I left Dad’s room and found a janitor’s closet in the hallway – closed the door and yelled:  “You are killing my dad and if you don’t switch the antibiotic immediately, he will die!” The phone went silent, and then the ID doc told me “I will change the antibiotic. And when your dad dies, it will be on you.” 

I returned to Dad’s room and watched as the nurse switched my dad’s IV.  I checked the label and indeed Dad had been returned to the lower molecular weight antibiotic. As one can imagine, I couldn’t take my eyes off my dad.  Every beep of a monitor was like an ambulance siren.  Every twitch was like it was his last breath.  I stayed there, completely terrified, until visitor hours were over and I was forced to go home. That night I kept my phone next to my bed for fear I’d get THE call.  But it never came.  When I got to the hospital the next day, Dad’s bed was empty.  Panicked, I ran out to the nursing station only to see Dad walking around the unit talking about the U of MN Gopher Basketball team with the nurses Aid. No kidding.  And where was that ID doctor when I wanted to say “I told you so?”  Off-Call. 

Citations

1)   Tetracyclines: Multitasking Fighters of Inflammation

https://www.pharmacytimes.com/view/tetracyclines-multitasking-fighters-of-inflammation

2) Characteristics of compounds that cross the blood-brain barrier  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697631

About the author:  Anna Shelander is a journalist and question-asker who rarely accepts “no” for an answer.  Which is why, when her dad (the object of this blog and associated website) became ill with an unexplainable disease, he asked her to come along for the ride. The two worked unsuccessfully within the medical community to find a diagnosis, then branched into the research community where answers finally began to appear. It was at this level of science that Anna and her father began to parse together the drug protocols that dramatically improved DEC’s cognition. Unfortunately, the medical community continued to interrupt matters, which is why DEC ultimately succumbed to his illness. Fortunately, Anna kept impeccable records so that someday soon DEC’s efforts may yield a Cure for Alzheimer’s Disease.

 

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