by Mark Kelly
The video ended and Simmons turned the lights on. He leaned lazily against the podium, a mischievous grin on his face. “Sorry, that didn’t take as long as I thought it would. We have ten minutes left, you’ll have to listen to me lecture.”
A chorus of groans greeted his announcement and his grin widened. “I’m paid by the word—get ready.”
He clicked through the files on his laptop, opened a powerpoint slide deck and began to lecture.
“Think about it…the discovery of Penicillin, arguably one of the most important medical discoveries of all time, was a happy accident. Happy for Fleming, of course, he won a Nobel prize, but even happier for the rest of us. Millions of lives have been saved by antibiotics—but it isn’t all good news.”
He clicked to the next page of the presentation. A quote in block letters appeared on the lecture hall’s large screen.
“…there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant…”
He stepped around to the front of the podium, a few feet away from the students in the first row, and pointed to the screen. “Does anyone know who said that?”
Blank stares all around. He answered for them. “Alexander Fleming—during his Nobel prize acceptance speech on December 11th, 1945, a few months after the end of the second world war.”
A couple of knowing nods but mostly blank looks. That might have been a little hard. Let’s try something more obvious.
“Any idea what he was talking about?”
A young woman, her brown hair tied up in a ponytail caught his eye. She wore horn-rimmed glasses and looked studious but the hand that waved furiously in the air was anything but.
“Professor Simmons…Professor Simmons!”
“Yes…Miss?” She looked vaguely familiar.
“Emma...Emma Rice,” she said, sounding disappointed he had forgotten her name. “I applied for one of your student lab assistant positions this year.”
He smiled as if he remembered. He didn’t.
“Okay, Emma, what was it that Fleming was talking about?”
She squinted through her glasses. “Resistance to antibiotics?”
“Very good, but what was it that specifically concerned him?” He addressed the question to her and then looked at the other students when she didn’t answer.
“Anyone?” Silence and blank stares. Come on you guys, the answer is right there on the screen.
He waited a few more seconds and then answered his own question. “Fleming was concerned that over an extended period of time, bacteria would acquire resistance to antibiotic treatment if the dosage used wasn’t high enough to kill them. Was his concern justified?”
The young woman tentatively raised her hand again. “It was, right?” she asked, her forehead wrinkled in uncertainty.
“Yes,” he answered and clicked on the powerpoint slide deck.
“…Drug-resistant infections are already responsible for more than half a million deaths globally each year…”
-REVIEW ON ANTIMICROBIAL RESISTANCE, 2015
“Antibiotic-resistant bacteria are arguably one of the greatest medical risks facing mankind—you should be worried, I am.” He pointed at the screen. “That number will increase twenty-fold in a post-antibiotic world. More people will die from infections than cancer.”
He walked over and stood in front of her. “Imagine a world where an under-cooked hamburger with E. coli bacteria doesn’t just make you feel lousy, it kills you”
Her eyes widened and she asked, “What causes it?”
He began to count on his fingers. “Prophylactic antibiotic premedication, use of antibiotics as growth enhancers in food animals, horizontal gene transfer.” He stopped at three as her eyes glazed over.
“Sorry, I’ll explain. Prophylactic use of antibiotics is when you give small doses of them to food animals as a preventative measure. The animals don’t get sick and the farmer is happy. It sounds good in principle—right?”
She nodded tentatively and he looked around the room. A few more heads nodded. Good—they’re listening.
He shook his head. “Wrong! What actually happens is the bacteria the farmer is supposedly protecting his animals from slowly develops resistance to the antibiotic. After a while—a few years, a decade perhaps—the antibiotic stops being effective.”
He walked back to the podium and fiddled with his computer until he found the news article he was looking for. An unreadable magazine article appeared on the screen.
“Sorry about the print size. I’ll paraphrase.”
“Bacteria are incredible organisms, the ultimate survivor.” He became more excited as he spoke. “Part of their adaptive survival mechanism is the ability to transfer genes from one strain to another. That’s called horizontal gene transfer.
This article is about Colistin, a very old antibiotic. It’s been around for a long time but isn’t widely used in humans because it’s toxic at the effective dosage rates.
But it’s cheap, and not toxic in small quantities, so it’s been used as a prophylactic in animal feed for years. Guess what happened over time?”
The room was silent. He had their attention.
“E. coli bacteria in pigs developed resistance to Colistin and that resistance trait is now showing up in other bacteria—bacteria that affect humans. The resistance occurs as the result of a gene called MCR-1. It’s very easily swapped amongst different strains of bacteria using something called Plasmid-mediated resistance transfer.”
“Is that how superbugs are created?” the young woman asked. “I read about them appearing in a hospital in California. I think they had to close it because a bunch of people got sick.”
He hated that term, but the media loved it. “The scientific community doesn’t usually call them superbugs but yes, that’s one of the ways they develop.”
The sound of a throat being cleared reminded him he was holding up the next class. He nodded to the other professor and turned back to his students.
“Time’s up folks. This material won’t be on the exam but I strongly encourage you to read up on it. If you’re interested in discussing it further, stop by my office during the hours posted on my website.” Anxious to leave, most of the class ignored his offer and hurried out of the lecture hall.
He followed them out and strolled across campus towards Regents Hall, the location of his office and lab. By the time he reached the building, the lecture was forgotten but his morning cup of coffee and bagel with cream cheese wasn’t.
He darted into the bagel shop and was standing at the cash register when the muffled trill of his cell phone sounded from deep inside his briefcase. Damn it…never fails.
The cashier offered him change. He shook his head with a nod towards the tip jar and grabbed his food. He looked for an empty table. They were all full. He spotted his department head, John Thompson, a crusty old man in his late sixties sitting alone.
It would have to do.
When he placed his food on the table, he spilled his coffee on the paper the old man was reading. He mimed an apology. I’ll never get tenure now, he thought as he fished through his briefcase and pulled out his phone.
“Hello?”
“Dr. Simmons?” the voice asked with a British accent.
“Yes, speaking.”
“Dr. Simmons, my name is Edward Gore, Dr. Edward Gore. I'm a researcher at the Cambridge Institute for Medical Research. We met two years ago at the infectious disease symposium in Budapest.”
Simmons paused and searched his memory. The symposium was a busy event. He didn’t recall Edward Gore, but he had met a number of people from the Cambridge institute.
“What can I do for you?”
“I apologize for imposing,” Gore said, “but I have a favor to ask. I've been looking at what I believe are mutations in ribotype 027 and would appreciate a second set of eyes. I've read your work and can't think of anyone more suited.”
>
RT 027 was a virulent strain of Clostridium difficile bacteria. It was responsible for a worldwide epidemic in hospitals around the world. First seen in the 1980’s, it disappeared only to reappear twenty years later in an even more virulent form. Simmons wasn’t just familiar with it, he was an expert on it and had done groundbreaking research studying its genetic structure.
“The mutations are in the tcdR and tcdC genes,” the Brit added.
If the C. diff bacteria was likened to a car, the tcdR gene was the accelerator and the tcdC gene, the brake. One increased toxin production while the other slowed it down. Both genes were relatively stable
“A significant mutation in those genes isn’t likely,” he replied skeptically. “How do you know it's mutated? Have you compared it to the reference genome?” He tried not to sound critical. If the other man took offense, he didn’t show it.
“I’ve compared it and it does appear to have mutated, but a second look by a more experienced pair of eyes would confirm it. You're the first person I thought of with your expertise, .”
Still dubious, Simmons paid no attention to the compliment. “Where did the sample come from?”
“I'd rather not say,” Gore said apologetically. “I hope you understand.”
He wasn’t surprised by the man’s reluctance to share. Publish or perish wasn’t a myth, it was a reality. No one wanted to risk giving away too much, too soon, in case the competition got a jump on them.
“I'm quite busy right now, but if you send me the DNA sequence data, I'll take a quick look.”
“Thank you. There may also be mutations in the tcdA and tcdB genes, but I haven’t had time to look more closely.”
The probability of all four genes mutating at the same time was low, but the Brit didn’t sound incompetent. It might be worth a quick look.
“Do you have my email address?” he asked.
“I do—thank you so much.”
By the time Gore had hung up, Simmons was already thinking about the bacteria’s genetic structure. He slid the phone into his pant’s pocket and hurried away from the table, not realizing until he reached the door of the cafe that he had forgotten his coffee and bagel. When he returned, Thompson shook his head in disbelief. Simmons grinned and grabbed the food. A few seconds later, he was back again. “Forgot my briefcase.”
7
TOUGH DAYS, TOUGHER NIGHTS
March 23rd, 12h50 GMT : Bellevue Hospital, NYC
Still bleary-eyed from the previous day’s double-shift, Mei waved a half-hearted greeting to the nurse behind the counter of the nurses’s station.
The isolation room beside it was empty.
“Where's Mr. Muir?”
“Surgery—went into septic shock this morning.”
She frowned. He was stable last night. The antibiotics should have helped. “Are the results from his lab work-up handy?”
“Have them right here,” the nurse said and handed them to her.
Her eyes widened as she scanned lab report. The concentration of A/B toxins in his intestines was high—off-the-chart high. 1,603 micrograms per liter for the A toxin and 247 for the B toxin—nearly thirty times normal. At those levels, his gastrointestinal tract would be falling apart.
“These don’t look right,” she said, confused by the results.
The nurse shrugged. “Do you want them re-done?”
She nodded and continued to flip through the chart. His white blood cell count was nearly eleven-times normal as well. But was that the C. diff or something else? “Any signs of leukemia or other infections?”
The nurse opened his file on the computer and looked. “Nothing listed here.”
She re-read the chart. Something’s wrong, either the test results are haywire—it wouldn’t be the first time—or Mr. Muir has the worst C. diff infection ever recorded.
She dropped the folder on the counter and started towards the bank of elevators. “I’ll be back in ten minutes.”
She stepped off the elevator on the fifteenth floor and looked at the schedule posted on the wall. Muir was in OR-2. She hurried to the observation deck and quietly joined a group of surgical interns. They were intently watching the procedure taking place in the operating room below.
“What's the prognosis?” she whispered
“Toxic megacolon,” an intern whispered back.
“How severe?”
“Very…multiple perforations and sepsis.”
That explains the high white blood cell count, she thought. His immune system was producing them to fight the infection. But C. diff rarely resulted in toxic megacolon. She couldn’t remember the last time she had seen it—maybe never.
The empty chairs in the observation deck filled quickly as more interns came to watch the rare procedure.
The operating team had turned on the microphones. The entire room watched in silence as the surgeons worked on Muir, removing chunks of his colon as they fought to save his life. Unable to keep up with the furious pace of the infection, they failed. His organs shut down, one by one.
“Let’s call it.” The lead surgeon said as he pulled off his gloves and threw them in a disposal bin. "Time of death…8:26 am.”
Confused, she slouched back in her seat. Muir had been ill. There was no doubt about that but something was wrong. No one dies from a CDI that quickly.
Robinson needed to know but she had no idea what to tell him. She took one last look at Muir’s body and jumped from the seat. Her tiredness was gone.
Ten minutes later, she sat in the waiting room outside of Robinson’s office tapping her foot impatiently. “He’s very busy,” his secretary had scolded her, “You can’t just show up and expect a meeting, Dr. Ling, but I’ll see what I can do.”
The more Mei thought about it, the more it bothered her. She didn’t see a lot of C. diff patients in the E.R. but even so, everything about this case seemed wrong. The patient was middle-aged, not elderly. There was nothing to suggest he was at risk. Most surprising of all was how quickly the infection spread through his intestines.
The phone buzzed and the woman at the desk picked it up, listened for a second and then spoke. “You can go in now.”
Mei stood and steeled herself for the inquisition that would come. Robinson’s office was on the north side of the 16th floor of the administration building. It had a commanding view of the city. Through the large plate glass window, she could see the iconic spire of the Empire State Building towering over the streets of Manhattan.
The walls were covered with artwork, mostly prints of famous renaissance works she recognized but had no idea who the artist was. His degrees and awards were displayed in glass-covered plain black frames and filled the wall behind his desk. A large floor globe on an ornate stand sat in the corner.
She half-expected him to be sitting in a smoking chair puffing on a pipe. But he wasn’t, he was sitting behind a large oak desk glaring at her.
He beckoned her forward. “This couldn’t wait until the staff meeting on Friday, Dr. Ling?” he asked with an impatient huff.
“Sit…Sit,” he added even more impatiently.
She pulled out one of the ornate chairs and sat.
“You have my undivided attention,” he said as he clasped his hands together and looked at his watch, “for the next fifteen minutes. What can I do for you, Dr. Ling?”
She didn’t waste any time. “The British patient from yesterday—I’d like to request an autopsy and file a NORS report.”
He pushed his bifocals down to the tip of his nose and peered at her over them. “What British patient?”
“The one with the C. diff infection. You saw him during rounds yesterday. He died this morning.”
“The obese man with diarrhea,” she added, jogging his memory.
Robinson wore a look of distaste on his face as he remembered and frowned. “What about him?”
“I think we should file an outbreak report with NORS and request an autopsy.”
The National Outbreak Repo
rting System (NORS) had been launched a few years earlier to track gastrointestinal outbreaks across the country.
“A report?” he scoffed. “One foreigner with a C. diff infection is hardly an outbreak.”
“Or have there been others?” He leaned forward suddenly, his brow wrinkled as he studied her.
He was worried about his ER, it’s reputation. No hospital wanted the stigma of a C. diff outbreak. She shook her head. “No, no other cases.”
He relaxed.
“Come see me when you have more cases—even one more would be a good start.” He removed his glasses and placed them on the desk. ”And what’s this nonsense about an autopsy—an autopsy for what?”
“The patient died suspiciously.” She cringed at her unfortunate choice of words.
He frowned. “What was suspicious about it? I thought you said he died from a C. diff infection.“
“Actually, it was toxic megacolon that killed him but the root cause was the infection,” she replied, digging herself a deeper hole.
“How can you possibly know that, Dr. Ling? C. diff infections aren’t the only cause of toxic megacolon and even if it was the cause, were you the attending physician?”
“No,” she said reluctantly, knowing the conversation was over.
“Have the next of kin been contacted?
“I don’t know.”
“Then you don’t know if an autopsy was requested or if they approved one?”
“No.”
“Well, then I think, we’re finished with this discussion.” He pushed his bifocals up the bridge of his nose and leaned back in his chair.
“What about the department of health? You could ask them to request one.” Now she was grasping at straws.
His eyes widened as he looked at her. “And be laughed at? Come see me when you have more, Dr. Ling.”
He pushed back his chair to stand and was half-way to his feet when he winced and stumbled forward.
“Are you okay?” She was on her feet, moving towards him.
He held out his hand to stop her and clenched his jaw. “I’m fine—something I ate. It’s not agreeing with me.”
He stepped around his desk and he took her arm. “You have to leave now,” he said as he escorted her to the door. “I have another meeting scheduled.”
