In medical circles, antibiotic resistance is considered to have a price. When bacteria become immune to antibiotics – that is, mutate into superbacteria – they sacrifice something vital. Allocating resources to avoid antibiotics is very tiring for superbacteria, and they are no longer able to spread. Infectionists often prescribe treatment based on this property, but it turns out that the paradigm is changing: superbacteria are becoming more adapted and virulent. In other words, they are becoming smarter and stronger.
And this is most directly related to my research. From the short answer of the CBEC, it was clear that I underestimated the risk of my clinical trial for patients. I would inspire them with a false sense of security by promising that I could cure their infections and shorten their hospital stay. In fact, such a prediction would be extremely presumptuous. I did not mention efflux – a phenomenon when a bacterium uses microscopic molecular vacuum cleaners to absorb and pump out antibiotics or other chemical modifications that bacteria can use to neutralize dalba. I did not note that the bacteria are becoming more aggressive and that my drug may not work. The protocol needed to be rewritten.
Trying to understand the situation, I turned to several experts to understand their approach to clinical trials and antibiotic research. I started with Brad Spellberg, the Los Angeles County Medical Director and the University of Southern California Medical Center, the best health research center. Spellberg is a thoughtful and dedicated doctor, scientist, and he is also a provocateur. At a major conference in San Diego, I enthusiastically listened to him from the rostrum saying the names of pharmaceutical companies that had not conducted proper clinical research. (He actually told the crowded gym that Allergan was lacking in spirit to conduct a sepsis study with one of his medications.)
Spellberg and his colleagues believe that resistance already exists for all antibiotics, including those that we have not yet discovered. To understand how this is possible, we need to recall the theorem of endless monkeys, which claims that a monkey, randomly hitting the keys on a computer keyboard for an infinite amount of time, will sooner or later create a coherent text, for example, the complete works of Shakespeare. In the same way, microbes constantly mutate by pressing the “keys” in new combinations, and these sequences produce enzymes and pumps that can distract or destroy any antibiotic. Spellberg and his team note that antibiotic resistance has been discovered even “among bacteria living in underground caves that have been geologically isolated from the planet’s surface for four million years.” This is a terrifying thought, and it casts doubt on the very essence of my clinical research. I turned to Spellberg because I appreciated his skepticism and thought that he could help me take a sensible look at the matter.
“There are already widespread mechanisms of drug resistance in nature that we haven’t even invented yet,” he told me one morning before going around. – When we launch a new antibiotic, many people think that mutations occur after the start of using the drug, but this is not so. A much bigger problem is that there is already some level of resistance mechanisms that we cannot yet detect. When we release a new antibiotic into the environment, we reluctantly create conditions for the selection of more resistant bacteria. In the end, we simply will not have targets for new drugs. We must be smarter, ”he added. – Bacteria use antibiotics wisely. But people do not.
To my appeal, Spellberg replied that the main thing is to look at everything in the long run.
“We don’t need a bunch of new antibiotics,” he said. “We need a slow but steady increase.” Putting a number of antibiotics on the market at the same time can be problematic, because resistance will develop in tandem. We are desperate for new antibiotics, and it would be a mistake to test all candidate molecules at the same time.
After talking with experts, of whom someone wished to remain anonymous because of their cooperation with Big Pharma, I revised the Dalba protocol, recognizing that the risks were underestimated, and resubmitted it.
“Let’s hope so,” I told Tom. “I have a good feeling about that.”
The keynote of his impressive career was solving insoluble problems, and I believed that together we could push our research through a sieve of approvals and rules.
“Now it remains only to wait,” he answered.
I returned to patients, and Tom to writing grants. Amazingly, while we were waiting for an answer from the CBEC, the number of patients who were hospitalized due to the ineffectiveness of antibiotics increased significantly. They had common infections – pneumonia, urinary tract infections, which in previous years could be cured at home by taking pills for a week. But now the treatment was too weak. The bacteria really were getting smarter and stronger. In the week that has passed since the protocol was sent for reconsideration, Jackson got into our emergency room twice. He told me that the infection prevented him from attending his daughter’s performance and his son’s first basketball game.
“Nothing takes this infection,” he said.
And he was right. He had a chronic infection, and he hoped to cope with it without infecting anyone.
A change in the treatment procedure, the transition from oral to intravenous antibiotics, led to a crisis brewing in the hospital. Sometimes waiting for a free bed in the front desk reached thirty hours. We could not always take an ambulance. There were simply no empty seats, and patients were sent to other hospitals. Jackson was just one of the hundreds of superbug patients that came to me then. Many of these people died, and even more remained deeply exhausted. One woman, a 59-year-old administrator from Staten Island, told me that even if a recurring spinal infection does not kill her, she believes that it would be better to kill her – she brings so much torment.
“I’m tired of playing this game,” she said, adding that she spends much more time in the emergency department than at home. – Enough.
It is impossible to predict who will become infected or get sick. We were all in danger because the bacteria do not care who we are – they attack everyone indiscriminately: young people, the elderly, middle-aged people … Bacteria bypass us, and at some point it begins to seem that we are returning to the pre-antibiotic era, as if all scientific progress was simply erased. While I was waiting for an answer from the CBEC, I wondered: “Why is it so difficult to make a new antibiotic?”
To assess the challenges that antibiotic developers are facing, it’s useful to look at the history of medical surveillance in the United States a bit. Then it becomes clear where the FDA got the powers it has now, and why the approval of antibiotics is so depressingly slow. In addition, this will help to figure out what needs to be done to correct this state of affairs.
As you know, once the FDA – an overgrown bureaucratic apparatus with a four-billion-dollar annual budget – looked very different. The department was opened in the 19th century, when a handful of scientists from the Chemical Bureau in the Department of Agriculture worked in it – they did laboratory tests and issued reports on the quality of products and medicines. But with the extraordinary rise in free trade at the beginning of the twentieth century, its mission has changed.
Realizing the link between unrestricted trade, unsanitary working conditions and public health, indignant citizens forced Congress to create a structure to protect food. In 1906, just a few months after the publication of Epton Sinclair’s Jungle 6, President Theodore Roosevelt signed into law the Food and Drug Purity Act, which prohibited the transportation of fake or labeled food products from the state to the state. With a stroke of the pen, a small group of government scientists were given tremendous power. From now on, chemists had to regulate the field of activity in which companies regularly falsified data on their products in order to increase profits. Wholesalers often masked spoiled foods (for example, with the help of copper sulfate, rotten vegetables can be given a fresh look) or improved the color and smell of drugs. An embalming liquid was often added to milk so that it did not deteriorate. Until 1906, these practices were not regulated, which led to thousands of deaths that went unpunished.
In the years following the adoption of the law, pharmaceutical companies improved production and mastered the art of marketing and mass distribution. A flood of new products has poured into the market, including chemotherapy drugs, stimulants and powerful painkillers.
State supervision developed simultaneously with these events – the bureau was officially named by the FDA in 1927, but a problem arose. The agency did not have sufficient authority to guarantee the safety of drugs until they reach patients.
In the fall of 1937, Gerhard Domagck’s precious antibiotic, sulfonamide, hit the US market shortly after it was used to treat Roosevelt Jr. for sinusitis. Seller from Massengill Co. in Bristol, Tennessee, reported that there is a demand in the southern states for a liquid drug for the treatment of pharyngitis. The company’s chief chemist found that sulfonamide readily dissolves in a sweetish liquid called ethylene glycol. Massengill made several preliminary experiments regarding the taste and aroma of the medicine and sent it to Tennessee. If the drug worked for Roosevelt, then it will probably work for others.
The drug was not tested for toxicity, since such requirements simply did not exist. Doctors and patients had no idea that this wonderful antibiotic was supplied in an antifreeze solution. When the government understood what was happening, its intervention was sluggish and ineffective. Many of the dead were children. Massengill was fined $ 26,000 – the largest amount the FDA has ever charged.
The sulfanilamide tragedy showed how little authority the FDA had. The following year, President Franklin Delano Roosevelt signed into law on food, medicine, and cosmetics, reinforcing the role of government control over drug quality by authorizing a preliminary safety test. He gave the FDA the right to ban drugs with incorrect labeling, recall ineffective drugs, and identify drugs that can only be used under the supervision of a doctor. This has allowed the FDA to determine what is safe and what is not – this right remains with the board to this day. This was made possible because indignant citizens demanded change.
The FDA has begun to seize thousands of dubious drugs from the market, controlling the registration of a huge number of safe and effective new drugs. By the beginning of the 1950s, mainly drugs were prescribed that did not exist in 1938. In this short period of time, more effective treatment methods have been developed than in the entire previous history of mankind, and regulatory authorities have made every effort to keep up. The FDA’s premises expanded rapidly, the budget was bloated – the best scientists were brought in from the public and private sectors to support the golden age of antibiotic development.
One of these new collaborators was Francis Oldham Kelsey, a doctor with a doctorate in pharmacology. In 1960, she was asked to consider the FDA’s tranquilizer application, which became popular in Europe due to its effectiveness in treating morning sickness. A pharmaceutical company in Cincinnati wanted to sell a new drug in the US, and Dr. Kelsey was asked to review the regulations. Thalidomide did alleviate some symptoms in pregnant women, but it had the property of allowing it to cross the placenta, which neither the doctors nor the patients knew about. This led to the birth of children around the world with malformations, including phocomelia, a disease that manifests itself in the absence of upper limbs or their departments.
For almost two years, Dr. Kelsey refused to approve thalidomide in the United States, while the drug manufacturer publicly blamed her. (She was used to such treatment: Kelsey was accepted for doctoral studies at the University of Chicago, because due to her name and short hair combed back, the professors first decided that this was a man.) Kelsey felt that something was wrong with the medicine, and demanded conduct additional testing before giving the drug to patients. The thalidomide tragedy in the United States was largely averted thanks to Kelsey’s meticulous work and her refusal to comply with public pressure. John F. Kennedy awarded her with the Presidential Award for Outstanding Civil Service. Until the age of ninety, she worked at the FDA as a security guard.
Whenever I am saddened by the slowness of drug approval, I recall Francis Oldham Kelsey.
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