Medicine - the enemy within us / Marin McKenna

A new pattern of antibiotic resistance spreading around the world may soon leave us helpless in the face of a menacing array of bacterial infections

In the early summer of 2008, Timothy Walsh of Cardiff University in Wales received an e-mail message from an acquaintance of his, Christian Gisk, who serves as a physician on the staff of the Karolinska Institute in Sweden. Gisk treated a 59-year-old man who was hospitalized in January of that year in Örebro, a town 160 kilometers from Stockholm. The man suffered from diabetes for many years, had several strokes and recently developed deep pressure ulcers. But all these were not the reason for his letter. In fact, Gisk was disturbed by the presence of a bacteria that was surprisingly discovered in the man's routine urine culture. Will Walsh, director of a lab that studies the genetics of bacterial resistance to antibiotics, be willing to take a look at the bacteria?

Walsh agreed and conducted more than a dozen tests on the isolated bacteria. It was Klebsiella pneumoniae, one of the most common causes of pneumonia and sepsis in hospitalized patients. But this strain contained something new, a gene Walsh had never seen before. The gene caused Klebsiella, which is also resistant to many types of antibiotics used in intensive care units, to be resistant to the last group that still worked effectively and safely: carbapenems, also known as drugs of last resort. The only drug that worked on the resistant strain was colistin, a drug that has long been out of general use because of its toxic effect on the kidneys. Walsh named the enzyme that this gene produces NDM-1, New Delhi metallo-beta lactamase, after the city where the man contracted the infection, just before returning home to Sweden.

If there is one such case, Walsh reasoned, there must be more, and he set out to look for them with Gisek and other partners. In August 2010, they published the results of the study in the Lancet's Infectious Diseases Monthly. They discovered 180 patients who were infected with bacteria carrying the gene. The NDM-1 protein is prevalent in Klebsiella bacteria in India and Pakistan that have also arrived in Britain in the bodies of residents who traveled to South Asia for medical treatment or to visit friends and family. Worse than that, in some cases the gene even spread to a type of bacteria different from Klebsiella: Escherichia coli (known for short as E-coli), which lives in the intestines of every warm-blooded creature and is found in every corner of our environment. This transition raised the possibility that the gene would not remain within the boundaries of hospitals and would not characterize only hospital infections, but would begin to spread silently in the everyday world, carried in bacteria in the intestines of ordinary people, and spread without being detected in handshakes, kisses and doorknobs.

Another possibility also arose: that the delicate, swinging balance between bacteria and drugs, which began in 1928 with the discovery of penicillin, is about to end with the victory of the bacteria. If indeed this happens, many deadly infections that have been eradicated through antibiotic treatments over the course of decades may soon return with a storm.

A new model of durability

The end of the magical antibiotic era is not a new issue. From the day antibiotics were created, there has been antibiotic resistance. The first bacteria that showed resistance to penicillin appeared even before the drug reached the market in the 40s. And almost since then, doctors have been warning about the expiration of the effectiveness of the drugs, warnings that began due to the global spread of penicillin-resistant organisms in the 20s. In the 50s, resistance to methicillin was discovered, and in the 80s - resistance to vancomycin.

But this time, the predictions of post-antibiotic doom originate in a different part of the bacterial world. The genes conferring carbapenem resistance, and not only that NDM-1 But a host of other genes have appeared in the last ten years in a particularly challenging group of bacteria, collectively known as gram-negative bacteria. This nickname, named after a Danish scientist from the 19th century, indicates a reaction to the color that illuminates the cell membrane. But it indicates much more complex bacterial properties. Gram-negative bacteria easily exchange DNA segments between them, so that a resistance gene originating from Klebsiella, for example, quickly migrates to E. coli, Actinobacter and other gram-negative species. (Unlike resistance genes in gram-positive bacteria that tend to stay in the same species.) Gram-negative bacteria are also more difficult to eradicate with antibiotics because they have a double cell membrane that even the strongest drugs have trouble penetrating. They also have some intracellular defenses, and fewer options to treat them. These days, pharmaceutical companies are developing only a few new types of antibiotics, and no new drug can overcome the stubborn gram-negative bacteria that are able to mutate quickly. Because of this, the disaster could easily spread from medical centers to the community.

Resistance to antibiotics from the carbapenem group has already made infections that are common in hospitals, such as the Klebsiella infection in the first Swedish patient, almost untreatable. Apart from carbapenems, there are only a handful of drugs that doctors are reluctant to use, because they fail to reach all the hiding places of the bacteria in the body, or because they are unsafe due to severe side effects.

Although infections that occur in hospitals are difficult to treat, they can be detected because those who are in them - the elderly or people confined to their beds or intensive care units - are often under close supervision. However, the scenario that prevents sleep from the eyes of the health authorities is that genes conferring resistance to carbapenems will spread, unwittingly, outside the hospitals within organisms that cause common diseases, such as E. coli, which is responsible for a significant part of the millions of urinary tract infections every year. Walsh, who first identified NDM-1, gave as an example a woman who presented to the doctor with what appeared to be a common bladder infection. Without suspecting resistance, the doctor will prescribe drugs that are ineffective in this case, while the infection spreads unstoppably up the urinary tract to the kidneys, and eventually, fatally, to the bloodstream. "There will be no way to treat her," he says.

The miracle of antibiotics is fading

The 83-year battle between the bacteria and the drugs designed to kill them ranges from a game of "hit the mole" to the atomic bomb strategy of guaranteed mutual annihilation. Bacteria have developed a resistance factor that protects them from almost all types of antibiotics that have been developed. In response, the drug companies developed stronger drugs - but no more.

Over the years, the struggle has gradually tilted to the side of the organisms, like a seesaw gradually coming out of balance. After all, evolution is on the side of the bacteria. It takes 20 minutes to produce a new generation of bacteria, but ten years, or more, to research and develop a new drug. Moreover, any use, even reasonable use, of antibiotics, causes resistance to appear because the use activates a mechanism known as selective pressure. Usually, some bacteria with random mutations, which are beneficial to them, manage to survive the onslaught of antibiotics. They multiply, fill the habitats where the antibiotics removed their non-resistant species and made room for them, and pass on the genes that protected them. (This is why it is important to take the full dose of antibiotics - to eliminate all the bacteria causing the infection, not just the most sensitive ones.) But resistance is not only spread through heredity. By changing DNA segments, bacteria can acquire resistance without ever being exposed to the drug that the genes protect against.

The evolution of Staphylococcus aureus, a Gram-positive bacterium (with a single cell membrane), demonstrates the development of drug resistance: first the bacteria developed resistance to penicillin, then to synthetic penicillin, including methicillin, which gave the resistant bacterium the name MRSA (methicillin-resistant staphylococcus), then resistance Cephalosporins like Keflex, and finally vancomycin resistance - the last line of defense against MRSA. Gram-negative bacteria have a similar development model, in which they have overcome penicillins, cephalosporins, macrolides (erythromycin and azithromycin, or zithromax) and lincosamides (clindamycin). But until very recently, it was possible to use carbapenems safely and effectively against even the most stubborn infections, and therefore they were considered the last resort in the fight against gram-negative bacteria, the last barrier between treatable and non-treatable infections. They were cheap, reliable, broad-spectrum - worked against many organisms - and extremely strong.

Research may be able to get us out of the problem with a new type of antibiotic, at least until the bacteria win again. But with no new drugs against superbugs in the drug pipeline for the next decade, we may have to live for an uncomfortably long time with the risk of many untreatable infections.

"It has been difficult to discover new compounds that work against gram-negative bacteria and are not toxic to humans," says David Schleiss, a physician, drug development consultant, and author of Antibiotics: The Perfect Storm (Springer, 2010). "When you think about it, what we're trying to do with antibiotics is to kill something inside us, without harming ourselves. It's a challenge." The newest antibiotic against gram-negative infections was doripenem, from the carbapenem family, which was approved for use by the US Food and Drug Administration in 2007.

The situation was serious enough even if there were several hundred cases in which the gene was discovered NDM-1. But over the past five years, another gene that confers similar resistance, and the machine KPC (Acronym for Klebsiella pneumoniae carbapenemase), is spreading rapidly throughout the world. Its pattern of spread appears to be similar to that of penicillin-resistant organisms in the 50s, or MRSA in the 90s: epidemics first break out among vulnerable patients hospitalized, and then the gene spreads throughout the community.

Exposing a hidden threat

When Walsh and Gisk published their NDM-2010 study in the summer of 1, it immediately sparked international outrage. The health authorities in India cried out, claiming that the Western doctors are trying, in their jealousy, to harm the thriving medical tourism industry in the subcontinent.

In contrast, the first identification of KPC Didn't cause a riot at all. It appeared quietly, in one of the hundreds of bacteria samples collected in 1996 from hospitals in 18 states in the US, in a project called ICARE (an acronym for the Intensive Care Project against Epidemics of Resistant Bacteria). The project represented a joint effort by the US Centers for Disease Control and Prevention (CDC) in Atlanta and neighboring Emory University. The goal of the project was to monitor antibiotic use in intensive care units and other hospital departments, with the hope that it would be possible to estimate where the next resistant organism would emerge.

One culture, sent from an unnamed North Carolina hospital, was of Klebsiella. The find itself was not unusual. This is a common infection in hospitals, an almost inevitable result of the use of antibiotics in intensive care rooms. High doses of broad-spectrum antibiotics destroy the ecology of the intestine and cause diarrhea, which contaminates the patients' environment and the hands of the care staff. "Think of patients in the intensive care unit, sedated and on ventilators who can't get up and go to the bathroom," says Arjun Srinivasan, CDC director of hospital infection prevention programs. "If they have diarrhea, the staff has to clean them. There is a lot of equipment near the patients, and there are many surfaces that can become contaminated."

If Klebsiella infection in intensive care units is not surprising, the results of the culture analysis were. As expected, the bacterium isolated in North Carolina was resistant to a grocery list of antibiotics, including penicillin and some similar drugs. But it was also resistant to two carbapenems, amipenem and morphenem, which so far have always worked on Klebsiella. The culture was not completely resistant, but CDC test results suggested that an extremely high dose of carbapenems would be required to treat an infection caused by this bacterium. The enzyme that conferred the resistance attacked the carbapenems before they even managed to cross the bacteria's inner cell membrane.

No one had ever seen a pattern of resistance like the one provided by the garden KPC. The epidemiologists who examined the culture were worried, as if they heard distant alarm sirens. "This is a new type of resistance, but when there's only one such culture, you don't know how widespread it will be," says Jean B. Patel, deputy director of the CDC's Office of Antimicrobial Resistance. "And similar cultures have not been discovered for a long time."

An outbreak in New York

For several years, the Klebsiella sample from North Carolina remained a case of concern. But in the middle of 2000, patients in four intensive care units at Tisch Hospital, which is part of New York University Langone Medical Center in East Manhattan, began to develop particularly serious Klebsiella infections, which were resistant to almost all the groups of drugs that the unit's doctors usually use. It was the first time that doctors at New York University encountered infections resistant to carbapenems. Fourteen patients developed pneumonia, surgical infections, and sepsis, all highly drug-resistant, and ten others carried bacteria with KPC without symptoms. Eight of the 24 died. Hospital tests revealed that the strain of Klebsiella they carried contained the gene KPC Like the original specimen from North Carolina.

The hospital soon learned how difficult it is to stop the spread of a resistant bacteria. When so many drugs are ineffective, the only option is to enforce the old-fashioned method of strict cleaning, to ensure that the resistant bacteria does not migrate to the hands of the medical staff. The Langone Medical Center hospitalized the patients in isolation, requiring everyone who entered the room to wear gowns and gloves and enforce hand washing and the use of disinfectants. But that was not enough, so they replaced the washing solutions in intensive care units. But when the infections recurred, they looked at the treatment received by infected patients and found that some patients with urinary tract infections splashed urine when their collection bags were changed. These splashes contaminated the medical staff and the environment. It took a year to stop the epidemic of infections.

Two years later, somehow, the same resistant bacteria appeared in hospitals in Brooklyn, further evidence of the difficulty in stopping the spread of the Klebsiella bacterium that carries the gene KPC. One hospital discovered two infected patients in August 2003. The patients were placed in isolation, the hospital tightened infection control procedures, but by the end of February 2005, 30 additional cases had already been diagnosed throughout the hospital. Another hospital identified an infected patient in December 2003, two more in February 2004, and another 24 by the end of May. All the patients were infected in the hospital itself, despite enormous efforts to block the spread of the bacteria.

Thematic bacteria KPC emerged at Harlem Hospital, where they caused an outbreak of seven sepsis cases in the spring of 2005. Only two patients survived. The bacteria also surfaced at Mount Sinai Medical Center in Manhattan. The researchers there began to examine all the patients admitted to the three intensive care units in the hope of understanding the reasons for the rapid spread of the epidemic. Their findings helped explain why the bacterium poses such a big problem: 2% of all intensive care unit patients carried the resistant strain without symptoms, but still put others at risk.

The hospitals in New York City have become a breeding ground for resistant bacteria, as federal data also shows. In 2007, 21% of Klebsiella samples collected in New York carried the gene KPC, compared to 5% of the samples in the rest of the US. In 2008, one hospital in New York reported that the prevalence of the bacteria was high KPC increased to 38%.

Patients in intensive care are by definition critically ill. They suffer from trauma, cancer, failure of central organs, so it is difficult to determine the cause of death. But in some cases related toKPC, there is no doubt about the cause, says John Quayle, an associate professor of medicine at Sunny Medical Center in Brooklyn who treated some of the first cases in New York. "Clearly, there were cases where the treatment failed despite all efforts," he says. "And patients died."

Global spread

The spread of the carrier Klebsiella bacterium KPC Began in New York City. First they found the bacteria in the favorite travel destinations of city dwellers, such as New Jersey, Arizona and Florida. After that, in much more distant places.

An infectious disease with resistance to carbapenem is not a reportable disease, so a clinical laboratory that detects the resistant bacteria is not required to notify public health authorities. Therefore, the full extent of the distribution of the garden KPC is not known. But in 2009, half of Chicago's hospitals discovered the gene KPC in some of their patients. A year later, the proportion of Chicago hospitals reporting attendance increased KPC to 65%. By the end of 2010, KPC bacteria had caused serious illness in hospitals in 37 of the US states. From the moment the CDC started tracking the bacteria, public workers discovered that hospitals were not prepared for it. "Over and over again we have seen how a culture sent to us is actually not the first to be discovered in the hospital," says Patel of the CDC. "When they look at older records, they find early cases that just weren't of interest."

In February 2005, an 80-year-old man, who had been suffering from prostate cancer for five years, sought emergency treatment near his residence in Paris. After his hospitalization, the doctors discovered that he had brought with him a carrier clavicle KPC which probably originated from an operation he underwent in New York a few months before. It was KPC's first foray outside the US, but not the last. Thematic organisms were soon found KPC from New York in patients in Colombia, Canada, China and Greece. They caused an outbreak that infected 45 people in a hospital in Tel Aviv, and from there, through patients and medical staff, the outbreak continued on its way to England, Norway, Sweden, Poland, Finland, Brazil and Italy.

What next?

Health authorities are now seeing the global spread of carbapenem-resistant bacteria through genes KPC, NDM-1 and other genes, "a public health event of international concern," as the World Health Organization put it in November 2010. (This international body designated World Health Day on April 7 "for antimicrobial drug resistance and its global spread".) This statement was made in part because not much could be done to stop the carbapenem-resistant organisms. Only a small number of antibiotics still work against them, and these drugs are far from perfect.

Most of these infections still respond to tigecycline, a newer drug, and colistin, a decades-old drug. Tigecycline came on the market in 2005, the first of a new group of antibiotics called glycylcyclines. Because bacteria have not previously encountered the mechanism of action of this drug, they do not develop resistance quickly. But tigecycline does not diffuse efficiently into the bloodstream or the bladder, so it is not effective for blood or urinary tract infections caused by bacteria KPC או NDM-1. (Also, in 2010 the FDA updated the label of tigecycline, adding a warning that for some reason the use of the drug may increase the risk of death in some patients with serious infections.) Colistin, on the other hand, belongs to a small group of drugs known as polymyxins, which originated in the -40 of the 20th century. This drug has its own serious problems: besides damaging the kidneys, it does not penetrate the tissues well. These problems have prevented the drug from being widely used for many decades, and may be what has preserved its effectiveness for so long. Since the use of colistin has increased in recent years, the rate of resistance to the drug has also increased.

Apart from tigecycline and colistin, we have almost nothing. Between 1998 and 2008, the FDA approved 13 new antibiotics. Only three had new mechanisms of action, ones against which bacteria still have no resistance. In 2009, the Infectious Diseases Society of the USA counted the research done on new types of antibiotics. Out of hundreds of applications to the FDA for new drug registrations, they found only 16 types of antibiotics in any stages of development. Eight of the drugs were intended for the treatment of gram-negative bacterial infections, but none of them for the treatment of highly resistant gram-negative bacteria, such as carrier bacteria KPC and-NDM-1.

These statistics convey the message: without openly announcing it, most pharmaceutical companies have come to the conclusion that the development of drugs to treat carbapenem-resistant infections, despite the great challenge involved, is not economically viable. Because the use of such drugs is for a very short time until resistance develops, so the research and development time for these drugs is not worthwhile. "We are approaching the stage where we need to seriously start investing a lot of money in developing new compounds. Compounds that we haven't come across before, and more importantly, that the bacteria haven't seen before," Walsh says. "And we don't need one or two, but ten or twenty."

The spreading epidemic has forced hospitals to reexamine the effectiveness of infection control measures. Institutions that have succeeded in curbing the bacteria say these efforts require enormous focus. The protocols include washing patients with disinfectants daily and cleaning surfaces in patient rooms down to the smallest nooks and crannies on screens and computers, sometimes every 12 hours. "I'm worried about disinfecting surfaces. This is the area where hospitals often fail," says Michael Phillips, head of infection control at Langone Medical Center, the center where the first outbreak occurred in New York. Phillips helped develop a new project known as the "Cleaning Team" that pairs infection control experts with hospital service workers. The team lowered the amount of infections during hospitalization in the first six months of its work.

The most recent reports on KPC show the level of cleanliness required of the medical staff. Last year, 28 patients in two French hospitals were infected with resistant Klebsiella bacteria using endoscopic, flexible optical fibers threaded through the throat into the digestive system. The hospitals thought they had disinfected the equipment, but KPC still managed to penetrate.

Medical teams are also stepping up surveillance, hoping to identify carriers so they can be isolated before they infect others. France, for example, requires a rectal swab to detect resistance to some drugs, for all patients hospitalized in other countries, on the first day of their continued hospitalization in France. "At my hospital, a patient was transferred to us from Morocco who was a carrier of carbapenem resistance," says Patrice Nordmann, head of the bacteriology and virology departments at Bicester Hospital in Paris, who treated the first French case of KPC in 2005. "We put the patient in isolation. We sounded an alarm and prevented an outbreak."

In 2009, the CDC published detailed guidelines to help hospitals control carbapenem-resistant bacteria. But the authority did not recommend the French strategy of testing every patient before hospitalization, because they say the bacteria are not spread uniformly enough to justify the cost and the hours of work.

Removing carbapenem-resistant organisms from hospitals is not only important for preventing outbreaks in critically ill patients, but it is also essential to prevent the bacteria from spreading to the medical staff. Quayle and others who have documented the spread of KPC throughout New York speculate that some of the bacteria were inadvertently passed on by doctors, nurses and other staff at several institutions. It is even more important to prevent bacteria from carrying KPC Transfer the genes for resistance to other types of bacteria, such as E.coli, which are found in hospitals but also thrive outside. The carrier E. coli bacterium KPC may seep out of the hospital, and escape the reach of any surveillance programs.

Such an event has already occurred at least once. In 2008, Israeli doctors treated an elderly man who arrived at the hospital very ill but without signs of resistance to carbapenem. In his first week in the hospital, he contracted a carrier bacterium KPC. Within a month the kindergarten was over KPC from the Klebsiella infection to E. coli bacteria in the man's intestine, creating a new strain that was very resistant but still responded to high doses of antibiotics. The gene transfer took place in the hospital, under the selective pressure of the drugs given to the man. But in January of this year, researchers in Hong Kong reported that such a transition is also happening outside hospitals. A patient who came to a local clinic was found to be a carrier of E coli with the gene NDM-1. According to the records, the man had never been hospitalized before.

Looking ahead, researchers predict that fully resistant strains of gram-negative bacteria will emerge, long before drugs that can treat them appear. And there are those who do not need to predict the future, they have already seen it materialize. Three years ago, doctors at St. Vincent's Hospital in Manhattan treated two cases of Klebsiella that were resistant to every drug at their disposal. One patient survived. one dead "It is a rare situation for doctors in the developed world that a patient dies from a serious infection for which there is no medicine," they wrote in a medical journal. "We had no effective treatment to offer." And if the evolution of bacteria does not slow down or the development of drugs does not speed up, such cases will become far too common.

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And more on the subject

Carbapenem-Resistant Enterobacteriaceae: A Potential Threat. MJ Schwaber and Y. Carmeli in Journal of the American Medical Association, Vol. 300, no. 24, pages 2911-2913; December 24, 2008.

The Spread of Klebsiella pneumoniae Carbapenemases: A Tale of Strains, Plasmids, and Transposons. LS Munoz-Price and JP Quinn in Clinical Infectious Diseases, Vol. 49, no. 11, pages 1736-1738; December 1, 2009. http://cid.oxfordjournals.org

Does Broad-Spectrum Beta-Lactam Resistance Due to NDM-1 Herald the End of the Antibiotic Era for Treatment of Infections Caused by Gram-Negative Bacteria? P. Nordmann et al. in Journal of Antimicrobial Therapy. Published online January 28, 2011.