MRSA breakthrough may spell the end for drug-resistant bacteria
Ever since the first case of Methicillin-resistant Staphylococcus aureus infection, or MRSA, struck Hong Kong in 2004, researchers have sought a cure for the deadly flesh-eating bacteria.
In 2007, the drug-resistant bug infected 173 people in the city, while 1,258 people were diagnosed with it last year.
The scourge of MRSA is worsening in the city because the infection is developing a resistance to antibiotics which countered ordinary staphylococcus infections, but are no longer effective.
Richard Kao Yi-tsun, an eminent microbiologist who discovered a compound to defeat Severe Acute Respiratory Syndrome, which killed almost 300 people in the city in 2003, is at the forefront of the research.
As associate professor at the Department of Microbiology at the University of Hong Kong, his greatest professional concern is that the treatment of MRSA has become more difficult, and even healthy people are at risk.
Since 2009, Kao and his research team at the university have been working to discover how MRSA multiplies, spreads and affects its host.
As the research leader, Kao has focused on identifying the factors that make MRSA so virulent. At the top of his agenda was a formidable pathogen, the evolved strain of S. aureus, which is resistant to virtually all antibiotics.
“There is no one measure effective at controlling drug-resistant bacteria — or superbugs, as people call them. MRSA are drug-resistant bacteria,” Kao said.
Though there is no official data on MRSA’s mortality rate in Hong Kong, Kao calculated the figure during discussions with frontline physicians. The average death rate among pneumonia patients with MRSA is one in two.
“It’s a can of worms arising from indiscriminate use of antibiotics. If we don’t hurry to find an effective medication to curb MRSA, it’s going to be more catastrophic,” Kao said.
After almost a decade of work, he made a breakthrough earlier this year when he discovered M-21, a non-antibiotic compound capable of preventing MRSA from producing multiple toxins.
M-21 binds to an enzyme called ClpP and inhibits its activity. ClpP, a major cause of virulence in MRSA, controls the production of two toxins that rupture white blood cells and cause skin abscesses. They are major contributors to the virulence of MRSA.
“M-21 works as if it hampers MRSA from manufacturing ammunition. It doesn’t kill the bacteria but is capable of subduing the virulence inside it,” Kao said. “Simply put, we want to use M-21 to make the once-harmful MRSA harmless. Leave the ‘killing’ job to the human immune system.”
The search for M-21 was long and daunting, but Kao is the world’s leading scientist on solutions to fight MRSA through a novel approach that does not require antibiotics.
Control strategies
Since MRSA emerged in the United Kingdom in 1961, scientists worldwide have been searching for new antibiotics to control it. However, the superbug has continued to mutate rapidly, is highly resilient, and many efforts to control it have failed.
The bacteria no longer respond to an entire class of penicillin-like antibiotics called beta-lactams. Though an aggressive antibiotic called vancomycin has been used as a last resort, it is costly and causes side effects. A vancomycin-resistant S. aureus strain, though rare, emerged in 1988 in France.
In response, Kao abandoned orthodoxy. In 2009, he went against the prevailing attitude that called for new antibiotics to fight the superbug a year before the World Health Organization declared MRSA a “global threat”.
“The fight against superbugs resembles the ‘Tortoise and the Hare’. It’s hard for humans to catch up with the speedy hare — in this case, the rapidly changing antibiotic-resistant bacteria,” he said. As in the old fable, the best hope is that “slow and steady wins the race”.
Antibiotics killed bacteria but the tougher, more resilient bugs mutated, making themselves resistant to antibiotics before swiftly multiplying and taking over previous strains. Kao wanted to break that circle.
He devised a luminescence-signaling system that indicates the amount of toxins secreted by MRSA — the dimmer the luminescence reading, the fewer toxins generated. More than 50,200 non-antibiotic compounds were tested for their reactions to MRSA. Among them, Kao found that after being injected with M-21 the bug exhibited significantly lower luminescence. “This indicated that M-21 hinders MRSA from producing toxins,” he said.
A stealthy enemy
To Kao, S. aureus is a stealthy enemy. About one-third of people worldwide have some in their nose or on their skin. This pattern of coexistence is decades old, but the pathogen rarely attacks the host.
Staph infection only happens when the bacteria penetrates the body, either through a break in the skin or through the digestive or respiratory tracts. The infection causes damage ranging from minor skin lesions to more serious conditions such as pneumonia or endocarditis, an infection of the heart‘s inner lining.
In 2009, Ho Pak-leung, honorary consultant at Hong Kong’s Queen Mary Hospital, confronted an intimidating MRSA infection.
A 42-year-old man who had A-type swine flu (aka H1N1) acquired MRSA in the community — known as CA-MRSA — and died two days after being admitted to the hospital.
“We treated him using aggressive medications, but they were of no help,” Ho recalled. “The patient died of pneumonia.”
MRSA not only destroyed lives, it drove up medical costs, mainly due to patients’ prolonged stays in hospital. According to a 2013 California study, the average hospital cost was around $14,000 per MRSA case, around twice the cost of other hospital stays.
Before, most MRSA occurrences emerged from hospitals or healthcare institutions, where the risk of infection was higher, and were identified as hospital-associated MRSA, or HA-MRSA.
Though Hong Kong’s first official CA-MRSA case was recorded in 2004, Ho said the first case actually occurred in March, 2001, when an 8-month-old boy who displayed a number of severe illnesses died 26 hours after being hospitalized.
Since then, Ho, chairman of the Health Protection Program for Antimicrobial Resistance at the Centre for Health Protection, has been monitoring and observing the transmission of the superbug.
Ho, a close colleague of Kao, is an avid researcher. He contributed to Kao’s non-antibiotic study, and both men believe the overuse of antibiotics has helped S. aureus develop resistance to many of them.
Growing use
In the first half of this year, Hong Kong saw 632 CA-MRSA infections, according to the Center for Health Protection, more than twice the number reported during the whole of 2008.
According to a recent survey, about 49 percent of 1,200 people questioned in the city said they took antibiotics last year, up from 34.6 percent in 2011.
In a separate study, 97.9 percent of 1,255 interviewees said they obtained
The percentage should have been lower, given that only 10 percent of flu symptoms are caused by bacterial infection and antibiotics act against bacteria but not viruses. Therefore, it seems likely that a large number were prescribed to treat viral infections, such as common colds, sore throats and flu.
On the positive side, antibiotics have been prescribed as preventive measures. Patients with viral infections have weakened immune systems, which makes them vulnerable to secondary bacterial infections. Antibiotics may help to prevent that, Kao said.
Margret Ip, honorary consultant at the Department of Microbiology at Prince of Wales Hospital, said Hong Kong’s public hospitals imposed vigorous regulation of antibiotic prescription after SARS, so antibiotic misuse may be rife in the private health sector.
As pathogens keep evolving and become more complex, the symptoms of bacterial and viral infections are now more indistinct, Ip said: “It’s possible that doctors in private clinics, without sufficient and updated patient data to refer to, mistakenly prescribe antibiotics for the wrong ailments.”
She suggested establishing a platform to share information between hospitals and clinics, so family doctors can keep track of changes in contagious diseases and the best remedies to employ.
Hong Kong’s private practitioners can log antibiotic prescriptions on an electronic health record system, but it’s voluntary.
The city is using the platform to monitor antibiotic use in private clinics, but many people have questioned its effectiveness because physicians rarely report excessive prescription if it is not mandatory to do so. antibiotics from a
Rising consumption
physician.
Globally, surveys indicate that antibiotic consumption in high-income economies was relatively constant from 2000 to 2015, and the rise was predominantly driven by low- andlower-middle income economies, such as India, China and Pakistan.
Moreover, humans are not the major consumers. Instead, animals account for large amounts of antibiotics that are used to treat or prevent disease, or fatten them for market.
In 2013, global use of antibiotics in food animals was around 131,100 metric tons, and is projected to rise to around 200,000 tons by 2030.
“It would be best to ban all antibiotic applications on farms. However, that would lead to rising food prices and make life tougher for people on lower incomes,” Kao said. “Most poultry in Hong Kong is imported, and in light of that it’s hard to impose controls.”
Last year, the Ministry of Agriculture on the Chinese mainland issued measures to reduce antibiotics in poultry and livestock, and authorities intend to abolish more than 100 high-risk drugs currently used on animals. By 2020, more than 97 percent of poultry, livestock and aquatic products on the mainland are likely to qualify as secure food sources, with antibiotic residues well within safety standards.
In November, the Hong Kong government published a five-year plan to combat drug resistance.
By 2022, it aims to bar breeders from using antibiotics on livestock unless the drugs are prescribed by vets. In addition, the Agriculture, Fisheries and Conservation Department will stop issuing antibiotic permits that allow farmers to purchase and possess antibiotics used on farm animals.
Greater recognition
Recent lab tests on mice show that those infected with CA-MRSA had a 40 percent survival rate after seven to 10 days. A separate group, injected with non-antibiotic M-21, Kao’s breakthrough, all survived.
The findings were published in July in the journal Proceedings of the National Academy of Sciences of the United States of America.
Ip, of Prince of Wales Hospital, supports Kao’s approach. “In light of today’s sweeping antimicrobial resistance arising from antibiotics, the non-antibiotic approach is the way to rein in the problem,” she said. Ip is exploring natural compounds in herbs such as skullcap root and Chinese goldthread to see if they can produce drugs to beat superbugs.
However, Qian Pei-yuan, chair professor of the Division of Life Science at the Hong Kong University of Science and Technology, said MRSA may still acquire the ability to fend off M-21, as it did antibiotics.
This year, he identified an enzyme called D-stereospecific resistance peptidases, seen in many bacteria, which is a key factor in MRSA’s ability to break down peptide antibiotics, including vancomycin.
Kao anticipates that M-21 will be manufactured as a medication and undergo clinical trials after five years, before being tested on human patients. If it’s proven safe, he expects the first batch of M-21 to be used to treat patients with CA-MRSA.
The M-21 breakthrough, a quantum leap in the fight against antimicrobial pathogens, earned Kao’s team first prize at the Innovation Academy Awards at the International Consortium for Prevention & Infection Control last year.
The consortium is a leading platform for scientists from more than 100 countries to discuss measures to tackle antimicrobial resistance.
“The award demonstrates that global infectious disease experts are giving the nod to our non-antibiotic approach. They see it as a promising way to possibly iron out problems arising from rampant drug-resistant bacteria,” Kao said.