The war against infection: Superbugs vs super drugs

The war against infection: Superbugs vs super drugs

Originally published on Noted

Doctors and scientists are stepping up the fight against infections and treatment-resistant superbugs. But is our golden age of quick-fix antibiotics and safe surgeries about to end? Donna Chisholm reports.

When the headaches, cold sweats and the shakes started, Miranda Milne hoped she wasn’t coming down with the flu. Hours later, when her temperature spiked at 40°C, her blood pressure plummeted to 79/59 and her kidneys began to shut down, she probably wished she had been. Milne was not battling a virus, but a life-threatening immune response to infection – what doctors call sepsis. As she was wheeled into Tauranga Hospital’s intensive care unit in April 2014, the sepsis was winning.

A minor gynaecological procedure at a private hospital earlier that week had allowed the usually harmless enterococcus bacteria to migrate from her reproductive tract into her bloodstream and wreak almost fatal damage on her body. This had put her immune system into high gear, triggering a cascade of chemical messengers demanding the body respond.

The first cells to arrive at the frontlines are neutrophils, which kill the invaders by eating them – almost literally. When the neutrophils are overwhelmed, as they were for the first couple of days in Milne’s case, the body rushes more and more of them to the battleground. But these troops become less discriminating about what they kill. Not only is the bacteria targeted, but healthy tissue comes under “friendly fire”. The body now has two foes: the bacteria’s toxins and its own immune system. Damage is being inflicted on multiple organs in numerous ways.

Milne’s inflamed blood vessels were leaking fluid into her tissues, causing her blood volume to drop dangerously. To “fill the tank”, doctors had to pump her with intravenous fluids, causing visible bloating as the excess seeped into her tissues through leaky capillaries. At the same time, her limbs were visibly and rapidly wasting as her immune system broke down her muscles to release the sugars and amino acids that enable the liver to make new proteins to fight infection.

“Pretty much everything was deteriorating: her heartbeat, her respiration, her oxygen saturation levels,” says Milne’s husband, Alex Wheatley. “I had to shake her and say, ‘Take a few deep breaths – your oxygen levels are getting too low.’ She was starting to go into organ failure. Once you see the monitors, it’s pretty obvious when you’re in a downward spiral and if you don’t arrest that downward spiral, there’s only one outcome.”

But Milne was lucky. Doctors say her treatment was a textbook example of prompt and effective – and lifesaving – care. About 25% of people who contract sepsis will die from it. Official figures under-represent the reality, because of the way infection-related deaths are coded by the Ministry of Health. If you died of meningococcal disease, for example, you’d have sepsis, but your death would be recorded as the result of meningitis. Infectious diseases experts say that means sepsis isn’t given the recognition it deserves as a significant public health issue – and that inaction, together with the inexorable rise of antibiotic resistance – is costing lives.

In many cases, delayed recognition of sepsis is fatal. Milne was only hours away from being “past the point of no return”, says Tauranga infectious diseases specialist Diane Hanfelt-Goade, who treated her. When Milne arrived at the hospital’s emergency department on 11 April 2014, her symptoms suggested meningitis, and she was first prescribed two intravenous antibiotics recommended for this condition, ceftriaxone and vancomycin. Only the latter was active against the enterococcus bacteria in Milne’s blood; luckily, even by guessing wrongly at the cause of her symptoms, doctors had given an effective treatment. Nevertheless, her situation was dire.

Hanfelt-Goade, already alert to the likelihood Milne’s infection was related to her gynaecological procedure – an endometrial ablation to stop heavy periods – and knowing sepsis can trigger muscle aches and headaches, changed her antibiotics when she first saw her on 12 April. “She was right at the edge,” she says of Milne’s precarious condition. “We had to move quickly.”

But all too often, action, when it’s taken, is too late. “When you are just looking at someone under a blanket who’s feeling a bit breathless and tired, unless you have all the information in front of you, sepsis isn’t necessarily your first thought,” says Waikato DHB infectious diseases specialist and Sepsis Trust founding trustee Paul Huggan. The trust was formed last year to help put sepsis “front of mind” when doctors and nurses are assessing patients.

“We didn’t feel that sepsis had its own identity, its own personality within the hospital. There’s Code Stroke, Code Heart Attack… urgent therapy for all sorts of things, but there was a sense nobody really owned sepsis, because cases were admitted under many different clinical teams. Sepsis is a bigger issue than it’s been given credit for.”

Waikato is one of several DHBs promoting what’s known internationally as the Sepsis Six – the key steps doctors and nurses should take to recognise and treat potential cases, which doubles patients’ survival chances. “Sepsis is not a mild illness. You don’t walk around having a bit of it,” says Huggan. Red-flag symptoms include lack of responsiveness, confusion, low blood pressure, high heart and respiratory rate, low oxygen saturation, rashes and poor urine output.

Since the Waikato “Sepsis Ready” programme was launched in September last year, every adult patient identified in the emergency department with sepsis has seen a doctor within an hour, and most within half an hour – before, some patients waited six hours to be seen. While there’s no proof yet, Huggan believes the changes will save lives and shorten hospital stays.

Although Huggan acknowledges the increasing threat from antibiotic resistance, he says most bacteria remain sensitive to treatment and earlier diagnosis still has the potential to make the biggest impact, at least short-term.

So how realistic are the warnings of a coming antibiotic apocalypse, a future in which treatment-resistant superbugs render even routine surgery problematic and put entire populations at risk of a disease pandemic? Remember WHO director-general Dr Margaret Chan’s warning from 2015 that we were heading towards a post-antibiotic era in which common infections would once again kill? “If drug resistance causes doctors to lose more mainstay antibiotics, this will mean the end of modern medicine as we know it.”

Doctors and scientists interviewed for this story all regarded climate change as a bigger global threat – but they aren’t underestimating the risks of resistance. In a report published in 2016, the Institute of Environmental Science and Research (ESR) said total antibiotic consumption in New Zealand in 2013 was higher than 22 of 29 European countries that participated in a surveillance programme. Consumption here increased by 49% from 2006 to 2014, a rise across all regions, ages and ethnic groups.

One of the report’s co-authors, Ayesha Verrall, now an infectious diseases specialist at Wellington Hospital and a senior lecturer at the University of Otago, Wellington, says the results surprised her. “But you can’t tell in the kind of analysis we did whether it is a problem with over-prescription or high need, or a combination of both. You could say more prescriptions are going to Māori or Pasifika, so it’s higher need, but it might also be people over-calling illness in those groups. But we know we have a problem, because the overall consumption rate is what drives antibiotic resistance.”

In May, the Health Quality & Safety Commission released data showing 49% of people who visited their GP in 2017 received at least one antibiotic. Antibiotic use was highest in those aged four and under, or older than 85 and living in aged care. The commission says the data suggests antibiotics are being prescribed for colds and flu, “showing an opportunity to reduce use”.

Infectious diseases are the largest contributor to hospital admissions in New Zealand – and the percentage is rising, up from 20.5% in the early 1990s to 26.6% between 2004 and 2008.

Verrall says although resistance is a growing problem, “it doesn’t feel as dramatic as an outbreak. It feels to me like it’s creeping slowly and there will eventually be a tipping point and there are things we used to be able to do safely we won’t be able to do safely anymore. To consent to surgery, patients rely on us being able to say, ‘Yes, there is a risk of infection, but it’s treatable.’ But if that isn’t the case, then even the routine becomes much more risky.”

In April, United States health authorities warned about a new threat from a yeast, Candida auris, that’s causing fatal wound and bloodstream infections in hospital patients there and in 20 other countries, and doesn’t respond to anti-fungal treatment. Although no cases have been reported here, this illustrates what antimicrobial-resistant infection looks like, says University of Otago professor of public health, Professor Michael Baker. “It will probably not be a single catastrophic event like a pandemic, but more a series of reminders that we cannot rely on antimicrobial drugs to work in the same way as they have in the past. In most cases, these infections will be a particular threat to the most vulnerable, such as those with underlying illness, on immune-suppressive treatment, and the very young and elderly.”

Although the infectious disease burden is less than it was 50-100 years ago, it’s increasing in some disadvantaged groups who are contracting diseases related to poverty and poor living conditions, such as rheumatic fever, caused by streptococcal bacteria.

Mark Thomas, associate professor of infectious diseases at the University of Auckland, who began his registrar training 40 years ago, says advances such as HIV drugs, better childhood immunisation, higher vaccine uptake, cleaner hospitals and a few new antibiotics have improved outcomes in recent years. Growing resistance may increase deaths from infection by “an infinitesimal amount”, but the overall proportion will still be small.

That’s not to say resistance problems aren’t a daily issue for doctors. He says when he started training, almost every germ that caused bladder infections in women could be easily treated with oral antibiotics. “But now, once a week or month in our hospitals, there are women admitted for intravenous antibiotics to treat cystitis. It gets cured, but it is expensive and inconvenient. They need only to be admitted for a few days, but that’s a big change. It’s gone from being very, very rare that it couldn’t be treated orally to happening in maybe 5-15% of cases.”

Christchurch pharmacist Kathy*, 33, who has battled a series of antibiotic-resistant urinary tract infections, now regards antibiotics as something she’d take only in “life or death” situations. She developed a severe UTI in 2011 after shockwave treatment for kidney stones and was admitted to hospital with sepsis. Although she responded to intravenous gentamicin and Augmentin, she believes she was colonised with antibiotic-resistant bacteria during her hospital stay; when she subsequently developed a UTI within a couple of months of her discharge, it didn’t respond to three oral antibiotics and she had to be readmitted to hospital.

Antibiotics are the most common drugs she dispenses – and about 10% of prescriptions are for women with UTIs. She believes antibiotics in general are overused. “People come in with what I think is an uncomplicated viral cold that can sometimes take weeks to get better, and they think they need antibiotics. In some situations, doctors may feel the pressure if the patient is pushing for something, and feel obliged to give them, but a lot of the time things would resolve on their own. I don’t think people realise how dangerous antibiotic resistance could be.”

Kathy now takes a supplement that prevents bacteria adhering to the bladder wall and drinks plenty of water and cranberry juice. “I know I’m prone to resistant infections, so it really worries me and I have to concentrate on keeping well.”

*Name has been changed

Sepsis Trust patron Professor Steve Chambers from the University of Otago, a recently retired infectious disease specialist, says addressing community expectation will be an important part of the pushback against antibiotic resistance. “Antimicrobial use shows a rather startling rise over the whole country, and in my opinion, that’s not due to usage going up in hospitals – the vast majority is in the community. Finger-pointing at anyone is a really bad idea, but there is increasing demand for hospital services, and because of that, increasing pressure on GPs to keep people out of hospital. And there is the pressure of money. In days gone by, if someone went to the GP, the doctor might say come back and see me in a couple of days [if you don’t improve]. Now the patient says, ‘Well, doc, I don’t want to have to come back and see you,’ so there is pressure to prescribe then and there.”

In hospitals, Chambers says, we’re doing pretty well – better than the UK and Australia, at least. Our number of “defined daily doses” of antimicrobials is 700 per 1000 occupied bed days (the internationally recognised measurement), while Australia is 900 and the UK around 1200. It means that only small gains are likely to be made there. Another area to watch is rest homes and aged-care communities, says Chambers, who warns the loss of trained nurses to better-paid jobs in hospitals could impact infection control in these at-risk populations.

The other issue over which we have little control is the number of travellers and migrants who pick up resistant bacteria abroad before entering or returning to the country. “If you travel in India and don’t take antibiotics, you have about a 25% chance of having a resistant organism in your bowel flora by the time you come back. And if you do take antibiotics while there, you’ll have at least a 50% chance,” says Mark Thomas.

One of his most dramatic cases involved an Indian man who came to visit family in New Zealand after minor surgery on his toe. By the time he landed, the small wound was discharging pus, and a swab found it contained an E coli bacteria of a type that could be treated by only one antibiotic that had to be given intravenously. After 10 days’ treatment, his kidney function deteriorated so much the treatment had to be stopped and he required dialysis, but the infection hadn’t been halted. “He was persuaded to have the foot off so the infection was removed.”

Thomas advises against taking antibiotics if you can help it when travelling. “You might have diarrhoea for a couple of days and think, ‘That’s terrible, I need to take some antibiotics.’ You’re better not to, by and large. In our intestines, more than anywhere else in our body, we carry billions of bacteria that are adjusted to us and we have been carrying for a long time. When we take an antibiotic, it clears out a large proportion of those that are sensitive to that antibiotic and leaves fertile fields where other seeds being tossed onto them can grow. Overseas, you will be swallowing enough of the local germs that if they find a gap, they will fill that gap. So when you come back to New Zealand, there’s a greater chance you will have antibiotic-resistant germs living in your bowel. If you don’t have any problems over the next few months, year or maybe two years, they will probably be supplanted again by your local not-so-bad ones. But if they get into your kidney or into a wound in your foot in the weeks or months after you come back, yes, you may then have an infection that’s untreatable.”

Thomas has taken antibiotics just once in the past 20 or 30 years – when he was given eye drops after cataract surgery. “I was told to take it for two weeks and thought, ‘This is a load of rubbish,’ and I stopped after two days.” Don’t believe what you hear about having to finish a full course, he says.

“With a few infections – when the doctor looking after you for tuberculosis, for example, says keep taking your antibiotics, you keep taking them. When the doctor looking after you for HIV says keep taking your antivirals, you keep taking them. But when the doctor gives you Augmentin or Amoxil or Doxycycline because you have a cough and a sore throat and says you’ve got to keep taking them for 10 days, that’s rubbish. Stop taking them when you are better. The more antibiotics you take, the more you will make the bugs resistant.”

The most important message, he says, is not to take antibiotics if you don’t need them – badly. “Do you have an illness you had many times before and you got better? Just because it’s a bacterial infection doesn’t mean you need antibiotics for it.”

He says when otherwise healthy people develop a sudden, severe sepsis that kills them, it usually means the damage has already been done by the time the correct treatment starts, rather than that the bacteria is resistant. “The person usually has the germ running amok in their body before the antibiotics start.”

And the same bug can wreak havoc in one person and not another. “For some, even a few hours after starting antibiotics, you can tell they are on the slippery slope… they’re sometimes called dead men walking.” In meningococcal disease, for example, “once the rash begins, you might be thinking, well, there is a 20-50% chance they are going to die despite all we do”.

If anyone had the contacts to survive a life-threatening superbug infection, it was San Diego professor of psychiatry Thomas Patterson. His wife, Steffanie Strathdee, is an infectious disease epidemiologist at the University of California, but when Patterson contracted the deadly antibiotic-resistant Acinetobacter baumannii on a bucket-list trip to Egypt in 2015, even she turned in desperation to the internet for alternative treatments after more than a dozen antibiotics couldn’t cure him. The infection left him in a coma on a feeding tube and near death from septic shock.

Strathdee found references to a therapy in which bacteriophage viruses are used to infect and kill bacteria. “It’s like nature’s own alternative to antibiotics,” Strathdee told the Today show in the US. “You have a miniature Godzilla, the bacteria, and we’re sending in a miniature King Kong to attack it.” The treatment is mainstream in parts of the former Soviet Union and Poland, but not in the rest of the western world.

In February 2016, researchers looked for bacteriophages specific to Patterson’s bacterial culture. The treatment began on 15 March. Patterson woke on 20 March and is now fully recovered – although he was in hospital for another four months.

In a laboratory at Massey University’s Albany campus, scientist and senior lecturer Heather Hendrickson and her undergraduate and PhD students are on a phage-finding mission. They’ve discovered 24 new phages, which she calls nature’s ninjas in the battle against superbugs. Phages are in and on us, and also in the environment around us. They have been isolated from soil, compost bins and gardens – even an abandoned door in the middle of a field. “Phages are 10 times more numerous than bacteria,” says Hendrickson. “We co-evolved with bacteriophages and we are constantly consuming them. Some sit in the mucins in our nose and as we breathe in bacteria, they amplify and destroy some of those.” Phages also have a role in fighting off infections normally, but sometimes there might not be the right phages in the right place to prevent them.

Although phage therapy was discovered about a century ago, antibiotics were much easier to use and bacteriophages were largely forgotten – until recently. “Now that we are running out of antibiotics, people are returning, and saying there is something here we should be considering more carefully. There is still a huge amount to learn in this field, but I think they could be of major importance.”

There are likely two issues with the clinical use of phages, she says. One is that when phages destroy bacteria, toxic parts of the bacterial cell wall can break loose and cause more harm. A focus of research efforts has been on cleaning up cell debris from so-called “phage cocktails” given to patients.

The other issue is that phages are very specific to the bacteria they destroy, so a patient’s bacteria needs to be tested against a global “library” of phages.   “You can try a hundred different bacteriophages against a single bacteria and they might not work.”

Hendrickson’s students are part of an undergraduate training programme at Massey, which is affiliated to the US-based Howard Hughes Medical Institute’s Science Education Alliance. She says her six students have discovered bacteriophages that are able to kill Mycobacterium smegmatis, a cousin of the bacteria that causes tuberculosis, and which can trigger lung diseases in vulnerable people such as those with cystic fibrosis, but is not harmful in healthy people. “We estimate many of these phages can either already kill M. tuberculosis or can be easily evolved to do this.”

The technology is also being used in the fight against the honey-bee pathogen, American foulbrood. Beekeepers around the country are sending soil samples from under their hives to the Massey team in the hope the scientists can find bacteriophages that may be able to protect the bees. “If you put them in hives, and the infectious organism shows up, they might mean the infection never develops because the phages will kill the pathogen before it gets to the bees.”

About 20km south of Hendrickson’s lab, at the University of Auckland, microbiologist Siouxsie Wiles is also on the hunt for new weapons against bacteria, this time from fungi, the plant that in the 1940s gave us the world’s first mass-produced antibiotic: penicillin. Wiles wrote the short book Antibiotic Resistance: The End of Modern Medicine? in 2017, which concluded: “A future without effective antibiotics and other antimicrobials will affect us all. The stakes are enormous and time is running out.”

“Antibiotics are amazing,” says Wiles. “We wouldn’t be in quite this pickle had we been using them wisely. Resistance is inevitable because that is what microbes do: they evolve. We probably could have kept the drugs more useful for longer had people been paying attention to [penicillin inventor] Alexander Fleming when he said in his Nobel acceptance speech that we need to be careful how we use these drugs, because the bacteria can become resistant. It’s clear we need different strategies.

“It’s humanity’s arrogance, I guess, that we think we know best and have been using them willy-nilly. Also as we started to see fewer infectious diseases and more of other things, we thought, ‘Oh, these are drugs we don’t need now, we can go off and do something else,’ so that means the cupboard has been getting barer and barer.”

She and her team are looking to fill the cupboard by scouring fungi collected by Manaaki Whenua Landcare Research. Mycologists (people who study fungi) add to the collection, begun in the 1950s, every year when they and other enthusiasts go into the community on “fungal forays” to search for new species. Wiles’ team has screened around 700 different species and she says many show antibacterial activity; several are novel compounds never identified before.

We are living in what might later be viewed as a golden age, Wiles believes. “The way I am slowly coming around to this, and this is a bleak view, is that we are incredibly lucky and privileged. We live in an era where life expectancy has risen, there is good sanitation, incredible vaccines and good drugs, and most children don’t die before the age of five. For much of our species’ existence, that has not been the way we have lived. People 1000 years from now will look back and think, ‘Wow, weren’t they lucky?’ We are in an arms-race with an opponent who evolves faster than we can.”

Otago University researcher Professor Tony Kettle, who’s been involved in that arms race for 30 years, largely as a result of his mother’s tuberculosis, has focused on the role of the white blood cells that kill bacteria by producing chlorine bleach, similar to what we’d use to clean the toilet. But while neutrophils kill bacteria such as Staphylococcus aureus “really quickly”, they are much less effective at killing mycobacteria (a group including those that cause TB and leprosy).

“TB is very clever at evading our immune system, so more and more neutrophils come in to the site of the infection to try to kill the bacteria. In the process, neutrophils end up damaging the lung, so you get a friendly-fire situation. The immune system is what ends up killing the person because it destroys the lung in the process of trying to kill the bugs.”

Research for new antibiotics is often aimed at outwitting bacterial defence mechanisms against antibiotics. Some have pumps that expel antibiotics from the cells, others might make their cell walls more resistant to the antibiotic. Mycobacteria – the bugs involved in the development of tuberculosis – produce small sulfur compounds that shield them against the action of the immune system.

Christchurch-based Kettle and his team from the Centre for Free Radical Research received a $5 million, five-year grant from the Health Research Council in 2015. Part of their brief was to investigate drugs designed not to kill the mycobacteria, but to disarm their defence mechanisms against the neutrophils, allowing the immune system to kill them. “We think these sulfur compounds are going to be a major target for drugs. We want to work with drug companies to see what chemicals they have in their libraries – they have millions of them – that might prevent the bacteria from producing the sulfur compounds.” It’s a novel approach to help the immune system fight infections. “We’re saying, let’s not just try to develop a new antibiotic, because the bugs are going to become resistant to it in a matter of years. Let’s use a bit of stealth so the bugs are much less likely to find ways to resist drugs.”

Ironically, says Victoria University’s biotechnology programme director Professor David Ackerley, the profligate use of antibiotics in the last half of the 20th century and the growing risk of resistance has made the search for new antimicrobials suddenly more attractive to scientists. “Things started to peter out towards the end of the 1970s because previously unknown compounds were becoming much harder to find. Resistant bacteria weren’t yet a major problem and it seemed like we might already have nearly all the antibiotics we’d ever need. The sexiness of the field diminished substantially at that point, but we’ve been so irresponsible in the way we’ve used antibiotics that all of a sudden it’s really important to get new ones.”

The problem is, the increasing knowledge about the responsible use of novel compounds means it’s likely they’ll be used far more sparingly in future and only against resistant strains, which also decreases the potential value of new drugs, at least in the short term, to pharmaceutical companies.

Ackerley is working with postdoctoral fellow Dr Alistair Brown and PhD student Hannah Lee-Harwood to combat so-called “Gram negative” bacteria. These are traditionally harder to treat, in part because they’re very efficient at pumping antibiotics out of their cells. The team is collaborating with Dr Janine Copp, a New Zealand scientist based in Vancouver, to repurpose niclosamide, an existing treatment for tapeworms, as an antibiotic. The researchers discovered niclosamide can work extremely well if partnered with drugs that stop the bacteria pumping it out. The advantage is it’s an existing, proven and well-tolerated drug and in 2014, Ackerley and Copp filed a patent for its use to treat Gram-negative infections.

It’s an example of how scientists are taking a new look at old drugs, using technology unavailable a few decades ago. In the same way, Ackerley’s colleague Dr Jeremy Owen is harnessing the power of genetic sequencing to isolate and identify the antibiotic blueprint of microbes collected from soil samples. Most antibiotics we use today are produced in nature by microbes to fight other microbes, but historically, only about 1% of the bacteria from the environment has been able to be cultured in the laboratory and from there developed into useful drugs.

Owen isolates and characterises the bacterial DNA, the blueprint that encodes the chemical machinery needed to make the antibiotics, and then inserts that into new host bacteria, which can be grown in the lab and coaxed into making useful new molecules. He’s already discovered a number of compounds not seen before that show antimicrobial activity. “If we were to walk into your backyard and just grab a scoop of soil, there would be many, many bacterial species in there that are completely unknown to science.” It’s thought there are typically about 10,000 different bacterial species in a single gram of soil.

Nature might have given us the diseases – but it’s also giving us the tools to fight them.

Five years on, Miranda Milne is still coming to terms with the psychological impact of her near-death experience. “I haven’t had ongoing physical consequences, but it’s affected me on an emotional level,” she says. “It has changed me. It’s caused me a lot of anxiety and my robustness and ability to cope has lessened, so I’m trying to build that up again. It was an emotional ordeal.”

She is thankful to the doctors and nurses at Tauranga Hospital, especially her specialist, Diane Hanfelt-Goade. “Sepsis nearly killed me. So many people were working very hard to save my life and they did. They did a fantastic job.”

“We used to joke about having plastic surgery,” says her husband Alex, “but not anymore. You wouldn’t have it unless it was going to save your life, because it could end your life.”

This article was first published in the June 2019 issue of North & South.

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