The battle against drug resistance just got tougher

Do we have any leverage against drug-resistant organisms? Dr Maciej Boni explains the biological fitness cost of drug resistance and the worrisome scenarios that could develop if we lose this small advantage in our fight against drug-resistant pathogens. Dr Boni is a Wellcome Trust–Royal Society Sir Henry Dale Fellow leading a research programme on the epidemiology and evolution of influenza in the tropics. Parts of his doctoral and postdoctoral work focused on developing public health strategies aimed at rolling back drug resistance.

Can we eliminate drug resistance?

In some areas of global health we have made great strides over the past decade. Although much remains to be done, great progress has been made in the fields of malaria, HIV, the neglected tropical diseases, tuberculosis and many other infections. Maternal and child health have been improving, and funding for global health programmes has increased significantly. But the rise of drug resistance puts many of these advances at grave risk.

Drug resistance became a major public health problem in the later decades of the 20th century, as the world’s most serious pathogens began to repeatedly demonstrate the ability to elude our best treatments. In the 21st century this international threat to public health cannot be ignored.

Under extreme pressure from antibiotics, antivirals or other drugs, the majority of the world’s pathogens have – sometimes quickly, sometimes slowly – evolved resistance to the drugs we use to combat them. For the pathogens, this benefit of drug resistance has typically come at a cost; although resistant pathogens have a biological advantage in the presence of an antibiotic, they are less fit than sensitive pathogens when the antibiotic pressure is removed and tend to die out. Thus, it appeared that natural selection had given us a foothold on this problem by making drug-resistant organisms more flawed than their drug-sensitive counterparts. However, recent results from a team of Wellcome Trust investigators and a team of NIH-funded investigators have shown that some pathogens are now able to develop drug resistance without that biological cost.

“This would be a nightmare scenario”

“This would be a nightmare scenario,” says Dr Jeremy Farrar, Director of the Wellcome Trust, “that resistant pathogens might be selected when exposed to antibiotics, but would expand in numbers even if the antibiotic pressure is removed”.

“Much of the wonderful progress in global health over the last 20 years would be at risk, and this is not just an issue for the resource-limited world – it would change the way we practice medicine in this country” he says.

From past experience we know that bacteria have invented pumps to remove antibiotics from the confines of the cell wall, but operating these pumps requires energy that could otherwise be used for reproduction. Influenza viruses have changed the shape of one of their surface proteins that is bound by the drug oseltamivir (Tamiflu), but this altered protein shape means that new virus particles experience difficulty exiting the cells they are born in. This slows down the cell-to-cell spread of the virus.

In each of these examples these pathogens have been forced to trade some of their usual Darwinian fitness to become more drug-resistant.

Survival of the fittest

Fitness, the centrepiece of Darwin’s theory of natural selection, determines both how likely an organism is to survive to reproductive age and how many offspring it will have once it gets there. As the generations pass, fitter organisms that produce more offspring crowd out organisms that produce fewer offspring, and this increases the chances of extinction for the less fit organisms.

If drug-resistant organisms are forced to compete with non-resistant strains, they will be outcompeted if the drug they are resistant to is not present. This is due to the fitness cost associated with drug resistance mutations, and it means that we may have a chance at eliminating certain types of drug resistance. A real-life example of this was seen in Malawi in the 1990s with the elimination of chloroquine-resistant malaria; this was possible because the resistant strains were noticeably less fit than the chloroquine-sensitive strains.

It’s not quite as simple as it sounds though. The big catch is that drug-resistant organisms can only be forced into this losing scenario in the absence of drug treatment. In Malawi, chloroquine was completely withdrawn from use in 1993, but this was only possible due to the availability of other antimalarials. Switching to using different antimalarials removed the benefit of chloroquine resistance, allowing chloroquine-sensitive strains to outcompete the chloroquine-resistant strains. The chloroquine-resistant strains disappeared after eight years.

The good news is that with the availability of multiple types of antimalarials and multiple types of antibiotics, we may have an opportunity to selectively withdraw certain drugs – or at least to reduce their use by managing the simultaneous use of multiple types of drugs. The more types of drugs that are available, the more easily this can be done. In both academic and pharmaceutical-industry research planning this simple fact should serve to underscore the critical need for continual development and discovery of new drug classes.

‘Resistance management’ strategies have been gaining popularity over the years, and if executed correctly they might help turn the tables in our battle against drug resistance. But all of these strategies rely on the simple biological assumption that if a certain drug is prescribed infrequently, drug-resistant strains will be outcompeted, and resistance to that drug should fade.

The bad news is that recent research has shown this assumption may not always hold true.

Unwelcome developments

Late last year, Wellcome Trust-funded and NIH-funded scientists published results showing that recently emerged drug-resistant strains of Salmonella enterica and influenza virus have not been associated with any fitness costs. With no obvious fitness cost to the organisms, even if we were to completely change our treatment guidelines for these pathogens, these drug-resistant strains would be predicted to spread worldwide.

“…entire classes of drugs would be rendered useless, and the situation would be irreversible”

If the laboratory results from these studies hold up in a natural setting, entire classes of drugs would be rendered useless, and the situation would be irreversible.

In the lab

Dr Stephen Baker, a Wellcome Trust–Royal Society Sir Henry Dale Fellow, and Head of Enteric Infection Research at the Oxford University Clinical Research Unit in Vietnam, was interested in showing how costly fluoroquinolone resistance would be to Salmonella bacteria – the causative agents of typhoid fever. Fluoroquinolones are the globally recommended first-line treatments against typhoid fever, and determining the fitness cost of fluoroquinolone resistance would help in planning public health strategies to reduce resistance levels. “We were shocked to find in our lab experiments that the fluoroquinolone-resistant strains were better at replicating than the sensitive strains, in the absence of any antimicrobial pressure,” says Dr Baker. “If these characteristics translate to a clinical setting, it means that we are left with no options for reducing fluoroquinolone resistance. These resistant genotypes are here to stay.”

“If these characteristics translate to a clinical setting, it means that we are left with no options for reducing fluoroquinolone resistance. These resistant genotypes are here to stay.”

On the other side of the world in New York City, Dr Nicole Bouvier’s group at the Icahn School of Medicine at Mount Sinai has been performing similar experiments on the H7N9 influenza subtype that emerged in coastal China in early 2013. The most effective class of drugs against influenza virus infections is the neuraminidase inhibitors – drugs that bind and disable the influenza protein neuraminidase, which is critical for viral spread in lung tissue. “We set out to determine the fitness differences between drug-sensitive and drug-resistant influenza strains, as the drug oseltamivir is likely to be used in a wide range of clinical settings for treating H7N9 infections,” says Dr Bouvier. “Unfortunately, we found that the sensitive and resistant viruses showed no detectable differences in the rate of replication in human lung tissue, in virulence effects in mice, or in their ability to transmit among guinea pigs. Transmission was inefficient for both of the H7N9 viruses that we tested in our experiments, but, surprisingly, transmission of the drug-resistant virus was no less efficient than that of the drug-sensitive version.”

Global concern

If oseltamivir resistance becomes entrenched in H7N9 influenza viruses, it may be impossible to eliminate, neutralising the most important drug we have to treat influenza infections.

Both typhoid fever and avian influenza carry a high risk of death if left untreated. Case fatality rates for untreated typhoid are between 10 per cent and 20 per cent, while the various avian influenza outbreaks the world has experienced since 1997 have come with reported mortality rates of between 30 per cent and 60 per cent. If drug resistance erases our ability to treat these infections, patient outcomes in clinical settings are likely to worsen.

For typhoid this could translate into a major public health concern, as there are an estimated 22 million cases of typhoid reported globally per year. The availability of second-line drugs, such as third-generation cephalosporins, ameliorates the problem to some extent, but these drugs have poor penetration against intracellular infections like typhoid and are less effective.

For avian influenza we are not so lucky, as there are few alternate drug classes available to treat this viral infection. Our only hope is that new therapies are developed and that such infections remain rare.

It is impossible to say if other types of drug resistance will present us with the same challenges, but we know that new types of drug resistance emerge every year. Perhaps the next research challenge in this field will be classifying these resistance mechanisms by whether they do or do not carry a fitness cost. Drug-resistant pathogens that do not carry fitness costs present a significant challenge as we currently have few available tools to fight these newly adapted pathogens.

“We are at a tipping point when the rise of drug-resistant untreatable infections is a very real possibility”

Wellcome Trust Director Jeremy Farrar comments: “I believe the most important emerging infection challenge of the 21st century will be the development of drug resistance in existing infections. We are at a tipping point when the rise of drug-resistant untreatable infections is a very real possibility.  This work, which challenges the dogma, highlights how important this issue is.

“I qualified in medicine just at the start of the HIV epidemic when the infection was untreatable. It was a horrific time when people died for the lack of any effective treatment. The emergence of drug resistance across many infections risks us returning to the pre-antimicrobial era when simple infections were similarly untreatable.”

The research papers referred to in this feature are:

Hai R, Schmolke M, Leyva-Grado VH, Thangavel RR, Margine I, Jaffe EL, Krammer F, Solorzano A, Garcia-Sastre A, Palese P, Bouvier NM (2013).  Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nature Communications 4:2854.

Baker S, Duy PT, Nga TVT, Dung TTN, Phat VV, Chau TT, Turner AK, Farrar J, Boni MF (2013).  Fitness benefits in fluoroquinolone-resistant Salmonella Typhi in the absence of antimicrobial pressure. eLife 2:e01229.

Image Credits: Testing antibiotic sensitivity – Sotiris Zafeiris, Wellcome Images, Chloroquine -  Lauren Holden, Wellcome Images, Salmonella enterica - Mark Jepson, Wellcome Images