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Infections and Antibiotics
By Dr. Shafiq Qaadri, MD

What is avian flu and are we expecting this alleged pandemic soon?
Avian flu actually describes a wide variety of influenza that occurs in birds. In general, bird influenza viruses are distinctly different from human influenza viruses. And while they can cause significant damage to the poultry industry, they are not usually particularly harmful to humans.

The avian flu that we are currently worried about is different and distinctive. It is a virus that is not only virulent in many species of bird, including chickens and ducks, but is also capable of infecting humans and causing serious illness.

Is this particular virus a half-breed, meaning part animal, part human?
No. We have always believed that new human influenza viruses should be those cross-species viruses, part bird and part human.

This virus appears to be, if you like, all bird, but has the potential of evolving and becoming more human. This isn’t what we were expecting with the next pandemic.

Frequently, the pharmaceutical industry is releasing another antibiotic—a new generation, new classes. Is this value-added, or an exercise in patent extension?
New antibiotics are a combination of value—new value for public health, and new value for drug companies.

There are some antibiotics, for example the respiratory fluoroquinolones, which are me-too drugs in the sense that they are all fluoroquinolones, but their activity is significantly different from ciprofloxacin. It does look like they are good things to have on the market.

Some other drugs, for example some of the newer cephalosporins, from a treatment perspective, are just me-too drugs. It’s also difficult to know early on if some drugs, like Ketek, are going to be useful for some isolates that are macrolide resistant, or whether they are so close to a macrolide that they really don’t add anything.

Sometimes you can’t tell until resistance evolves, whether a new drug will be useful or not.

What exactly is antibiotic resistance, and is it inevitable that all antibiotics will develop resistance issues?
It is inevitable that when you use antibiotics you select for resistance in bacteria—that’s a statement of evolution. How quickly this happens and how much trouble it causes is highly variable.

For example, we have been using penicillin for more than 50 years and all group A streptococci are still completely susceptible to penicillin. We keep waiting for something to happen, but it appears that these bacteria just can’t develop resistance to penicillin.

But with the introduction of antibiotics such as the quinolones, we had resistance issues develop within a few years.

Now it is true, that resistance will appear at some stage, there are some antimicrobial agents that continue to work well for a long time, and some that seem to select for resistance fairly quickly.

What are some of the key issues surrounding the use of antibiotics today?
There are two particularly important points about antibiotic use these days. Firstly, we learned from the major move to reduce the use of antibiotics in the mid to late 1990s that this was very effective in preserving antibiotics. So the 20 to 25 percent decrease in the community use of penicillins and cephalosporins in Canada has preserved the activity of penicillins and cephalosporins against our common pathogens like Streptococcus pneumoniae.

This is an important lesson that we need to keep working towards—not using antibiotics where we don’t need them, or where we can avoid them.

The second new point regarding antibiotics is that we are just beginning to understand that it’s possible to use antibiotics in ways that might reduce the selective pressure. So it’s not just about using fewer antibiotics, but it’s about rotating antibiotics, and choosing your drugs wisely.

For example, there’s accumulating evidence that very long half-life antibiotics, such as azithromycin, select for resistance more than other antibiotics. So we should be getting away from using these.

With regard to antibiotic resistance, are there different issues in children compared to adults?
No. In fact, although you see antibiotic resistance more often in kids, we’re understanding that that’s a function of the fact that we use antibiotics more in kids.

So it isn’t about adults and kids—it’s more about usage.

Can you estimate the percentage overuse of antibiotics?
There’s really not clearly such a thing. For example, so much of the time we will use antibiotics to treat a syndrome, and it’s not clear whether the syndrome was due to bacteria or viruses.
But we do know, for example, that we use three times per capita the number of antibiotics as are used in some of the countries in Northern Europe.

Now, it does seem that some of those countries are willing to tolerate a higher level of pain and complications than we might be. So I’m not sure that we want to set the same target for antibiotic use as the Netherlands. But clearly there is room for improvement in our overall antibiotic use…We need to be constantly vigilant advising people of areas in which they don’t need to be using antibiotics for a particular syndrome.

Let’s say you’re in a family practice setting, treating not only a child but the anxious mother, who does not feel adequately serviced unless she walks out of the office with a prescription for antibiotics. What would you say?

The first problem is that it takes a little more time to walk through not having antibiotics. That, of course, is a concern in a busy practice setting.
But it’s also about explaining that their children will have symptom relief. Antibiotics will work for symptom relief in mild bacterial infections, but you can do as well with antipyretics and other symptom-relievers.

It’s also about assuring parents that if there is a deterioration in their child’s condition, they will have access to follow-up. And it’s also about assuring people that the syndrome is not going to get better faster with antibiotics.

What are the mechanisms of antibiotic resistance?
Depending on what the antibiotic is, there are a number of ways that bacteria develop resistance. One of them is simple mutation: so when DNA is copied to make new bacteria, there’s a certain error rate in that copying. And when you change the DNA a little bit, generally there’s no functional difference. But occasionally this DNA mistake leads to the situation in which an antibiotic will not to bind as well to the bacteria. In the presence of antibiotic, those resistant mutant bacteria will then grow and multiply better. And these can be followed by second step mutations that follow.

Would you share some of the highlights of the recently published study on antibiotic resistance?
They looked at how physicians deal with patients who they think have a serious bacteremic pneumonia or serious infections due to Streptococcus pneumoniae—and whether they can predict if patients have an antibiotic resistant bacteria, and whether they should change the antibiotic based on that knowledge.
So they studied people coming into metropolitan Toronto and Peel Region hospitals who were coming in with bacteremic pneumococcal pneumonia. We asked what factors would predict antibiotic resistance.
They identified that overwhelmingly the most important factor was if patients had had an antibiotic for any reason in the three months before they were infected. If they had had a macrolide antibiotic, or a quinolone antibiotic, then the chances that their bacteria would be resistant to the same class of antibiotic was dramatically elevated.

So, if a patient comes in with a serious infection, you need to find out what antibiotic they have been on in the past three months, and then choose a different class of antibiotics.

They also identified in that study with fluoroquinolone antibiotics people who acquired their infection in a nursing home or in hospital were much more likely to have a resistant isolate. And that’s an important marker of the fact that we transmit resistant bacteria in nursing homes and hospitals.

In Toronto, in particular, this tells you that if a patient comes from a nursing home with a serious respiratory infection, you should no longer be using fluoroquinolone monotherapy to treat those infections—because we are losing the activity of these antibiotics.

Is that the main point on history that the physician should focus on—previous antibiotic use?
For everything except fluroquinolones, the only question you need to ask to know about antibiotic resistance in pneumococci in Canada, is whether you used an antibiotic in the last three months. This is a useful simple question.

For resistance to fluoroquinolones, you need to know if the patient has recently been in a hospital or a nursing home.

Are some antibiotics more likely to promote resistance, and why is that? Is it at the level of the DNA, the cell wall, or some other mechanism of action?
To a certain extent we don’t know. We’re working on parallel tracks, looking at what happens in the lab for selection for resistance, and at the same time looking at what happens in populations or communities.
We believe that antibiotics that have a long half-life select for resistance, and that’s a question of very long term exposure to very low levels of antibiotic. That, of course, is a laboratory way to select for resistance—that’s how you would actually set out to do that.

One of the other ways that bacteria get resistant is by acquiring pieces of DNA from other bacteria that are already resistant.

There is also some suggestion that antibiotics that achieve high levels in the particular tissues that are infected, kill the bacteria there. And the line is—‘Dead bacteria don’t mutate.’ That’s why we think the new fluoroquinolones are better than ciprofloxacin—because of more effective killing.

What is an estimate the financial burden of bacterial resistance?
In the billions of dollars.

What is your final message?
The most effective way with dealing with antibiotic resistance is preventing infections in the first place. That’s about using all of the vaccines you have; for example, the vaccine that we use least effectively is the 23-valent polysaccharide pneumococcal vaccine for adults. So get all your adults vaccinated for pneumococcus.

Wash your hands and teach your patients to wash their hands five times a day.

Dr. Shafiq Qaadri is a Toronto family physician and Continuing Medical Education lecturer. www.doctorQ.ca

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