Is Drug Resistance our Fault?

David McCormick

David McCormick

The Office of Public Health Practice hosted their annual symposium on Wednesday, and the theme was “Can the World be TB Free”?  I only had a chance to attend one of the talks (by Dr. Joseph McCormick), which dealt with the rising problem of multi-drug resistant tuberculosis (MDR-TB) and how our treatment strategies for TB may have helped this new disease to emerge.  In what is sadly a familiar story for many bacterial diseases, the discovery of streptomycin (the first antibiotic that was effective against TB) was hailed as the first step in the elimination of the disease, but as time as passed the drug has become less and less effective, forcing us to search for new treatments.  In the wake of the HIV/AIDS epidemic, TB has exploded and the growing problem of antibiotic resistance makes treating these people very difficult.

A wonderful cartoon from Wikipedia showing how drugs kill the tuberculosis bacteria, and how the bacteria respond.

So why does drug resistance happen, and how is it our fault? There are about 10 million (or 10^7 if you’re feeling scientific) individual tuberculosis bacteria living in each cavity.  About one bacteria out of every 10-100 million will randomly develop a mutation that confers resistance to any one of the two major first line drugs, rifampin and isonazid.  These mutations are quite rare, but given that bacteria are nothing if not effective reproducers, it’s safe to assume that approximately one bacterium per cavity is resistant to rifampin, and that another is resistant to isonazid.  This situation may not sound all that bad, but consider what would happen if the patient were to be treated with rifampin alone – every single bacterium would die except for the one that had developed resistance.  This bacterium is now presented with perfect growth conditions – no competition and lots of food – so it begins to multiply, and after a few days have passed, 10 million bacteria live in the cavity again – but this time all of them are resistant to rifampin.  Given the large number of bacteria involved, it’s now reasonable to expect that one of these resistant bacteria will then develop a resistance to isonazid, and following another single-drug treatment cycle with isonazid, MDR-TB is born.

What do we do to stop this from happening? Multidrug therapy. The current treatment recommendations are a 6-9 month administration of at least two antibiotics simultaneously, the most common being rifampin and isonazid.  Nine months is a long time, and it’s hard to convince people to stay on medication for so long, especially if they start to feel better soon after taking them.  Complicating the matter, most of those infected live on less than $2 per day, and the costs of this treatment are disproportionately high for them.  If you lived on $2 per day, it’s a safe assumption that you’d stop taking these expensive drugs as soon as you started feeling better too. In order to promote compliance, many countries now use directly observed therapy, where a local health worker will provide you the drugs and ensure that you take them for the full course in order to prevent resistance from developing.  While DOTS sounds like an ideal solution, it’s hard to implement and there are many social factors, including overcrowding, access to healthcare, and poverty that further complicate treatment.

To make a long story short, antibiotic resistance isn’t really our fault, as the bacteria develop these mutations spontaneously.  However, incomplete treatment with antibiotics imposes massive selection pressure on the resistant bacteria, and makes the process occur more quickly than it if nature were left to it’s own devices.  And although MDR-TB (and XDR-TB) wouldn’t exist if we hadn’t helped them along, it’s still much more important that we continue to treat those who need it most – and understanding why these problems occur is the best way to prevent them.

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