Malaria Treatment Increases Ciprofloxacin Resistance

I've written before about antibiotic resistance in the developing world. Because these poor communities don't have access to many antibiotics, one wouldn't expect high frequencies of resistance to antibiotics. Resistance to ciprofloxacin ('Cipro') is all the more shocking because these communities don't have access to this relatively expensive drug*. Not only is ciprofloxacin resistance observed, but, in these communities, it occurs at higher frequencies than in intensive care units in developed countries.

So what's a possible culprit?

Sadly, a recent paper in PLoS ONE suggests that treatment of malaria with chloroquine leads to ciprofloxacin resistance. Chloroquine inhibits proteins (polymerases) that make DNA; mutations in these genes confer resistance against chloroquine--and ciprofloxacin. While chloroquine is effective against malaria (and cheap), it is only weakly effective against bacteria. Also, chloroquine stays in the body for days (which, again, is good for treatment malaria which has a resistant phase in its life cycle). This is a perfect situation for the evolution of resistance: a continuous, low-dose exposure.

The authors found that patients treated with chloroquine acquired ciprofloxacin resistant E. coli. These resistant E. coli had mutations in the expected genes. When the authors selected for resistance to chloroquine in E. coli in the lab, they found... ciprofloxacin resistance.

Keep in mind that ciprofloxacin resistance, in severely ill patients, increases the chance of death four-fold. These strains aren't difficult to treat per se, but ciprofloxacin therapy, which is often used to treat severe infections (particularly in developing countries), will fail. Meanwhile, the patient is getting sicker, sometimes irreversibly so.

This is why we need new classes of antimalarials that kill malaria in novel ways.

*Ciprofloxacin, by developed world standards, is quite cheap, which should give you some idea just how destitute these communities are.

Cited articles: Davidson RJ, Davis I, Willey BM, Rizg K, Bolotin S, et al. 2008 Antimalarial Therapy Selection for Quinolone Resistance among Escherichia coli in the Absence of Quinolone Exposure, in Tropical South America. PLoS ONE 3(7): e2727 doi:10.1371/journal.pone.0002727

Lautenbach E, Metlay JP, Bilker WB, Edelstein PH, Fishman NO. 2005. Association between Fluoroquinolone Resistance and Mortality in Escherichia coli and Klebsiella pneumoniae Infections: The Role of Inadequate Empirical Antimicrobial Therapy. Clinical Infectious Diseases 41:923-929.

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So first, let me say I couldn't agree more that we need to develop novel malaria drugs; indeed this is the nature of my graduate work.
That said, something about this doesn't sit right with me.
There are over 500 million cases, and 1 million deaths of malaria a year (source: http://www.who.int/mediacentre/factsheets/fs094/en/index.html- in case you don't know, these are conservative figures).
Yet, either because the people that die of malaria are by and large far away, or because we get overwhelmed by those numbers, or because of something more sinister... we focus on something close to home- nosocomial infections in the US.

Let's say we have 1.7 million cases of nosocomial infections (source: http://www.cdc.gov/ncidod/dhqp/pdf/hicpac/infections_deaths.pdf).
Of those, let's say that 25% are of kleb and e coli (from the paper, which says ">20%")
Then we have 425,000
We can assume that of these, 75% will be suceptible to fluoroquinolones (source: "Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use" -JAMA 2003 Feb 19;289(7):885-8.). Therefore, 25% are resistant...
That gives us 106,250 cases of drug resitant infection. The paper you cited gives a 13% death rate for the drug resitant infection- that gives us 13,812 deaths/year. That's a lot of deaths (this is pretty pessimistic scenario). But it is a drop in the bucket of reasons we need malaria meds.

Note, on re-reading how you're framing this, I'm not all all bothered... you didn't really make the US nosocomial infection case at all.
Still, I suspect antibiotic resistance is dwarfed compared to malaria.
And the comment that "chloroquine works well" is maybe still true in parts of South America, but misleading generally.

Becca,

In other posts, I've discussed how it's the 'boring' bacteria that cause a tremendous amount of mortality in the developing world, particularly in kids under five. In terms of overall mortality, bacteria pneumonia and dysentery cause roughly the same amount of deaths as malaria. In that post, and the one I linked to in this one, I discuss some of the reasons why 'ordinary' bacterial diseases aren't getting the attention they should (not that AIDS, malaria, and TB should be ignored).

At my previous job, we were working with clinicians in Africa who had data suggesting that a lot of putative malarial cases were actually misdiagnosed Streptococcus pneumoniae; there's a lot of misdiagnosis (due to lack of lab culture) which is another source of the problem.

So the NIH started this Molecular Libraries Initiative for collaborating scientists to try and find new classes of drugs. This opportunity is great for the 'poor-man' killers because youre right Mike we really do need to find new classes of drugs. It's a bummer that large companies cannot fund the research to find new drugs...due to the lack of payback...but its understandable. I'm just happy that we now have a way to screen new drugs as academic researchers. In fact Sayed et al found a new drug for schistosomiasis using this library.

Yikes. I'm already on "permanent deferral" from donating blood because I lived in Nigeria for 3 years, now I find that my antimalarial and my autoimmune drug may have screwed me over for Cipro?

I've always wanted to turn some blood over at the WHO Tropical Diseases Center at the Texas university where I lawyer just to see if they can find anything weird.

this is a fantastic article. couldn't agree more and you write very succinctly.