Resistance to ciprofloxacin, a member of one of the most commonly used groups of antibiotics in the world, has been discovered by a team of Canadian researchers among people in remote South American villages who are believed to have never taken this medication.
The researchers found high levels of ciprofloxacin resistance in Escherichia coli in Amerindians from the Guyanese rainforest. These individuals are reported as never having received treatment with ciprofloxacin or related fluoroquinolone antibiotics. The Amerindians had, however, received frequent treatment for malaria (which is a parasite and not a bacterium) with chloroquine. Chloroquine is used widely around the world to combat malaria, and it also is a close chemical cousin of the fluoroquinolones.
Fluoroquinolones began widespread use in the late 1980s and now are among the most commonly used antibiotics in North America and Europe.
Because the bacteria carried by the Guyanese Amerindians were resistant to ciprofloxacin, the researchers suggest that it is possible that exposure to chloroquine may make the bacteria that people carry in their intestines resistant to fluoroquinolones--a theory that, if corroborated by further research, could have important public health implications in developing countries and in the developed world.
"We also found resistance in many other species of bacteria--including Salmonella--that are found in rectal swabs. We only screened that area of the body, but since the same process is occurring in multiple bowel species, it is likely occurring in non-bowel species as well," said the senior investigator Dr. Michael Silverman, an infectious disease specialist at the Lakeridge Health Centre in Oshawa, Ontario. "This means that chloroquine use for malaria may make the fluoroquinolones less effective for many common tropical diseases such as typhoid fever, diarrheal illnesses, and possibly also tuberculosis and pneumonia in the developing world."
He added that plans are being considered by major global health-promotion organizations to launch a campaign of widespread use in Africa and South America of a new anti-malarial treatment regimen called Artemesinin combination therapy ('ACT'). ACT usually includes quinoline drugs similar to chloroquine. These drugs are closely related to both chloroquine and fluoroquinolones. "We plan to carry out further studies to identify whether some quinolines may be less likely to induce quinolone resistance than others, and thus may be safer for malaria control programs," he said.
Dr. Silverman and 19 other volunteer health care professionals traveled by airplane from Bartica, a town that serves as the gateway to the interior of the Guyanese rainforest, to a handful of remote villages as part of annual humanitarian medical missions between 2002 and 2005. They took rectal swabs from 535 people in Bartica and the remote villages. They also asked the local inhabitants about whether they had ever been exposed to chloroquine or fluoroquinolones, and took water samples. They took the samples home and analyzed them.
The team found that 5.4% of the rectal-swab samples contained ciprofloxacin-resistant Escherichia coli, with a 4.8% resistance rate among the remote-village samples. This is a very high rate--particularly when compared to the 4% rate found in a recent study of ciprofloxacin resistance in American intensive care units where fluroquinolones are very intensively used. It is also particularly remarkable, noted Dr. Silverman, because fluoroquinolones had never been available in these communities.
The ciprofloxacin-resistant E. coli samples were also all found to be highly resistant to chloroquine, and to have characteristics that would confer resistance to all fluoroquinolones including the newer drugs levofloxacin and moxifloxacin. Furthermore, the team found that one of the water samples they took in 2004 contained ciprofloxacin-resistant E. coli and another contained a small amount of chloroquine, likely from human waste contamination.
Because of a widespread malaria outbreak in rural Guyana in late 2002, 30% of the villagers tested by the Canadian team in 2003 said they had been given chloroquine within the past six months, and in 2005 86% said they had used chloroquine within the past two years. The rates of chloroquine use may in fact have been much higher the investigators believe. This is because patient reports are not always reliable, and because of the very extensive treatment with chloroquine during the late-2002 malaria epidemic. The data also showed that community-wide fluoroquinolone resistance rose dramatically shortly after the malaria outbreak, further suggesting a link between chloroquine use for malaria and bacterial resistance to fluoroquinolones.
These clinical findings were confirmed by team members from Dalhousie University in Halifax, Nova Scotia, led by Drs. Ross Davidson and Ian Davis who demonstrated that in the laboratory E. coli that were exposed to chloroquine became resistant to fluoroquinolones including ciprofloxacin.
"Together, these data suggest that we must focus our efforts on prevention of malaria using mosquito-control measures such as bednets and by developing vaccines," concluded Dr. Silverman. "For the short term, however, we still will have no choice but to use these lifesaving antimalarial drugs. However we need to investigate which of the antimalarials can be used in the future with the least impact on bacterial drug resistance."
- Davidson et al. Antimalarial Therapy Selection for Quinolone Resistance among Escherichia coli in the Absence of Quinolone Exposure, in Tropical South America. PLoS One, 2008; 3 (7): e2727 DOI: 10.1371/journal.pone.0002727
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