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The Ecology of Drug Resistance

October 2003

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The perils of prophylaxing against one disease only to introduce drug-resistant strains of another bug were the topic of a poster at the annual conference of the Infectious Disease Society of America (IDSA) in San Diego.

Researchers from the Universities of Maryland and Malawi joined forces to find out which opportunistic infections were striking people with HIV in Malawi and what drugs would be useful for treating and preventing those infections. This was done in preparation for a clinical trial of trimethoprim-sulfamethoxazole (TS, Bactrim) to be used as prophylaxis against salmonella and streptococcus, two pathogens that cause serious intestinal and respiratory disease in Africans with HIV. Yet there is a concern that, in Malawi at least, these organisms may have developed resistance to TS. A further concern is that widespread use of TS will produce cross-resistance to one of the only affordable drugs left to treat malaria in the region, sulfadoxine-pyrimethamine (SP). TS acts in a way similar to SP, but it has far less activity against malaria.

The researchers enrolled 548 HIV-positive adults and children with a mean CD4 count of 247 cells/mm3. More than half of the participants were women. The rates of hospitalization and death, not surprisingly, were increased in those with lower CD4 counts.

The most common diagnoses in this group during 2537 person months of observation were:

  • uncomplicated malaria (84 events);
  • non-specific diarrhea (69);
  • unspecified respiratory illness (60);
  • bacterial pneumonia (52);
  • fever of unknown origin (49);
  • oral candidiasis (48);
  • bacterial sepsis (38);
  • pulmonary TB (21); and
  • PCP (5).

One striking finding in this population is the low frequency of PCP, the signature infection of the AIDS epidemic in the U.S. and the rationale for TS prophylaxis in developed countries for persons with fewer than 200 T-cells.

Bacterial samples (62) were collected and analyzed by disc diffusion for antibiotic susceptibility. Salmonella typhimurium represented 52% of the pathogens, with 90% of those isolates having resistance to TS and 46% with resistance to azithromycin. Streptococcus pneumoniae accounted for 17% of the pathogens, with 91% of isolates resistant to TS, but all isolates retaining susceptibility to azithromycin. All other gram negative rods (E. coli and Klebsiella) were resistant to TS; 25% retained susceptibility to azithromycin.

Since most of the pathogens isolated were resistant to TS, the authors question the efficacy of TS as prophylaxis in the region. Any potentially effective prophylactic agent would have to prevent non-typhi Salmonella and Streptococcus pneumoniae and have broad-spectrum activity against respiratory and enteric pathogens. Such antibiotics, like azithromycin or ciprofloxacin, would likely be unaffordable. While the introduction of TS prophylaxis may not be very effective, the greater concern is the potential for harm if the prevalence of SP- resistant malaria in the region were to increase as an unintended result.

Coming Crisis in Malaria Treatment

Treatment for severe malaria in Africa is approaching a crisis point. The global burden of malaria is worsening due to drug resistance, with mortality increasing as resistance spreads. Resistance to chloroquine, a cheap drug that had been used for years, is now nearly universal. Its replacement, sulfadoxine-pyrimethamine (SP) is also cheap and effective, but its days are numbered as resistance spreads.

Resistance to SP originated in Asia, appeared in South America, and is rapidly spreading through Africa. The development of SP resistance may owe its origins to the earlier, widespread use of pyrimethamine by itself. SP resistance is now so common in South Africa that the drug is no longer used there. Resistance has gradually spread north to Mozambique, probably carried by mosquitoes. Although resistance to SP has been reported in many other African countries, including Kenya, Malawi and Tanzania, many outbreaks of malaria can still be treated by SP. However, if drug resistance against SP continues spread, the region will be left without an affordable weapon against this deadly infection.

When SP is no longer an option, the next alternative will cost 10 times as much, rendering it virtually unobtainable in most malarious regions. With no likely vaccine candidate on the horizon for at least 10 years, a new drug -- and a new approach -- for treating severe malaria in Africa is needed. And while there is no obvious successor to SP, in the future it seems certain that combination therapy -- the norm for treating TB and HIV -- will have to be adopted for malaria if the tide of drug resistance is to be stopped and malaria rolled back.

One of the most promising candidates for the next generation of malaria drugs is arteminisin, a plant-derived compound that originated in China. References to the plant as a malaria treatment have been found in documents dating back 1700 years, yet its activity was only rediscovered in 1972. Arteminisin is one of the most potent and fast acting malaria treatments available, killing up to 99.99 percent of parasites. In killing a young form of the parasite, it acts earlier during the 48 hour cycle of an episode of severe malaria than conventional drugs.

Thailand leads the world in drug-resistant malaria. After SP ceased to be effective there, mefloquine was introduced in 1984, yet resistance to it developed within 6 years. Faced with untreatable malaria, a combination of mefloquine with artesunate was attempted, which proved successful, producing sustained levels of efficacy greater than 95 percent. There was a reduction in the incidence of malaria and parasites were less mefloquine-resistant than before combination therapy was introduced. Transmissibility also seemed to be reduced. With this success, randomized trials of artesunate plus existing drugs were conducted in Africa. Although the existing drugs at that point were mostly worthless, the combinations had better efficacy than either drug alone. This led to a program in KwaZulu Natal in South Africa that employed mosquito control along with a fixed- dose combination of artesunate plus mefloquine as therapy. The result was virtual eradication of malaria in the region. This plan is now being replicated in Mozambique.

Artemether, another arteminisin derivitive, is an oil-based compound that requires intramuscular injection. A 1,900-person randomized trial of artemether versus quinine to treat severe malaria reported fewer deaths with the new drug, although marginal statistical significance has limited the impact of the study. Although this form of the drug is unlikely to be well absorbed, which may have limited its efficacy, it was shown to be safe, with the neurotoxicity seen in animals not observed in humans. Artesunate, a water-based compound, is now being manufactured, but current supply sources do not meet FDA approved manufacturing standards, and it could years before an acceptable formulation appears. One practical formulation of artesunate for the tropics may be a rectal suppository that the WHO is now assessing.

Artesunate champion Nicholas John White argues that a crucial principle for the success of new treatment campaigns will be to make the drugs available for free. In markets where ineffective drugs are common and inexpensive, the only way to introduce an effective drug is to out-compete the ones that don’t work. Free drugs will forestall an influx of counterfeit artesunate as was seen in Cambodia two years ago.

Much progress stands to be made in rolling back malaria and the tools, spraying, bed nets and treatment, are available and affordable. Dr. White argues that it is important to prove that progress can be made while the interest of funders is high. Malaria offers a more tractable problem than treating HIV or TB in the short run, yet the gains made in malaria would help the situation with those diseases as well. With effective drug combinations, eradication could be achieved with an investment of between $1 billion to $2 billion a year, and countries could see results within 5 years.

Yet there is much education and convincing to be done. Most proposals submitted to the Global Fund for malaria treatment rely on chloroquine and SP. Dr. White responded, "Countries are asking for drugs that don’t work. We have to provide an incentive for them to ask for drugs that do work. It may be best to argue from an economic perspective; that it makes economic sense to ask for effective treatments."

MSF Supports ACT

The Campaign for Access to Essential Medicines organized by Medicins sans Frontieres (MSF) has issued a call to support artemisinin-based combination therapy (ACT) for malaria treatment in African countries facing resistance to classical antimalarials. In 2002, "after extensively documenting resistance to current treatments in MSF projects and carefully considering data gathered by ministries of health in endemic countries," MSF decided to switch to ACT in all its programs.

MSF produced a report that criticised some international donors for supporting a "leave it alone" policy that doesn’t press endemic countries to break away from failing past practices and programs that depend on single-drug, resistance-prone drugs. Financial and technical support is needed to help these countries implement more effective strategies.

Next on the agenda is a movement to get WHO to push harder for implementation of its own recommendation that malaria treatment programs get their ACT together.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
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