Return to pre-antibiotic era? AMR hits developing countries hardest

HONG KONG – New antibiotic agents are urgently needed to overcome the burgeoning problem of antimicrobial resistance (AMR) in infectious bacteria, but novel agents alone may not be sufficient to prevent a return to the dark days of the pre-antimicrobial era, an infectious disease specialist has warned.

The medical, social and economic effects of increasing levels of AMR are also likely to be most severe in the lower-income countries, especially those in Southeast Asia and sub-Saharan Africa, with these effects looking set to worsen unless drastic measures are taken.

In the wealthier countries of the West, multidrug-resistant bacteria such as methicillin resistantStaphylococcus aureus (MRSA) are generally a problem confined to hospitals, but the origins and effects of AMR fall mostly within communities in lower-income countries, wrote Stephen Baker in a perspective in the March 6, 2015, issue of Science.

Baker, a molecular microbiologist and head of the Enteric Infections Research Group at the Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme and the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam, pointed out that bacteria usually cause more severe infections in poorer countries, where there are fewer health care services and guidelines and restrictions on use of antibiotics.

"The impact of MDR is likely to be greater in low-income countries [where] circulating pathogens tend to cause more severe infections and access to good health care is not reliable," Baker told BioWorld Today, noting that such pathogens can include those responsible for typhoid fever and tuberculosis meningitis.

"The major cause of AMR is the overuse of antimicrobials in lower-income countries," said Baker, who is also a senior lecturer at the London School of Hygiene and Tropical Medicine in the UK.

In lower-income countries, "antimicrobials are widely available for sale in the community without medical consultation and without government policies restricting their use [so] community overuse and underdosing are common," he said.

Compounding the AMR problem is the fact that animals and humans often are treated with the same antimicrobial agents in lower-income countries, which can also be instrumental in encouraging the development of resistant strains.

In addition, very few patients receive conclusive diagnostic testing either before or after being treated with an empirical antimicrobial regimen. In many Asia countries, for example, febrile infections are frequently treated with fluoroquinolones or third-generation cephalosporins, which are also widely used in animal husbandry to increase production.

Restricting the use of the same classes of antibiotics in humans and livestock must therefore be an immediate priority, wrote Baker, including banning the use in animals of any new antibiotics that are developed for treating infections in humans.

In addition, antimicrobials, in particular newly developed compounds, should only be given to those patients who really need them, meaning that the capacity to perform microbial diagnostics and susceptibility testing needs to be greatly improved in lower-income countries, as does the development of rational prescribing practice.

"Reducing antimicrobial usage, either cycling or combining different drugs," can also help prevent the development of AMR, advised Baker, as can the use of new antimicrobial agents.

NEW ANTIBOTICS

The identification and development of new antimicrobials offers one potential solution for the problem of MDR, but this is a difficult, time-consuming and prohibitively expensive process, as well as an area that has been neglected by the pharmaceutical sector in recent years.

Indeed, there have been very few new broad-range antimicrobials brought to market in the past 30 years, despite an alarming rise in serious infections by gram-negative bacteria in particular, noted Manos Perros in aScience Perspective accompanying Baker's article.

Perros, who is vice president and head of infection innovative medicines at Astrazeneca plc., pointed out that basic research on bacterial resistance and antimicrobial drugs "has suffered a double blow of chronic underfunding and short-term focus."

And even if such a novel therapy were to become available, its introduction into the low-income setting, where it is arguably most needed, might well be futile, as it would almost certainly lead to the rapid development of resistance to any such new agent.

For example, before the advent of the antimicrobial era, typhoid fever had a mortality rate of around 20 percent, which was dramatically reduced when effective antimicrobial therapies were introduced.

Following the emergence of MDR strains against those early antimicrobials, the fluoroquinolones became the recommended therapy for Salmonella spp in the 1990s. However, reduced susceptibility to these compounds emerged almost immediately.

"We are on the verge of widespread resistance to fluoroquinolones in typhoid fever," warned Baker.

"There are few alternatives, and thus a very real possibility of a return to conditions like those in the pre-antimicrobial era," he said. This retrograde step could possibly be avoided "by limiting use and promoting combination therapy," Baker reiterated, "although data coming from low-income countries trying these approaches are limited and this may turn out to be too little too late."

Nevertheless, he pointed out that any new antimicrobial drugs would have to be introduced within a larger context of improved health care and regulation, for the medicines to have an impact on infections in lower-income countries.

But by far the major problem presented by AMR with regard to the discovery and development of new antibiotics is the shortage of time in which to accomplish this, Baker told BioWorld Today.

"We need to start tackling this issue now and we need new programs to find new drugs [and] the other major issue here is that we may not have too many new targets," he cautioned, since "the AMR mechanisms now circulating may additionally provide cross-resistance to new drugs."

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