TACKLING ANTIBIOTIC

RESISTANCE: WHAT DO WE

KNOW AND WHAT DO WE NEED TO

KNOW?

RAMANAN LAXMINARAYAN

By now, anyone who has not heard that

our antibiotics no longer work as well as

they used to probably has not picked up a

newspaper or magazine in years. Why?

you may ask. Rewind to when antibiotics

TAPAPQRELRPM@S?A@RMRPA=RELBA?REMSQdiseases just 72 years ago. They were

miracle drugs that were able to travel

through the body and kill living bacterial

cells while leaving human cells unharmed.

Even back then, Alexander Fleming, who

discovered penicillin as a result of an

experiment gone bad, predicted that, over

time, the constant selection pressure created

by the use of penicillin and other antibiotics

would give rise to new strains that would

be untreatable with the use of antibiotics.

Resistance had emerged even before he had

collected on his Nobel Prize and has been

increasing ever since.

CULTURES Vol 2, Issue 2 Page 51

Page 52 Across the Divide Laxminarayan

Changing behavior is our best bet to reduce the threat of resistance. A recent Lancet Infectious Diseases study showed that, in a set of six premier U.S. hospitals, one-third of antibiotic prescriptions were given in instances where there was no sign of infection. Campaigns have been shown to work in reducing the demand for antibiotics. Annual mass media campaigns in Belgium reduced antibiotic prescriptions by 36% between 1999 to 2000 and 2006 to 2007. It is unclear whether such campaigns could work in low- and middle-income countries and if WKHHHFWVZLOOEHVXVWDLQHGDIWHUthe campaigns have come to an end. However, behavior change problems have been encountered before in contexts as varied as smoking in public places, drunk driving, and driving without wearing a seatbelt. Those were WKRXJKW WR EH GLFXOW FRQWH[WVin which to change behavior, but,

in each instance, change was accomplished through a lengthy process of social education. In the case of antibiotic use, we have gaps in our understanding of how to nudge doctors to prescribe less and patients to demand fewer antibiotics.

The actual level of resistance is highly variable across time and geography. Much of what we know about resistance levels around the world comes from tertiary hospitals that are likely to cater to the sickest patients and therefore present the greatest level of resistance. If we inadvertently convey an incorrect message that most antibiotics are no longer working, we run the risk of physicians prescribing unnecessary antibiotics to reduce the chance that a patient does

Scanning electron micrograph of methicillin-resistant

Staphylococcus aureus surrounded by debris (above)

and killing and escaping from a human white blood cell (below).

not fail treatment with the more readily available first- and VHFRQGOLQH DQWLELRWLFV:KDWZHGRQRW NQRZ LV KRZ WR FRQYH\the treatment of resistance, without inadvertently making the problem worse by pushing doctors and patients into using unnecessarily powerful antibiotics.

A third unknown relates to how to price antibiotics. If priced too high, they become inaccessible to those who need them. If priced too low, WKH\DUHRYHUXVHGDQGEHFRPHLQHHFWLYH7KHVRFLDOO\DSSURSULDWHprice of antibiotics has to be considered in arriving at a socially optimal policy for antibiotic pricing.

CULTURES Vol 2, Issue 2 Page 53

TOP: Images from Flemings original penicillin article in 1929.

BOTTOM: Laxminarayan gives a TED Talk in September 2014.

The CDC conservatively estimates that at least 23,000 people died of

drug-resistant infections last year in the U.S.

alone. Meanwhile, few companies are in the antibiotics business, having moved onto

chronic diseases where there is much more money to be made.

RAMANAN L AXMINARAYAN

A fourth unknown relates to the focus on new drug development. Although all agree that new antibiotic classes are needed, there is much that could be done by way of innovation involving combination therapies, such as amoxicillin-clavulanate, that target both essential IXQFWLRQV DQG UHVLVWDQFH IDFWRUV 'HYHORSPHQW HRUWVcould repurpose old drugs to optimize dosing levels and the duration and route of administration and leverage pharmacokinetics and pharmacodynamics to identify promising combination drug therapies. For example, optimizing the dosing RI FROLVWLQ D GUXJ UVW LQWURGXFHG LQ the 1950s, can reduce toxicity and LPSURYHHFDF\Today, bacterial infections like pneumonia and gonorrhea, which could be treated with penicillin for SHQQLHV D GRVH UHTXLUH DQWLELRWLFVthat cost hundreds of dollars. The CDC conservatively estimates that at least 23,000 people died of drug-resistant infections last year in the U.S. alone. Meanwhile, few companies are in the antibiotics business, having moved onto chronic diseases where there is much more money to be made. But that does not make sense. Shouldnt pharmaceutical companies be interested in selling antibiotics in a world with more resistance and where people are dying of infectious diseases? After all, if payers or individuals would pay tens of thousands of dollars for a new cancer drug that extends life by two months, they should be able to pay a few hundred dollars for a new antibiotic that can extend life by decades? Turns out that few payers would approve such an expensive antibiotic because of fear that it would be overused and bankrupt them. The most expensive antibiotic that Medicare will pay for is Synercid at a cost of $236 per injection. In comparison, the most expensive cancer drugs cost over $50,000 per month and extend life by just a few months. Another issue is

CULTURES Vol 2, Issue 2 Page 55

C H E C K O U T RAMANAN

L AXMINARAYAN GIVING A TED TALK

THE COMING CRISIS IN ANTIBIOTICS IN

SEPTEMBER 2014. VIEW IT AT

http://ow.ly/MHcvW

Page 56 Across the Divide Laxminarayan

that only a trained oncologist can prescribe anticancer drugs, but any GP (general practitioner) can prescribe antibiotics. It is the medicine that most doctors think they know how to use but that few appreciate the value of.

It is unclear why we should expect new antibiotics to be cheap. After all, we have exhausted the lowest hanging fruit of antibiotics that were easily, even serendipitously discovered. Inevitably, newer antibiotics ZLOOEHKDUGWRQGDQGPRUHH[SHQVLYHWREULQJWRPDUNHWLQWKHVDPHway that oil costs a lot more money now than thirty years ago. This, by itself, is not a bad thing. Just as the rising price of oil is a signal to us that we should not count on oil lasting forever, the rising price of new antibiotics is a signal that we should be more careful about how we use the drugs we have. 2I FRXUVH WKHUH DUH WKRVH ZKRPD\QRWEHDEOHWRDRUGWKHQHZantibiotics, but the same is true for expensive gene therapy or cancer GUXJVDQGZHVKRXOGQGZD\VRIensuring that no one dies because of a lack of access to medicines that WKH\FDQQRWDRUGIn 2014, the federal Biomedical Advanced Research and Development Authority (BARDA) agreed to pay GlaxoSmithKline $200 million for work on new antibiotics, with no guarantee of success. It is unclear if this either solves the problem of a depleted pipeline or of incentivizing conservation. Even if there were a new antibiotic as a result of the process, what incentive would anyone have for conserving the ones we have if we thought the government was going to step in each time WRQGXVDQHZDQWLELRWLF"1RRQHZRXOGDUJXHWKDWZHVKRXOGVXEVLGL]HWKHGLVFRYHU\RIQHZoil wells to keep the price of oil low. So why would we make that argument in the case of antibiotics? Instead, the government should

)OHPLQJVUVWSXEOLVKHGDUWLFOHRQthe discovery of penicillin in 1929.

RAMANAN L AXMINARAYANRamanan Laxminarayan is director and senior fellow at the Center for Disease Dynamics, Economics & Policy, and senior research scholar and lecturer at Princeton University. Through his work on the Extending the Cure Project in the United States and the Global Antibiotic Resistance Partnership, he has worked to improve the understanding of drug resistance as a problem of managing a shared global resource. Laxminarayan is a series editor of the Disease Control Priorities in Developing Countries, 3rd edition.Laxminarayan has worked with the World Health Organization (WHO) and the World Bank on evaluating malaria treatment policy, vaccination strategies, the economic burden of tuberculosis, and control of noncommunicable diseases. He has served on a number of advisory committees at WHO, the Centers for Disease Control and Prevention, and the Institute of Medicine. In 2003 to 2004, he served on the National Academy of Science/Institute of Medicine Committee on the Economics of Antimalarial Drugs and subsequently KHOSHGFUHDWHWKH$RUGDEOHMedicines Facility for malaria, a QRYHOQDQFLQJPHFKDQLVPWRGHOD\resistance and improve access to antimalarial drugs. In 2012, he created the Immunization Technical Support Unit in India, which has been credited with helping to rapidly improve immunization coverage in that country.

CULTURES Vol 2, Issue 2 Page 57

aim to make sure that reimbursement through Medicare and Medicaid is appropriate to the cost of new antibiotics, make sure that those new drugs are used appropriately when taxpayers pay for them, and get out of the way.

Despite these unknowns, we know enough to slow down the rate at which antibiotic resistance has emerged and spread. Lack of evidence should not be a reason to improve how antibiotics are XVHGLQRXUKRVSLWDOVDQGFRPPXQLW\EXWDQLQYHVWPHQWLQOOLQJLQthese gaps in our understanding is a clear need.

Front CoverTable of ContentsLetter From The EditorHappening NowFoundations of Microbiology: Our Legacy and Gateway to New FrontiersThe Rise of CulturesThe Cutting Edges of Contemporary DiagnosticsMeasles and Rubella Elimination: Why Now?Tackling Antibiotic Resistance: What Do We Knowand What Do We Need to Know?Cultures interviews Ellen Jo BaronEmerging careers in microbial scienceBack CoverQuestions, Comments,& CorrectionsPhotography Credit