[Ip-health] Forbes: The Grim Prospect Of Life Without Antibiotics

Joanna Keenan-Siciliano joanna.l.keenan at gmail.com
Thu Jun 5 02:44:45 PDT 2014

The Grim Prospect Of Life Without Antibiotics
By David Longtin and Henry I. Miller

It was not until the years just after World War II when streptomycin, the
first truly broad-spectrum antibacterial agent, came onto the market, and
penicillin began to be widely available that the Golden Age of antibiotic
therapy really began.  Before that, even seemingly trivial infections of
the skin, lungs or other organs could lead to sepsis and death.  We may now
be on the verge of returning to a pre-antibiotic era, a prospect that
public health experts find terrifying.

Bacteria are champions of Darwinian selection: As we try to kill them with
antibiotics, they mutate in myriad ways in order to survive.  And they have
quite a repertoire: Among other tricks, they develop less permeable walls
to keep the antibiotics out, create ways to degrade or extrude them or
alter the intracellular targets so that the antibiotics no longer work on
them.  Bacteria can even transfer these evolutionary adaptations from one
species to another, making it ever more imperative for us to come up with
new antibiotics that work through novel mechanisms.  It’s a never-ending
escalating arms race, and the harsh reality is that the bacteria are
winning it.

Increasingly, microorganisms are developing resistance to not only to
single antimicrobial agents, but to several.  These latter organisms are
called multidrug-resistant, or MDR, strains.  In some cases, the
microorganisms have become so resistant that no available antibiotics are
effective against them.  This led Dr. Arjun Srinivasan, assistant director
of the Centers for Disease Control and Prevention (CDC), to paint this dire
picture last year:

We are quickly running out of therapies to treat some of these infections
that previously had been eminently treatable. There are bacteria that we
encounter, particularly in health-care settings, that are resistant to
nearly all — or, in some cases, all — the antibiotics that we have
available to us, and we are thus entering an era that people have talked
about for a long time. . . We’re in the post-antibiotic era.  There are
patients for whom we have no therapy, and we are literally in a position of
having a patient in a bed who has an infection, something that five years
ago even we could have treated, but now we can’t.

According to the CDC, in 2011 there were approximately three quarters of a
million hospital-acquired infections in U.S acute care hospitals, and about
75,000 patients died during their hospitalizations.  This daunting tally
excludes people who acquire infections in other health-care settings, such
as outpatient surgery centers, where more than 60% of all operations are
now performed, and long-term care facilities.  As pathogens such as
methicillin-resistant Staphylococcus aureus (MRSA) have moved beyond
health-care facilities, drug-resistant infections have become common in the
community at large.

Drug resistance has important implications.  People infected with
drug-resistant organisms are more likely to have longer and more expensive
hospital stays and are more likely to die as a result of the infection.
When the first-line drug of choice for treating an infection won’t work,
physicians must resort to second- or third-choice drugs that may be less
effective and more toxic.

At the same time that bacterial resistance to antibiotics is increasing,
the number of drug and biotech companies developing new antibacterials is
shrinking.  This decline is due to a number of factors, including lack of
industry productivity, the low return on investment of antibacterials
compared with other therapeutics, difficulty in identifying new compounds
with traditional discovery methods, regulatory requirements that require
large and complex clinical trials for approval, and initiatives that
encourage antibiotics to be used as sparingly as possible (to minimize the
spread of resistance).

Neither the federal government nor private scientific philanthropy is
adequately supporting research on antibiotics and antibiotic resistance.
The National Institutes of Health’s National Institute of Allergy and
Infectious Diseases is “funding and conducting research on many aspects of
antimicrobial (drug) resistance, including basic research on how microbes
develop resistance, new and faster diagnostics, and clinical trials
designed to find new vaccines and treatments effective against
drug-resistant microbes.”  And another agency within the U.S. Department of
Health and Human Services, the Biomedical Advanced Research and Development
Authority (BARDA), funds antibiotics R&D, including costly late-stage
(Phase III) clinical trials, at some of the few pharmaceutical companies
still in the field.  Since 2010, BARDA has partnered with six drug makers
and has sponsored nine molecular candidates in Phase II/III clinical trials
to test the drugs’ efficacy against biothreats (e.g., plague) and some of
the worst bacterial pathogens now threatening society.

A 2002 change in FDA requirements for the clinical testing of antibiotics
helped to create the shortage of new antibiotics.  To enhance the
statistical power – and therefore, the confidence level — of Phase III
antibiotic clinical trials, FDA more than doubled the number of patients
required.  As antibiotics researchers David Shlaes and Robert Moellering
observed in that same year, because in the pharmaceutical industry business
considerations play a critical part in setting R&D priorities, corporate
programs with modest potential markets and large costs are automatically
deprioritized unless there is some other, overriding strategic issue to be
considered.  Thus, one unintended result of promulgating these guidelines
will be a decrease in the number of companies performing antibacterial

Their prediction was accurate: Since 2002 all but a handful of the major
pharmaceutical companies have abandoned their antibiotics R&D programs.

>From 2009 to 2012, in part at the urging of members of Congress who had
strong opinions but little understanding of the clinical testing of
antibiotics, FDA’s policy toward antibiotics testing became so risk-averse
and punitive that clinical trials of new antibiotics virtually ground to a
halt.  FDA even proposed that patients enrolled in clinical trials for
hospital-acquired pneumonia would be ineligible if they had received
another antibiotic within 30 days prior to their participation, making such
studies virtually impossible to conduct in the United States.

In July 2013, however, the FDA released new draft guidelines for the
conduct of antibiotic clinical trials – part of a self-described “reboot”
of policy at the agency.  The new guidelines may help, but some experts,
such as UCLA Professor of Medicine Brad Spellberg, have warned that the new
guidelines don’t represent significant change, and that much more
improvement is needed for trials to become feasible again.

FDA should adopt a promising concept originally proposed by the Infectious
Diseases Society of America (IDSA) known as the Limited Population
Antibacterial Development (LPAD) pathway, via which “a drug’s safety and
effectiveness would be studied in substantially smaller, more rapid, and
less expensive clinical trials” — similar to the way “orphan drugs” are
developed for rare diseases. Once approved, LPAD-type products would be
labeled for use in small, well-defined populations of patients for whom the
drugs’ benefits had been shown to outweigh their risks.  In this model,
studies of potential new antibiotics would need to enroll hundreds of
patients instead of the thousands now required and could be carried out
relatively quickly.

However, as Shlaes and Moellering have pointed out, to revive antibiotic
R&D, along with regulatory reform we will also need “value-based” pricing,
so that return on investment from antibiotic development is comparable to
that of other drug classes.

Consequently, we should expect LPAD-style antibiotics to cost as much as
$20,000-30,000 per course.  This is not unreasonable, given that many
marginally effective cancer drugs cost many times that amount; a new
two-drug regimen, sofosbuvir and ribavirin to treat Hepatitis C, is about
$84,000 wholesale; and Truvada, the drug combination of emtricitabine and
tenovir for HIV prophylaxis, costs $15,000 per year.  In 2010, Forbes
compiled a list of nine little-used drugs whose cost for the average
patient exceeded $200,000 per year.

One proposed legislative fix for the market failure in antibiotics
development is the bipartisan “Developing an Innovative Strategy for
Antimicrobial Resistant Microorganisms (DISARM) Act of 2014,” which would
require the Centers for Medicare and Medicaid Services (CMS) to reimburse
significantly more for LPAD-like antibiotics.  Currently, hospitals may
actually lose money because reimbursements fail to cover the cost of the
drugs.  (Hospitals would not be encouraged to over-use the drugs, however,
because reimbursement would cover only their cost, but no profit-margin.)

Another possible stimulus to R&D on antibiotics derives from a 2007 law — a
transferable “priority review voucher” awarded by FDA upon approval of a
new drug for a neglected tropical disease.  This PRV would entitle the drug
developer to move a new product of its choice to the head of the FDA review
queue, or it could be sold to another company.  The company that ultimately
redeems the voucher with the FDA could cut months from the review time of a
New Drug Application, which could be worth hundreds of millions of dollars
to a company eager to begin marketing a potential blockbuster.  This
voucher program should be expanded to include drugs for any infection.

Another incentive to encourage companies to undertake antibiotics R&D was
recommended in a 2009 analysis from the London School of Economics: a
guaranteed government purchase of a defined supply of the antibiotic that
would go into a national stockpile. A precedent for this is drugs developed
for pandemic influenza and anthrax.

With more enlightened regulation and improved return on investment, which
are necessary to make antibiotic development attractive, perhaps we can
avoid the extinction of the antibiotic era – and the reversal of our
species’ increasing longevity. Perhaps.

David Longtin is a Washington DC-based biomedical writer.  Henry I. Miller
is a physician and molecular biologist; he was the founding director of the
FDA’s Office of Biotechnology and is currently the Robert Wesson Fellow in
Scientific Philosophy and Public Policy at Stanford University’s Hoover

Joanna Keenan
Press Officer
Médecins Sans Frontières - Access Campaign
P: +41 22 849 87 45
M: +41 79 203 13 02
E: joanna.keenan[at]geneva.msf.org
T: @joanna_keenan


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