Invited Commentary: Brad Spellberg, MD

Pulmonary Central: This month brings us two interesting articles with opposite conclusions about the prevention of MRSA transmission in the ICU using screening and barrier precautions. The VA study showed a 60% reduction in infections; a multicenter civilian study showed no impact. What can we take away from these seemingly contradictory findings from two well-done studies in the New England Journal of Medicine?

Dr. Spellberg: These two articles highlight the fact that we don’t actually know what works, and why things work when they work, in most areas of infection prevention. There are elements of these bundles that must be working. It’s hard to write off the VA study as being due to bias or error -- it’s a large study and showed a large effect. And there are other rigorously controlled studies that show that bundled interventions work. But we have no idea which elements in the bundles are responsible.

It’s very easy for multicomponent bundles to be tweaked in small ways, and in so doing you could easily neutralize the effects of the bundle. But the bottom line is, we don’t know which parts of any of these bundles are what works.

PC: You were the first author on the Infectious Disease Society of America’s policy paper published this month, “Combating Antimicrobial Resistance: Policy Recommendations to Save Lives.” Antibiotic resistance is a huge issue in the ICU, of course. What do you think could be done differently, or better?

Dr. Spellberg: First, I don’t think the kind of interventions that people have studied -- like central line bundles, VAP bundles, MRSA bundles -- are going to affect antibiotic resistance rates. Their goal is not to decrease the spread of genetic mechanisms that cause resistance. Their goal is to prevent spread of microbes onto people, whether the microbes are resistant or not.

My own bias is that human beings naturally tend to assume that we are responsible for all the things we observe, and I think in fact we rarely are. I think there are variables that go into the biology of resistance that are simply not understood or recognized. There are strain changes for these organisms over time that no one understands. 

The biggest changes we are advocating for are more at a policy level -- namely, removing the huge financial and regulatory barriers to new antibiotic development, promoting implementation of antibiotic stewardship programs at every healthcare center in the US, creating a more coordinated federal network and surveillance mechanism to detect and respond to resistance, etc.

PC: Do you think our overprescribing broad spectrum antibiotics in the ICU is a major contributor to antibiotic resistance?

Dr. Spellberg: I believe that the standard of care now, and appropriately so based on evidence, is that when you have sick patients in the ICU, you don’t sit there and obsess about what the exact bug is. You hit them as broadly as you can to cover all possible bugs.

But then you narrow. And that’s the key where I think physicians could do a lot better job. Sometimes you can narrow to the etiologic organism. And if you have the organism and don’t narrow, that’s a shame. You absolutely have no excuse not to narrow.

Unfortunately, we often never know the bug. As you well know, it’s very common. There, you’re not talking about narrowing; you’re talking about stopping. Those are hard decisions to make.

What I can say is to think about duration therapy. We treat infections for too long, almost across the board. Even in severe HAP or VAP, there’s no reason (with very few exceptions) to treat longer than a week. Evidence shows that except in the very small percentage of nonfermenting gram negative bacteria, a week of therapy is equivalent to two weeks. So to say “I’m going to treat everyone for 14 days because of those organisms,” you’re running the risk of more side effects for an unknown benefit. And going beyond the data besides.

But when you’re in the ICU – it's undeniable, you’re in the gray zone, and working in constant uncertainty. No policy or guideline can possibly apply in every situation. But let's at least have the conversation so people are thinking about it. 

PC: What's on the horizon, and on the agenda for attacking the problem?

Dr. Spellberg: Pharmaceutical companies have almost completely stopped creating new antibiotics. When the need is as great as ever before, and rising. And they have good reasons not to. The regulatory pathway to approval, the noninferiority pathway for new antibiotics is right now a swirling maelstrom. It’s confused and muddled and we need clarity from the FDA.  And clarity isn’t enough.  The trial designs the FDA demands must be feasible to conduct and clinically relevant, and what we’ve seen come out of the FDA for the last several years has been generally infeasible and clinically not relevant out of a desire for statistical perfection.  They have forgotten Voltaire’s wisdom, “The perfect is the enemy of the good.”  And if they don’t figure that out, more patients are going to die of extreme and pan-drug resistant infections.  On top of the regulatory problems, resistant infections in the hospital tend to be tiny markets for drug companies, it's a $50 million or $100 million a year market, compared to $15 billion a year for Lipitor at its peak. And so their behavior is completely understandable.

On top of that, current regulatory pathways are often antithetical to appropriate use of antibiotics.  Take a drug like tigecycline.  Here’s a drug that has activity against nearly pan-resistant Acinetobacter yet the primary use of the drug is for skin infections and community acquired pneumonia, both of which we have many, many narrower treatment options for.  Does that make any sense?  But skin and CAP are what it is FDA indicated for because the trials done by the company leading to approval were for skin and CAP.  By law, the company can only market a drug for the indications approved by the FDA.  So we have drug reps marketing tigecycline to hospitals resulting in huge inappropriate use for skin and soft tissue infections, when what we should be using it for is Acinetobacter ventilator associated pneumonia. But tigecycline doesn't have an FDA indication for that! So "appropriate" use is completely out of line with FDA indications today.

What we are trying to do is work with FDA to create pathways that meet actual need, such as superiority trials for XDR and PDR infections.  We also are suggesting new indications through organism-specific studies, not disease-specific studies. For areas of extreme medical need. For example, demonstrate efficacy for KPC Klebsiella, or XDR Acinetobacter or Pseudomonas causing infections wherever they occur in the body, rather than just focusing on VAP, or just focusing on intra-abdominal infections. Plus in certain circumstances these studies could be conducting using historical controls instead of active controls, with postmarketing studies.

PC: Any success on the policy or legislative side thus far?

Dr. Spellberg: After 7 or 8 years of not getting anywhere, the last year we've seen tremendous traction on Capitol Hill. 

There are multiple pieces of legislation, with two major initiatives having a reasonable chance of getting through someday soon. One is called Generating Antibiotic Incentives Now (GAIN), sponsored by Phil Gingrey, who is actually a physician, an Obstetrician, and a representative from Georgia, to create economic incentives to draw the pharmaceutical industry back into the antibiotic business. 

The other is called Strategies to Decrease Antibiotic Resistance, and it would create infrastructure to make the federal response to antibiotic resistance more coordinated. 

PC: Anything else you wish we would be thinking about as we wield our prescribing pens?

Dr. Spellberg: When you have sick patients and you're in the gray area you're in a tough position. But part of the decision should involve asking, how much damage am I doing to society and the environment when I prescribe these drugs? 

There were 36,000 kilograms of vancomycin used in U.S. hospitals last year. That number probably represents more than the sum total of vancomycin produced in nature in the history of the world. And we used it in one year in the U.S. The collective impact on society is staggering. And we can no longer pretend it doesn't matter.

Brad Spellberg, MD is Assistant Professor of Medicine at the University of California Los Angeles, an Infectious Disease Society of America Fellow, and the author of "Rising Plague." 


Infectious Diseases Society of America website

"Bad Bugs, No Drugs ... 10 New Antibiotics by 2020" (IDSA)

(Posted April 29, 2011)