Friday, November 20, 2015

The Crisis of Antibiotic Resistance: Are We Entering the Post-Antibiotic Era?

I had a wonderful opportunity to speak at a hospital in the Richmond community this week about antibiotic resistance and stewardship; I was asked to speak by that health system's Antimicrobial Stewardship Program as part of their activities around "Get Smart About Antibiotics" week. I was asked to write up my talk so they could share it with their health system. My write-up is below. 

The Crisis of Antibiotic Resistance: Are We Entering the Post-Antibiotic Era?

In November we celebrate the CDC’s “Get Smart About Antibiotics Week,” an event designed to raise awareness about the crisis of antibiotic resistance and to outline possible solutions. To answer the question of whether we are entering a post-antibiotic era: in a word, yes. But there is hope.
Antibiotics are potentially life-saving compounds, and their discovery has been critical to many of the medical and surgical advances we have seen in the past 75 years. Without antibiotics patients would not be able to survive the infectious complications of things like chemotherapy, organ transplantation and immune suppression for rheumatologic diseases.

We truly are at a crisis point with antibiotic resistance, especially for multi-drug resistant gram negative rods (MDR GNR). For many patients with MDR GNR infections we have essentially returned to 19th century medicine: in the absence of antibiotics we are left with pursuing aggressive ‘source control’ for infected tissues, when possible. An example would be a patient with a diabetic foot infection: whereas surgery and antibiotics can often cure these infections, a patient with an infection with a pan-resistant GNR may require amputation. This is not a doomsday scenario, this is reality for many of our patients in 2015.

The CDC estimates that 2 million people acquire infections with antibiotic-resistance bacteria yearly and 23,000 die as a direct result of these infections. It is estimated these infections lead to upwards of 35 billion dollars in excess healthcare costs in the United States alone. These statistics do not fully capture the scope of the problem, however, as the morbidity associated with these infections can be significant.

Here is the problem in a nutshell: antibiotic use selects for resistant organisms and the emergence of resistance has outpaced the development of new antibiotics. Most of the antibiotics in use today are natural products that organisms have been using to battle one another for millennia; we have ‘discovered’ these and adopted them for use in humans and animals. The antimicrobial ‘resistome’ (the resistance capacity of organisms to overcome antibiotics) already exists in nature, presumably for most if not all antibiotics. This is why we see resistance emerge fairly rapidly whenever ‘new’ antibiotics are deployed.

Antibiotic use extends far beyond therapeutic use in humans. It is estimated that 70% of antibiotic use is in animals for non-therapeutic use. Antibiotics are often used in the animal industry to grow larger, fatter animals faster. Any solutions to the crisis of antibiotic resistance have to span the continuum of use in both animals and humans.

Our relationship with the microbes who live on and inside is not well understood; there is increasing evidence that there may be a symbiotic relationship with our ‘microbiome,’ however. There are an astounding 10 bacterial cells for every 1 human cell in the human body. There is some intriguing data that suggests altering our microbiome with antibiotics can lead to things like allergies and obesity. Antibiotics should not be seen as innocuous.

It is estimated 50% of all antibiotic use in human medicine is unnecessary. The reasons for this are myriad. Front-line providers need rapid, accurate, affordable tests to diagnose the etiology of things like upper respiratory infections and urinary tract infections. We also need better protocols for treating various infectious conditions informed by properly performed clinical trials. We need better surveillance technologies to identify antibiotic resistance and standardized, risk adjusted data on antibiotic prescribing at the provider level.

Beyond all of the above we need new antibiotics to combat drug-resistant bacteria. To date there is no new anti-GNR compound with a novel mechanism of action in the antibiotic creation ‘pipeline.’ Although the FDA approval mechanism for antibiotics has become more streamlined in recent years, we have seen far fewer antibiotics in development. Many pharmaceutical companies have abandoned antibiotic development altogether.

So what can be done in 2015 to combat this issue by individual providers? First and foremost we should strive to prevent infections. Vaccinate patients according to national guidelines, wash your hands before and after patient contact and use appropriate contact precautions in the inpatient environment. We can also prevent the emergence of antibiotic resistance by optimizing our antibiotic use, especially for inpatient medicine. Record the indication, dose and expected duration when ordering antibiotics. Take a daily ‘time out’ for each patient on antibiotics to re-assess their use and continued need. Be aggressive with diagnostics early on to aid in de-escalation later. And perhaps most importantly partner with your Antimicrobial Stewardship Team. These teams exist to assist you in optimizing antibiotic use and can be a terrific resource.

Many of our patients have already entered the ‘post-antibiotic era.’ The development of antibiotic resistance has outpaced new drug development. The issue is complex but first and foremost we need to be aware of just how dire the problem is and that we all have a role to play in its solution. It has been 75 years since we saw the widespread deployment of antibiotics. Unless major changes occur in antibiotic use and production we are in danger of fully returning to 19th century practice for many of our patients. 

Tuesday, November 10, 2015

PK/PD in Clinical Practice

Multi-drug resistance gram-negative rods (CDC)
There is a great article in the November 1st issue of Clinical Infectious Diseases where Labreche and colleagues discuss recent updates on using pharmacokinetics-pharmacodynamics (PK/PD) in antimicrobial susceptibility testing.

Given the current crisis of gram-negative resistance and the paucity of new drugs in development it is critical that physicians learn to optimize their use of the drugs left in our armamentarium. For most antibiotics/ organisms susceptibility results are simply listed as "S"usceptible, "I"ntermediate, or "R"esistant. Oftentimes the Minimum Inhibitory Concentration (MIC) of the organism is not provided; even when these values are provided they are difficult for most physicians to interpret. What is needed is a better understanding of PK/PD principles as well as how to navigate the complex recommendations of the many organizations providing antibiotic susceptibility cutoffs.

Labreche and colleagues provide a nice overview of core PK/PD principles and also discuss the different agencies that provide breakpoints for different organisms and drugs (FDA, CLSI, EUCAST). For the latter, differences in how the organizations come up with recommendations are highlighted. Several useful examples of recent changes are provided and how these changes can be applied to clinical practice.