Archive for March, 2015

How many bacteria/viruses are actually removed by the body’s natural defenses while we are sick?

March 10, 2015 Leave a comment

The answer to this question is completely dependent on the context of infection. For instance, when you brush your teeth, you introduce bacteria from your mouth into your blood stream and become temporarily bacteremic. Fortunately, the immune system clears these bacteria quickly. In this daily event, thousands of bacteria enter the bloodstream. After brushing, bacteria in the blood were below 104 cfu/ml, as estimated by PCR, and exact numbers are nearly impossible to quantify (Lockhart et al. 2008).

In contrast,  Ebolavirus replicates to ~107 – 108 virions/ml in the blood of non-human primates (Bente et al. 2009). The average person has ~5 liters of blood. Very conservatively, an Ebola survivor will have cleared ~5 x 1010 virions from just the blood. That’s 50 billion virions.

Keep in mind that this is also just a snapshot of a moment during infection. Viruses are constantly propagating, and a single virally infected cell can produce thousands of viral particles in a single day. It’s possible that over the course of a 2 week infection, 1011 – 1012 virions may be produced and cleared (it’s probably much higher). While this number is staggering, it somehow pales in comparison to the magnitude of the U.S. debt, which currently stands at ~$18 trillion, or $1.8 x 1013.

Geisbert et al. 2004 Nat. Med.

Geisbert et al. 2004 Nat. Med.

I also estimated the rough number of virions from the liver and spleen, two organs with significant ebola titer, and the total is nowhere near the magnitude of virions in the blood.* Additionally, ebola virus is being shed through mucosa and other bodily fluids. People generate ~ 4 liters of mucus daily in the gastrointestinal tract. I could not find an accurate estimate of Ebola viral titers in the mucus, but it’s unlikely to be near the levels of that in the blood. Granted, mucus could still contribute significantly to viral titer. There’s also the possibility that other organs harbor high titers of ebola virus, especially the gut.

*Approximately 104 – 105 virions/gram were detected in the liver and spleen using a mouse model for Ebola (Bray et al. 1996). Given that the average mass of a human liver is 1.5kg and a spleen is 140g (Molina et al. 2012), and using conservative estimates, about 1.6 x 107 virions from the spleen and liver alone, over 1000 times less than that from the blood.

What’s a Superbug anyways?

March 5, 2015 Leave a comment

About 23,000 deaths due to approximately 2 million infections by antibiotic resistant bacteria occur each year in the US. Additionally, failed antibiotic treatments result in an estimated $20 billion spent on health care. The bacteria that cause these deaths have been called “superbugs.” Most recently, 7 deaths from “superbugs” at a UCLA hospital were spread from patient to patient through endoscopes that were not yet FDA approved. The media has been using the term “superbug” for years now, but what does it even mean?

In the mid 90s, the term “superbug” was used sporadically in peer reviewed journals. Notably, these articles highlighted emerging antibiotic resistance in strains of E. coli, Streptococcus, Enterococci, and importantly Staphylococcus. Methicillin resistant Staphylococcus aureus (MRSA) emerged only one year after the first use of methicillin as an antibiotic in 1959. MRSA is now one of the most widespread pathogens and common causes of hospital acquired infection. As a result of methicillin resistance, one of the antibiotics most widely used to treat MRSA in the 90s was vancomycin.

In 2002 in Michigan, one of the first reports of vancomycin resistant MRSA, now dubbed VRSA, came to light. An article in Nature used to term “Superbug” to describe the vancomycin resistant organisms. Now superbug is commonly used by the media to describe any variety of antibiotic resistant bacteria. Unfortunately “superbug” is not descriptive, and has been used to headline deaths by not only MRSA, but also antibiotic resistant strains of Klebsiella pneumoniae, Clostridium difficile, Acinetobacter baumannii, Mycobacterium tuberculosis, to list a few of the dozens.

antibioticmechanismsThere are several classes of antibiotics, each which exert their antimicrobial action in a different way. Similarly there are several different mechanisms by which antibiotic resistance occurs. For example, aminoglycoside antibiotics are able to bind to and block the bacterial ribosome, which effectively inhibits or alters bacterial translation, resulting in cell death. Some bacteria have acquired genes that encode proteins that can bind to and modify these aminoglycoside antibiotics. Modification of the aminoglycoside renders it inert, and unable to kill the cell. Several classes of antibiotics are shown in the figure above, along with a few mechanisms of resistance. “Superbug” doesn’t describe the type of bacterial infection, nor does it inform about the mechanism of resistance.

Scannell et al. 2012 Nat Rev Drug Dev

Scannell et al. 2012 Nat Rev Drug Dev

The problem

Only 12 FDA approved antibiotics have been developed since 2000. In the 90s, 20 antibiotics were FDA approved, and 43 in the 80s. The steady decrease in antibiotic development is a result of several compounding factors.

1) A new drug takes an estimated 10 years to develop from scratch. Most drugs fail at some point between initial discovery, in vitro testing, animal testing, and clinical trials.

2) Drugs are expensive to develop. If you want a profit you make a drug that people take for life, not week like most antibiotics. This ties into point 3.

3) Antibiotic resistance is often detected within years of its initial use in the clinic. Therefore the time an antibiotic is actually relevant and useful is relatively low compared to drugs that treat arthritis or cardiovascular disease.

4) The low hanging fruit have been harvested, and nobody wants to pioneer the more difficult work. A majority of the antibiotic research presented at conferences, such as ICAAC, deal with betalactamases. The first antibiotic to be discovered, penicillin, is a betalactamase antibiotic. Dozens of investigators flocked to study the betalactamases after penicillin’s discovery. Graduate students and trainees from those labs then went to start their own labs, doing research on betalactamases. And now 50 years down the line, despite having a dozen classes of antibiotics, a majority of the antibiotic-focused academic labs study betalactamases. It’s easy to study betalactamases because it’s what we’ve been doing for half a decade. Moving forward is easier when the foundation is already set.

The solution

A recent article in Wired emphasized the need for more spending in the field of antibiotics. Only 1.2% of all funding from the NIH goes toward antibiotic resistance. The NIH budget has remained stagnant in the last decade, with a whopping 0.5% increase for 2015 to a grand total of ~$30 billion. To put this in perspective: The total federal budget in 2014 was ~$3.5 trillion. We don’t just need more money going toward antibiotics. We need more money going toward research in general.