Thread by @AvrahamCooperMD

1/14
Why doesn't daptomycin treat pneumonia?

The answer also explains why dapto raises serum CK levels.

#medtwitter #tweetorial

2/
First let's establish that daptomycin (bactericidal against gram positives) lacks efficacy in treating lung infections.

⚡️ In this study with mouse lungs, daptomycin didn't reliably kill strep pneumo or MRSA, even at high doses of the drug.

pubmed.ncbi.nlm.nih.gov/15898002/

3/
What about lung infections in humans?

Compared to ceftriaxone,  daptomycin had lower cure rates for treatment of community acquired pneumonia (CAP).

pubmed.ncbi.nlm.nih.gov/18444848/

4/
Next we need to review daptomycin's structure and mechanism of action.

💡 It's structure consists of a hydrophilic lipoprotein core with a lipophilic, fat-soluble “tail”.

ncbi.nlm.nih.gov/pmc/articles/P…

5/
As a lipopeptide with a fat-soluble tail, daptomycin inserts into bacterial membranes (and cell walls) in the presence of calcium.

ncbi.nlm.nih.gov/pmc/articles/P…

6/
Once inserted into a bacterium's cellular membrane, daptomycin disrupts its integrity.

🔑 This disruption leads to K+ efflux out of the cell and loss of membrane potential, which causes failure of cellular machinery and eventually cell death.

ncbi.nlm.nih.gov/pmc/articles/P…

7/
Now that we understand how daptomycin works, let's learn why it doesn't work in the lungs.

You may have heard that it has something to do with pulmonary surfactant...

8/
(Very) brief pulmonary surfactant review:

Surfactant, similar to daptomycin, is a lipoprotein with fat and water soluble components. It reduces surface tension at the air-liquid interface in the lung and prevents alveolar collapse.

pubmed.ncbi.nlm.nih.gov/30552091/

9/
It turns out that adding surfactant to daptomycin in vitro leads to almost immediate loss of antibacterial activity.

pubmed.ncbi.nlm.nih.gov/15898002/

10/
Why?

Recall that daptomycin has a hydrophobic tail that allows it to insert into/disrupt phospholipid bacterial membranes (tweets 4,5).

💥 Pulmonary surfactant instead acts as a decoy for dapto, trapping it in lipid aggregates (at least in vitro).

pubmed.ncbi.nlm.nih.gov/15898002/

11/
We are left with the mechanism for why daptomycin is ineffective in the lungs:

Pulmonary surfactant sequesters dapto via its hydrophobic tail. This prevents access to bacterial membranes.

🔑 In effect, daptomycin's very mechanism of action precludes treatment of pneumonia.

12/
A final interesting correlate:

Creatine kinase (CK) elevation, and even skeletal muscle myopathy, are known complications of daptomycin therapy.

Can you think of how this might relate to its mechanism of action?

13/
While the cause isn't definitively known, serum CK elevation is thought to result from daptomycin-induced disruption of skeletal muscle membranes.

This is the exact same type of membrane damage that causes bacterial killing.

ncbi.nlm.nih.gov/pmc/articles/P…

14/
💡Daptomycin disrupts bacterial membranes via a fat-soluble “tail”
💡It’s ineffective in lung infections b/c pulmonary surfactant traps it in lipid aggregates
💡Serum CK elevation likely results from the same mechanism (impacts on integrity of skeletal muscle membranes)