Why doesn’t daptomycin reliably treat pneumonia?
For this episode, the team examined an odd limitation of the antibiotic daptomycin – it doesn’t treat reliably bacterial pneumonia? This is a clinical pearl that nearly everyone learns in medical school. And yet most don’t fully understand the mechanism.
There is in vitro animal and clinical human data demonstrating that daptomycin does not effectively or reliably treat pneumonia. One study published in the journal of infectious diseases from 2005 showed that daptomycin was ineffective at treating streptococcal and MRSA pneumonia in mice.
In humans, daptomycin had lower cure rates for community-acquired pneumonia compared to ceftriaxone, though it is worth noting that 75% of patients treated with daptomycin alone did have clinical cure. This suggests that daptomycin is less effective than our standard community-acquired antibiotic treatment regimens. But perhaps it does retain some efficacy.
What explains daptomycin’s limited ability to treat bacterial pneumonia? For background, recall that daptomycin is a bactericidal antibiotic used to treat gram-positive bacterial infections. Structurally it is a lipopeptide, with a hydrophilic or water-soluble peptide core and a lipophilic or fat-soluble tail.
It uses the fat soluble tail to insert itself into bacterial membranes and cell walls. Once inserted, daptomycin physically disrupts the integrity of the cellular membrane of the bacterium. These disruptions allow for uncontrolled potassium efflux out of the cell. This excessive potassium efflux leads to the bacterium being unable to maintain normal membrane potential, failure of cellular machinery, and then cell death.
While many may not be able to recall the exact mechanism explaining daptomycin’s poor efficacy in the lung, most have heard that it relates to surfactant. And this is absolutely true – pulmonary surfactant plays a key role.
Surfactant is similar to daptomycin in that it is a lipoprotein with both fat and water soluble components. The phospholipid component of surfactant has the concise chemical name of dipalmitoylphosphatidylcholine. It’s produced by type II pneumocytes and it’s action in the lungs involves reducing surface tension at the air-liquid interface in the lung. This prevents alveoli from collapsing in on themselves. Surfactant helps maintain normal compliance by preventing atelectasis and helps regulates airway moisture and innate and adaptive immune responses.
Here’s the key: if you add surfactant to daptomycin in vitro you see an immediate loss of antibacterial activity for daptomycin. And an experiment published in the Journal of Infectious Diseases in 2005 showed a striking finding: if you combine surfactant and daptomycin, the surfactant surrounds and physically traps the daptomycin molecules. The surfactant acts sort of as a decoy, trapping the daptomycin in lipid aggregates.
Pulmonary surfactant sequesters daptomycin via its hydrophobic tail, which prevents daptomycin from having access to – and being able to disrupt – bacterial membranes. In essence, daptomycin’s very mechanism of action precludes treatment of pneumonia.
This is in effect an organ-specific inhibition of an antibiotic’s action. But daptomycin may still be effective in treating blood-borne pulmonary infections like septic emboli or abscesses, where the infection is not primarily alveolar. And there is data supporting this notion. In a small clinical trial from 2008, in the Journal of Antimicrobial Chemotherapy, daptomycin was compared to vancomycin and gentamicin for MRSA bacteremia and right-sided endocarditis. In the subset of patients with pulmonary septic emboli, clinical cure rates were the same between daptomycin and the vancomycin-containing regimen.
One final connection. If you’ve used daptomycin you’ll recall needing to monitor creatine kinase (CK) levels to screen for rhabdomyolysis. But why would it cause rhabdomyolysis? The leading theory involves daptomycin intercalation into muscle cellular membranes, damaging myocytes. Those muscles are full of CK and with the membrane damage done by daptomycin, they release that CK into the blood. As the theory goes, if that damage is allowed to continue then rhabdomyolysis can result.
Take Home Points
- Daptomycin kills bacteria by disrupting bacterial membranes via a fat-soluble “tail”
- It’s less effective than other antibiotics at treating pneumonia because pulmonary surfactant traps daptomycin in lipid aggregates, blocking its access to the bacteria themselves. This is unique organ-specific inhibition.
- Serum creatine kinase elevation and risks of rhabdomyolysis likely results from the same mechanism, with impacts on integrity of skeletal muscle membranes
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Credits & Citation
◾️Episode written by Avi Cooper
◾️Show notes written by Tony Breu and Avi Cooper
◾️Audio edited by Clair Morgan of nodderly.com
Cooper AZ, Abrams HR, Breu AC. Of Antibiotics and Soap. The Curious Clinicians Podcast. January 19, 2022
Image credit: https://www.camberpharma.com/products/daptomycin/