Daptomycin for Septic Pulmonary Emboli? Maybe

The hits keep coming and they don’t stop coming. I’ve had a bit of a lull lately, but am back to bring short, and hopefully, sweet post. Daptomycin has become a go-to antibiotic for MRSA infections, namely bacteremia, as organisms with resistance to vancomycin have risen in the past few years. The 2006 Fowler study (1) evaluated its use for staphylococcus bacteremia and found that at a dose of 6mg/kg, it was non-inferior to vancomycin. Of course, daptomycin is not without its shortcomings. Namely, elevation in CK and eosinophilic pneumonitis are some of the well-known adverse events. Further, its use in pneumonia is contraindicated given its inactivation by pulmonary surfactant. What about septic pulmonary emboli? This is a common complication from right sided endocarditis, with infected clots full of MRSA lodged in the pulmonary vasculature. Does daptomycin work in that scenario?

It is unclear, unfortunately. Following the initial approval of daptomycin, the drug was evaluated in apair of randomized, double-blind trials comparing it to ceftriaxone (2). 743 patients were evaluated in the pooled ITT population and found the clinical cure rates in the daptomcyin arm were lower than in the ceftriaxone arm, which also held true in the clinically evaluable population:

When looking at the group of patients who did not receive any effective therapy prior to the start of the trial, the difference is more staggering:

An animal study found that in the bronchial-alveolar model, daptomycin did not lead to a reduction in bacterial burden when compared to ceftriaxone (3). Further, when looking at the hematogenous pneumonia model, daptomycin achieved a more significant reduction in bacterial burden when compared to both vancomycin and nafcillin:

Moreover, the antistaphylococcal activity of daptomycin was significantly decreased when tested in the presence of bovine-derived surfactant, suggesting that even a small amount of surfactant can lead to a significant increase in MIC:

In a mouse model of hematogenous pulmonary infection, both vancomycin and daptomycin were found to have a significant reduction in both the number of abscesses and the number of bacteria in the lungs

(4):

The log reduction of viable bacteria at day 3 of antibiotic therapy was comparable between vancomycin and daptomycin, however the abscess size was numerically lower for daptomycin.

We have data to suggest daptomycin may not work that well for pneumonia and we have animal data to suggest it may be ok to give in instances of septic emboli. Unfortunately, there is very little in terms of clinical data to make any great conclusions. The original Fowler study only had 25 patients with complicated right sided endocarditis (1) and found no statistical difference in rates of treatment success, 38.5% for daptomycin vs 50% for vancomycin (absolute difference -11.5, 95% CI -50.3 to 27.2). A post hoc analysis (5) analyzed the outcomes of all patients with IE, and when looking at patients with septic pulmonary emboli there was no difference in treatment success (60% vs 67%):

Not a lot to go off on, unfortunately. Several case studies have suggested the use of daptomycin may work. For instance, a series of four cases of septic pulmonary emboli with MRSA with no endocarditis found that 6mg/kg of daptomycin in combination of rifampin led to the resolution of bacteremia in all cases (6). In another case, MSSA bacteremia was initially treated with cefazolin, however it was complicated by the development of a tricuspid valve vegetation and septic pulmonary emboli (7). The patient was switched to daptomycin 6mg/kg, with resolution of both the vegetation and emboli. More recently, a retrospective study of 29 patients (8) with MRSA bacteremia complicated by septic pulmonary emboli who received either daptomycin alone or daptomycin in combination with ceftaroline found no difference in the primary outcome of composite success (71.4% for monotherapy vs 80% for combination, p =0.68).

Despite these encouraging findings, other case reports exist failure of daptomycin. One involved a 24 year-old female with IV drug abuse who was initially treated with daptomycin for mitral and tricuspid valve endocarditis with septic pulmonary emboli (9). Unfortunately, there was worsening of cavitary lesions and was deemed a failure. Similarly, a line-associated MRSA bacteremia complicated by septic pulmonary emboli in a 73-year-old male was complicated by worsening respiratory failure requiring intubation and mechanical ventilation (10) despite therapy with daptomycin.

There is a bit of noise here, suggesting that the use of daptomycin in septic pulmonary emboli is a reasonable thing to do. The data we have (mostly subgroup analysis and animal data) suggests there is no harm in doing so, but there is no real robust information to make a decision with this regard. Physiologically, it would make sense to keep daptomycin on board with septic pulmonary emboli, so if someone is doing well while on it despite septic pulmonary emboli, I see no reason to change antibiotics.

References:

1. Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fätkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE; S. aureus Endocarditis and Bacteremia Study Group Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006 Aug 17;355(7):653-65. doi:10.1056/NEJMoa053783. PMID: 16914701.

2. Pertel PE, Bernardo P, Fogarty C, Matthews P, Northland R, Benvenuto M, Thorne GM,Luperchio SA, Arbeit RD, Alder J. Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia. Clin Infect Dis. 2008 Apr 15;46(8):1142-51. doi: 10.1086/533441. PMID: 18444848.

3. Silverman JA, Mortin LI, Vanpraagh AD, Li T, Alder J. Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact. J Infect Dis. 2005 Jun 15;191(12):2149-52. doi: 10.1086/430352. Epub 2005 May 5. PMID: 15898002.

4. Harada Y, Yanagihara K, Yamada K, Migiyama Y, Nagaoka K, Morinaga Y, Nakamura S, Imamura Y, Hasegawa H, Miyazaki T, Izumikawa K, Kakeya H, Kohno S. In vivo efficacy of daptomycin against methicillin-resistant Staphylococcus aureus in a mouse model of hematogenous pulmonary infection. Antimicrob Agents Chemother. 2013 Jun;57(6):2841-4. doi: 10.1128/AAC.02331-12. Epub 2013 Mar 18. PMID: 23507279; PMCID: PMC3716188.

5. Kanafani Z, Boucher H, Fowler V, Cabell C, Hoen B, Miró JM, Lalani T, Vigliani G, Campion M, Corey R, Levine D. Daptomycin compared to standard therapy for the treatment of native valve endocarditis. Enferm Infecc Microbiol Clin. 2010 Oct;28(8):498-503. doi: 10.1016/j.eimc.2009.07.015. Epub 2010 Feb 25. PMID: 20188444.

6. Gomez EO, Jafary A, Dever LL. Daptomycin and rifampin for the treatment of methicillinresistant Staphylococcus aureus septic pulmonary emboli in the absence of endocarditis. Microb Drug Resist. 2010 Sep;16(3):241-4. doi: 10.1089/mdr.2010.0001. PMID: 20617926.

7. Cunha BA, Hamid N, Kessler H, Parchuri S. Daptomycin cure after cefazolin treatment failure of Methicillin-sensitive Staphylococcus aureus (MSSA) tricuspid valve acute bacterial endocarditis from a peripherally inserted central catheter (PICC) line. Heart Lung. 2005 Nov-Dec;34(6):442-7. doi: 10.1016/j.hrtlng.2005.05.006. PMID: 16324966.

8. Morrisette T, Lagnf AM, Alosaimy S, Rybak MJ. A comparison of daptomycin alone and in combination with ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bacteremia complicated by septic pulmonary emboli. Eur J Clin Microbiol Infect Dis. 2020 Nov;39(11):2199-2203. doi: 10.1007/s10096-020-03941-5. Epub 2020 Jun 13. PMID:32535805.

9. Zainah H, Zervos M, Stephane W, Chamas Alhelo S, Alkhoury G, Weinmann A. Daptomycin Failure for Treatment of Pulmonary Septic Emboli in Native Tricuspid and Mitral Valve Methicillin-Resistant Staphylococcus aureus Endocarditis. Case Rep Infect Dis. 2013;2013:653582. doi: 10.1155/2013/653582. Epub 2013 Nov 25. PMID: 24371532; PMCID: PMC3859033.

10. Hagiya H, Hagioka S, Otsuka F. Ineffectiveness of daptomycin in the treatment of septic pulmonary emboli and persistent bacteremia caused by methicillin-resistant Staphylococcus aureus. Intern Med. 2013;52(22):2577-82. doi: 10.2169/internalmedicine.52.0023. PMID: 24240800.

11. Crass RL, Powell KL, Huang AM. Daptomycin for the treatment of Staphylococcus aureus infections complicated by septic pulmonary emboli. Diagn Microbiol Infect Dis. 2019 Feb;93(2):131-135. doi: 10.1016/j.diagmicrobio.2018.09.004. Epub 2018 Sep 14. PMID: 30279024.