Thread by @pharmdiv

Hey #IDTwitter… what are your thoughts on intermittent (e.g. TIW frequency) liposomal amphotericin B (L-AmB) dosing for OPAT?

@MayoPharmRes @MsSmallsO @johnsontannerm @Stevens_AK @SIDPharm #opat #TwitteRx

Let’s look at the evidence… For starters, amphotericin B (AmB) = broad spectrum anti-fungal that binds to ergosterol

1st-line for serious ocular candida, CNS cryptococcus, severe histo/blasto, and mucor

2nd-line for cocci & aspergillosis

pubmed.ncbi.nlm.nih.gov/11801575/

There are 4 formulations of AmB, but the liposomal form (L-AmB) is typically dosed at 3-5 mg/kg/day = ⬇️ nephrotoxicity (vs. deoxycholate) and ⬇️ infusion reactions (vs. ABLC) + liposome allows for ⬆️ tissue conc and a prolonged t1/2.

pubmed.ncbi.nlm.nih.gov/11722981/

Despite improved safety profile, L-AmB nephrotoxicity is still occurs in 28-80% pts w/ 49% w/o SCr recovery 30 days post-tx D/C.
hindawi.com/journals/ijn/2…

Most common risk factors = concomitant nephrotoxic drugs, higher doses, age < 65 link.springer.com/content/pdf/10…

What is known about L-AmB in OPAT? (1/2)

Study Population: Single center, OPAT, 42 pts, most common IFI = histo (but many represented), most common dosing = 3-5 mg/kg/day
ncbi.nlm.nih.gov/pmc/articles/P…

(2/2) OUTCOMES: 52% pts on L-AmB were readmitted w/in 30 days, but only 12% attributed to L-AmB. Reasons for L-AmB readmit =⬇️K+ and⬆️SCr.⬆️L-AmB dose associated with AKI. In pts w/ AKI 35% converted to azoles, 20% changed to alternate frequency dosing (Q48h or TIW)

So what is the rationale behind TIW dosing? Well…

L-AmB t1/2 = 100-153 hr due to lipophilicity/slow redistribution from tissues. Css achieved in ~4 days of tx.🤔Given this PK, could⬇️frequent dosing maintain adequate drug conc and help⬇️nephrotoxicity?

Ok… But has it been done? (1/2)

Yes, case reports have shown feasibility of TIW dosing including this multicenter cohort study.

Population: 18 pts w/ mixed IFI on TIW L-AmB (mostly 5 mg/kg) s/p median of 56 (14-193) days daily dosing.

academic.oup.com/mmy/article/58…

(2/2) Outcomes: 94% pts w/ partial response to daily prior to TIW. Reversible nephrotox = 56% pts. Infx resolution = 72% of pts w/ 1-yr mortality = 6%.

More studies needed to establish noninferiority compared to daily dosing.

academic.oup.com/mmy/article/58…

In Summary:

✅AmB = broad-spectrum antifungal
✅L-AmB =⬇️nephrotoxicity vs other forms
✅L-AmB PK (long T1/2) lends well to intermittent dosing
✅Limited clinical data suggest possibility of TIW strategies s/p period of daily dosing
✅More clinical evidence is needed