Salvage Treatment for Invasive Aspergillosis and Mucormycosis: Challenges, Recommendations and Future Considerations

Figures & data

Table 1 Antifungal Combination Therapy for Mucormycosis in Mice

Treatment	Model	Effect on Fungal Burden Reduction (Compared to Placebo)	Survival Rate (21-Day)	Ref.
LAmB (5 mg/kg/day) + micafungin or caspofungin (1 mg/kg/day)	Neutropenic mice infected by Rhizopus oryzae	< 1 log (kidneys)	< 80%	[60]
LAmB + isavuconazole	Neutropenic mice infected with Rhizopus delemar and Mucor circinelloides	2.0–3.5 log (lungs and brain)	> 80%	[97]
LAmB (10 mg/kg) + fosmanogepix (78 mg/kg)	Immunosupressed mice infected with R. arrhizus var. delemar	2-log (lungs and brain)	70%	[87]

Abbreviation: LAmB, liposomal amphotericin-B.

Table 2 Overview on Pharmacokinetics of Current Salvage Treatment for Invasive Aspergillosis and Mucormycosis

Fungal Disease	Liposomal Amphotericin B, i.v.	Posaconazole, Per os (tbl.)^$	Posaconazole, i.v.	Isavuconazole, i.v. or per os	Caspofungin, Intravenous i.v.
	IA, MM	IA, MM	IA, MM	IA, MM	IA in Combination
Standard dose in Adults*	3–4 (5) mg/kg (IA) and 5–10 mg/kg (MM) once daily I.V.	Loading dose, 300 mg b.i.d. on day 1, Maintenance dose 300 mg once daily	Loading dose, 300 mg b.i.d. on day 1, Maintenance dose 300 mg once daily	Loading dose, 200 mg t.i.d. on day 1 and day 2, Maintenance dose 200 mg once daily	Loading dose 70, maintenance dose 50 (70 if body weight > 80 kg)
Cmax [µg/mL]	14–29 (90)	2	2.6	2.6	10
Vd [L/kg]	0.05–2.2	5	3.7	~6.5	0.3–2.0
Protein binding [%]	95–99 (of amphotericin B, liberated from lipid-encapsulation)	98–99	98–99	98–99	92.4–96.5
t1/2[h]	13–24	35	27	80–120	8
CL [mL/h/kg]	1–23	130	100	~30–70	~10
Metabolism and Elimination	Bile, RES long-term disposition, final elimination not yet clear; no metabolism	Metabolisms involving CYP3A4, P-gp substrate		Hepatic metabolism involving UGT, and CYP3A4	Independent from cytochrome, P-450 (CYP)
Renal impairment	No dose adjustment, consider nephrotoxicity	No dose adjustment	Avoid because of SBECD accumulation, When GFR < 50 mL/min	No dose adjustment	Standard dose
Hepatic impairment	No dose adjustment, consider hepatotoxicity	No dose adjustment	No dose adjustment	Mild to moderate, enhanced levels, no dose reduction recommended by the manufacturer	Enhanced exposure in moderate hepatic impairment, dose reduction
Remark	Tinf ≥ 4 h recommended	Strong inhibitor of CYP3A4 causing numerous drug-drug interactions	Strong inhibitor of CYP3A4 causing numerous drug-drug interactions	Inhibitor of CYP3A4, P-gp and BCRP	Dose reduction in critically with liver dysfunction may cause underexposure; insufficient efficacy in first-line treatment, limited data for salvage treatment of IA
PK/PD target	Cmax/MIC	AUC0–24h/MIC	AUC0–24h/MIC	AUC0–24h/MIC	AUC0–24h/MIC or Cmax/MIC

Notes: *Dosages in pediatric patients are displayed elsewhere {Downes, 2020 #4940}. ^$Posaconazole suspension differs from tablet formulation. For suspension: dosing 4x200mg, intake with fatty meals. Variable oral bioavailability.

Abbreviations: Cmax, peak level; AUC, area under the concentration time curve; Vd, apparent volume of distribution; t_1/2, half-life; CL, clearance; CYP, cytochrome P 450; SBECD, sulfobutylether-β-cyclodextrin; GFR, glomerular filtration rate; TDM, therapeutic drug monitoring; AUC_0–24h, area under the concentration-time curve over 24 hours; MIC, minimal inhibitory concentration; i.v., intravenous; tbl., tablet; CYP, cytochrome P 450; UGT, uridine diphosphate glucuronosyltransferase, P-gp, P glycoprotein, BCRP, breast cancer related protein.

Figure 1 Present salvage therapy recommendations for invasive aspergillosis/ mucormycosis and additional future options. *Voriconazole (4–6mg/kg/d), isavuconazole (3x 200mg d1+2, then 200mg qd), posaconazole (300mg b.i.d. day 1 table/IV then 300mg qd) caspofungin (70mg/d IV day 1 then 50mg/d), micafungin (100mg - 150mg/d), anidulafungin (200mg qd day1 the 100mg qd).

Notes: Created with BioRender.com.Abbreviations: LAmB, liposomal amphotericin B; Rx, medical prescription; DDI, drug-drug interaction; AE, adverse event; IV, intravenous; b.i.d., twice daily; qd, once daily.

Ibrahim AS, Gebremariam T, Fu Y, Edwards JE Jr., Spellberg B. Combination echinocandin-polyene treatment of murine mucormycosis. Antimicrob Agents Chemother. 2008;52(4):1556–1558. doi:10.1128/AAC.01458-07

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