Table 4.

Conclusion on combination treatment as a new treatment of tegumentary leishmaniasis in the systematic review.

Treatment	Dose	Route of Administration/Time	Time	Efficacy	Safety	Practice/clinical implications	Study source
MA + IM	IM: Lesion ≤3 cm: 1 dose of 7.5% cream. Lesion > 3 cm: 2 doses of 7.5% cream. Each dose = 125 mg.	IM: topical - daily	20 days	Efficacious	Acceptable risk with specialized monitoring	Investigational	Arevalo et al., 2007
	MA: 20 mg/kg/day.	MA: IV - daily
	IM: 5% cream.	IM: topical- 3 times per day	IM: 28 days	Likely efficacious	Acceptable risk with specialized monitoring	Investigational	Firooz et al., 2006
	MA: 20mg Sb5+/kg/day.	MA: IM daily	MA: 14 days
	IM: 5% cream.	IM: Topical- daily.	IM: 20 days.	Efficacious	Acceptable risk without specialized monitoring	Clinically useful	Miranda- Verastegui et al., 2005
	MA: 20mg/kg/day.	MA: IM daily in children, and IV infusion in older subjects.	MA: 20 days.
MA + PE	MA: 20mg5+/kg/day	MA: daily	MA: 30 days	Efficacious	Acceptable risk with specialized monitoring	Clinically useful	Machado et al., 2007
	PE: 400mg	PE: oral – 3 times daily	PE: 30 days
	MA: 20mgsbv/Kg/day	MA: IV- daily	MA: 20 days	Not efficacious	Acceptable risk with specialized monitoring	Not useful	Brito et al., 2017
	PE: 400m	PE: oral- 3 times daily	PE: 20 days
MA+ cryotherapy	Cryotherapy: freeze time (10-25 s)	Cryotherapy: on the lesion until 1-2 mm of surrounding normal tissue appeared frozen	Every two weeks	Likely efficacious	Acceptable risk without specialized monitoring	Possibly useful	Farajzadeh et al., 2015
	MA: 15 mg/kg/day	Intramuscular	Every day for 3 weeks
MA + (LEISH-F1 + MPL-SE)	LEISH-F1: 5, 10 or 20 μg + 25 μg MPL-SE.	LEISH-F1: SUB – 3 times.	LEISH-F1: On day 0, 28 and 56.	Likely efficacious	Acceptable risk with specialized monitoring	Possibly useful	Nascimento et al., 2010
	MA: 10 mg/ Sb5+kg/day.	MA: IV – 10-days cycles followed by 11 days of rest.	MA: The first 10-days cycle on Day 0. Additional cycles on days 21, 42, and 63
MA + GM-CSF	GM-CSF: 1-2 mL (10 µg/mL).	GM-CSF: topical – 3 times per week.	GM-CSF: 3 weeks	Efficacious	Acceptable risk without specialized monitoring	Investigational	Almeida et al., 2005
	MA: 20 mg Sb5+/kg/day.	MA: IV – daily.	MA: 20 days
MA + OM	MA: 30mg/kg/day	MA: IM- daily	MA: 3 weeks	Likely efficacious	Acceptable risk with specialized monitoring	Clinically useful	Nilforoushzadeh et al., 2008
	OM: 40mg	OM: oral - daily	OM: 3 weeks
il MA + silver PD	MA: il	MA: Intradermally in each one centimeter square of a lesion until blanching occurred intralesional, once weekly.	42 days	Not efficacious	Acceptable risk with specialized monitoring	Investigational	Khatami et al., 2013
	Silver PD: on the lesion	Silver dressing: topical – once daily
il MA + topical honey	MA: il	MA: il enough to blanch the lesion and 1 mm rim of the surrounding normal skin, once weekly.	Until complete healing or for maximum 6 weeks	Not efficacious	Insufficient evidence	Investigational	Nilforoushzadeh et al., 2007
	Honey: soaked gauze	Honey: topical – twice daily
il MA + cryotherapy	Cryotherapy: freeze time (10 - 25 s)	Cryotherapy: on the lesion until 2-3 mm halo forms around, weekly, before IL MA.	Until complete cure or for up to 12 weeks	Likely efficacious	Acceptable risk without specialized monitoring	Possibly useful	Meymandi et al., 2011
	MA: (0.5 – 2 ml)	MA: intradermally, all directions, until the lesion had completely blanched, weekly.
SSG + (LEISH-F1+ MPL-SE)	LEISH- F1: 5, 10 or 20 µg + 25 µg MPL-SE.	LEISH-F1: SUB – 3 times.	LEISH-F1: On day 0, 28 and 56.	Efficacious	Acceptable risk with specialized monitoring	Investigational	Llanos Cuentas et al., 2010
	SSG: 20mg/kg/day	SSG: IV – daily	SSG: day 0 to 27
SSG + IM	IM: 5% cream.	IM: Topical - 3 times per week.	IM: 20 days	Efficacious	Acceptable risk without specialized monitoring	Clinically useful	Miranda- Verastegui et al., 2009
	SSG: 20 mg/kg/day	SSG: IV – daily.	SSG: 20 days
il SSG + im SSG	il SSG (100 mg/mL), the dose varied between 0.3-3.0 mL. Maximum dose 20mg/Kg/day.	il: Infiltrated in multiple sites until complete blanching and a 1-mm wide ring of the surrounding normal skin.	il SSG on days 1, 3, 5 in one session - up to 3 cycles.	Efficacious	Acceptable risk with specialized monitoring	Possibly useful	El-Sayed & Anwar, 2010
	im SSG (a part of the dose 20mg/Kg/day already given provided to IL SSG in the same days).	im: one injection on days 1, 3, 5 - up to 3 cycles with 4 weeks interval.
il SSG + KE	il SSG (100mg/mL), the dose varied between 0.3-3.0 mL, maximum dose 20mg/Kg/day.	il: Infiltrated in multiple sites until complete blanching and a 1-mm wide ring of the surrounding normal skin.	il: on days 1, 3, 5 in one session - up to 3 cycles.	Efficacious	Acceptable risk with specialized monitoring	Possibly useful	El-Sayed & Anwar, 2010
	KE: 200 mg.	KE: 3 times daily.	KE: 4 weeks.
il SSG + cryotherapy	il SSG: 1-2ml.	il SSG: into margin of each lesion, all around, until blanching with cryotherapy preceding the first injection.	il SSG: 3 injections SSG with intervals of 1-3 days.	Efficacious	Acceptable risk without specialized monitoring	Clinically useful	van Thiel et al., 2010
	Cryotherapy: local with a double freeze-thaw cycle. 20 seconds for freezing cycle and thawing time between cycles of 45-90 seconds.		Cryotherapy: treatment was repeated until clinical improvement (range 1-163 days).

MA, meglumine antimoniate; PE, pentoxifylline; GM-CSF, granulocyte macrophage colony-stimulating factor; IM, imiquimod; il SSG, intralesional sodium stibogluconate; im SSG, intramuscular sodium stibogluconate; KE, ketoconazole; il MA (intralesional meglumine antimoniate); nonsilver PD, nonsilver containing polyester dressing; silver PD, silver containing polyester dressing; SSG, sodium stibogluconate; LEISH-F1, lyophilized LEISH-F1 protein; MPL-SE, adjuvant; OM, omeprazole; IV, intravenous; IM, intramuscular; SUB, subcutaneously.