Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: A systematic review

Jacob M Bezemer; Jacob van der Ende; Jacqueline Limpens; Henry J C de Vries; Henk D F H Schallig

doi:10.1371/journal.pone.0249628

. 2021 Apr 7;16(4):e0249628. doi: 10.1371/journal.pone.0249628

Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: A systematic review

Jacob M Bezemer ^1,^2,^*, Jacob van der Ende ³, Jacqueline Limpens ⁴, Henry J C de Vries ⁵, Henk D F H Schallig ¹

Editor: Kristien Verdonck⁶

PMCID: PMC8026199 PMID: 33826660

Abstract

Cutaneous and mucocutaneous leishmaniasis affect a million people yearly, leading to skin lesions and potentially disfiguring mucosal disease. Current treatments can have severe side effects. Allylamine drugs, like terbinafine, are safe, including during pregnancy. This review assesses efficacy and safety of allylamines for the treatment of cutaneous and mucocutaneous leishmaniasis. It followed the PRISMA statement for reporting and was preregistered in PROSPERO(CRD4201809068). MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, Web of Science, Google Scholar, and clinical trial registers were searched from their creation to May 24^th, 2020. All original human, animal, and in vitro studies concerning allylamines and cutaneous or mucocutaneous leishmaniasis were eligible for inclusion. Comparators—if any—included both placebo or alternative cutaneous or mucocutaneous leishmaniasis treatments. Complete cure, growth inhibition, or adverse events served as outcomes. The search identified 312 publications, of which 22 were included in this systematic review. There were one uncontrolled and two randomised controlled trials. The only well-designed randomised controlled trial that compared the treatment efficacy of oral terbinafine versus intramuscular meglumine antimoniate in 80 Leismania tropica infected patients showed a non-significant lower cure rate for terbinafine vs meglumine antimoniate (38% vs 53%). A meta-analysis could not be performed due to the small number of studies, their heterogeneity, and low quality. This systematic review shows that there is no evidence of efficacy of allylamine monotherapy against cutaneous and mucocutaneous leishmaniasis. Further trials of allylamines should be carefully considered as the outcomes of an adequately designed trial were disappointing and in vitro studies indicate minimal effective concentrations that are not achieved in the skin during standard doses. However, the in vitro synergistic effects of allylamines combined with triazole drugs warrant further exploration.

Introduction

Cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL), classified by the World Health Organization (WHO) as emerging neglected diseases, affect more than one million people yearly [1, 2]. CL manifests as skin lesions and MCL as potentially disfiguring mucosal disease of the nose, mouth, and larynx [3]. At least 20 different Leishmania parasite species can cause CL and MCL with differing clinical manifestations and responses to treatment [4]. Depending on the infecting Leishmania species, multiple treatment options are available but pentavalent antimonials (e.g., sodium stibogluconate and meglumine antimoniate) are still the most frequently used for American CL and MCL [5] and frequently used for old world leishmaniasis [6]. Yet, antimonial therapy is painful and requires multiple intralesional, intravenous, or intramuscular injections up to 30 days [5, 6]. Miltefosine, the oral alternative for systemic CL and MCL therapy, is not widely available and very expensive, limiting its use in clinical practice [7]. Moreover, pentavalent antimonials can result in hepatotoxicity, renal insufficiency, pancreatitis, cardiac arrest, and other serious side effects and there is no safe alternative systemic drug for use in pregnant women [8, 9]. Furthermore, depending on the region and species, poor treatment responses exist for pentavalent antimonials and miltefosine [10]. Consequently, there is a pressing need to identify alternative oral, safe, available, affordable, and efficacious treatment options for CL and MCL.

Thirty years ago, Goad et al, reported an inhibitory effect of terbinafine on cultured promastigotes of the Leishmania mexicana complex species [11]. Terbinafine is a member of the allylamine drug group, together with butenafine and naftifine.

Allylamines inhibit squalene-2,3-epoxidase causing accumulation of squalene and depletion of sterols in Leishmania amastigotes, resulting in growth inhibition and parasite death [12]. Terbinafine is used as a first line oral treatment for fungal infections and is the preferred systemic treatment for toenail infections in elderly people for safety reasons. Because of its use as antifungal, terbinafine is widely available in pharmacies all over the world at reasonable prices in oral and topical formulations [13].Terbinafine might be a safe systemic option in pregnancy, as no teratogenic side effects have been described [14, 15].

Since allylamines might be an attractive alternative CL and MCL treatment option, a systematic literature review was performed to assess the efficacy and safety of allylamines in CL and MCL treatment and to define priorities for future investigations. All original human, animal, and in vitro studies concerning allylamines and CL or MCL were eligible for inclusion. Comparators—if any—included both placebo or alternative CL and ML treatments. Cure rate in humans, change in lesion diameter in animals, promastigote and amastigote viability and growth, and adverse events served as outcome.

Methods

Search strategy

This systematic review, registered in PROSPERO (registration number CRD42018090687, 2018) and available at: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=90687, followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [16].

A medical information specialist (JL) searched the following electronic databases for studies on leishmaniasis and allylamines, using controlled terms and text words, from their creation to May 24^th, 2020: MEDLINE (OVID), EMBASE (OVID), the Cochrane Central Register of Controlled Trials (CENTRAL), The Global Health Library, Web of Science, Google Scholar (1^st 150 hits) and the clinical trial registers, ClinicalTrials.gov and WHO_ICTRP. No language, date or other restrictions were applied. The complete search strategies are presented in the S1 File. Reference lists and the citing articles of the identified relevant papers were cross-checked in Web of Science for additional relevant studies. The records retrieved were imported and de-duplicated in EndNote.

Study eligibility

All original human, animal, and in vitro studies were eligible if they examined the effects of systemic or topical allylamines with the following endpoints: cure rate in humans, skin lesion diameter in animals and promastigote or amastigote in vitro growth or viability in the laboratory. The presence of Leishmania parasites had to be confirmed in the study by either microscopy, culture, or molecular techniques. If one Leishmania species was known to cause >90% of the CL or ML cases in the study area in human studies, this species might be assumed as the causative species in all patients.

Study selection

JB and JvdE independently screened the identified studies using EndNote and resolved differences through discussion or consultation with a third reviewer (HS). Studies included during title and abstract screening were subsequently assessed as full text. Authors of conference abstracts were contacted to request unpublished data. If the full report was written in another language than English, Spanish, German, Dutch, French, or Portuguese authors were requested to provide a translation.

Data extraction

The following data from all included studies were entered in Excel: study setting, study population, probable Leishmania species, allylamine studied and treatment combinations. From human studies the following information was recorded: age, gender, lesion type and duration, drug presentation, treatment scheme, cure rates, adverse events, and information for assessment of risk of bias. Cure rates were calculated according to intention to treat analysis and cure was defined as complete epithelialization of ulcers or decrease in induration size > 75% of nodules at last available follow up.

From animal studies the following information was recorded: age, gender, lesion type and duration, drug presentation, treatment scheme, effect on lesion diameter, adverse events, and information for assessment of risk of bias. From in vitro studies the following information was recorded: drug concentrations, promastigote or amastigote growth or viability, and culture cytotoxicity. JB and JvdE extracted data in duplicate and resolved differences through discussion.

Risk of bias assessment

JB and JvdE independently assessed the quality of the clinical trials and resolved differences through discussion. Randomised controlled trials were assessed using the revised Cochrane collaborations tool (RoB2) and non-randomised controlled trials with the Cochrane tool for non-randomised controlled trials (ROBINS-1) [17, 18]. Animal studies were assessed with the SYRCLE´s risk of bias assessment tool [19]. In vitro studies were assessed with the tool developed by the United States national toxicology program [20]. Results of risk of bias assessments were visualized using the Cochrane risk-of-bias visualization tool [17].

Results

Studies included

The literature search identified 312 manuscripts of which 75 were included for full text assessment after screening of titles and abstract. After full text examination, 22 studies were included. Major reasons for exclusion were: `different topic´ and `textbook or review´. The data of two conference abstracts, could not be retrieved by contacting the authors [21, 22], and were therefore excluded from the study. The authors of a study presented in Chinese and another study in Farsi could not provide the data or the English translation of the report and these studies were therefore excluded [23, 24] (Fig 1).

Characteristics of the included human trials (n = 3) [25–27], mice studies (n = 2) [28, 29], and amastigote and promastigote studies (n = 12) [11, 30–40] are presented in Tables 1 and 2. The case reports (n = 5) [41–45] are presented in S1 Table.

Table 1. Characteristics of human and mice trials reporting treatment of cutaneous leishmaniasis with terbinafine.

Zakai [28]	Sampaio [29]	Farajzadeh [25]	Farajzadeh [26]	Bahamdan [27]	First Author
2000	2003	2015	2016	1997	Year
major	amazonensis	tropica	tropica	tropica	Leishmania species
20	15	40	44	27	Number of participants
40	29	40	44	NA	Number of controls
systemic	systemic	systemic	topical	systemic	Presentation
NA	NA	cryotherapy	meglumine antimoniate	NA	Combination
0,2mg	100mg/kg	125-500mg	32,25–75.5mg	500mg	Dose / day
28	20	28	20	28	Days treated
untreated	placebo	meglumine antimoniate + cryotherapy	meglumine antimoniate + placebo	NA	Control 1 treatment
Itraconazole	sodium stibogluconate	NA	NA	NA	Control 2 treatment
5^c	35^b	NA	NA	NA	Mean Lesion diameter (mm)
7	36	NA	NA	NA	Control 1 mean lesion diameter
1^c	28^c	NA	NA	NA	Control 2 mean lesion diameter
NA	NA	0,38	0,14	0,15	Cure rate^a
NA	NA	0,53	0,20	NA	Control cure rate^a
none	none	none	none	none	Adverse event rate

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NA: Not Applicable

^a Defined as complete epithelialization of ulcers or decrease in induration size > 75% of nodules at last available follow up and calculated according to intention to treat analysis

^b no significant difference with untreated controls

^c significant difference with untreated controls

Table 2. Characteristics of in vitro studies reporting on effects of allylamines in cutaneous and mucocutaneous leishmania species.

	Zakai [40]		Vannier-Santos [39]	Tariq [38]	Rangel [37]	Goad [11]	Chance [36]		Bezerra Souza [35]		Berman [34]	Beach [33]	Andrade Neto [32]	Andrade Neto [31]		Andrade Neto [30]	First Author
	2003		1995	1994	1996	1985	1999		2016		1987	1989	2009	2011		2013	Year
mexicana	major		amazonensis	tropica	mexicana / braziliensis	mexicana	amazonensis		amazonensis / braziliensis		major	multiple	amazonensis	amazonensis		amazonensis	Leishmania species
terbinafine	terbinafine		terbinafine	terbinafine	terbinafine	terbinafine	terbinafine		butenafine	naftifine	terbinafine	terbinafine	terbinafine	terbinafine		terbinafine	Allylamine
NA	NA	NA	ketoconazole	NA	ketoconazole / D0870	NA	NA	NA	NA	NA	NA	NA	NA	NA	imipramine	LBqT01 / imipramine	Combination
promastigote	promastigote	promastigote	amastigote	promastigote	promastigote	promastigote	promastigote	promastigote	amastigote	amastigote	amastigote	promastigote	promastigote	promastigote	promastigote	amastigote	Leishmania model
NA	NA	NA	mice peritoneal macrophages	NA	NA	NA	NA	NA	mice peritoneal macrophages	human monocyte derived macrophages	human monocyte derived macrophages	NA	NA	NA	NA	mice peritoneal macrophages	Amastigote host cell type
NA	NA	NA	NA	NA	NA	NA	NA	NA	CC50: 98	>110	>110	NA	NA	NA	NA	80	Host cell toxic concentration (μM)
No effect	6	1	0,001 ^a	1373	5–15	34	34	34–81	30–38	45	31	27	4–9	8	15	23	Effective concentration (μM)
NA	IC50	MIC	MIC	MIC	MIC	MIC	>2-fold increase of squalene	ED50	ED50	ED50	ED50	26–93% growth inhibition	IC50	IC50	IC50	IC50	Parameter of effectivity

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NA: Not Applicable, IC50: Half maximal inhibitory concentration, ED50: Median effective dose, MIC: Minimum inhibitory concentration

^a combined with 0,001μM Ketoconazole

Risk of bias assessment

Two randomised controlled clinical trials [25, 26], a one arm non randomised trial [27], and two animal trials [28, 29] were assessed for risk of bias. Farajzadehs randomised controlled trial in 2015 had an acceptable risk of bias [25]. The study of Farajzadeh from 2016 lost 73% of patients to follow up [26] and Bahamdans study had severe deviations from intended interventions and 48% loss to follow up [27], leading to an overall judgement of high risk of bias for both. The two mice studies suffered from high risk of bias in various domains including allocation concealment and blinding of outcome assessment [28, 29]. The 12 in vitro studies presented minor methodological risks of bias (Figs 2–5).

Fig 2 — The Revised Cochrane risk-of-bias tool for randomised trials (RoB2) was applied for the evaluation.

Fig 5 — The risk-of-bias tool to address *in vitro* studies developed by the United States national toxicology program was applied for the evaluation.

Fig 3 — The Risk Of Bias In Non-randomised Studies–of Interventions (ROBINS-I) assessment tool was applied for the evaluation.

Fig 4 — SYRCLE’s risk-of-bias tool for animal studies was applied for the evaluation.

It was not possible to perform a meta-analysis of the study outcomes, due to the small number of studies, their heterogeneity and low quality.

Efficacy of terbinafine on L. tropica human infections and adverse events

The clinical trial of Farajzadeh 2015 [25] included 80 L. tropica infected patients randomised between two different treatment groups: 1) oral terbinafine 125-500mg (weight dependent) daily during four weeks, combined with cryotherapy every two weeks (n = 40) and 2) meglumine antimoniate 15mg/kg/day for three weeks combined with cryotherapy every two weeks (n = 40). Complete follow up was achieved for all patients at three months. Contrary to the hazard ratios presented by Farajzadeh, in this review the endpoint was the complete cure rate. In the terbinafine arm 15/40 (38%) patients were cured and in the meglumine antimoniate arm 21/40 (53%) cases were cured, a difference that was not statistically significant in Kaplan Meier analysis (p = 0,39). None of the in vivo studies reported adverse events [25–29].

Species specific effectivity of allylamine treatments

Growth inhibition of terbinafine in promastigote in vitro studies was reported for the L. major, L. tropica, L. mexicana, L. braziliensis, and L. guyanensis complexes. An interspecies comparison in promastigote cultures with terbinafine 27μM showed higher inhibition levels in old world (L. major, L. tropica, and L. aethiopica) species (Table 3).

Table 3. Overview of clinical and in vitro Leishmania species specific results of terbinafine in cutaneous leishmaniasis.

Leishmania Complex	Leishmania Species	Growth inhibition in promastigotes at 27μM	Effective doses in promastigotes	Effective doses in amastigotes	Cure rate in clinical study ^a
major	major	52–90%	IC50: 6μM	ED50: 31μM	NA
tropica	tropica	92–93%	MIC: 1373μM	NA	38%
	aethiopica	90%	NA	NA	NA
mexicana	mexicana	26%	no inhibition / MIC: 15–34μM	NA	NA
	amazonensis	74%	IC50: 4–9μM / MIC: 1μM	IC50: 23μM / MIC: 0,001μM^b	NA
braziliensis	braziliensis	72%	MIC: 1–5μM	NA	NA
guyanensis	guyanensis	49%	NA	NA	NA
	panamanensis	41%	NA	NA	NA

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IC50: Half IC50: maximal inhibitory concentration, ED50: Median effective dose, MIC: Minimum inhibitory concentration, NA: Not Applicable

^a Defined as decrease in induration size > 75% of lesions at last available at follow up and calculated according to intention to treat analysis

^b combined with 0,001μM Ketoconazole

Treatment with butenafine killed in vitro cultured amastigotes of L. amazonensis and L. braziliensis at a mean effective dose of 30–38μM compared to the median cytotoxic concentration of 98μM [35]. Naftifine killed L. major amastigotes with mean effective dose of 45μM whilst cytotoxicity levels were more than 110μM [34].

Case reports reporting cure with terbinafine

There were five case reports showing a curative effect of terbinafine. In two case reports terbinafine cured a L. tropica infected patient although the reason to start terbinafine was unclear [41, 42]. An HIV positive patient infected in Colombia and initially diagnosed with a skin mycosis, was treated, and cured with terbinafine when CL was diagnosed eventually. The causative Leishmania species was unknown [43]. In another case, terbinafine 250mg daily combined with a Crotamiton 10% + Sulphur 2% cream in the absence of other CL treatments cured a Kenyan patient with CL; the causative Leishmania species was unknown [44]. Terbinafine 500mg combined with itraconazole 200mg daily for six months was started without evident reason in a patient suffering from MCL, visceral leishmaniasis, and liver cirrhosis caused by L. infantum. Terbinafine proved surprisingly effective resulting in the cure of the nasal mucosal inflammation and improvement of the liver function [45].

Terbinafine drug combination treatment

Various in vitro studies evaluated the combination of terbinafine with drugs from the triazole group. Up to 300-fold improvement was demonstrated of the inhibition of L. braziliensis promastigotes when combining ketoconazole with terbinafine [37]. Another study reported that ketoconazole and terbinafine had a synergistic effect on the inhibition of L. amazonensis amastigotes resulting in a minimally inhibitory concentration of 0,001μM (Table 4) [39].

Table 4. Results of in vitro and clinical studies on the combination of terbinafine with other treatment in cutaneous and mucocutaneous leishmaniasis.

Study	Leishmania species	Target	Combined therapy	Result
Andrade-Neto 2013[30]	L. amazonensis	promastigote	LBqT01	synergistic effect^a
Andrade-Neto 2013	L. amazonensis	promastigote	imipramine	additive effect^b
Andrade-Neto 2013	L. amazonensis	amastigote	LBqT01	no significant effect
Andrade-Neto 2013	L. amazonensis	amastigote	imipramine	no significant effect
Vannier Santos 1995 [39]	L. amazonensis	amastigote	ketoconazole	synergistic effect^c
Rangel 1996 [37]	L. braziliensis	promastigote	ketoconazole	synergistic effect^d
Rangel 1996	L. braziliensis	promastigote	D0870	synergistic effect^d
Vellin 2005 [45]	L. infantum	MCL	itraconazole	complete epithelialization
Mawenzi 2018 [44]	unknown	CL	crotamiton + sulfur	complete epithelialization
Farajzadeh 2015 [25]	L. tropica	CL	cryotherapy	no significant effect
Farajzadeh 2016 [26]	L. tropica	CL	meglumine antimoniate	no significant effect

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^a Synergism defined as fractional inhibitory concentration index (FICI) ≤ 0,5

^b Additive effect defined as: 0,5 < FICI < 4

^c Synergism defined as total fractional inhibition higher than expected from adding up the fractional inhibition of each individual drug

^d Synergism defined as 300-fold reduction of the Minimum Inhibitory Concentration of ketoconazole with 1μM terbinafine.

Discussion

This systematic review assesses efficacy and safety of allylamines for the treatment of CL and MCL. It comprises an exhaustive search of eight electronic databases and trial registers. It assesses the risk of bias of two randomised controlled trials, a non-controlled trial, two animal studies, and 12 in vitro studies and summarizes the available evidence including five case reports. Generally, the quality of evidence was low and human studies were done only in L. tropica.

The only well-designed randomised controlled trial of Farajzadeh et al. that compared the treatment efficacy of oral terbinafine versus intramuscular meglumine antimoniate showed a non-significant lower cure rate for terbinafine (38% vs 53% of treated patients) [25].

Farajzadeh [26] and Bahmdans [27] clinical trials with terbinafine reported cure rates of 14% and 15% respectively, but the findings of these studies should be interpreted with caution due to high rates of loss to follow up. Two animal studies lacked allocation concealment and did not blind outcome assessment and therefore should be interpreted with caution [28, 29].

The in vitro studies showed that terbinafine, butenafine, and naftifine eliminated amastigotes at concentrations between 23 and 45μM, that is approximately five times higher than the terbinafine levels achieved in the skin during terbinafine treatment [46–48]. Therefore, we conclude that allylamines are not promising for CL and MCL treatment.

Farajzadeh recommends terbinafine as an alternative to meglumine antimoniate in the case of allergy or resistance [25]. Although the work reports on hazard ratios and time to healing, it does not mention the complete cure rates in the abstract and conclusion sections. The cure rate of 38% was not significantly lower than the 53% cure rate with meglumine antimoniate, and we consider it too low to propose it as a new alternative treatment. The lack of significance of the lower cure rate of terbinafine compared to meglumine antimoniate could be explained by a low effectivity of the latter.

Whilst this review shows that there is no evidence for efficacy of terbinafine in the treatment of CL and MCL, it is highly effective in the treatment of mycotic skin disease. The difference may be due to the high sensitivity of skin fungus to terbinafine compared to Leishmania amastigotes. Terbinafine eliminates skin fungus in vitro at a mean concentration of 0,014μM [49], thus is approximately 2500 times more effective than the elimination of Leishmania amastigotes.

Promastigote cultures are relatively easy and cheap to maintain but are not very reliable as predictors of in vivo effectivity as they represent the infective mosquito stage of the parasite whilst human infection is sustained by intracellular amastigotes [50, 51]. Therefore, the results of the in vitro study of Beach et al. that indicates effective concentrations of 1–34μM of terbinafine in L. braziliensis and L. amazonensis promastigotes should be interpreted with caution. Results of promastigote studies must be confirmed in amastigote studies.

Although triazole monotherapy does not seem effective as treatment of CL patients, results from in vitro studies indicate terbinafine combined with triazole drugs may be effective through a synergistic effect. Terbinafine combined with ketoconazole eliminated L. amazonensis amastigotes at levels of 0,001μM of both drugs. Terbinafine would reach those levels with an oral dose of 250mg but the best combination with a triazole drug still has to be defined [46]. Triazole drugs like ketoconazole and fluconazole are inhibitors of the enzymes CYP 2C9 and CYP 3A4, involved in terbinafine metabolism, and may cause significant rise in terbinafine plasma concentrations. Secondary effects of terbinafine combined with triazoles have not been studied extensively and would require large clinical studies before implementation [52, 53].

Conclusion

Based on a systematic review of available literature we conclude that there is no evidence for the efficacy of allylamine monotherapy against CL and MCL. Further trials of allylamines as a treatment for CL and MCL should be carefully considered as the outcomes of an adequately designed trial were disappointing and in vitro studies indicate minimal effective concentrations that are not achieved in the skin during standard doses of 250-1000mg oral terbinafine/day. However, the in vitro synergistic effects of allylamines combined with triazole drugs against amastigotes, warrant more investigation starting with high quality animal studies to define optimal doses and safety profiles and followed by well-designed trials in humans in case of positive findings.

Supporting information

S1 Table. Characteristics of case reports.

(DOCX)

Click here for additional data file.^{(16.6KB, docx)}

S1 File. Full electronic search.

(DOCX)

Click here for additional data file.^{(27.7KB, docx)}

S2 File. PRISMA 2009 checklist.

(DOCX)

Click here for additional data file.^{(70.4KB, docx)}

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

JB received a monthly volunteer allowance from Latin Link Nederland http://www.latinlink-nederland.nl/, which helped fund the study. JvdE is a volunteer for Fundacion Quina Care Ecuador and receives a monthly volunteer allowance from this organization which also helped fund the study. Latin Link and Fundacion Quina Care Ecuador had no role in study design, data collection and analysis, decision to publish, preparation of the manuscript. No additional external funding was received for this study.

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PLoS One. doi: 10.1371/journal.pone.0249628.r001

Decision Letter 0

Kristien Verdonck

16 Dec 2020

PONE-D-20-23096

Safety and efficacy of allylamines in the treatment of tegumentary leishmaniasis: a systematic review

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The methodology of the study seems sound, and the prisma guidelines have been followed. However, I feel the written manuscript needs significant editing both in content and form before it is suitable for publication.

General

-Editing is needed (see pdf for more examples)

• Numbers spelled out or in number (e.g. line 38 ; one/2)

• Abbreviations not used consistently

• in vitro is sometimes not in italics

• Tables cannot be viewed properly (last columns have fallen off page), please show in 'landscape orientiation'

• Punctuation needs to be checked, sometimes missing or inconsistent, left out wrongly, sometimes overused

-It seems the authors are quite focused on New World leishmaniasis, this should be adjusted if they want to talk about cutaneous and mucocutaneous leishmaniasis in general

• the term tegumentary CL is generally used more for the America's and is not common for Old World CL. But the study is also about L. tropica. Perhaps better to talk about cutaneous and mucocutaneous leishmaniasis?

• Not all leishmania lesions are necessarily ulcers, in many parts of the world, ulcers are not the dominant presentation

Abstract

-Make abstract more general, instead of mainly New World CL. Also now it seems almost all mucosal disease is lethal, which is misleading.

-Not all current TL treatment have severe side-effects. What about local treatments such as cryotherapy or miltefosine?

Introduction

-Rationale of why a review on this topic is needed should be more clearly explained. Why allylamines and not any other drug? Now the main reason why allylamines are proposed is safety. Its oral form, or low cost (?), availability(?) could be emphasized more

-In what capacity do you think allylamines could be used? Once this is defined the introduction can be made more targeted. Now it is explained as an alternative for all CL drugs, which are heaped together as bad and having severe side-effects. But there are plenty of promising treatment initiatives for CL treatment ongoing, thermotherapy, miltefosine.

• If used as an alternative for systemic pentavalent antimonials (where the major concern is safety) then lesions should also be severe enough to warrant systemic treatment.

• If intended for more simple lesions, describing the disadvantages of systemic treatment doesn’t make sense

• If you want to keep all lesions please explain why other promising safe treatment modalities are not an option

Methods

-Most studies are not on animals or humans. Any way to assess bias for in vitro studies?

Results

-Please also discuss studies with higher risk of bias, now only the 2015 trial is discussed. Just because they have bias does not mean they should be disregarded altogether, it just means they should be interpreted with caution.

-I would like to see a bit more info on the case reports. Did these patients fail to respond to other treatments? Why were they started on allylamines otherwise?

-I would prefer one table with all evidence on effectiveness and one table on characteristics of all studies, separated per study type. The high number of tables make it hard to get a clear overview.

-Please reconsider structure of results, results seem fragmented, some repetition (e.g. MCL/VL case)

-Please ensure tables are fully legible before approving pdf submission!

Discussion

-Do we have enough evidence to say allylamines do not work? It is important to stress that the quality of evidence found was poor, all human studies were only for L. tropica, while leishmaniasis is a very heterogenous disease.

-The discussion needs more structure.

-Discussion can be shortened significantly. Now some parts seem more suited for introduction, others for methods, results. There is no need to refer to tables any more in discussion, this is more for results Some more detailed suggestions can be found below.

• Line 218-228 seems to indicate the dose given to patients was too low (this paragraph can be made more concise). Explain whether it is not an option to increase dosage to reach required levels.

• Line 240-245 explain that based on the clinical papers, terbinafine does not seem promising. I think one paragraph summarizing all evidence and stating that the allylamines are not promising is clearer; this should be the first paragraph of the discussion.

• Line 246-248: This is more for introduction, it disrupts the flow of the discussion. Better to leave out details about mechanism of action. "Although triazole monotherapy does not seem effective as for treatment of CL patients, results from in vitro studies indicate terbinafine combined with triazole drugs may be effective through a synergistic effect".

• Line 254-260: this paragraph can be shortened and combined with the previous

Reviewer #2: 1. Summary of the research and overall impression

a. The authors delivered a well written systematic review that assessed the evidence available on the efficacy and safety of allylamine treatment for tegumentary leishmaniasis. The search strategy was extensive and inclusive, the methodology accurate and well described, and the conclusions clearly formulated. As a note, please be aware that the tables were not fully available (cut-off on the right side of the text) for reviewing, which might have influenced the comments made by the reviewer.

2. Evidence and examples

a. Major issues

i. Line 229 and 261: ‘this review shows that terbinafine is not effective’ versus line 244: ‘lack of evidence for the efficacy of terbinafine’. The authors base this conclusion primarily on one well-designed human trial, together with (indirect) arguments coming from in vitro studies (although this impression might be linked to incomplete availability of the data from the tables). From the text, it seems more correct to state that there is no proof of efficacy, rather than state that there is proof of inefficacy.

b. Minor issues

i. Abstract

1. Line 71: ‘Furthermore, poor treatment responses exist for TL drugs’. Please specify: is this so in general/for the majority of patients? Or specifically so for pentavalent antimonials,…? How does this sentence add to line 66 ‘… each species responds differently to treatment’?

2. Line 78: add space between ‘death[8]’

3. Line 84: ‘All original human, animal and in vitro studies, including studies comparing effects of allylamines with placebo or alternative TL treatments, were eligible for inclusion’. This sentence seems strangely formulated. Alternative suggestion: ‘all original human, animal and in vitro studies concerning allylamines and leishmaniasis were eligible for inclusion. Comparators – if any - included both placebo or alternative TL treatments’ ?

ii. Methods

1. Line 92: add period at the end of the line.

2. Line 97: ‘no language, date or other restriction were applied’. Replace: either ‘other restrictionS were applied’ or ‘other restriction WAS applied’.

3. Line 125: ‘presentation’. Add ‘drug’ for clarity (as was done for human studies in line 120).

iii. Results

1. Line 175: add space between ‘2015[21]’.

2. In the tables with Characteristics of trials (Table 1-4) it is not registered systematically whether or not the treatment was allylamine monotherapy or combination treatment. For human trials and case reports, a combination column is present, but this is not the case for mice studies (Table 2) or in vitro studies. I would suggest the authors to include this column for all tables on characteristics. At present it seems from the table 3 and 4 that in vitro studies all studied allylamine monotherapy, while it only becomes clear in line 194 that most tested combination therapies. [Since Tables 1-4 are not fully visible in the manuscript provided, it is possible that this column is indeed present in all tables, in which case the authors can ignore this comment.]

3. Line 196: add space to ‘L.braziliensis’. Similar mistake on line 198, 219, 237, 238, 244, 254, 264

iv. Discussion

1. Line 218: sentence is difficult to understand, try to rephrase? E.g. ‘A low sensitivity of amastigotes to the clinically achievable levels of terbinafine…’?

2. Line 256: add space to ‘defined[41]’

Reviewer #3:

The aim of this review article is to assess the safety and efficacy of allylamines in the treatment of tegumentary leishmaniasis. In this search, 22 publications were included, PRISMA statement for reporting was used and also risk of bias in human and animal studies was assessed with the Cochrane and SYRCLE´s tools, respectively.

Overall, the study is interesting and novel; however, the following concerns need to be corrected:

Abstract:

- The conclusion section is brief; please explain more about the message you want to present.

- You shouldn’t sort out the abstract, please check the instruction of the journal.

Introduction:

- Line 61: please delete “Background”.

Methods:

- Line 130: “Risk of bias”, please explain more about this section.

Results:

- Tables 1,2,3,4,8: I couldn't see some columns of these tables, please make the tables in the form of landscape or smaller.

- Line 153: After “One animal study reported the efficacy of terbinafine on L. amazonensis and the other on L. major” please mention the references.

- Line 155: After “allylamines in amastigote models” mention the references.

- Line 183: In the study of Farajzadeh et al., 2015, I found that oral terbinafine may have approximately the same efficacy as glucantime. So please explain more about the finding and conclusion of the study in both discussion and result sections.

- Line 191: After “compared to the median cytotoxic concentration of 98μ” please mention the references.

- Line 193: After “were more than 110 μM” please mention the references.

- Line 199: After “resulting in a minimally inhibitory concentration of 0,001μM.” please mention the references.

Discussion:

- Line 228: As I said, in the study of Farajzadeh et al., 2015; oral terbinafine demonstrates the same efficacy as glucantime. it seems that in some cases, oral terbinafine could be used for treatment of cutaneous leishmaniasis. So you should explain more about the finding of that study in the discussion.

Conclusion:

- The conclusion section is brief; explain more about the message you want to deliver.

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Attachment

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PLoS One. 2021 Apr 7;16(4):e0249628. doi: 10.1371/journal.pone.0249628.r002

Author response to Decision Letter 0

4 Feb 2021

Response to Reviewers

General

-Editing is needed (see pdf for more examples)

Response: Thank you very much for the revision. The comments in the PDF were applied to the manuscript as applicable. We want to explain that the outcomes are described at the end of the introduction in compliance with the PRISMA checklist. In the discussion we use the comparison with the effectivity of terbinafine in mycotic disease because it is the only generally accepted application of terbinafine in humans.

• Numbers spelled out or in number (e.g. line 38; one/2)

Response: Spelling of the numbers was corrected throughout the manuscript.

• Abbreviations not used consistently

Response: The use of abbreviations was corrected throughout the manuscript.

• in vitro is sometimes not in italics

Response: In vitro was written in italics throughout the manuscript.

• Tables cannot be viewed properly (last columns have fallen off page), please show in 'landscape orientiation'

Response: We apologize for the loss of columns during PDF creation and changed the text orientation of the tables that missed columns.

• Punctuation needs to be checked, sometimes missing or inconsistent, left out wrongly, sometimes overused

Response: Punctuation was corrected throughout the manuscript.

-It seems the authors are quite focused on New World leishmaniasis, this should be adjusted if they want to talk about cutaneous and mucocutaneous leishmaniasis in general

Response: Thanks to your comment, the focus of the written text was adjusted to leishmaniasis in general.

Response: Thanks to your comment, the term tegumentary was replaced with cutaneous and mucocutaneous throughout the manuscript, including the title.

• Not all leishmania lesions are necessarily ulcers, in many parts of the world, ulcers are not the dominant presentation

Response: Thanks to your comment, the text was adapted to include the different presentations of cutaneous leishmaniasis.

Abstract

-Make abstract more general, instead of mainly New World CL. Also, now it seems almost all mucosal disease is lethal, which is misleading.

Response: Thanks to your comment the focus of the text was adapted to leishmaniasis in general.

-Not all current TL treatment have severe side-effects. What about local treatments such as cryotherapy or miltefosine?

Response: Thanks to your comment, the statement about severe side-effects was adapted.

Introduction

Response: Thanks to your suggestion the oral form, availability, and cost of terbinafine was mentioned in the introduction.

Response: Allylamines could potentially be an oral or local, safe, easy to administer, and affordable alternative for the current arsenal of leismananial treatment options, many of whom are either expensive (e.g. miltefosine), painful (e.g. intralesional antimony) or bear severe side effects (e.g. systemic antimony or amphothericine-B)

• If used as an alternative for systemic pentavalent antimonials (where the major concern is safety) then lesions should also be severe enough to warrant systemic treatment.

Response: Our objective is a general systematic review that includes all possible cutaneous and mucocutaneous forms. Since the scarcity of data, we did not confine the review to severe forms that warrant systemic therapy only.

• If intended for more simple lesions, describing the disadvantages of systemic treatment does not make sense.

Response: Please, see the above written comment.

• If you want to keep all lesions please explain why other promising safe treatment modalities are not an option.

Response: Thank you very much for your valuable comment, we added the existence of multiple alternative treatments options in the introduction. The objective of this review is the utility of allylamines for cutaneous and mucocutaneous leishmaniasis. We consider it out of the scope of this paper to analyze the other possible promising safe treatment modalities, as this review compares with the mainstay treatment that’s pentavalent antimonials up to date.

Methods

-Most studies are not on animals or humans. Any way to assess bias for in vitro studies?

Response: Although no internationally accepted method for assessing bias in in vitro studies exists, thanks to your comment we applied the method developed by the US National Toxicology Program and implemented the figure in the manuscript.

Results

-Please also discuss studies with higher risk of bias, now only the 2015 trial is discussed. Just because they have bias does not mean they should be disregarded altogether; it just means they should be interpreted with caution.

Response: We thank you for your observation and kindly remind you that the results of the studies with high risk of bias can be observed in table 1, which is completely visible now. Additionally, we added a phrase in the methods section in the paragraph `Risk of bias assessment´ stating that studies with a high risk of bias are excluded from the analysis.

We feel that it is not wise to discuss the results of studies with high risk of bias, because it might suggest that those results were reliable. We clarified that in the methods section.

-I would like to see a bit more info on the case reports. Did these patients fail to respond to other treatments? Why were they started on allylamines otherwise?

Response: Thanks to your comment, the reason to start with terbinafine was stated in the S2 table and in the results section.

-I would prefer one table with all evidence on effectiveness and one table on characteristics of all studies, separated per study type. The high number of tables make it hard to get a clear overview.

Response: Although the heterogeneity of the studies did not permit the aggregation of all tables as proposed, we combined several tables and changed the ROB tables into figures, hoping that it will improve the manuscript reading.

-Please reconsider structure of results, results seem fragmented, some repetition (e.g. MCL/VL case)

Response: Thanks to your comments, the result section was restructured.

-Please ensure tables are fully legible before approving pdf submission!

Response: We apologize for the lost columns and adapted the table orientation.

Discussion

Response: Thanks to your comment the conclusion was adapted.

-The discussion needs more structure.

Response: Thanks to your comment the discussion was restructured.

Response: Thanks to your comment the references to tables were eliminated from the discussion.

• Line 218-228 seems to indicate the dose given to patients was too low (this paragraph can be made more concise). Explain whether it is not an option to increase dosage to reach required levels.

Response: Thanks to your comment the paragraph was adapted.

Response: Thanks to your comment, the first paragraph was adapted.

Response: We applicated your suggestion.

• Line 254-260: this paragraph can be shortened and combined with the previous

Response: We applicated your suggestion.

Reviewer #2: 1. Summary of the research and overall impression

2. Evidence and examples

a. Major issues

Response: Thank you very much for the revision and comments. The suggestion was applied.

b. Minor issues

i. Abstract

Response: Thanks to your suggestion the sentence was changed.

2. Line 78: add space between ‘death[8]’

Response: Thanks for the comment, it was applied.

Response: Thank you very much for the suggestion, it was applied.

ii. Methods

1. Line 92: add period at the end of the line.

Response: Thanks for the comment, it was applied.

2. Line 97: ‘no language, date or other restriction were applied’. Replace: either ‘other restrictionS were applied’ or ‘other restriction WAS applied’.

Response: Thanks for the comment, it was applied.

3. Line 125: ‘presentation’. Add ‘drug’ for clarity (as was done for human studies in line 120).

Response: Thanks for the comment, it was applied.

iii. Results

1. Line 175: add space between ‘2015[21]’.

Response: Thanks for the comment, it was applied.

Response: Thank you very much for the comment. We added the column indicating combination treatments to the tables with characteristics of trials and in vitro studies (Table 1 and 2 after fusion).

3. Line 196: add space to ‘L.braziliensis’. Similar mistake on line 198, 219, 237, 238, 244, 254, 264

Response: Thanks for the comment, it was applied.

iv. Discussion

1. Line 218: sentence is difficult to understand, try to rephrase? E.g. ‘A low sensitivity of amastigotes to the clinically achievable levels of terbinafine…’?

Response: Thanks for the comment, it was applied.

2. Line 256: add space to ‘defined[41]’

Response: Thanks for the comment, it was applied.

Reviewer #3:

Overall, the study is interesting and novel; however, the following concerns need to be corrected:

Abstract:

- The conclusion section is brief; please explain more about the message you want to present.

Response: Thanks to your comment, we extended the conclusion section of the abstract.

- You shouldn’t sort out the abstract, please check the instruction of the journal.

Response: We corrected the headings in the abstract as you suggest.

Introduction:

- Line 61: please delete “Background”.

Response: Thanks for the comment, it was applied.

Methods:

- Line 130: “Risk of bias”, please explain more about this section.

Response: Thanks to your comment, the Risk of bias section was extended.

Results:

- Tables 1,2,3,4,8: I couldn't see some columns of these tables, please make the tables in the form of landscape or smaller.

Response: We apologize for the loss of columns during the transformation to PDF. It was corrected.

- Line 153: After “One animal study reported the efficacy of terbinafine on L. amazonensis and the other on L. major” please mention the references.

Response: The phrase was removed from the manuscript in response to other comments.

- Line 155: After “allylamines in amastigote models” mention the references.

Response: The phrase was removed from the manuscript in response to other comments.

Response: Thanks to your comment we mention the difference in endpoint between Farajzadeh and our systematic review.

- Line 191: After “compared to the median cytotoxic concentration of 98μ” please mention the references.

Response: Thanks for the comment, it was applied.

- Line 193: After “were more than 110 μM” please mention the references.

Response: Thanks for the comment, it was applied.

- Line 199: After “resulting in a minimally inhibitory concentration of 0,001μM.” please mention the references.

Response: Thanks for the comment, it was applied.

Discussion:

Response: Thanks to your comment we explain that the same efficacy was possibly caused by resistance to meglumine antimoniate.

Conclusion:

- The conclusion section is brief; explain more about the message you want to deliver.

Response: Thanks to your comment we extended the conclusion section.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(28.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0249628.r003

Decision Letter 1

Kristien Verdonck

3 Mar 2021

PONE-D-20-23096R1

Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: a systematic review

PLOS ONE

Dear Dr. Bezemer,

Apart from a few minor issues, I would like to invite you to consider the suggestion to either include the studies at high risk of bias or to make a better case for excluding them (maybe based on study design? see below).

Please submit your revised manuscript by Apr 17 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Kristien Verdonck

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Abstract and methods: “Studies were excluded from analysis if high risk of bias was perceived during assessment”. How many studies were excluded in this way? This is an unusual approach, especially because you include studies with diverse designs. Unless you have good reasons to do otherwise, I would prefer that you use “study design” at the level of study selection, and report the “risk of bias assessment” as part of the findings (not as an exclusion criterion) and in the discussion. Within the findings of the review, you can then highlight that some studies had high risk of bias (explain the reasons) and that the findings of these studies should be interpreted with caution.
Abstract: terbinafine is safe during pregnancy. It is not only about safety during pregnancy? Consider rephrasing.
Introduction: “antimonial therapy is painful”. Please revise this sentence; I assume it is only painful when applied in the lesion.
Pentavalent antimonials are the most frequently used drugs for new world leishmaniasis. Is that also true for old world leishmaniasis? See for example https://apps.who.int/iris/bitstream/handle/10665/44412/WHO_TRS_949_eng.pdf?sequence=1&isAllowed=y (Box 2, page 69).
Methods, study eligibility: check spelling of “species”. The singular is species, not “specie”.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: minor suggestions:

- Line 35: remove comma after Leishmania tropica

- Line 51: ‘… are still the most frequently used ones’ ?

- Line 139 + 261: et al. (dot behind al)

- Line 250 : to propose it as (rather than propose it for)?

- Numbers are sometimes written in words, sometimes in numbers; this is not done coherently. Rule of thumb: numbers ten or below should be written out in words; above ten should be written as numbers

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #2: No

Reviewer #3: No

PLoS One. 2021 Apr 7;16(4):e0249628. doi: 10.1371/journal.pone.0249628.r004

Author response to Decision Letter 1

19 Mar 2021

Response to Reviewers

Response: Thank you very much for the revision. The studies at high risk of bias were not excluded from the systematic review, as explained below, and the phrases “Studies were excluded from analysis if high risk of bias was perceived during assessment” were eliminated from the abstract and methods.

Journal Requirements:

Response: The reference list was checked for retractions with the `scite reference check´ online tool, but none was detected.

Additional Editor Comments:

• Abstract and methods: “Studies were excluded from analysis if high risk of bias was perceived during assessment”. How many studies were excluded in this way? This is an unusual approach, especially because you include studies with diverse designs. Unless you have good reasons to do otherwise, I would prefer that you use “study design” at the level of study selection, and report the “risk of bias assessment” as part of the findings (not as an exclusion criterion) and in the discussion. Within the findings of the review, you can then highlight that some studies had high risk of bias (explain the reasons) and that the findings of these studies should be interpreted with caution.

Response: Thank you for the important comment. We recognize that the phrases about exclusion of studies at high risk of bias in the abstract and methods generated confusion as it was not our intention to exclude them from the entire review as can be seen in Table 1. Therefore, the two phrases were eliminated (line 31 and line 126 in the Revised Manuscript with track changes) and an additional comment was written in the discussion (line 243-246 in the Revised Manuscript with track changes).

Abstract: terbinafine is safe during pregnancy. It is not only about safety during pregnancy? Consider rephrasing.

Response: Thanks to your comment, the phrase was adapted to: `Allylamine drugs, like terbinafine, are safe, including during pregnancy. ´

• Introduction: “antimonial therapy is painful”. Please revise this sentence; I assume it is only painful when applied in the lesion.

Response: Thanks for your comment, but we prefer to maintain the sentence as antimonial therapy is either applied intra-lesional, intra-muscular, or intra-venously. We consider all three methods to be painful as they require injections.

• Pentavalent antimonials are the most frequently used drugs for new world leishmaniasis. Is that also true for old world leishmaniasis? See for example https://apps.who.int/iris/bitstream/handle/10665/44412/WHO_TRS_949_eng.pdf?sequence=1&isAllowed=y (Box 2, page 69).

Response: Thanks to your comment we adapted the statement for old world leishmaniasis to: ` are still the most frequently used for American CL and MCL [5] and frequently used for old world leishmaniasis [6].´(line 53 in the Revised Manuscript with track changes)

• Methods, study eligibility: check spelling of “species”. The singular is species, not “specie”.

Response: Thanks to your comment, the spelling of species was corrected

________________________________________

6. Review Comments to the Author

Reviewer #2: minor suggestions:

- Line 35: remove comma after Leishmania tropica

Response: Thanks to your comment, we removed the comma.

- Line 51: ‘… are still the most frequently used ones’ ?

Response: Thanks to your comment we adapted the statement for old world leishmaniasis.

- Line 139 + 261: et al. (dot behind al)

Response: Thanks to your comment, we added the dots behind al.

- Line 250 : to propose it as (rather than propose it for)?

Response: Thanks to your comment, the phrase was adapted.

- Numbers are sometimes written in words, sometimes in numbers; this is not done coherently. Rule of thumb: numbers ten or below should be written out in words; above ten should be written as numbers

Response: Thanks for your comment. We corrected a number 20 and a number 12 that were written out in words in the first paragraph of the introduction and of the discussion.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(27.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0249628.r005

Decision Letter 2

Kristien Verdonck

23 Mar 2021

Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: a systematic review

PONE-D-20-23096R2

Dear Dr. Bezemer,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Kristien Verdonck

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0249628.r006

Acceptance letter

Kristien Verdonck

29 Mar 2021

PONE-D-20-23096R2

Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: a systematic review

Dear Dr. Bezemer:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Kristien Verdonck

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Characteristics of case reports.

(DOCX)

Click here for additional data file.^{(16.6KB, docx)}

S1 File. Full electronic search.

(DOCX)

Click here for additional data file.^{(27.7KB, docx)}

S2 File. PRISMA 2009 checklist.

(DOCX)

Click here for additional data file.^{(70.4KB, docx)}

Attachment

Submitted filename: PONE-D-20-23096_reviewer_13oct.pdf

Click here for additional data file.^{(1.5MB, pdf)}

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(28.8KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(27.4KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: A systematic review

Jacob M Bezemer

Jacob van der Ende

Jacqueline Limpens

Henry J C de Vries

Henk D F H Schallig

Roles

Abstract

Introduction

Methods

Search strategy

Study eligibility

Study selection

Data extraction

Risk of bias assessment

Results

Studies included

Fig 1. PRISMA literature assessment flow diagram.

Table 1. Characteristics of human and mice trials reporting treatment of cutaneous leishmaniasis with terbinafine.

Table 2. Characteristics of in vitro studies reporting on effects of allylamines in cutaneous and mucocutaneous leishmania species.

Risk of bias assessment

Fig 2. Risk of Bias assessment of randomised controlled trials.

Fig 5. Risk of Bias assessment of in vitro studies.

Fig 3. Risk of Bias assessment of a non-randomised study in humans.

Fig 4. Risk of Bias assessment of animal trials.

Efficacy of terbinafine on L. tropica human infections and adverse events

Species specific effectivity of allylamine treatments

Table 3. Overview of clinical and in vitro Leishmania species specific results of terbinafine in cutaneous leishmaniasis.

Case reports reporting cure with terbinafine

Terbinafine drug combination treatment

Table 4. Results of in vitro and clinical studies on the combination of terbinafine with other treatment in cutaneous and mucocutaneous leishmaniasis.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Kristien Verdonck

Roles

Author response to Decision Letter 0

Decision Letter 1

Kristien Verdonck

Roles

Author response to Decision Letter 1

Decision Letter 2

Kristien Verdonck

Roles

Acceptance letter

Kristien Verdonck

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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