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. 2018 Jul 26;2018(7):CD013082. doi: 10.1002/14651858.CD013082

Drug therapy for Mycetoma

Peter Scolding 1,✉, Ahmed Fahal 2, Rie R Yotsu 3
PMCID: PMC6513665

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of drug therapy for mycetoma, including eumycetoma and actinomycetoma.

Background

Mycetoma is a chronic granulomatous inflammatory disease caused by certain bacteria (actinomycetoma) and fungi (eumycetoma), and was added to the World Health Organization (WHO) list of neglected tropical diseases in 2016. It is known to result in deformity, disability, amputation, and death (Zijlstra 2016). It is an ancient disease, described in the Indian Atharva Veda as pada valmikan (ant‐hill foot; Estrada 2012). More recent descriptions are also reported from India: in Englebert Kaempfer’s PhD thesis in 1694; in the work of John Gill who coined the term ‘madura foot' after the town where he worked in 1842; and from Vandyke Carter of the British army, who first named the condition ‘mycetoma’ (from the Greek mykes (fungal) and oma (tumour)) in 1874 (Kaempfer 1694; Lynch 1964; Hershkovitz 1992; Vandyke Carter 1874). The disease remains endemic throughout the ‘mycetoma belt’, between latitudes 15° south and 30° north, from Mexico and Brazil across Africa and the Middle East to India (van de Sande 2013; Zijlstra 2016). Data on global incidence is patchy, with the highest calculated rates in Sudan, Senegal, Mexico, and India (van de Sande 2013).

Globally, actinomycetoma is more common worldwide than eumycetoma. At least seven organisms are known to cause actinomycetoma, the most common being Actinomadura madurae, Streptomyces somaliensis, Actinomadura pelletieri, and Nocardia species. In contrast, 18 fungal species have been identified in eumycetoma, with many more remaining unidentified. Madurella mycetomatis is by far the most common, causing 26.4% of mycetoma cases overall (van de Sande 2013).

Infection is believed to occur through the delivery of the causative agent ‐ either bacteria or fungi ‐ from the soil (its suspected primary reservoir), into subcutaneous tissue via trauma, with thorns often found in the mass lesions (Thirumalachar 1968; Orchard 1980; Ahmed 2002; Fahal 2006). Mycetoma is reported to predominantly affect young men with occupations such as students, farmers, and herders (Abbott 1956; Lynch 1964; Fahal 2014; Fahal 2015).

Description of the condition

Both eumycetoma and actinomycetoma present with a pathognomonic triad of painless subcutaneous mass, multiple sinuses, and purulent or sero‐purulent discharge containing grains. Grains vary in size, colour, and microscopic features (for example filament width) according to the causative organism. Grains in actinomycetoma may be white, yellow, and red; whilst those in eumycetoma are often black, but may be white or yellow (Estrada 2012; Welsh 2012; Bonifaz 2014; Zijlstra 2016).

Mass lesions are predominantly on the feet and hands (84% of cases), although the trunk, legs, perineum, head, neck, and other areas may be involved (van de Sande 2013; Zijlstra 2016). Superficial appearances may correlate poorly with true extension (Scolding 2016). The mass lesion can progress, invading deep structures including bone ‐ resulting in grain‐filled cavities‐ and via lymphatic and vascular systems (el Hassan 1972; Fahal 2012; van de Sande 2013; Mohamed 2016). Aggressive disease can invade deep organs such as the lungs, spinal cord, and pelvic area, and may cause mortality (Fahal 1996; Hussein 2007; Mohammed 2012). Presentation with secondary bacterial infection is common, typically with Staphylococcus aureus or Streptococcus pyogenes (Ahmed 1998).

There is currently no universally‐used staging system for mycetoma. Clinically, lesions are graded as small (less than 5 cm without bone involvement), moderate (5 cm to 10 cm with bone involvement), and massive (greater than 10 cm with bone involvement and secondary bacterial infection). Recommendations for medical and surgical treatment are based upon this system (Suleiman 2016).

Global prevalence and incidence are unknown, with studies showing variation between and within countries, with a prevalence range of between 14.5 per 1000 population in field studies to 1.81 per 100,000 in national studies (both estimates from Sudan; van de Sande 2013; Fahal 2014). Mycetoma is known to cause significant morbidity and disability, particularly in advanced disease (Fahal 2015). Postoperative recurrence occurs in 25% to 50% of patients, due to a range of disease, clinician, and patient factors, necessitating further treatment and morbidity (Suleiman 2016).

Diagnosis

Diagnosis is often made clinically in endemic areas due to resource constraints, however ultrasound and fine needle aspirate (FNA) are widely used for confirmation.

The FNA from deep‐seated grains provides material for identification of the causative organism through culture and cytology. The fine filaments of actinomycetoma show with Gram staining, whilst the eumycetomatous filaments stain with periodic acid‐Schiff (Kwon‐Chung 1992). Histopathology from deep biopsy is also widely used despite drawbacks in differentiating species. Three types of tissue reaction are recognized. In type I reactions, neutrophils enclose and invade the grain leading to its disintegration, with surrounding layers of granulation and then fibrous tissue. Type II reactions involve macrophages and multinucleated cells engulfing the fragmented grain. Finally, a well‐developed epithelioid granuloma is seen in type III reactions (Fahal 1995).

Radiologically, up to 97% of lesions will also show on plain X‐ray, whilst both computed tomography (CT) and magnetic resonance imaging (MRI) scanning can reveal important diagnostic features (Bonifaz 2008; Abd El‐Bagi 2009; El Shamy 2012). X‐ray and MRI grading systems describe disease spread. X‐ray stages 0 to VI range from simple soft‐tissue swelling (Stage 0), to cortical erosion and central cavitation (Stage III), to multidirectional spread due to uncontrolled infection (Stage VI; Abd El Bagi 2003). The Mycetoma Skin, Muscle, Bone Grading System uses MRI to describe and grade disease as mild, moderate, and severe based on a score from 1 to 10 (El Shamy 2012). Ultrasound can demonstrate the presence of grains as hyper‐reflective echoes within cavities (Fahal 1997).

Finally, where available, polymerase chain reaction (PCR) provides more accurate diagnosis (Zijlstra 2016).

Description of the intervention

Treatment choices depend on the causative organism and disease progression. Actinomycetoma can generally be treated with long‐term antimicrobial combination therapy. However, eumycetoma often requires both long‐term antifungal medications and surgical intervention. The goals of therapy are to clear infection (actinomycetoma only), reduce morbidity, and prevent complications (Ameen 2008).

Actinomycetoma

Several classes of antibiotics have been used to treat actinomycetoma, including sulfonamides, aminoglycosides, tetracyclines, amoxicillin (with clavulanic acid), carbapenems, rifampicin, and oxazolidinones (Welsh 2013). Sulfonamides such as sulfanilamide and sulfadiazine have been in use since the 1940s (Dixon 1941; Peters 1945). A wide range of agents and combinations were trialled over the following decades, including minocycline, tetracycline, streptomycin, dapsone, rifampicin, and isoniazid (Ziprkowski 1957; Hubler 1976; Mahgoub 1976; Gugnani 1981; Kamalam 1987; Welsh 1987; Welsh 2014). By the 1960s, sulfamethoxazole with trimethoprim (co‐trimoxazole) had become the gold standard, and has since been used as first line therapy either alone (Mahgoub 1972; Khatri 2002; Dieng 2005), or in combination with a penicillin, dapsone, or an aminoglycoside such as streptomycin, amikacin, gentamicin, or netilmicin (Cockshott 1960; Mahgoub 1972; Rogers 1974; Mahgoub 1976; Welsh 1985; Ramam 2000; Khatri 2002; Ameen 2010; Welsh 2012).

More recently, the ‘Welsh regimen’ of co‐trimoxazole with amikacin in one to four five‐week cycles has been suggested for use in resistant disease (see Table 1), or where the thorax, neck, or head are involved (Welsh 1987; Welsh 2012). The ‘Ramam two‐step regimen’ replaces amikacin with the cheaper alternative of gentamicin in an ‘intensive phase’ of co‐trimoxazole and gentamicin for four weeks followed by a ‘maintenance phase’ of co‐trimoxazole and doxycycline given until five to six months after complete skin healing (Ramam 2007). Other modifications of the original Welsh regimen include adding rifampicin, dapsone, doxycycline, and streptomycin in different combinations, or increasing the number of cycles, particularly in cases of bony involvement (Damle 2008; Patil 2009; Praveen 2011; Agarwal 2013).

Table 1.

Example treatment regimens for actinomycetoma

Drug Dose Route Administration
First‐line Co‐trimoxazole (trimethoprim‐sulfamethoxazole) 960 mg BD Oral Minimum expected duration: 12 months
Then continue until criteria for cure fulfilled
Co‐amoxiclav (amoxicillin‐clavulanic acid) 1 g BD Oral
Folic acid 5 mg OD Oral
Second‐line Co‐trimoxazole (trimethoprim‐sulfamethoxazole) Trimethoprim 8 mg/kg/day
+ sulfamethoxazole 40 mg/kg/day
in 3 divided doses		 Oral 5 weeks
Amikacin 15 mg/kg/day in 2 divided doses IV/IM 1 to 4 cycles
1 cycle = 3 weeks
(2‐week intervals between cycles)
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Abbreviations: BD ‐ twice daily; OD ‐ once daily; IV ‐ intravenous injection; IM ‐ intramuscular injection

In highly drug‐resistant cases, agents such as netilmicin can replace amikacin (Welsh 2012). Alternative treatments for resistant disease include imipenem alone or with amikacin (Fuentes 2006; Ameen 2010), or amoxicillin with clavulanic acid (co‐amoxiclav), which is also safe to use in pregnancy (Gomez 1993; Bonifaz 2007).

During treatment, patient monitoring depends on the regimen used, but may include sensitivity testing for penicillins, monitoring of renal function with aminoglycoside use, audiometric testing with amikacin, and clinical review for dermatological and other effects associated with the use of co‐trimoxazole (Welsh 2014).

Eumycetoma

Antifungal treatment alone is seldom curative for eumycetoma and is used in combination with surgical excision or amputation. The aim of drug therapy is therefore to reduce the lesion in size and to produce local fibrosis, allowing for more limited, less mutilating surgery.

Itraconazole is currently the first line drug of choice (see Table 2; Smith 1997; Castro 2008; Fahal 2011; Zijlstra 2016). Ketoconazole was previously used for many years, but has been phased out since 2013 after concerns were raised by the US Food and Drug Administration (FDA) regarding liver injury, adrenal insufficiency, and drug interactions (Mahgoub 1984; Hay 1992; Venugopal 1993; FDA 2013). Other azole antifungals have been trialled more recently with mixed results, including voriconazole (Lacroix 2005; Loulergue 2006; Porte 2006; Gulati 2012; Oliveira 2013), and posaconazole (Negroni 2005; Crabol 2014; Sharma 2014). Fosravuconazole is currently undergoing human trials (NCT03086226).

Table 2.

Example treatment regimens for eumycetoma

Drug Dose Route Administration
Itraconazole 200 mg BD Oral Minimum 0 to 6 months preoperative, 6 months postoperative
Antibiotics (choice and dose according to culture and sensitivity) Oral Where secondary infection is confirmed Treat for 10 to 14 days
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Abbreviations: BD ‐ twice daily

A review of surgical treatment in 2016 recommended that medium to large lesions (less than 5 cm) be treated with itraconazole for six months, followed by wide local excision and a minimum of six further months of drug therapy until there is evidence of clinical, radiological, ultrasonic, and cytological cure. Treatment of small lesions may begin with wide local excision followed by three months of itraconazole (Suleiman 2016).

The combination of itraconazole with terbinafine, prior to surgery, has been recommended in resistant cases (Estrada 2012). Several other anti‐fungal treatments have shown poor in vitro activity, including griseofulvin, clotrimazole, fluconazole and echinocandins such as anidulafungin, caspofungin, and micafungin (Mahgoub 1976; van de Sande 2007; van de Sande 2010). Liposomal amphotericin B was associated with significant adverse effects and high relapse rates (Hay 1992), whilst a trial with terbinafine alone showed lower cure rates than itraconazole (N'Diaye 2006).

Given the high rates of concurrent bacterial infection (typically with S. aureus), combination therapy with an antibacterial (such as amoxicillin‐clavulanic acid) and an antifungal has been shown to improve therapeutic outcomes (Mhmoud 2014).

Due to the extensive treatment periods and the potentially toxic drugs used for eumycetoma patients, parameters such as liver function tests (in azole antifungal use) are routinely monitored. Commonly used agents have a further range of adverse effects and drug interactions (Welsh 2014). Follow‐up of eumycetoma patients may continue for up to 18 to 24 months given rates of recurrence up to 27% (Ameen 2008; Wadal 2016). There is a high relapse rate in eumycetoma due to problems including non‐completed medical therapy, incomplete surgical clearance, and drop‐out from follow‐up (Suleiman 2016).

How the intervention might work

Actinomycetoma can generally be treated with long‐term antimicrobial combination therapy. However, anti‐fungal treatment alone is seldom curative for eumycetoma and is used in combination with surgical excision or amputation. The aim of drug therapy for eumycetoma is therefore to reduce the lesion in size and to produce local fibrosis, allowing for more limited, less mutilating surgery (Suleiman 2016). The goals of drug therapy overall are to clear infection (actinomycetoma only), reduce morbidity, and to prevent complications and recurrence.

Why it is important to do this review

Mycetoma was added to the WHO list of neglected tropical diseases in 2016. Current practice in the treatment of actinomycetoma and eumycetoma varies between countries and centres worldwide, with different standards of diagnosis, choices of treatment, and measures of cure. Previous reviews have summarized research findings, but there is currently no study evaluating existing evidence for different therapeutic regimens.

At this time of increased global focus on mycetoma, a Cochrane Review will add value on several levels. Firstly, it will support clinicians in appreciating the evidence base for the therapeutic options at their disposal. Secondly, it may help to consolidate reference standards and terminology for diagnosis and outcome measurement within the literature on mycetoma. Finally, the process will contribute to the research agenda by highlighting gaps where further investigation is needed.

Objectives

To assess the effects of drug therapy for mycetoma, including eumycetoma and actinomycetoma.

Methods

Criteria for considering studies for this review

Types of studies

We will include prospective clinical studies; potentially, these may include both randomized and non‐randomized trials and observational cohort data. If we identify cohort studies for inclusion, we will prioritize those that use a control group.

Types of participants

People with a diagnosis of actinomycetoma or eumycetoma based upon clinical diagnosis and one or more of the following.

  • Microbiological or mycological identification of causative species

  • Histological confirmation

Types of interventions

Intervention
Actinomycetoma

At least six different regimens have been evaluated for treating actinomycetoma. Antimicrobials include penicillin, gentamicin, co‐trimoxazole, dapsone, sulphadoxine, amikacin, and doxycycline.

Eumycetoma

Four main categories of treatment are used in studies of eumycetoma treatment, with a base of either ketoconazole, itraconazole, fosravuconazole, or another antifungal such as griseofulvin, clotrimazole, or terbinafine.

Surgical interventions adjunct to drug therapy may include excision of the mycetomatous lesion and amputation.

Control

No treatment.

Types of outcome measures

Primary outcomes

  • Proportion of completely cured patients at the end of treatment course, defined as:

    • i. complete healing/closure of sinuses;

    • + ii. disappearance of swelling/mass;

    • + iii. no evidence of mycetoma on ultrasound or cytological examination or both;

    • ± iv. no disability (difficulty in executing normal daily activities due to pain or deformity).

Secondary outcomes

  • Partial response/improvement

  • Reduction in lesion size

  • Healing of sinuses or reduction in number of sinuses

  • Evidence of mycetoma remaining on X‐ray or ultrasound or cytology

  • Recurrence

  • Time to achieve cure

  • Change in disability

  • Adverse effects (that is, number of adverse events including drug toxicities and treatment interaction)

  • Duration of treatment

  • Surgery after medical treatment

Search methods for identification of studies

We will attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).

Electronic searches

We will search the following databases using the search terms and strategy described in Appendix 1: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); and LILACS. We will also search the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/search/en/), ClinicalTrials.gov (https://clinicaltrials.gov/), and the ISRCTN registry (www.isrctn.com/) to identify ongoing trials, using ‘Mycetoma' as a search term.

Searching other resources

We will search for additional studies for inclusion by reviewing the reference lists of all trials and relevant articles identified in the above methods. We will also contact leading researchers in this topic area to identify any unpublished data.

Data collection and analysis

Selection of studies

The Cochrane Infectious Diseases Group (CIDG) Information Specialist, Vittoria Lutje, will search the literature and retrieve studies using the search strategy outlined in Appendix 1. Two review authors, Peter Scolding (PS) and Rie R Yotsu (RRY), will independently screen the titles and abstracts of search results to identify studies that meet the inclusion criteria. We will retrieve the full‐text articles of published or unpublished study reports potentially relevant to this Cochrane Review for further assessment using a pre‐designed eligibility form based on the inclusion criteria. Either PS or RRY will contact the study authors for further details regarding study methodology if eligibility is unclear.

We will consult with Ahmed Fahal (AF) if there is any discrepancy in opinion between PS and RRY. If there is still disagreement between the review authors, we will consult one of the CIDG Co‐ordinating Editors or other experts to reach a consensus. We will examine study reports to ensure that we include multiple publications from the same study only once. We will list all studies excluded after full‐text assessment in the ‘Characteristics of excluded studies' table. We will illustrate the study selection process in a PRISMA diagram.

Data extraction and management

Two review authors (PS and RRY) will extract and summarize data from the included studies on standardized data extraction forms. We will resolve any differences in opinion through discussion, or by consulting a third review author (AF) if necessary. If important data are missing from the included studies, we will attempt to contact the study authors for further information.

We will extract the number of participants included in each initial study population, and the number of participants followed‐up, with a list of each study’s inclusion and exclusion criteria, a description of the intervention(s), and primary and secondary outcome measures. The data extraction form will also include baseline characteristics of participants such as age, sex, lesion characteristics and site, diagnostic results, therapy duration, adverse effects, outcomes, surgical interventions, and recurrence. One review author (PS) will enter the data into Review Manager 5 (RevMan 5; RevMan 2014).

For dichotomous outcomes (for example, complete healing of sinuses, disappearance of mass), we plan to extract the number of participants experiencing the event and the total number of participants in the treatment group. For continuous outcomes (for example, number or percentage of healed sinuses, or reduction in mass size or pain), we will extract the arithmetic means, standard deviations, and number of participants in each treatment group where possible.

If included studies have reported the data using medians, we will extract median and range values. For count data outcomes, we will extract the number of events, the total person time at risk, and standard error (SE) values for each treatment group where possible. For time‐to‐event data, we will extract hazard ratios and SE values.

Assessment of risk of bias in included studies

We will assess the risk of bias for each included RCT using the Cochrane ‘Risk of bias’ assessment tool. This covers six domains of bias: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other potential sources of bias, including study funding and study authors’ conflict of interest (Higgins 2011).

Regarding prospective observational studies, we will assess these in accordance with the methods adopted from “A Cochrane Risk of Bias Assessment Tool: for Non‐Randomized Studies of Interventions” (ACROBAT‐NRSI; Sterne 2016). This includes five domains of bias including the selection of participants into the study, measurement of outcomes, incomplete outcome data, selective reporting, and other potential sources of bias.

All review authors (PS, AF, RRY) will independently assess the risk of bias for each included study. We will assign a judgement of either ‘high’, ‘low’, or ‘unclear’ risk of bias for each component. We will resolve any discrepancies regarding ‘Risk of bias’ analysis results through discussion. We will consult one of the CIDG Co‐ordinating Editors or other experts if necessary. We will present the findings in a ‘Risk of bias’ table, and produce figures to summarize the risk of bias across included studies.

Finally, we will assess the certainty of the evidence from the included studies using the GRADE approach, evaluating the risk of bias, inconsistency, indirectness, imprecision, and publication bias.

Measures of treatment effect

We will present the effect of treatment within studies as the risk ratio for dichotomous outcomes (for example, complete healing of sinuses, disappearance of mass).

We will calculate the mean difference to compare continuous outcomes between treatment groups (for example, number or percentage of healed sinuses, or reduction in mass size or pain).

For count data outcomes, we plan to calculate the rate ratios using data presented in the study reports. We will use hazard ratios to compare time‐to‐event data from different treatment groups.

We will present all results with 95% confidence intervals (CIs). We plan to perform meta‐analyses if sufficient data are available and it is appropriate to do so.

Unit of analysis issues

If we identify studies for inclusion that have multiple intervention arms (such as Mahgoub 1976), we will include data from these studies by either combining treatment arms or by splitting the control group so that patients are included in the meta‐analysis only once.

Dealing with missing data

For missing data, we will attempt to contact the study authors to request missing information. If the study authors did not collect or assess the needed data as part of their study, or if the study authors do not reply after we contact them, we will analyse the available data only using a complete case analysis. We will also discuss the potential impact of the missing data and how this could affect our confidence in the estimates of treatment effects in the ‘Discussion' section of the review.

Assessment of heterogeneity

We will inspect forest plots visually to assess whether statistical heterogeneity is present. We will deem CIs that do not overlap as an indication of statistical heterogeneity.

We will also perform the Chi2 test and inspect the I2 statistic, using a cut‐off point of P < 0.10 from the Chi2 test to indicate statistically significant heterogeneity, and an I2 statistic value of greater than 50% to indicate considerable levels of heterogeneity.

Assessment of reporting biases

We will use funnel plots to investigate the possibility of publication bias, provided at least 10 studies meet the inclusion criteria of the review.

Data synthesis

We will stratify analyses by comparison (antimicrobial therapy versus alternative therapy). One review author (PS) will analyse the data using RevMan 5 (RevMan 2014); we will use the random‐effects model if we detect heterogeneity, and the fixed‐effect model if not.

We will not combine studies that show qualitative heterogeneity (that is, studies that significantly favour different treatment options), as the assumption that these studies are measuring the same underlying treatment effect may not be valid, and a meta‐analysis combining these results would be meaningless.

Subgroup analysis and investigation of heterogeneity

If we detect substantial heterogeneity, we will explore the possible causes by performing subgroup analyses. Possible subgroups for investigation may include causative fungal or bacterial species, lesion characteristics such as bony involvement, treatment duration, and patient location (country of treatment).

Sensitivity analysis

If there are sufficient studies, we will perform sensitivity analyses by excluding studies at high risk of bias.

Acknowledgements

The Academic Editor for this review is Dr Geraint R Davies.

The CIDG editorial base is funded by the UK Department for International Development (DFID) for the benefit of low‐ and middle‐income countries (Grant: 5242).

Appendices

Appendix 1. PubMed search strategy

Search Query
#1 Search mycetom* Field: Title/Abstract
#2 Search "Mycetoma"[Mesh]
#3 Search "Madurella"[Mesh]
#4 Search "Madurella" Field: Title/Abstract
#5 Search "madura foot" Field: Title/Abstract
#6 Search maduromycosis Field: Title/Abstract
#7 Search actinomycetom* or actinomicetoma Field: Title/Abstract
#8 Search eumycetom* or eumicetoma Field: Title/Abstract
#9 Search (((((#8) OR #7) OR #6) OR #5) OR #4) OR #3) OR #2) OR #1 Field: Title/Abstract
#10 Search treatment* or management or surgery or surgical Field: Title/Abstract
#11 Search sulfanilamide o sulfadiazine Field: Title/Abstract
#12 Search "Sulfonamides"[Mesh]
#13 Search streptomycin or amikacin or gentamicin or netilmicin or rifampicin Field: Title/Abstract
#14 Search imipenem or clavulanic acid" or co‐amoxiclav Field: Title/Abstract
#15 Search sulfamethoxazole or trimethoprim or co‐trimoxazole Field: Title/Abstract
#16 Search netilmicin or imipenem or "clavulanic acid" or co‐amoxiclav Field: Title/Abstract
#17 Search minocycline or tetracycline or streptomycin or dapsone or isoniazid Field: Title/Abstract
#18 Search (((((#10) OR #11) OR #12) OR #13) OR #14) OR #15) OR #16) OR #17)
#19 Search "Antifungal Agents"[Mesh]
#20 Search antifungal * Field: Title/Abstract
#21 Search Itraconazole or Ketoconazole or voriconazole or posaconazole or Fosravuconazole or terbinafine Field: Title/Abstract
#22 Search griseofulvin OR clotrimazole OR fluconazole OR echocandin* OR anidulafungin OR caspofungin OR micafungin Field: Title/Abstract
#23 Search ((#22) OR #21) OR #20) OR #19)
#24 Search (#9) AND #18
#25 Search (#9) AND #23
#26 Search (#24) OR #25
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This is the preliminary search strategy for MEDLINE (PubMed). It will be adapted for other electronic databases. We will report all search strategies in full in the final version of the review.

Contributions of authors

Peter Scolding conceived the review question, developed the protocol, and coordinated protocol development. He completed a first draft of the protocol, worked on revisions, and approved the final version prior to submission.

Ahmed Fahal edited the protocol and approved the final version prior to submission.

Rie Roselyne Yotsu edited the protocol, contributed to the protocol text, and approved the final version prior to submission.

Sources of support

Internal sources

  • Liverpool School of Tropical Medicine, UK.

External sources

  • Department for International Development (DFID), UK.

    Grant: 5242

Declarations of interest

Peter Scolding has no known conflicts of interest. Ahmed Fahal has no known conflicts of interest. Rie Roselyne Yotsu has no known conflicts of interest.

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