Journal of the Pediatric Infectious Diseases Society

L I T E R AT U R E R E V I E W

Mucormycosis in Children: Review and Recommendations

for Management
Joshua R. Francis,1,2 Paola Villanueva,3 Penelope Bryant,4 and Christopher C. Blyth5,6,7
Department of Paediatrics, Royal Darwin Hospital, Darwin, Australia; 2Menzies School of Health Research, Charles Darwin University, Darwin, Australia; 3Department of General
1

Medicine and 4Infectious Diseases Unit, Royal Children’s Hospital, Melbourne, Australia; 5Department of Paediatric Infectious Diseases, Princess Margaret Hospital for Children,
Perth, Australia; 6School of Medicine, University of Western Australia, Perth; and 7Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of
Western Australia, Perth

Mucormycosis represents the third most common invasive fungal infection in children, and recent studies have suggested a rising
incidence. Its case fatality rate is high, especially for neonates. Clinical presentation is influenced by underlying risk factors; asso-
ciations with immunosuppression, neutropenia, diabetes, and prematurity have been described. It has been implicated in several
hospital outbreaks. Diagnosis requires a high index of suspicion and evaluation with histopathology, culture, and, increasingly,
molecular identification. Surgical debridement and antifungal therapies are the cornerstone for combatting invasive mucormycosis.
However, the severity and relative rarity of this disease make comparative clinical trials for evaluating antifungal therapies in chil-
dren difficult to conduct. Hence, therapeutic decisions are derived mainly from retrospective case series, in vitro data, and animal
models. In this review, we summarize the literature on the epidemiology and diagnosis of this invasive fungal infection and provide
suggestions on the management of mucormycosis in children.
Keywords.  children; mucormycosis; zygomycosis.

Mucormycosis affects adults and children and is associated with MICROBIOLOGY

significant morbidity and death in immunocompromised and
immunocompetent hosts. Here, we review the literature regard-
ing mucormycosis in children and use the evidence to provide
recommendations for management.
METHODS
We conducted a search of the published literature through the
National Library of Medicine (PubMed) using the search terms
(“mucormycosis”[medical subject heading (MeSH) terms] or
“mucormycosis”[all fields]) or (“zygomycosis”[MeSH Terms]
or “zygomycosis”[all fields]) and (“child”[MeSH Terms] or
“child*”[all fields]) or “paediatrics”[MeSH Terms] or “pedi-
atric*”[all fields]). To supplement the search strategy, refer-
ence lists from all identified studies and key review articles on
mucormycosis epidemiology, diagnosis, and treatment were
reviewed to identify additional relevant articles that contain pe-
diatric data.
Received 13 June 2017; editorial decision 14 November 2017; accepted 17 November 2017.
Correspondence: J. R. Francis, Department of Paediatrics, Royal Darwin Hospital, Darwin,
Australia (josh.francis@nt.gov.au).
Journal of the Pediatric Infectious Diseases Society   2017;00(00):1–6
© The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the
Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/jpids/pix107
Mucormycosis is an infection caused by fungi that belong to the
order Mucorales. These ubiquitous fungi inhabit soil and organic
debris. They grow rapidly and sporulate quickly and abundantly.
Mucormycosis in humans is caused most frequently by species
of the Mucoraceae family of the Mucorales order, giving rise
to the term mucormycosis, which has replaced the commonly
used term zygomycosis. The most commonly encountered spe-
cies is Rhizopus arrhizus, but other organisms that are identified
frequently include Mucor species, Lichtheimia species (previ-
ously known as Absidia species), and Cunninghamella species
(Table 1) [1, 2].
EPIDEMIOLOGY
As a group, Mucoraceae represent the third most common
cause of invasive fungal infection after Candida and Aspergillus
species [3]. An increasing incidence of mucormycosis has
been suggested by epidemiologic studies [4]. Many factors
can contribute to this increase, including selection pressure
from antifungal prophylaxis by agents without mucormycosis
activity [1]. Voriconazole use in immunosuppressed patients
has been singled out as a significant independent risk factor
for mucormycosis (odds ratio, 10.37 [95% confidence inter-
val (CI), 2.76–38.97]; P < .001) [2]. However, there is evidence
that mucormycosis rates were increasing before the widespread
use of voriconazole, which indicates that other factors, such as
increased use of immunosuppressive therapies, also contribute
[5]. It is also possible that higher observed rates are related to

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 Table 1.  Genera of the Order Mucorales Associated With Human discharge and eventual spread of tissue necrosis (manifest as a
Mucormycosis
black eschar) involving the nasal mucosa, palate, overlying fa-
No. (%) of Patients cial skin, orbit, and brain. Pulmonary disease predominates
Organism Isolated (N = 636) [1, 2]
in patients with malignancy (92 [60%] of 154 in 1 study [9]).
Rhizopus sp 276 (43)
Children with pulmonary mucormycosis typically present with
Mucor sp 113 (18)
a progressive pneumonia associated with lung necrosis, hemop-
Lichtheimia sp 57 (9)
Cunninghamella sp 42 (7) tysis, and spread to contiguous structures. Cutaneous infection,
Apophysomyces elegans 29 (5) which makes up 19% of all cases [9] and 27% of cases in children
Rhizomucor pusillus 24 (4) [11, 12], presents with nonspecific signs of inflammation that
Saksenaea sp 22 (3) might or might not progress to form a necrotic eschar [6]. In the
Other 55 (9)
neonatal period, gastrointestinal and cutaneous diseases are seen
more frequently than in older age groups (54% and 36% of neo-
natal cases, respectively) [11]. Neonatal gastrointestinal infection
increased awareness and more aggressive diagnostic evaluation
can manifest as necrotizing enterocolitis and has been associated
rather than simply a true increase in the number of infections.
with late diagnosis and high case fatality rates (CFRs) (78%).

RISK FACTORS
DIAGNOSIS
Although immune dysfunction is a risk factor for invasive di-
Diagnosis of mucormycosis is made most frequently on the basis
sease, the association with immunodeficiency is less than that
of histopathologic characteristics (broad, hyaline, hyposeptated
seen with invasive aspergillosis. Mucormycosis is not classically
hyphae, in concert with angioinvasion and tissue necrosis) in
associated with any particular form of primary immunodefi-
the appropriate clinical setting. Culture is poorly sensitive be-
ciency [6]. Hematologic malignancy is a significant risk factor,
cause of the fragility of Mucorales hyphae, which frequently are
as is being a hematopoietic stem cell transplant or solid organ
damaged during sample collection. As a result, only approxi-
transplant recipient. Solid organ malignancy (without trans-
mately one-third of all microscopically positive specimens re-
plant) is not commonly associated with mucormycosis [7].
sult in a positive culture [15]. Specificity is also an issue, because
Diabetes also is a commonly identified risk factor, with 9% to
isolation from nonsterile sites is sometimes indicative of con-
36% of cases occurring in diabetics [7–9].
tamination rather than disease. Culture of a clinically relevant
Iron overload, deferoxamine therapy, intravenous drug
isolate enables identification and susceptibility testing of the
use, and renal failure are seen less frequently, particularly in
pathogen [16].
children, but remain well-recognized risk factors. Burns and
Histopathology and culture still form the basis of diagnosis
traumatic wounds are particularly associated with cutaneous
in most cases, although molecular techniques are being used
mucormycosis and account for a significant proportion of
increasingly to complement traditional methods [17]. Molecular
patients with no apparent immunodeficiency [6]. Outbreaks of
testing improves the accuracy of species identification compared
cutaneous infection are also known to occur after natural disas-
to phenotypic identification of culture isolates [15]. Nucleic
ters [10]. Underlying rheumatologic/autoimmune disorders
acid amplification techniques that target the ribosomal DNA
were reported more recently as a risk for infection and poor
gene targets 18S, 28S, and Internal Transcribed Spacer (ITS)
outcome [7]. Prematurity is a major risk factor for disease (es-
region are all used. The sensitivity and specificity of molecular
pecially gastrointestinal and cutaneous mucormycosis) in neo-
diagnosis performed directly on fresh or frozen tissue depend
nates [11–13]. In some pediatric cases (9.5% in 1 case series), no
on the DNA-extraction method used [15]. Fresh material is
specific underlying risk factors were identified [14].
preferred over paraffin-embedded tissue, because formalin
damages DNA [16].
CLINICAL MANIFESTATIONS

The most frequent types are rhinoorbitocerebral, pulmonary,

cutaneous, and gastrointestinal infections [6]. Dissemination
of disease occurs in 32% to 38% of pediatric cases and more
than half of neonatal cases [11, 12, 14]. The distribution of di-
sease is influenced significantly by underlying risk factors.
Rhinoorbitocerebral sinus disease is the most common manifes-
tation in patients with diabetes (22 [66%] of 33 in 1 study [9])
and is commonly associated with diabetic ketoacidosis. It pres-
ents with progressive sinusitis with fever, headache, and nasal
TREATMENT OF MUCORMYCOSIS
Surgical debridement and antifungal therapy are the mainstays
of management of invasive mucormycosis. They both are asso-
ciated with improved outcomes in adults and children, and in
most cases, a combined approach is indicated [9, 16].
Pooled pediatric data have shown that children who received
antifungal therapy and underwent surgery had a CFR of 18.5%,
compared with 60% for those who received antifungal therapy

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 alone [14]. A review of 255 cases of pulmonary mucormycosis
(including cases that involved dissemination) found that surgical
intervention reduced the CFR rate to 11% compared with 68% in
those treated with medical therapy only (P = .0004) [18]. A sur-
vival advantage is also conferred on those who undergo surgery
for disease localized to the lung [19–21]. Dissemination fre-
quently occurs before respiratory failure develops, and surgery
serves to reduce the risk of fungal sepsis and protect respiratory
function. Patients who have a good early response to antifungal
therapy can be managed conservatively, but in the absence of
clinical improvement and if operative risk is deemed acceptable,
consideration should be given to wedge resection, lobectomy,
or pneumonectomy, depending on the extent of disease [20].
Extensive surgical debridement is thought to be important in
treating cutaneous mucormycosis, and repeated surgery is often
required to ensure adequate debridement and address disease
progression [22, 23]. Similarly, aggressive resection is impera-
tive in the management of rhinocerebral mucormycosis, which
is associated with a high CFR in immunocompromised people
regardless of intervention [18, 24]. Surgery has not been shown
conclusively to improve outcomes for neonates with gastroin-
testinal mucormycosis, which is frequently fatal despite aggres-
sive management [11]. When possible, a combined surgical and
medical approach is recommended nonetheless, because it is
likely to offer the best chance of survival [25, 26].
Comparative clinical trials that evaluate antifungal agents
against mucormycosis are difficult to conduct because of the
rarity of the illness and the challenges associated with enroll-
ing sufficient numbers of subjects to demonstrate a significant
difference in treatment strategies. As a result, treatment recom-
mendations are based largely on retrospective case series, in
vitro data, and animal models [16].
Amphotericin B (AmB) has activity against Mucorales in
vitro [27, 28]. Both conventional AmB (cAmB) and AmB lipid
complex (ABLC) have been associated with improved survival
rates (324 [61%] of 532 and 80 [69%] of 116, respectively) com-
pared with 18% survival (59 of 333)  among those not treated
with antifungal therapy [9]. Pediatric analysis of ABLC (median
dose, 4.92 mg/kg per day) in the treatment of invasive fungal
infections included a very small number (n = 4) of children with
mucormycosis [29]. ABLC administered at 5 mg/kg per day is
safe and tolerated by children; however, it is not recommended
for those with central nervous system (CNS) involvement [16].
Liposomal amphotericin (LAmB) has better CNS penetration
than cAmB or ABLC [30] and is associated with fewer adverse
effects than is cAmB [31, 32]. Thus, LAmB has evolved as the
cornerstone of primary therapy for mucormycosis and has been
linked to improved outcomes in multivariate analysis when used
(at a dose of 3 mg/kg per day) to treat mucormycosis in patients
with a hematologic malignancy [33]. Recommendations for dos-
ing LAmB vary considerably, ranging from 3 to 10  mg/kg per
day [8, 16]. Consensus expert opinions suggest administering at
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least 5 mg/kg per day, and a higher dosage (10 mg/kg per day) is
favored for CNS infection [16, 32]. Dosages of LAmB as high as
15 mg/kg per day are tolerated, but doses higher than 10 mg/kg
per day do not result in an increased plasma concentration [34].
A pilot clinical trial that evaluated initial high-dose (10 mg/kg
per day) LAmB for mucormycosis (with surgery in two-thirds
of cases) found a 45% response rate at week 12, although renal
toxicity frequently occurred (40%) [35].
Most commercially available oral antifungal agents have
no in vitro or in vivo activity against mucormycosis [27].
Posaconazole is an exception; in vitro [36] and in vivo data sup-
port its use in salvage therapy and in step-down therapy of in-
vasive mucormycosis [16, 37]. Most available clinical data are in
the form of case reports, although 2 adult case series reported
complete or partial response in 60% (n = 91) and 79% (n = 24)
of patients, respectively [38, 39]. Most patients had been treated
already with LAmB and surgical debridement. Posaconazole
was given at a dose of 800  mg/day in divided doses, and no
adjustment for weight was made [38]. More recently, a retro-
spective analysis of 96 published case reports of oral posacon-
azole treatment found a complete or partial response in 64.6%
and 7.3% of patients, respectively [37]. Selection biases in such
salvage studies make interpretation difficult. In vitro and an-
imal studies have indicated variable susceptibility to different
Mucorales strains and overall superior performance of AmB
[36, 40]. One murine model found poor in vivo activity of
posaconazole against Mucor circinelloides [41], and another
study raised concerns about the effectiveness of posaconazole
against R arrhizus (previously known as Rhizopus oryzae) [41].
Newer formulations of posaconazole have become available.
The delayed-release tablet has improved bioavailability over
that of the oral suspension and enables once-daily dosing [41,
42]. Intravenous posaconazole is available also. These medica-
tions have not been studied yet for mucormycosis, but they have
been applied successfully in neutropenic murine models [43].
Clinical data for the use of posaconazole salvage therapy
in children are limited and insufficient to determine confident
dosing recommendations [44], although European clinical
guidelines suggest 18 to 24 mg/kg per day of oral posaconazole
suspension, given in 4 divided doses, for patients younger than
13 years who weigh less than 34 kg [16]. These recommenda-
tions are based on very limited data, and further pharmaco-
kinetic studies are underway to evaluate optimal dosing for
different pediatric age groups. Routine therapeutic drug moni-
toring is also recommended to ensure adequate concentrations
[45]. Posaconazole penetrates the cerebrospinal fluid (CSF) rel-
atively poorly, but CSF concentration is probably improved in
the setting of meningeal inflammation [46].
One pharmacokinetic study analyzed posaconazole plasma
concentrations in 12 children, 11 of whom received a standard
adult dose of 800  mg/day irrespective of their weight (range,
24–76 kg). One 8-year-old child (weight, 39.4 kg) received 400 mg/
Mucormycosis in Children • JPIDS 2017:00 (XX XXXX) • 3
 day. The average posaconazole plasma concentrations were highly
variable (range, 85–2891  ng/ml), but no association with age,
body weight, or body surface area could be found, and correlation
of plasma concentrations with treatment outcomes has not been
established. The mean for the 12 children was comparable to that
of a cohort of 194 adults treated with 800 mg/day of posaconazole
(children, 776 ng/ml; adults, 817 ng/ml) [47]. Treatment success
using posaconazole salvage therapy in 4 of 7 children with inva-
sive mucormycosis has been described, and only mild adverse
effects were observed [48]. In that study, which evaluated a total
of 15 children treated with posaconazole for invasive fungal in-
fection, the median total daily dose was 21 mg/kg per day (95%
CI, 17–25 mg/kg per day; range, 4.8–33.3 mg/kg per day). One
10-year-old received a daily dose of 1200 mg/day, which is signif-
icantly higher than the usual adult dose. Plasma levels were not
measured routinely. Only mild adverse effects, including fever,
abdominal symptoms, headache, and skin rashes, were observed,
and none of them necessitated the cessation of posaconazole [48].
Isavuconazole is a novel triazole with a wide spectrum of activ-
ity against yeasts and molds such as Mucorales [49] and Aspergillus
[50] species. A  multicenter open-label trial recently showed that
isavuconazole was safe in adults when used as primary treatment
against mucormycosis and had an efficacy similar to that of AmB
in a matched case-control analysis [51]. However, external control
patients received different formulations of AmB (cAmB, ABLC,
LAmB), and the small study size precluded further subanalysis.
Increasing evidence supports its use as a new treatment option for
invasive mold diseases, and its predictable pharmacokinetics and
high bioavailability make it an attractive option [52]. Although CSF
concentration is low, isavuconazole is thought to achieve adequate
brain penetration for treatment of CNS infections [53]. Current rec-
ommendations suggest its use for deescalation, in refractory cases,
or for patients intolerant to AmB for the treatment of mucormycosis
in adults [54, 55]. There is a lack of pediatric data, and no specific
dosing recommendations for treating children currently exist.
The total duration of antifungal therapy required is not known
and cannot be clearly established from the available literature
because of multiple confounding variables in published retro-
spective case series. The duration of therapy given typically varies
greatly depending on patient characteristics and the extent of dis-
eases caused by the Mucorales infection. In patients with adequate
renal function, at least 3 weeks of parenteral AmB followed by
deescalation to oral posaconazole has been suggested [56]. Early
reports indicate that a median length of amphotericin-based
therapy of 21 days was used for survivors. Nonsurvivors from
all patient groups had a shorter median length of treatment, but
that might simply represent more aggressive disease resulting in
premature death rather than an inappropriately short duration of
therapy [9]. One series of posaconazole-treated patients under-
went a median length of treatment of 5 months (range, 7 days
to 34 months) [37]. Treatment usually is continued for multiple
weeks and is discontinued only once clinical resolution is evident,
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follow-up culture results are negative, immunologic recovery has
occurred, and, when relevant, radiologic resolution on serial
imaging is evident [16, 56].
The high CFR associated with mucormycosis, even with opti-
mal surgical management and antifungal therapy, make combina-
tion antifungal therapy an attractive idea. Prospective clinical trials
in which combination therapy and monotherapy were compared
are lacking [32]. Synergy has been demonstrated in vitro between
posaconazole and AmB [57] and posaconazole and caspofungin
[58], although a murine model did not respond better to combi-
nation AmB plus posaconazole than to AmB monotherapy [59].
However, in a case series (n = 32) of patients with mainly hemato-
logic diseases, combinations of ABLC and posaconazole resulted
in 56% treatment response after 3 months [60]. The reason for the
synergistic effect of caspofungin in combination with other agents
is not well understood given its lack of activity against Mucorales
in vitro, although R oryzae has been shown to express the enzyme
1,3-β-d-glucan synthase, which is inhibited by caspofungin [61].
Encouraging results of ABLC plus caspofungin combination
therapy in a diabetic murine model [62] and of LAmB plus mica-
fungin in mice with disseminated mucormycosis [63] prompted
a group of clinician researchers to change their practice in the
management of a patient with rhinoorbitocerebral mucormycosis.
After treating 7 patients with a polyene–caspofungin combina-
tion therapy, they retrospectively analyzed their data and reported
success 30 days after hospital discharge in 6 (86%) of 7 patients
treated with polyene–caspofungin compared with 14 (41%) of 34
managed with polyene monotherapy (P = .040) [64]. Small num-
bers of patients in the study and a patient cohort limited to those
with diabetes make it difficult to adjust for covariates and limit the
generalizability of these findings [64]. In contrast, a retrospective
analysis of 106 patients with a hematologic malignancy found no
differences in mortality rates at 6 weeks between patients receiving
monotherapy and those receiving combination treatment as ini-
tial therapy for mucormycosis (43% vs 41%, respectively; P = .85)
[65]. Hence, the value of combination strategies remains unclear,
and additional research is needed in this area to evaluate ampho-
tericin-based treatment with the addition of an echinocandin or
triazole antifungal agent.
NOSOCOMIAL MUCORMYCOSIS
The numbers of reports of healthcare-associated mucormyco-
sis are steadily increasing. Reports of outbreaks have included
between 2 and 5 cases of suspected or confirmed mucormyco-
sis within a healthcare institution. A summary of 169 published
cases (163 of which were laboratory proven) identified immuno-
suppression (prolonged steroid therapy, solid organ transplant,
malignancy, and other immunodepression factors) in 78% of the
cases; 22% had diabetes mellitus, 21% were neonates, and only
6% had no comorbidity [66]. The mortality rate was reported at
50% but was higher (64%) in the neonatal population [66].
 Rhizopus species are involved most commonly, although
Mucor, Rhizomucor, and Absidia species have been identified
also [67]. In each published series, a source of contamination
has been hypothesized or proven. Adhesive tapes are impli-
cated frequently [68]. Wooden tongue depressors, ostomy bags,
hospital linen, ventilation systems, and construction sites have
been identified also as potential or proven havens of the path-
ogen in the context of different hospital outbreaks [66, 68–70].
Whenever 2 or more cases that involve the same organism have
been identified within a healthcare institution during a 6-month
period, a common source or sources for infection should be con-
sidered, and environmental investigations that include formal air
sampling and testing should be conducted [67, 71].
OUTCOME
On the basis of published reports of invasive mucormycosis, the
CFR is very high at 47% to 56% and rises to 96% for those with dis-
seminated disease [7–9]. The CFR might be inflated by reporting
bias, given epidemiologic findings that suggest lower CFRs than
those reported elsewhere in the literature [4]. Survival without
antifungal therapy is rare [9]. The CFR in older children is con-
sistent with those seen in adults, with a trend toward higher rates
in neonates (64% CFR in infants <1 month of age; 56% CFR in
children aged 1 month to 18 years) [11]. An age of less than 1 year
is a significant independent risk factor for death (odds ratio, 3.85
[95% CI, 1.05–7.43]) [12]. Dissemination and past hematopoietic
stem cell transplantation were also found to be independent risk
factors for mortality [14]. In the absence of dissemination or local
extension, cutaneous mucormycosis alone has not been associ-
ated with mortality in children [12, 14]. Gastrointestinal disease
in neonates, by comparison, is frequently (78%) fatal [11].
CONCLUSION
When the diagnosis is suspected, invasive mucormycosis
requires a high index of suspicion and urgent evaluation of clin-
ical samples. The disease is typically progressive and frequently
fatal. Surgical debridement should be considered and is usu-
ally necessary to prevent contiguous spread and dissemination.
Institution of medical therapy is also an urgent priority, because
delays have been associated with significant increases in deaths
[72]. Initial medical therapy should constitute an amphotericin
preparation, ideally intravenous LAmB dosed at 5  mg/kg per
day (10 mg/kg per day in case of CNS involvement). In patients
who are stabilized after surgery and commencement of paren-
teral antifungal therapy, step-down to oral posaconazole can be
considered. Posaconazole is also a suitable alternative to AmB
(in the absence of CNS involvement) if renal toxicity develops
or AmB is not tolerated for other reasons. For cases in which
deterioration occurs despite appropriate treatment, evidence
for other treatment approaches is very limited. Escalation of
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treatment could include repeated surgical debridement, an
increased dose of LAmB up to 10 mg/kg per day, the addition
or switch to posaconazole or isavuconazole, or the addition of
an echinocandin, but none of these strategies are proven to be
effective. Antifungal therapy should be continued until clinical
resolution, and monitoring for recurrence after discontinuation
of treatment is important. Hospital-acquired infection should
prompt consideration of possible sources of contamination,
with a view to the early identification of all potential outbreaks
and implementation of appropriate source control.
Note
Potential conflicts of interest.  All authors: No reported conflicts of
interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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