<ID17606/VJL/9.9.04>
<rl><!Antimicrobial agents: bacterial/fungal>
<rr><!Management of rare fungal infections Al-Abdely>
<ti>Management of rare fungal infections</ti>
<au>Hail M. Al-Abdely</au>
<ab>Purpose of review
Fungal infections caused by rare fungi have increased in recent years. This may
be due to the increase in the number immunocompromised patients. Some rare
fungi are geographically restricted, but with globalization and travel these
infections are seen worldwide. The aim of this review is to address recent
advances in the management of some uncommon fungal infections.
Recent findings
An increasing number of cases of invasive infections caused by dematiaceous
fungi (Phaeohyphomycetes) have recently been reported in both
immunocompromised and immunocompetent individuals. Cerebral involvement
and disseminated disease are serious and are associated with high mortality rates.
Surgical excision and broad-spectrum triazole antifungal therapy are associated
with better outcomes. Mucormycosis in diabetic and immune suppressed patients
is associated with high mortality. Radical surgical debridement and amphotericin
B-based regimens are a key to success. Preliminary data suggest a positive
response to posaconazole. Recently, basidiobolomycosis has been reported to
cause chronic granulomatous infection of the gastrointestinal tract. Treatment with
itraconazole and surgical resection are associated with favourable outcomes.
Invasive fusariosis in cancer patients is typically resistant to most antifungal
agents, but recent data have suggested reasonable activity of voriconazole.
Voriconazole also demonstrated activity against Scedosporium apiospermum, but
was less active against Scedosporium prolificans. Amphotericin B and
itraconazole are currently the treatments of choice for the southeast Asian fungus,
Penicillium marneffie.
Summary
Parallel to the increased number of patients susceptible to invasive infections
caused by rare and difficult-to-treat fungi has been an increase in the number of
broad-spectrum antifungal agents that have allowed for better therapeutic options.
High-quality data are lacking because of the rarity of such infections. In the future,
new triazoles and echinocandins will probably replace amphotericin B as the first
therapeutic choice for many of these uncommon fungal infections.</ab> 291
<AQ1>
<keywords>Keywords: Antifungal, Fusarium, mycosis, Penicillium marneffie,
phaeohyphomycosis, rare fungi, Scedosporium, zygomycosis</keywords>
<aff>Section of Infectious Diseases, Department of Medicine, King Faisal
Specialist Hospital and Research Center, Saudi Arabia</aff>
<corr>Correspondence to Hail M. Al-Abdely, PO Box 3354 (MBC 46), Riyadh
11211, Saudi Arabia
E-mail: abdely@kfshrc.edu.sa</corr>
<abr>Abbreviation
CNS central nervous system</abr>
<A head>Introduction
1
<txt>Most invasive fungal infections are opportunistic and take advantage of the
host’s immune system defects. Fungi are widely distributed in nature, but several
pathogenic fungi are restricted to some extent by geography, such as endemic
mycoses in the new world, especially coccidioidomycosis and Penicillium
marneffie in southeast Asia. More reports of fungi that were not previously known
to cause human disease are reported every year, and some of the rarely
encountered fungal infections are becoming more common [1*]. Many of these
rarely seen fungal infections are serious and can be life threatening. Data on the
management of such rare and serious infections are of low quality because of their
rarity. Therefore, we have to utilize what is available to us, such as anecdotal
reports, case series, animal studies or even in-vitro susceptibility tests. This review
will address the management of some, and not most, of the less commonly
recognized serious fungal infections.
<A head>Phaeohyphomycosis
<txt>Dematiaceous fungi (Phaeohyphomycetes) are the cause of wide spectrum
of infections that range from limited cutaneous to disseminated disease [2*].
Infections caused by these darkly pigmented fungi are given the name
phaeohyphomycosis. Several species of Phaeohyphomycetes are neurotropic,
and have been reported to cause mainly primary central nervous system (CNS)
infections [3**,4*]. Disseminated and CNS infections caused by these fungi are
associated with high mortality rates that exceed 70% [3**,5]. Cladophialophora
bantiana is the most common fungus reported to cause primary cerebral
phaeohyphomycosis [3**]. Ramichloridium mackenziei has been reported to cause
brain abscesses exclusively. Although C. bantiana has been reported worldwide,
R. mackenziei has been restricted to the middle-east and in particular the Gulf
region [6--9]. Cerebral infection as a result of such fungi has struck both
immunocompetent and immunocompromised individuals with similar dismal
outcomes. Disseminated disease caused by Phaeohyphomycetes is rare and has
affected mainly immunocompromised patients. A large number of species has
been reported to cause disseminated disease, with Bipolaris spicefera and
Wangiella (Exophiala) dermatitidis being the most common. Treatment for cerebral
infection is difficult as these fungi are commonly resistant to antifungal agents, and
its localization in the brain affects the concentration of the antifungal agent at the
site of infection. Surgical debulking is useful for solitary lesions, but is difficult to
attain for multiple lesions. Surgical options for disseminated disease are limited.
Amphotericin B was inferior to azoles against many of the Phaeohyphomycetes in
vitro, in animal models and in several reported cases [3**,10--12]. Liposomal
amphotericin B has better CNS concentrations than amphotericin B deoxycholate,
and is safe at high doses that may make it favourable in the treatment of cerebral
phaeohyphomycosis. Better survival was seen in the few cases of cerebral
phaeohyphomycosis that were treated with liposomal amphotericin B [13--15]. 5Flucytosine has activity against many of these fungi and could be a useful agent
when combined with other antifungal drugs. Broad-spectrum azoles such as
itraconazole have been used in the treatment of phaeohyphomycosis with variable
results [16]. Limited disease with cutaneous involvement or sinusitis had the best
response, whereas disseminated disease and cerebral involvement was
associated with more failures [17--19]. Voriconazole was unsuccessful in the
treatment of a brain abscess caused by C. bantiana, even when combined with
caspofungin in another case [20*,21*]. Voriconazole was used in one patient with
disseminated infection caused by Ochroconis gallopavum with a positive response
2
[22*]. Posaconazole was successful in animal models of Ramichloridium and
Cladophialophora experimental cerebral infections [10,23]. It was also used in the
treatment of a few cases of phaeohyphomycosis, including a recent case of R.
mackenziei brain abscess [24*]. Terbinafine was successful in the treatment of
refractory subcutaneous infection caused by Exophiala jeanselmei, which may
suggest a possible future rule of this agent in the treatment of phaeohyphomycosis
in combination with other antifungal agents [25,26]. No clinical data are yet
available on the rule of echinocandins against infections caused by
Phaehyphomycetes, but one in-vitro study has shown activity of anidulafungin
against several dematiaceous fungi [27].
<A head>Zygomycosis
<AQ2>
<B head>Mucormycosis
<txt>Mucormycosis is an aggressive fungal infection caused by the order
Mucorales of the class Zygomycetes. Most of the cases of mucormycosis are
caused by Rhizopus species, but other Mucorales are also well known to cause
the same clinical disease. These fungi are rapidly growing and angioinvasive,
which leads to rapidly progressive tissue necrosis. Diabetic patients, especially
with acidosis, are typically susceptible. Immunocompromised patients on
immunosuppressive agents or with neutropenia are susceptible to this infection,
which can be disseminated [28]. Iron chelating therapy with deferroxamine is a
well-recognized risk factor especially in renal failure patients. Occasionally, cases
of cutaneous disease can develop from breaks in the skin after trauma. Most
cases involve the nasal mucosa and sinuses, with rapid spread to the orbit and the
brain. Other organs can be involved, including the lung, gastrointestinal organs, or
can disseminate to involve multiple sites. Mortality is in the range of 70% for
rhinocerebral disease, and approaches 100% for disseminated disease [29].
Cutaneous infection has the best outcome, with a mortality rate of approximately
15%. The cornerstone in the management of mucormycosis is radical surgical
debridement of devitalized tissue [30,31]. The timing of surgery is important
because this is a rapidly progressive infection, and therefore requires urgent
surgery. Adjunctive antifungal therapy is essential, and should be initiated
immediately. Amphotericin B in high doses of 1--1.5 mg/kg a day is the only
currently available agent with activity against the Mucorales. The duration of
amphotericin B therapy needs to be adjusted according to the disease extent,
patient progression and toxicity. The typical cumulative dose required ranges from
2 to 4 g. Lipid formulations of amphotericin B have been reported to be successful
in many cases of mucormycosis [32--34]. They could be the initial therapy for
patients with this infection, because most of them will not tolerate high doses of
amphotericin B deoxycholate. Recent reports indicate good activity of the
investigational triazole posaconazole against mucormycosis. An animal model of
mucormycosis in mice treated with posaconazole suggested efficacy against this
infection [35,36]. A case report [37*] then a series of 23 cases treated with this
agent [38*] have indicated comparable outcomes to historical cases of
mucormycosis treated with amphotericin B. Other azoles and echinocandins have
not shown significant in-vitro activity against the Mucorales. In one report [39]
micafungin was associated with the resolution of probable sinus mucormycosis in
an autologous bone marrow transplant recipient.
<B head>Entomophthoramycosis
3
<txt>Entomophthorales are Zygomycetes that consist mainly of the Basidiobolus
and Conoidiobolus species. Basidiobolomycosis is a fungal infection that has been
reported mainly in tropical and subtropical regions [40*]. It is caused by
Basidiobolus ranarum. Most reports have described the infection as mainly
involving subcutaneous tissue [41]. Several reports have recently described
invasive visceral infection involving mainly the gastrointestinal tract, especially the
colon in immunocompetent individuals [42*,43]. Such reports have come from
Arizona, Brazil, Kuwait, Saudi Arabia and other countries. In the report from Saudi
Arabia of six cases, all patients were in the paediatric age group and were
clustered in one subtropical region in the southwest of the country. Cases reported
from Arizona were adults. No particular risk factors could be identified. The
infection is characterized by a chronic granulomatous inflammation and
eosinophilic infiltration, which results in large abdominal masses [44]. These
infections are initially misdiagnosed as cancer, tuberculosis or Crohn’s disease.
Successful treatment has been reported mainly with surgical resection and triazole
treatment, with itraconazole and ketoconazole. Mortality was significant and was
attributed to gastrointestinal haemorrhage. Conidiobolomycosis, caused by C.
coronatus and C. incongruous, has been reported to affect mainly the face and
ear, nose and throat organs. It causes subcutaneous and submucosal disease
[40*]. The infection is indolent and is characterized by enlarging masses.
Histopathologically, this infection does not differ from Basidiobolomycosis. Surgical
excision and antifungal treatment with itraconazole is reasonable. Different
antimicrobial agents have been tried for the treatment of conidiobolomycosis with
variable responses. These include trimethoprim/sulfamethoxazole, terbinafine,
potassium iodide and amphotericin B [45--47].
<A head>Fusariosis
<txt>Fusarium species are the cause of a wide variety of fungal infections, which
range from keratitis, onychomycosis, eumycetoma in the immunocompent to
invasive and disseminated disease in the immunocompromised patient, especially
in patients with haematology cancer and neutropenia [48]. Fusariosis is a
recognized infection in the pre and post-engraftment of allogeneic bone marrow
transplantation. The incidence of invasive fusariosis has increased over time in
several cancer centres in the United States [49]. The most common species
associated with human infection are Fusarium solani, Fusarium oxysporum and
Fusarium moniliforme. Any organ can be affected in disseminated fusariosis,
although the skin and lung are the two most commonly involved organs. Skin
lesions are variable in number, size and characteristics, and are frequently
associated with fusarium fungemia [50*,51]. Fusarium resistance to almost all
antifungal agents and the severely depressed host defence mechanisms in
haematological malignancies made this infection commonly fatal. The number and
function of phagocytes is the most important determinant of outcome. White blood
cells growth factors, granulocyte and granulocyte-macrophage colony stimulating
factor or granulocyte transfusions should be considered in neutropenic patients.
Surgical excision of a solitary cutaneous lesion is indicated to prevent local
progression or dissemination. Voriconazole was recently approved for the
treatment of fusariosis after in-vitro data and human reports indicated activity
against fusariosis [52--54]. Successes have also been reported with amphotericin
B and its lipid formulations. Posaconazole showed activity against Fusarium spp.
in vitro, in vivo and in one case report [55--57]. Echinocandins have not
4
demonstrated in-vitro activity against Fusarium spp., but there was one report of a
response to caspofungin in a patient with leukemia [58].
<A head>Scedosporiosis
<AQ3>
<B head>Scedosporium apiospermum
<txt>Infections caused by Scedosporium apiosprmum (teleomorph;
Pseudoallescheria boydii) in the normal host are typically chronic and involve
subcutaneous tissue and bone to form eumycetoma [59]. It can occasionally
disseminate in victims of near-drowning. Invasive disease is usually observed in
the immunocompromised host. Lung infection is the most common, but the
sinuses and brain are recognized sites. Occasionally it can disseminate to involve
multiple organs. This fungus is commonly amphotericin B resistant, and the drugs
of choice are the extended-spectrum azoles such as itraconazole and
voriconazole. Voriconazole has United States Food and Drug Administration
approval for this infection, and was shown to be successful in a few cases [60-62]. Posaconazole was successful in one case report of cerebral infection [63].
Surgical excision remains a mainstay treatment of this infection whenever feasible;
this is especially true for soft tissue and bone involvement. Echinocandins are
active in vitro against S. apiospermum but as yet there are no reports on the
treatment of this organism in patients.
<B head>Scedosporium prolificans
<txt>This fungus is considered by some mycologists to be a Phaeohyphomycetes
as it is darkly pigmented in culture media. It is a rare cause of human disease, with
most cases being reported from Australia and Spain [59]. Neutropenia in patients
with haematological malignancies was the most common risk factor associated
with disseminated infection. Locally invasive joint and bone disease was mostly
associated with trauma in immunocompetent patients. Disseminated disease
caused by Scedosporium prolificans is usually fatal [5]. The fungus is universally
resistant to all currently available antifungal agents. A few patients with S.
prolificans infection have responded to voriconazole [64,65]. Phagocytic function
and the extent of disease are the most important prognostic factors. Therefore,
granulocyte colony stimulating factor can accelerate neutrophil recovery and the
response to antifungal therapy. Terbinafine has shown in-vitro activity against this
fungus, and has been shown to be successful in combination with triazoles such
as voriconazole [66--68]. Surgical excision is the mainstay treatment for locally
invasive disease.
<A head>Penicilliosis marneffie
<txt>Penicillium marneffie is a fungus geographically restricted to southeast Asia.
It is the only known fungus of the Penicillium species to be thermally dimorphic.
Since its description 1956 as a cause of infection in bamboo rats (Rhizomys
sinensis) in Vietnam, it has been recognized as a human pathogen, with all the
cases coming from southeast Asia or individuals who have travelled to that area.
In recent years, there has been an enormous increase in the incidence of this
infection in endemic areas, largely corresponding with the increase in the number
of AIDS cases [69]. Disseminated disease is most commonly associated with
advanced HIV infection.
5
The infection is usually associated with prolonged fever, chills and debilitation, with
weight loss and anaemia; generalized lymphadenopathy and hepatomegaly are
common. Diffuse papular lesions with central umblication resembling moluscum
contagiosum lesions are common in HIV patients.
If untreated, penicilliosis marneffei is usually fatal. Amphotericin B with or without
5-flucytosine has been successful in treating penicilliosis marneffei infection.
Azoles, particularly itraconazole and ketoconazole, have been very active against
P. marneffei in vitro and in patients. Fluconazole is the least active of the currently
available azoles and is associated with more failures [70]. Treatment options are
determined by the clinical status of the patient and the availability and cost of the
drugs. For severely sick patients, amphoterecin B (0.5--0.7 mg/kg a day) is the
drug of choice. For less sick patients, azole treatment with itraconazole
400 mg/day is indicated. The duration of treatment varies with the immune status
of the patient. For HIV-infected patients, long-term suppressive therapy is
indicated unless they have immune reconstitution with highly active antiretroviral
therapy and an increase in the CD4 cell count to more than 100 cells/ml.
Itraconazole was extremely effective in preventing relapse in patients with AIDS
[71]. A high response rate of 97% was demonstrated in a non-randomized trial of
amphotericin B 0.6 mg/kg a day for 2 weeks, followed by 10 weeks of itraconazole
400 mg a day [72]. Echinocandins have demonstrated some in-vitro activity
against P. marneffie, but clinical data are lacking [73].
More recognized rare fungal species are reported every year as a cause of human
disease. There is the emergence of several yeast-like fungi such as the
Trichosporon species, Blastoschizomyces capitatum and Rhodotorula in
immunocompromised patients. Mould infections caused by Paecillomyces spp.
and Trichoderma spp. are increasingly being recognized [1*,74*].
<A head>Conclusion
<txt>The management of rare fungal infections is obviously difficult. Surgical
excision in an anatomically limited disease should always be considered. Fungal
culture and the identification of the causative fungus is essential in designing the
best approach for management. In-vitro susceptibility testing or animal studies
may be the only clue in the choice of the appropriate antifungal agent.
Augmentation of the host immune response, whenever feasible, is a critical factor
in the better outcome of immune suppressed patients with fungal infections.
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immunocompromised patients. Clin Microbiol Infect 2004; 10:499--501.
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A nice review of Fusarium fungemia, with associated features, therapy and
outcomes.
51 Nucci M, Anaissie E. Cutaneous infection by Fusarium species in healthy and
immunocompromised hosts: implications for diagnosis and management. Clin
Infect Dis 2002; 35:909--920.
52 Consigny S, Dhedin N, Datry A, et al. Successsful voriconazole treatment of
disseminated fusarium infection in an immunocompromised patient. Clin Infect Dis
2003; 37:311--313.
53 Guimera-Martin-Neda F, Garcia-Bustinduy M, Noda-Cabrera A, et al.
Cutaneous infection by Fusarium: successful treatment with oral voriconazole. Br J
Dermatol 2004; 150:777--778.
54 Vincent AL, Cabrero JE, Greene JN, Sandin RL. Successful voriconazole
therapy of disseminated Fusarium solani in the brain of a neutropenic cancer
patient. Cancer Control 2003; 10:414--419.
55 Paphitou NI, Ostrosky-Zeichner L, Paetznick VL, et al. In vitro activities of
investigational triazoles against Fusarium species: effects of inoculum size and
incubation time on broth microdilution susceptibility test results. Antimicrob Agents
Chemother 2002; 46:3298--3300.
56 Lozano-Chiu M, Arikan S, Paetznick VL, et al. Treatment of murine fusariosis
with SCH 56592. Antimicrob Agents Chemother 1999; 43:589--591.
57 Sponsel WE, Graybill JR, Nevarez HL, Dang D. Ocular and systemic
posaconazole (SCH-56592) treatment of invasive Fusarium solani keratitis and
endophthalmitis. Br J Ophthalmol 2002; 86:829--830.
58 Apostolidis J, Bouzani M, Platsouka E, et al. Resolution of fungemia due to
Fusarium species in a patient with acute leukemia treated with caspofungin. Clin
Infect Dis 2003; 36:1349--1350.
59 Steinbach WJ, Perfect JR. Scedosporium species infections and treatments. J
Chemother 2003; 15 (Suppl. 2):16--27.
60 Danaher PJ, Walter EA. Successful treatment of chronic meningitis caused by
Scedosporium apiospermum with oral voriconazole. Mayo Clin Proc 2004; 79:707-708.
61 Klopfenstein KJ, Rosselet R, Termuhlen A, Powell D. Successful treatment of
Scedosporium pneumonia with voriconazole during AML therapy and bone
marrow transplantation. Med Pediatr Oncol 2003; 41:494--495.
62 Bosma F, Voss A, van Hamersvelt HW, et al. Two cases of subcutaneous
Scedosporium apiospermum infection treated with voriconazole. Clin Microbiol
Infect 2003; 9:750--753.
63 Mellinghoff IK, Winston DJ, Mukwaya G, Schiller GJ. Treatment of
Scedosporium apiospermum brain abscesses with posaconazole. Clin Infect Dis
2002; 34:1648--1650.
64 Studahl M, Backteman T, Stalhammar F, et al. Bone and joint infection after
traumatic implantation of Scedosporium prolificans treated with voriconazole and
surgery. Acta Paediatr 2003; 92:980--982.
65 Steinbach WJ, Schell WA, Miller JL, Perfect JR. Scedosporium prolificans
osteomyelitis in an immunocompetent child treated with voriconazole and
caspofungin, as well as locally applied polyhexamethylene biguanide. J Clin
Microbiol 2003; 41:3981--3985.
66 Howden BP, Slavin MA, Schwarer AP, Mijch AM. Successful control of
disseminated Scedosporium prolificans infection with a combination of
voriconazole and terbinafine. Eur J Clin Microbiol Infect Dis 2003; 22:111--113.
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67 Gosbell IB, Toumasatos V, Yong J, et al. Cure of orthopaedic infection with
Scedosporium prolificans, using voriconazole plus terbinafine, without the need for
radical surgery. Mycoses 2003; 46:233--236.
68 Meletiadis J, Mouton JW, Meis JF, Verweij PE. In vitro drug interaction
modeling of combinations of azoles with terbinafine against clinical Scedosporium
prolificans isolates. Antimicrob Agents Chemother 2003; 47:106--117.
69 Al-Abdely HM, Graybill JR. Penicilliosis marneffie. In: Guerrant R, Walker D,
Weller P, editors. Tropical infectious diseases, principles, pathogens and practice.
<AQ4> Churchill Livingstone; 1999. pp. 641--644.
70 Supparatpinyo K, Nelson KE, Merz WG, et al. Response to antifungal therapy
by human immunodeficiency virus-infected patients with disseminated Penicillium
marneffei infections and in vitro susceptibilities of isolates from clinical specimens.
Antimicrob Agents Chemother 1993; 37:2407--2411.
71 Supparatpinyo K, Perriens J, Nelson KE, Sirisanthana T. A controlled trial of
itraconazole to prevent relapse of Penicillium marneffei infection in patients
infected with the human immunodeficiency virus. N Engl J Med 1998; 339:1739-1743.
72 Sirisanthana T, Supparatpinyo K, Perriens J, Nelson KE. Amphotericin B and
itraconazole for treatment of disseminated Penicillium marneffei infection in human
immunodeficiency virus-infected patients. Clin Infect Dis 1998; 26:1107--1110.
73 Nakai T, Uno J, Ikeda F, et al. In vitro antifungal activity of Micafungin (FK463)
against dimorphic fungi: comparison of yeast-like and mycelial forms. Antimicrob
Agents Chemother 2003; 47:1376--1381.
74* Bouza E, Munoz P. Invasive infections caused by Blastoschizomyces
capitatus and Scedosporium spp. Clin Microbiol Infect 2004; 10 (Suppl. 1):76--85.
A nice review of some of the less commonly encountered fungi.
QUERIES TO AUTHOR
No. Query
1
The abstract must be no more than 250 words in length, therefore could you
please cut it from the present 291 words, without removing definite articles and
using abbreviations, which are not allowed in the abstract
2
Please insert an introductory sentence or paragraph here to separate
headings
3
Please insert an introductory sentence or paragraph here to separate
headings
4
Ref 69 -- please provide location of publisher Churchill Livingstone
11