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- New Orleans, Louisiana September 7-10, 2000 Authors:
Anne Gershon, MD; Thomas Hooton, MD; Jeffrey Nadler, MD; Kathy Neuzil,
MD; William G. Powderly, MD; David Relman, MD; Bruce Walker, MD; Robert
Weinstein, MD
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- Emerging Fungi -- Resistant, Resilient, and Not So Rare
By William G. Powderly, MD
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- The newer antifungal agents, such as fluconazole and
itraconazole, have been quite successful in treating and preventing common
fungal infections caused by Candida albicans and other species. However,
the price of this success has been the emergence of resistant strains of
C albicans as well as other Candida species and other fungal organisms
inherently more resistant to our current drugs. At this year's IDSA meeting,
experts on emerging fungal infections dealt with the increasing problem
of resistance in Candida species, phaeohyphomycosis, zygomycosis and other
rare mold infections.
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- Emerging Antifungal Resistance in Candida -- Beyond Non-albicans
Candida Candida infections have become a common problem in hospitals. With
the increase in the population of older patients, wider broad-spectrum
antimicrobial usage, and more immunocompromised patients, nosocomial candidemia
now represents the fourth most common bloodstream infection seen in the
United States. Although we have tended to think usually of Candida albicans
as the major player, other species (non-albicans Candida) have emerged
as significant pathogens in the last decade, bringing unique and important
issues in pathogenesis and drug resistance, according to Dr. Kieren Marr[1]
from the Fred Hutchinson Cancer Center and the University of Washington
in Seattle.
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- C albicans is a considerable problem -- the fungus is
undoubtedly the most pathogenic of the Candida species, deriving much of
its virulence from specific enzymes (such as protease and phospholipase)
as well as possibly from its ability to exist in yeast and hyphal states.
It invades through the gastrointestinal tract, and colonization precedes
invasion in most cases. All these properties are shared with C tropicalis.
In general, C albicans and C tropicalis are susceptible to antifungals
but share the possibility that resistance can develop. An allied species,
C dubliniensis, is often mistaken for C albicans in clinical microbiology
labs (it is also germ-tube positive, and most routine biochemcal tests
cannot distinguish it from C albicans). C dubliniensis, however, tends
to be less susceptible to the azole antifungals. First described in patients
with AIDS who had resistant oropharyngeal disease, C dubliniensis is now
recognized as a pathogen in other populations, such as in those undergoing
treatment for cancer. C albicans and C tropicalis can become resistant
to azole antifungal treatment. Azole resistance was first seen in patients
with AIDS, especially those with very advanced disease who had considerable
exposure to fluconazole, but azole resistance has now also been noted in
other very immunocompromised patients, such as those undergoing bone marrow
transplantation.[2]
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- A number of resistance mechanisms have been well described.[3]
These include overexpression of the target enzyme of the azoles (14-alpha
demethylase), point mutations in this or other fungal enzymes, or the appearance
of efflux pumps that rapidly eliminate the drug from the cell. These pumps
can be fluconazole-specific (which means that other azoles can still be
active) or can act to remove all azole drugs. One worrying recent observation
regarding C albicans is that there may be a trend to decreasing susceptibility
to polyenes (ie, amphotericin B) as well.
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- Species such as C albicans and C tropicalis are virulent
and occasionally resistant (playing the role of Iago in the candidal world,
according to Dr. Marr), whereas C krusei and C glabrata are resistant but
only occasionally virulent (playing the Othello role). These yeasts are
clearly becoming more common, and in some surveys, account for up to 50%
of candidemias. They are inherently less susceptible to azoles (C krusei
is completely resistant to azoles, and C glabrata readily acquires azole
resistance) and also are somewhat less susceptible to polyenes (although
the clinical significance of this is less certain).[4] They are also less
virulent and thus are usually pathogenic in more immunocompromised patients,
such as neutropenic patients and those in intensive care units.
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- There is growing evidence that C krusei and C glabrata
are selected where there is widespread use of fluconazole.[2] Dr. Marr
cited data from the bone marrow program in Seattle where, prior to the
use of fluconazole prophylaxis, the annual incidence of Candida infection
was 11.4% -- predominantly C albicans and C tropicalis. Since the introduction
of fluconazole, the incidence has fallen to 4.6%, but the infections are
caused mainly by C krusei and C glabrata. Furthermore, there is worrisome
information that, although less virulent, infection with these pathogens
is associated with a worse outcome in susceptible hosts.[5] The other yeast
to emerge as an important player in the last 10 years has been C parapsilosis
-- a species with a very different character altogether (perhaps more akin
to Falstaff?) This species is clearly associated with intravenous catheterization
and is much more common in children. Many cases are nosocomial in origin
and may be acquired from hospital staff.
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- Phaeohyphomycosis
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- Phaeohyphomycosis is a group of superficial and deep
infections caused by dark or black, melanin-pigmented dematiaceous fungi,
and according to Dr. Elias Anaissie[6] from the University of Arkansas,
Little Rock, this problem is increasingly being seen. Included in this
group are species such as Alternaria, Bipolaris, and Curvularia. Melanin-containing
molds are important causes of superficial and deep cutaneous infection
in the tropics. They are generally only seen in the developed world as
an invasive (and often systemic) infection in immunocompromised patients,
especially in transplantation patients and in those with neutropenia. These
molds generally cause invasive sinusitis and/or brain disease and thus
are associated with considerable morbidity.
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- The keys to treatment include surgery, antifungal therapy,
and reversal of immunosuppression (if possible). Surgery is key, but often
not practical in immunosuppressed patients because of thrombocytopenia.
Surgery is especially indicated in patients with pulmonary disease -- eg,
significant hemoptysis, severe or worsening cavitation, and local extension
into the mediastinum or pericardium. Surgery is also recommended for bone
and joint infection, progressive sinusitis, and endophthalmitis.
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- The antifungal of choice is amphotericin B, given in
relatively high doses. Itraconazole may also have activity. Susceptibility
tests may help in the selection of appropriate antifungals but are not
standardized. Dr. Anaissie concluded his review by addressing possible
prevention. He postulated, as he has at previous meetings about Aspergillus,
that the primary source of such molds is water and that, in nosocomial
settings, it might be important to monitor water in showers or sinks.
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- Zygomycosis
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- The Zygomycetes class is a group of ubiquitous molds
found in soil and decaying matter. The predominant genus is the Mucorales,
and the most important species is the Rhizopus group. These molds predominantly
affect patients with immune defects, either in macrophage or neutrophil
function, noted Dr. Corina Gonzalez[7] from Children's National Medical
Center, Washington, DC.
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- These molds grow rapidly and invade blood vessels, causing
tissue infarction. Neutropenic patients and those on steroids (such as
transplantation patients) are quite susceptible to disseminated or pulmonary
infection. Rhinocerebral infection is classically associated with diabetic
ketoacidosis. It is believed that the acidosis (interfering with macrophage
function) rather than the hyperglycemia is the key perturbation. Direct
inoculation predisposes patients with burns or traumatic wounds and intravenous
drug users to localized infection. One interesting association is the risk
of zygomycosis in renal dialysis patients receiving the iron chelator,
desferoxamine -- it is thought that increased iron increases the fungal
growth rate.
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- As with phaeohyphomycosis the key to management is surgery,
antifungal therapy, and reversal of immunosuppression. Early diagnosis
is critical. Dr. Gonzalez suggested that in diabetics, survival is clearly
linked to the absence of brain involvement. Amphotericin B remains the
drug of choice, but it must be used in relatively high doses (1.0-1.5 mg/kg/day)
for prolonged periods -- a fact that often necessitates the use of the
lipid formulations. Hyperbaric oxygen has been used in some cases with
reported success; however, data from controlled comparative trials are
lacking.
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- Other Filamentous Fungi
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- Other mold infections that tend to be more resistant
to amphotericin B, such as Fusarium, Scedosporium, and Aspergillus terreus,
also tend to be seen in immunocompromised hosts, but by virtue of their
relative resistance to amphotericin B (and to commonly available azoles),
they can be difficult to treat and are associated with a poor outcome,
stated Dr. Thomas Walsh[8] from the National Cancer Institute, Washington,
DC. In vitro data and some animal studies suggest that some of the newer,
currently investigational triazole compounds (voriconazole, posaconazole,
and ravuconazole) have activity in these infections, and case reports of
success are starting to appear. Because of the need for alternative antifungal
therapy, a microbiologic diagnosis is very important and should be sought
in suspected cases. Further research into these rare but potentially increasing
fungi is also needed.
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- What Should We Do Now?
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- Emerging and resistent fungal pathogens are an important
area for infectious disease specialists and others treating immunosuppressed
patients. However, one is left with a sense that because these are relatively
rare infections in sick patients, most of the clinical data are anecdotal.
After Dr. Anaissie's presentation, Dr. Richard Graybill from the University
of Texas in San Antonio issued a plea for multicenter studies and asked
for investigators interested in phaeohyphomycoses to collaborate in a comparative
study of itraconazole and posaconazole. Iecho his sentiments and suggest
that such an approach be applied to all of these infections.
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- References
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- Marr KA. Candida species: emergence of drug-resistant
pathogens. Program and abstracts of the 38th Annual Meeting of the Infectious
Diseases Society of America; September 7-10, 2000; New Orleans, Louisiana.
Abstract S65. Marr KA, Seidel K, White TC, Bowden RA. Candidemia in allogeneic
blood and marrow transplant recipients: evolution of risk factors after
the adoption of prophylactic fluconazole. J Infect Dis. 2000;181:309-316.
White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors
that contribute to antifungal drug resistance. Clin Microbiol Rev. 1998;11:382-402.
Nguyen MH, Clancy CJ, Yu VL, et al. Do in vitro susceptibility data predict
the microbiologic response to amphotericin B? Results of a prospective
study of patients with Candida fungemia. J Infect Dis. 1998;177:425-430.
Viscoli C, Girmenia C, Marinus A, et al. Candidemia in cancer patients:
a prospective, multicenter surveillance study by the Invasive Fungal Infection
Group (IFIG) of the European Organization for Research and Treatment of
Cancer (EORTC). Clin Infect Dis. 1999;28:1071-1079. Anaissie E. Phaeohyphomycosis:
new perspectives on diagnosis and treatment. Program and abstracts of the
38th Annual Meeting of the Infectious Diseases Society of America; September
7-10, 2000; New Orleans, Louisiana. Abstract S66. Gonzalez C. Zygomycosis:
Emerging pathogens and new treatment strategies. Program and abstracts
of the 38th Annual Meeting of the Infectious Diseases Society of America;
September 7-10, 2000; New Orleans, Louisiana. Abstract S67. Walsh TJ. Amphotericin
B resistant filamentous fungi: Fusarium, Pseudallescheria, and other tenacious
moulds. Program and abstracts of the 38th Annual Meeting of the Infectious
Diseases Society of America; September 7-10, 2000; New Orleans, Louisiana.
Abstract S68.
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