To those who then say they are NOT stuying candida, or know nothing about fungus they have already studied it a lot.
IBS is not caused by an infectious disease and will not progress into anything worse. IBS is a functional disorder, how the colon functions itself. The large colon, sigmoid colon, although functional disorders can overlap, which is also relatively common. IBS and GERD for example.
Infectious Diseases Treatment Updates
Managing Fungal Infections in the New Millennium CME
Author: John H. Rex, MD
Reviewer: Ronald Liteplo, MD
Clinical Editor: Joan Solomon Zolot, RPA-C
Review Date: April 6, 2000
Release Date: April 7, 2000
Valid for CME until April 7, 2001
Overview of Fungal Infections: Where Have We Come From and Where
Are We Going?
Invasive fungal infections are more prevalent than ever, due to an increasingly large populations
of patients at high risk secondary to immunosuppression. Underlying disease or chronic
conditions such as cancer, bone marrow or solid-organ transplantation, HIV infection, and
chronic corticosteroid administration make patients vulnerable to opportunistic fungal pathogens.
In the hospital, complicated surgical procedures, widespread use of implanted devices, and
administration of broad-spectrum antibiotics have dramatically increased the incidence of
nosocomial fungal infections. Clinicians of all specialties will have to contend with the growing
threat of fungal pathogens, if they have not already.
At a recent symposium held on January 29, 2000, at the MD Anderson Cancer Center, noted
experts in fungal infections gathered to present the latest information about diagnosis and
treatment of fungal infections in the immunocompromised patient.
In an overview of fungal infections, Kenneth V.I. Rolston, MD, of the MD Anderson Cancer
Center, Houston, Texas, stated that Candidaspecies are now the fourth most common cause of
nosocomial bloodstream infection, and they are associated with an extremely high mortality rate
of 40%.[1] From 1980 to 1990, the incidence of fungal infections in US hospitals nearly doubled,
from 2.0 to 3.8 per 1000 patients discharged.[2]The most marked increase in fungal infection
rates occurred not in transplant units or oncology centers, but on surgical services, with medical
services also showing increases. These changing patterns demonstrate that fungal infections are
no longer limited to the most severely immunosuppressed patients.
Nor are fungal infections limited to large teaching hospitals; small teaching hospitals and
nonteaching hospitals of all sizes have also experienced increases in fungal infection rates. In
addition, fungal infections are not occurring only in intensive care units (ICUs) housing the
sickest patients: just over half are in ICUs, but 43% are among patients in medical or surgical
units.[2]
"Living Petri Dishes" -- Who Is at Risk?
Most fungi are harmless to healthy individuals. But to patients with underlying medical problems
or immunosuppression, fungi can become devastating, opportunistic pathogens. Patients with
multiple risk factors have been likened by Michael G. Rinaldi, MD, to petri dishes, into which
any one of a number of microbes can fall and launch devastating infection, with minimal host
resistance.
In his talk on emerging fungal pathogens, Dr. Rinaldi, of the University of Texas Medical
Branch, Galveston, discussed a variety of factors that predispose to fungal infection. In fact,
many hospitalized patients have several risk factors, with each one multiplying the risk of fungal
infection. Prior or concurrent use of broad-spectrum antibiotics is an important risk factor,
because the reduction of protective bacteria may permit the growth of colonizing fungi. The use
of devices that breach protective barriers, especially central venous catheters used for
hyperalimentation, enables fungal pathogens to access the vulnerable host. An ICU admission,
especially when prolonged, increases the likelihood of fungal infection. Specific conditions or
procedures that predispose to fungal infection include: major surgery, transplantation (both solid
organ and bone marrow), the administration of antirejection therapy, steroid administration, the
presence of graft-versus-host disease (GVHD), intubation, malnutrition, hemodialysis, azotemia,
HIV infection or AIDS, and a variety of cancers.
Spectrum of Historically Common Fungal Pathogens
Since the 1950s and 1960s and until recently, the key opportunistic fungal pathogens with which
clinicians had to contend were Candida albicans, Aspergillus fumigatus, and the Zygomycetes,
which cause mucormycosis (Table 1). Today, non-albicans Candida have become more
frequent, as have other Aspergillus species.
Table 1. Well-Known Medically Significant Fungi
Cutaneous/Subcutaneous Infection
Systemic Disease of
Healthy Individuals
Opportunistic
Pathogens
Dermatophytes
Coccidioides
Candida
Agents of Mycetoma
Histoplasma
Cryptococcus
Sporothrix
Blastomyces
Aspergillus
Paracoccidioides
Zygomycetes
The Changing Epidemiology of Candidal Infections
During the past 2 decades, a substantial shift in the epidemiology of candidemia due to different
Candida species has occurred. In the 1960s and 1970s, Candida albicans accounted for 85% to
90% of cases of candidemia. However, an MD Anderson Cancer Center study of the
epidemiology of candidal infections from 1988 to 1992 found the incidence of non-albicans
Candida had surpassed that of C albicans. Only 42% of candidemia cases were caused by C
albicans, while non-albicans Candida accounted for the remainder, including C tropicalis
(18%), C parapsilosis (17%), C glabrata (11%), C krusei (4%), and others.[3] The authors of
the study surmised that fluconazole prophylaxis was largely responsible for the shift, in that it
reduced the incidence of C albicans infections. Similar results have been reported by other
groups in noncancer settings as well.[4]
Similar trends apply in the neonatal setting. There, recent data suggest that C albicans causes
only about 50% of infections, with C parapsilosis now being seen as the dominant non-albicans
species in this patient group.[5]
The emergence of Candida infections due to non-albicans species is particularly important to
practicing clinicians, because candidal isolates resistant to azole therapy have appeared, making
species identification and sensitivity testing crucial (Table 2). Microbiology labs should no
longer be reporting results such as "Candida species," "Candida - nonalbicans," or "yeast." The
species of the organism must be provided, because the species differ in their susceptibility to
antifungal agents and present different implications for outcome. C tropicalis has been shown to
cause invasive disease and disseminated infection.[3] C parapsilosis, however, is typically less
virulent.[6] C krusei is problematic because it almost universally exhibits resistance to azole
therapy (eg, fluconazole) and may have reduced susceptibility to other therapies.[7]
Table 2. Candida species: Human Pathogens
C albicans
C glabrata
C guilliermondii
C krusei
C lusitaniae
C parapsilosis
C pseudotropicalis
C rugosa
C stellatoidea
C tropicalis
Candida: The Diagnostic Paradox
Localized manifestations of candidal infection, such as mucocutaneous candidiasis, esophagitis,
and urinary tract infection (candiduria), are typically not life-threatening. And fortunately, such
localized infections do not usually progress to hematogenous dissemination.[8] However,
presence of Candida at any site is a risk factor for potentially lethal disseminated or systemic
candidiasis. Presence of the organism is not enough -- the host must also be impaired in some
fashion. Typical addditional risk factors are stay in an ICU, use of central venous catheters, use
of broad-spectrum antibiotics, diabetes, and dialysis.
Diagnosing disseminated candidiasis is unfortunately not straightforward. The single best tool is
the blood culture, but this tool has limited value. Even in patients with severe neutropenia or
immunosuppression, in whom disseminated candidiasis is strongly suspected, blood cultures are
positive only 50% of the time.[9] Non-culture-based strategies for diagnosing invasive
candidiasis have been intensively studied, but a highly reliable technology has yet to emerge.
There are some additional clues that, while not common, may be useful in selected patients.
Nodular cutaneous lesions may occur in very immunocompromised patients with candidemia,
and clearly indicate that bloodstream invasion and dissemination have already occurred.. Biopsy
of the lesions would confirm the diagnosis. Radiographic imaging, including CT scanning or
MRI, is also useful in diagnosing disseminated lesions on the lung, liver, spleen, or kidney,
although the radiographic findings may not be pathognomonic.
cont.
Aspergillosis
Invasive primary Aspergillus is an important cause of mortality among neutropenic patients,
particularly among patients with leukemia or solid-organ transplantation. Aspergillus species
cause 70% of noncandidal fungal infections following bone marrow transplantation.[10] The most
common pathogenic species is A fumigatus, although others can cause devastating opportunistic
infection (Table 3).
Table 3. Aspergillus: Key Human Pathogens
A fumigatus
A flavus
A nidulans
A niger
A terreus
Aspergillosis manifests quite differently from Candida. Localized disease appears as cutaneous
lesions, sinusitis, tracheobronchitis, and aspergilloma (a bronchopulmonary granuloma).
Invasive pulmonary aspergillosis and invasive sino-orbital aspergillosis are more common than
hematogenous aspergillosis. Sino-orbital disease can progress to fatal cerebral abscess.
Aspergillus is ubiquitous in the environment, and the portal of entry is most commonly the lungs.
The organism has a predilection for vascular tissue, and often invades blood vessels to the extent
that the supplied organ is infarcted. Radiologic findings in neutropenic patients with pulmonary
aspergillosis include pleural wedge-shaped lesions, nodular densities, cavitary lesions,
necrosis, diffuse bilateral infiltrates, and, less commonly, bloody pleural effusion. A "halo"
lesion is sometimes seen on lung CT and is strongly suggestive of tissue necrosis due to an
angiocentric mould. Blood cultures from patients with disseminated Aspergillus infection are
rarely positive. Biopsy, culture, and histologic examination of tissue reveal the organism.
Primary cutaneous Aspergillus infection typically occurs at the site of insertion of an intravenous
catheter, or it is associated with adhesive cutaneous dressings, where black eschar can form.
Biopsy of the eschar reveals the organism. The lesion can invade local blood vessels and lead to
vascular necrosis and infarction, a complication that does not occur with Candida. It must be
treated with surgical debridement and antifungal therapy.
Zygomycetes
A 60-year-old patient with poorly controlled diabetes and end-stage cirrhosis who underwent
liver transplantation was recently reported in The New England Journal of Medicine.[11]
Following the transplantation, he developed several complications, including poor graft
function, intrahepatic cholestasis, hyperglycemia, progressive renal failure,
vancomycin-resistant Enterococcus faecium bacteremia, and Candida parapsilosis fungemia.
During his hospitalization, a lesion developed on his forehead. It rapidly enlarged and became
necrotic. The lesion was biopsied and histopathology revealed a nonseptate hyphal fungus.
Culture grew Rhizopus oryzae. The patient died 1 month after transplantation from
complications of septic shock.
Classically referred to as mucormycosis, his infection is now called zygomycosis. The most
common causative agent is Rhizopus, a common bread mould that lives on any organic material.
Other pathogens include Mucor, Rhizomucor, and Absidia. Zygomycetes include 20 different
fungi, all appearing the same histologically. All are treated similarly, with amphotericin B or a
lipid formulation of amphotericin B.
The severely immunocompromised patient may become infected with Zygomycetes via
respiratory inhalation. Clinical manifestations may be rhinocerebral (involving skin of the face),
pulmonary, cutaneous, gastrointestinal, or neurologic. The disease manifests with vascular
invasion and tissue necrosis, forming black eschar (Figure 1).
Figure 1. Infections are frequently fatal.
Emerging Fungal Pathogens
A wide variety of fungi now isolated from neutropenic patients were not previously recognized
as human pathogens. Many of these are soil or plant fungi -- organisms that clinicians have not
been trained to recognize -- and present considerable challenges in diagnosis and treatment,
especially if the appropriate antifungal agent is not known.
Fusarium
More than a dozen fungi have been identified that appear histologically identical to Aspergillus.
Fusarium is one of these genera. It is the most prevalent plant fungus worldwide, and it is now
recognized as a human pathogen as well. Fusarium is infecting neutropenic patients with
increasing frequency. It manifests with fever and large ulcerative cutaneous lesions that progress
to necrosis -- the appearance also complicates distinguishing this fungus from Aspergillus.
However, and quite distinct from Aspergillus, patients with disseminated fusariosis will often
have a positive blood culture for this fungus.
Fusarium infections can occur in immunocompetent or immunosuppressed individuals.
Immunocompetent patients develop infection following trauma, burns, or major surgery.
Infections are more devastating, however, in immune-suppressed patients, such as those with
GVHD or neutropenia.
Hematogenous dissemination of Fusarium involves multiple sites and organs, including sinuses,
lungs, skin, brain, bone, and joints. Fungemia from disseminated Fusarium infection is revealed
by blood culture 50% of the time[12] or more, since Fusarium is quite angioinvasive and is
actually present in the bloodstream in sufficient amounts to be detected by current blood
culturing methods. Histopathology of Fusarium reveals filamentous fungus with branching
septate hyphae -- indistinguishable from Aspergillus. Fusarium infection is life-threatening and
associated with a poor prognosis.[13]
Paecilomyces
Paecilomyces lilacinus gained notoriety more than a decade ago as one of the moulds capable of
causing fungal keratitis in wearers of soft contact lenses.[14] Deep invasive infection due to this
organism now occurs more frequently in immunocompromised patients. The disease manifests
with skin lesions. This mould appears histologically, as do both Aspergillus and Fusarium.
Phaeohyphomycosis
Phaeohyphomycosis is an infection that manifests as a chronic, tissue-destroying, sinus-forming
process. As the infection usually follows traumatic inoculation, the most common site for disease
is an extremity, most often the feet. Phaeohyphomycosis can be caused by a variety of fungal
genera, including Bipolaris, Exserohilum (which grows on grass), and Exophiala, all of which
are darkly pigmented fungi. All the fungi that can cause this appear identical in tissue. Therefore,
they must be grown in culture and examined histologically. The infection is usually treatable
with surgical resection of the lesion and antifungal therapy.
Trichosporon
Trichosporon beigelii is fungus that lives on hair shafts of the scalp, body, and pubic hair as part
of the normal flora, and can cause a superficial fungal infection called white piedra. The
prevalence of hematogenous trichosporonosis is increasing among neutropenic patients.[12]
Disseminated disease manifests as multiple, erythematous papular or purpural skin lesions.
Systemic Trichosporon infection is often fatal.[12]
Other Fungi
Many other fungi are gaining attention as human pathogens. Malassezia is part of the normal
human flora and can cause infection in immunocompromised hosts. Penicillium marneffei and
Pythiosis insidiosi are environmental fungi that can cause serious, life-threatening infections in
immunosuppressed patients. P marneffei has gained particular attention during the AIDS
pandemic, as it may produce disease that is clinically indistinguishable from disseminated
histoplasmosis. Pseudallescheria boydii is a mould that lives in the soil and in vegetation and is
an agent of mycetoma, a subcutaneous infection. In immunosuppressed patients, it causes
pseudallescheriasis, a soft-tissue and pulmonary disease that resembles aspergillosis (clinically
and histologically) and can spread hematogenously.
The Importance of Thinking Fungus
In the 1970s and 1980s, gram-negative sepsis was the chief nosocomial infection of concern.
The most clinically significant pathogens were Klebsiella, Escherichia coli, Enterobacter, and
Pseudomonas. During the 1980s and 1990s -- and today -- hospital-acquired gram-positive
sepsis is the overriding concern, most commonly due to Staphylococcus or Enterococcus. Now
Candida has become the fourth leading cause of hospital-acquired sepsis, surpassing even E
coli.
Mycology has developed into a field that demands the attention of all clinicians treating patients
in the hospital. During the 1980s, the incidence of bloodstream infection due to Candida species
increased almost 500%.[15] The proportion of nosocomial bloodstream infections due to Candida
increased from 2% in 1980 to 5% in the late 1980s.[16] The trend continued in the 1990s, with
8% of hospital-acquired bloodstream infections attributed to Candida.[15] A study published in
1999 found 12% of nosocomial bloodstream infections in the ICU were due to fungi.[17]
Now that fungi represent a substantial proportion of the pathogens in "living human petri dishes,"
it is crucial to consider the possibility of a fungal infection in hospitalized patients -- and
consider it early.
The High Cost of Thinking Fungus Too Late
The mortality rate in neutropenic patients with fungal infections is high. Among neutropenic
patients with Aspergillus infection, it can exceed 90%.[18,19] Neutropenic patients with Fusarium
or Trichosporon infection have a mortality rate approaching 100%.[13,20] Even candidemia is
associated with a mortality rate of 50%.[21-23]
Mortality is higher when the diagnosis of fungal infection is not made early. In one study,
patients with lymphoma were housed in a protective environment -- single-patient rooms under
positive pressure with high-efficiency particulate air filtration -- while undergoing bone marrow
or peripheral stem cell transplantation.[24] Despite these protective measures, 5.2% of patients
developed nosocomial invasive aspergillosis. Although mortality rates among the patients with
localized or pulmonary disease were substantial (42%), they were better than those of the
patients who began treatment after the disease was already disseminated. In fact, none of the
patients with documented disseminated disease survived.
A multicenter study of Aspergillus infection in immunosuppressed patients, most of whom had
bone marrow or solid-organ transplantation, leukemia, lymphoma, or AIDS, confirmed the
importance of early diagnosis.[25] Patients with only pulmonary disease had greater rates of
complete response and fewer treatment failures than patients with disseminated or central
nervous system disease (Table 4).
Table 4. Response to Therapy by Site of Infection
Pulmonary
Disseminated (Without CNS)
CNS
Complete Response
29 (19%)
8 (17%)
-
Treatment Failure
61 (39%)
29 (63%)
18 (78%)
Other Failure
32 (20%)
5 (11%)
3 (12%)
Partial Response
25 (16%)
3 (6%)
-
Stable
8 (5%)
1 (2%)
1 (4%)
N/A
1 (1%)
-
1 (4%)
Patterson, ICAAC, 1996 The High Cost of Thinking Fungus Too Late
The mortality rate in neutropenic patients with fungal infections is high. Among neutropenic
patients with Aspergillus infection, it can exceed 90%.[18,19] Neutropenic patients with Fusarium
or Trichosporon infection have a mortality rate approaching 100%.[13,20] Even candidemia is
associated with a mortality rate of 50%.[21-23]
Mortality is higher when the diagnosis of fungal infection is not made early. In one study,
patients with lymphoma were housed in a protective environment -- single-patient rooms under
positive pressure with high-efficiency particulate air filtration -- while undergoing bone marrow
or peripheral stem cell transplantation.[24] Despite these protective measures, 5.2% of patients
developed nosocomial invasive aspergillosis. Although mortality rates among the patients with
localized or pulmonary disease were substantial (42%), they were better than those of the
patients who began treatment after the disease was already disseminated. In fact, none of the
patients with documented disseminated disease survived.
A multicenter study of Aspergillus infection in immunosuppressed patients, most of whom had
bone marrow or solid-organ transplantation, leukemia, lymphoma, or AIDS, confirmed the
importance of early diagnosis.[25] Patients with only pulmonary disease had greater rates of
complete response and fewer treatment failures than patients with disseminated or central
nervous system disease (Table 4).
Table 4. Response to Therapy by Site of Infection
Pulmonary
Disseminated (Without CNS)
CNS
Complete Response
29 (19%)
8 (17%)
-
Treatment Failure
61 (39%)
29 (63%)
18 (78%)
Other Failure
32 (20%)
5 (11%)
3 (12%)
Partial Response
25 (16%)
3 (6%)
-
Stable
8 (5%)
1 (2%)
1 (4%)
N/A
1 (1%)
-
1 (4%)
Patterson, ICAAC, 1996
The Challenge of Diagnosis
There are no rapid, accurate diagnostic tests that can confirm with certainty the presence of
invasive fungal disease. Unless the clinician considers fungal disease early, disease can
progress rapidly while the patient is treated aggressively with broad-spectrum antibiotics.
Not only are fungal infections difficult to distinguish from bacterial or other infections, but the
clinical manifestations of many fungal infections are shared among a variety of fungal pathogens
as well.
Standard microbiology is often adequate to provide a diagnosis. Short of tissue biopsies, fungal
cultures are not always positive in the presence of invasive disease. Moreover, positive cultures
do not definitively signify invasive disease; they may represent colonization. Nonetheless, in
patients who are immunosuppressed, a positive culture and invasive disease are highly
correlated.[26] A high-risk patient with a positive culture should be considered to have invasive
disease until proven otherwise.
Radiographic imaging can be useful in certain situations. X-ray and CT can assist in identifying
early Aspergillus infection.[27] Pulmonary aspergillosis may manifest as focal areas of patchy
consolidation, pulmonary nodules, cavitary lesions, a crescent air sign, or a "halo" on computed
tomography.[28] A halo sign, an area of low attenuation (increased density), surrounding a nodular
pulmonary lesion in a neutropenic or bone marrow transplant patient is highly suggestive of
aspergillosis[27]; in solid-organ transplant patients, however, the significance of the halo sign has
not been established.
In one study, early CT scans performed in febrile neutropenic patients with x-ray infiltrates and
probable invasive pulmonary aspergillosis (IPA) identified halo signs in 92% of patients,
reducing the time to diagnosis of IPA from 7 to 1.0 days.[29] Following antifungal treatment with
or without surgical resection of pulmonary lesions, 72% of patients were cured or improved.
The improved response rates were attributed to earlier diagnosis and initiation of therapy.
Serologic methods based both on detection of fungal antigens and fungal DNA are being pursued
and may assist in making earlier and more specific diagnoses. However, the clinical utility of
serologic testing for fungal infection has not been established. Sensitivity and specificity are
often inadequate, with false positives and cross reactivity occurring. For example, serum
Aspergillus antigen testing by ELISA may be associated with a false-positive rate of almost
10%.[30] Sensitivity of PCR may depend on the extent of invasion of disease; a higher frequency
of detection by PCR is seen for invasive aspergillosis than for pulmonary aspergilloma.[31]
Biopsy of the lesion, culture, and histologic examination remain important components in the
work-up and diagnosis of fungal infection.
An Overview of the Newer Antifungal Agents for Deep Mycoses
Several new antifungal agents have been developed because of limitations among the already
available agents, according to Thomas F. Patterson, MD, of The University of Texas Health
Science Center at San Antonio. Limitations of current therapeutic options include: inadequate
spectrum of activity, lack of efficacy due to growing resistance, poor safety profile, multiple
drug interactions, inadequate pharmacokinetic profile, and excessive cost.
The ideal antifungal would have a broad spectrum of activity, be fungicidal rather than
fungistatic, be available in oral and injectable formulations, cause minimal drug interactions, be
safe at efficacious doses, be cost-effective, and be stable to resistance. Development of
antifungal agents is a challenge because there are very few potential drug targets unique to fungi
-- and not present in humans. Also, because diagnosis and identification of fungal species is
elusive, it may be difficult to find an adequate-sized patient population to test experimental
agents in large-scale trials.
Treatment of deep fungal infections often begins empirically, since obtaining the diagnosis can
be difficult and often is delayed. Amphotericin B remains a drug of first choice in many settings,
although it may not always be effective for Aspergillus infections in highly immunosuppressed
patients.[25] The triazoles are first- and second-line agents for a variety of infections, but
emerging resistance may limit their role (Table 5). Newer agents include lipid amphotericin B,
which is already available; new azoles, some of which are already on the market; and candins,
which have not yet been released.
Table 5. Current Treatment Recommendations for Selected Deep Fungal
Infections
Fungal Pathogen
First-line Agent(s)
Second-line Agent(s)
Candida
Amphotericin B, fluconazole
Itraconazole
Aspergillus
Amphotericin B, Itraconazole
Zygomycetes
Amphotericin B
Itraconazole
Fusarium
Amphotericin B
Itraconazole
Phaeohyphomycosis
Itraconazole
Trichosporon
Fluconazole
Lipid Formulations of Polyenes
The parent drug of lipid amphotericin formulations is amphotericin B. Amphotericin B is an
intravenous drug with a very narrow therapeutic index. Three lipid amphotericin formulations
-are now available and have a greatly improved toxicity profile (Table 6).
Table 6. Polyenes
Generic Name
Trade Names
Amphotericin B deoxycholate
Fungizone
Liposomal amphotericin B
Ambisome
Amphotericin B colloidal dispersion (ABCD)
Amphotec or Amphocil
Amphotericin B lipid complex (ABLC)
Abelcet
Legend: The names of the forms of amphotericin B are shown. When referring to the
group of lipid formulations, the most appropriate general term is "lipid-associated
formulation of amphotericin B," or LFAB. Use of the phrase "liposomal amphotericin
B" should be avoided as it produces confusion: does the speaker mean Ambisome or
just one of the LFABs?
Only one of the products is a true liposome. This compound has the generic name of liposomal
amphotericin B and a trade name of Ambisome. The other two products, amphotericin B lipid
complex (ABLC; trade name Abelcet) and amphotericin B colloidal dispersion (ABCD; trade
names Amphotec, Amphocil), are not true liposomes. ABCD is associated with more
administration toxicity and offers no advantages compared with the other two products.[32] All 3,
however, are generally less nephrotoxic than amphotericin B. All lipid amphotericin B agents
still cause increased creatinine levels and electrolyte disturbances. Because amphotericin B
causes membrane permeability to increase, amphotericin B agents can destabilize the cardiac
conduction system in the presence of hypokalemia or hypomagnesemia, causing ventricular
fibrillation and death during infusion. Therefore, it is critical to monitor electrolytes in patients
receiving any form of the drug.
A recent study published in The New England Journal of Medicine demonstrated comparable
efficacy and survival rates among neutropenic patients randomized to receive liposomal
amphotericin B or conventional amphotericin B as empirical antifungal therapy.[33] Patients who
received the liposomal drug, however, had significantly fewer infusion-related reactions, such
as fever (17% vs 44%) and chills or rigors (18% vs 54%). Nephrotoxicity was also
significantly lower (19% vs 34%). In another study, standard amphotericin B was shown to be
less effective than lipid amphotericin B against invasive Aspergillus infection in a highly
immunosuppressed patient population.[34] Patients who received the lipid formulation had higher
response rates (50% vs 20%, proven Aspergillus infection; 52% vs 29%, suspected or proven
Aspergillus infection) and lower mortality rates (22% vs 38%). Amphotericin B lipid complex
was studied in an open-label, single-patient, emergency-use study of patients refractory to or
intolerant of standard amphotericin B (Figure 2). A complete or partial response was
demonstrated in 42% of patients with aspergillosis, 67% of patients with disseminated
candidiasis, 71% of patients with zygomycosis, and 82% of patients with fusariosis. While these
data are not comparative, they suggest that lipid amphotericin B may be effective against several
mycoses.
Figure 2. ABLC Historical Control Study
ABLC (n=151)
Control (n=122)
Complete Response
Partial Response
Stable Disease
Failure
N/A
23 (15%)
38 (25)
16 (11)
71 (47)
3 (2)
13 (11%)
15 (12)
5 (4)
83 (68)
6 (5)
Compared with amphotericin B, a much higher dose of the LFABs must be administered for
therapeutic efficacy.[36,37] Amphotericin B is usually dosed up to 1 mg/kg/day. Because they are
less potent, the doses of LFABs may range from 3 to 6 mg/kg/day. Antifungal activity improves
with increasing doses of the agent.[38] But, the LFABs offer a much wider therapeutic index than
amphotericin B and toxicity is less likely even with the highest doses administered for longer
periods of time. These agents are indicated to treat invasive fungal infections in patients who are
refractory to, or intolerant of, amphotericin B therapy. Liposomal amphotericin B (Ambisome)
also carries a specific indication for use as empiric therapy for presumed fungal infections in
neutropenic patients.
The LFABs are expensive. While a standard day's dose of amphotericin B costs $20, a
lipid-associated form of amphotericin B may cost up to $1000 per day. The cost differential
requires the clinician to weigh the benefits of the safety profile of lipid amphotericin B versus
the increased expense. How likely is the patient to develop nephrotoxicity if standard
amphotericin B is used? Can the risk be quantified?
When making the decision of whether to administer amphotericin B versus an LFAB, one should
also consider the labeling of the product: In general, the LFABs are off-labeled for use in
patients refractory to or intolerant of amphotericin B. But, nephrotoxicity can be predicted in
some patients. For example, I believe that a diabetic patient with proteinuria and a preexisting
creatinine of 2.5 mg/dL should certainly receive an LFAB. This concept is supported by a study
of 239 immunosuppressed patients receiving amphotericin B for aspergillosis in which that a
creatinine level greater than 2.5 mg/dL predicted nephrotoxicity and the need for dialysis, which
in turn directly increased mortality.[39]
A "New" Azole. Itraconazole in Cyclodextrin
Itraconazole is a triazole drug (Table 7) that has long been available as a capsule and, more
recently, as a solution. It has a wide spectrum of activity with extensive efficacy and safety data
gathered. It is no more effective than amphotericin B for Candida, but it is efficacious for other
types of systemic fungal infections, such as histoplasmosis, blastomycosis, and
aspergillosis.[40,41]
Table 7. The Azoles
Imidazoles
Triazoles
2nd-Generation Triazoles
Ketoconazole
Fluconazole
Voriconazole (fluconazole congener)
Itraconazole
Ravuconazole (fluconazole congener)
Posaconazole (itraconazole congener)
Oral absorption of the capsule is variable and improved by intake with food, but now a liquid
formulation is available that confers 30% greater bioavailability. This formulation, a solution in
cyclodextrin, should now be administered preferentially to the capsule for all
immunocompromised patients with systemic fungal disease. Cyclodextrin is a ring of glucose
molecules that stabilizes the azole drug and increases its absorption, resulting in improved blood
and tissue levels of itraconazole.
The clinical utility of itraconazole has previously been limited by lack of a parenteral
formulation. An intravenous formulation of the drug, also solubilized in cyclodextrin, has
recently become available that offers improved absorption and serum drug levels, compared
with either oral preparation. The drug is indicated as a second-line agent against aspergillosis
and as a first-line agent for histoplasmosis and blastomycosis.
Intravenous administration for 2 weeks followed by oral administration of itraconazole for 12
weeks was shown to yield complete or partial responses in about half of immunocompromised
patients with invasive pulmonary aspergillosis.[42] Itraconazole levels exceeded 250 mg/mL in
91% of the patients. Because itraconazole is metabolized by the liver and cyclodextrin is
excreted renally, the drug should be used with caution in patients with reduced renal function;
data on the drug in patients with renal dysfunction will not be available immediately. Therefore,
this drug is contraindicated in the presence of nephrotoxicity (creatinine clearance less than 30
mL/min).
Adverse effects of itraconazole include dose-related nausea and abdominal pain, hepatic
dysfunction, and, at very high doses, hypokalemia and edema. Because it is metabolized by the
cytochrome P-450 enzyme system, itraconazole is associated with many drug interactions.
Cont.
Truly New Azoles
New azoles -- a second generation of triazoles -- are currently in development. They will offer a
broader spectrum of activity against many species of the key genera, compared with currently
available triazoles. In particular, they are active against C krusei, one of the candidal species
more frequently resistant to fluconazole.
Voriconazole is a second-generation congener of fluconazole active against a wide variety of
candidal species.[43] Voriconazole may have more potent activity than fluconazole against some
Candida species, including C krusei.[44] Voriconazole has also demonstrated in vitro activity
against Aspergillus species resistant to amphotericin B[45] as well as against a variety of
filamentous fungi.[46] One study in humans showed reasonable complete or partial response rates
with intravenous followed by oral voriconazole administration for invasive aspergillosis
(Figure 3). It also has a satisfactory safety profile. It will be available for twice-daily dosing by
oral or intravenous administration.
Figure 3.
Ravuconazole (BMS-207,147) is also a second-generation fluconazole-based drug. It has a
broad-spectrum of activity, and in particular is active against a wide spectrum of candidal
species.[43] This drug has adequate oral bioavailability. Clinical trials of this agent are currently
under way.
Posaconazole (SCH-56962) is a congener of itraconazole currently under investigation. It has an
excellent safety profile and was efficacious in vitro against many candidal species[43] and was
also very active against Fusarium in a murine model.[48] This agent is in advanced clinical trials.
New Classes: The March of the Peptides
For the first time in many years, a new class of drugs, the candins, is being developed to treat
fungal infections. The candins inhibit fungal cell wall synthesis and therefore have been referred
to as "penicillin for fungi." Their target in cell wall synthesis, (1,3)-beta-D-glucan synthase,[49] is
not present in mammalian cells. By contrast, polyenes and azoles act on a cell membrane
common to fungal and mammalian cells, accounting for the toxicity of these agents.
Candin agents in development include the pneumocandin caspofungin (formerly MK-991) and
the echinocandins LY-303,366 and FK-463. All the candin agents are fungicidal against all
species of Candida,[43] and they are also active against Aspergillus.[49]
The pneumocandin caspofungin is the agent furthest along in development. It is active against
Candida species and Aspergillus species,[50] and was effective in vitro against azole-resistant
candidal strains.[51] Caspofungin was also effective against Histoplasma and Pneumocystis in
mice.[52] The agent was not active in vitro against Fusarium, Rhizopus, or Paecilomyces.[50]
Because it has poor oral bioavailability, it will be available as a parenteral medication only.
The agent is currently in late phase II and III clinical studies.
LY-303,366 and FK-463 are 2 echinocandins under investigation. Their spectra of activity are
similar to that of caspofungin.
The Future: What Is in Store for Mycology?
Infectious disease is entering a new era, the golden age of mycology. A new generation of
antifungal treatments has begun to unfold. Lipid amphotericin compounds, intravenous azoles,
and candins show promise. Future work will examine the role of these new agents both alone
and potentially in combination.
Other possible future treatment options, now shiny specks in the distance, include the other types
of peptide-based antifungal agents, the sordarins (which inhibit translation elongation factor 2),
other amphotericin congeners, and combination therapies with cytokines. These are all in the
early stages of exploration.
Significant investment is required for the next generation of antifungal agents. While discovery
and development is a challenge, an unprecedented number of antifungal agents will ultimately
join the clinician's armamentarium against emerging fungal pathogens.
--------------------
My website on IBS is www.ibshealth.com
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Re: Thanks for the info Shawneric -nt-
