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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