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`Drugs 2001161 Suppl. 1 1.125
`mizroswonmotcolarszr 50m
`REVIEW ARTICLE
`a'C.‘ Adis Internationci Limited. All rights reserved
`
`Current Management of
`Fungal Infections
`
`Iacques RGM. MeisL2 and Paul E. Verweij 2
`
`1 Department of Medical Microbiology, Canisius-Wilhelmina Hospital, Niimegen, The Netherlands _
`2 University Medical Center St Radboud, Nijmegen, The Netherlands
`
`
`The management of superficial fungal infections differs significantly from the
`management of systemic fungal infections. Most superficial infections are treated
`with topical antifungal agents, the choice of agent being determined by the site
`and extent of the infection and by the causative organism, which is usually readily
`identifiable. One exception is onychomycosis, which usually requires treatment
`with systemically available antifungals; the accumulation of terbinafine and
`itraconazole in keratinous tissues makes them ideal agents for the treatment of
`onychomycosis. Oral candidiasis in immunocompromised patients also requires
`systemic treatment; oral fluconazole and itraconazole oral solution are highly
`effective in this setting.
`Systemic fungal infections are difficult to diagnose and are usually managed
`with prophylaxis or empirical therapy. Fluconazole and itraconazole are widely used
`in chemoprophylaxis because of their favourable oral bioavailability and safety
`profiles. In empirical therapy, lipid-associated formulations of amphotericin-B
`and intravenous itraconazole are safer than, and at least as effective as, conven-
`
`tional amphotericin-B (the former gold standard). The high acguisition costs of
`the lipid-associated formulations of amphotericin~B have limited their use.
`
`Abstract
`
`I | r
`
`In humans, fungal infections can be classified
`
`into three broad groups: superficial, subcutaneous
`and systemic (see Garberl”). Superficial infec-
`tions of keratinised tissues such as nails and
`
`hair are usually by dermatophytes. whereas
`mucous membranes are most frequently infected
`by Candida spp. A variety of organisms cause sub-
`cutaneous infections, which are usually acquired
`by traumatic inoculation. The most serious life-
`threatening fungal infections are systemic. In some
`geographical locations systemic fungal infec-
`tions are endemic, such as histoplasmosis in
`the Mississippi valley. However,
`immuno-
`compromised patients worldwide are at risk of
`systemic infection from commensal and ubiquitous
`
`species, primarily Candida spp. and Aspergillus
`spp.
`
`The recent increase in the number of patients at
`risk of systemic fungal infections (patients with
`HIV, cancer patients receiving intensive chemo-
`therapy)”4| has highlighted the need for effective
`therapy of fungal infections. Some superficial fun-
`
`gal infections can be treated or prevented with top-
`ical antifungal agents but others require systemic
`treatment with oral antifungals. Systemic infec-
`tions are treated with orally and intravenously ad-
`ministered agents. Here we discuss the use and po-
`tential of the three classes of antifun gal agents used
`most frequently — polyenes, azoles and allylamines
`(table I).
`
`Page 3 of 15
`
`

`

`14
`Meis Er VermcijW
`
`Table I. Selected properties of antifungal agents
`
`Drug
`Polyene macrolldes
`Amphotericln-B
`
`Nystatin
`
`Altylamlnes
`Terbinafine
`
`Imldazolel
`Ketoconazole
`
`Miconazole
`
`Spectmm ol actwtty
`
`Properties/lormulattons
`
`Candida spp., Aspergillus spp. and other filamentous fungi.
`life-threatening infections with the endemic fungi
`Coccidioides immiiis. Histoplasma capsulatum and
`Blastomyces dermatitidis
`Fteports of resistance in non-albrcans Candida sop,
`
`Candida spp, and Aspergiilus spp.
`
`Candida spp.‘ Aspergiilus spp.. dermatophytes and
`dimorphic tungi
`
`Candida spp., all comatophytes. Maiassezia rut-fur,
`B. darrnatitidis. C. immitis. H. capsulaium. Paracoccidroides
`brasiliensis and Phialophora spp.
`NOT Aspergillus spp.
`C. albrbens. Pseudallescheria boydii, Mr iurfurand all
`common dermatophytes
`NOT Aspergillus spp.
`
`Delivered topically or systemically, most
`frequently used in IV form tor treatment of
`systemic fungal infections: oral tablets used
`mainly to treat thrush and gastrointestinal
`candidiasis; conventional formulations are
`nephrotmric; lipid-associated lormulations have
`reduced nephrotoxicity
`Oral formulation used for topical treatment of
`oropharyngeal candidiasis
`
`Topical and oral formulations used in treatment
`of cutaneous and nail dematophyte infections;
`llpOphlllC and accumulates in skin. hair. sebum
`and nail plate
`
`Oral formulations previously used in treatment
`of systemic infections: largely supplanted by
`other azote antitungals
`
`Available as topical cream. oral gel and N
`formulation; parenteral lorrn rarely used.
`because of toxicity
`
`Trtezoles
`Fluconazole
`
`ltraconazole
`
`Cryptoooccus spp. and many Candida spp., including
`C. albicans
`NOT Aspergillus spp. or some non-albrbans Candida spp..
`9.9. C. glabrara and C. krusei
`Reports ol resistance
`
`Water-soluble oral capsules (or tablets).
`suspension or IV lormulation used extensively
`ln prophylaxis; treatment of choice for
`muoocutaneous candidiasis in neutrOpenic
`patients and one of the preferred treatments for
`oral candidiasis in patients with Hill inlection
`Candida spp, Aspergiilus app. 5. dermaiiiidis.
`Oral capsules taken with food; oral (taken
`H. capsulatum. Cryprocoocus spp.. C. immitis. Trichophyfm
`before food) and JV solution have improved
`spp.. Sporoihrix schenckii. Penicillium mameffei and
`bloavallability; drug of choice for some rare
`F! brasiliensis
`fungal infections; valuable for prophylaxis and
`Reports of resistance in Asperyillus iumigatus
`treatment at systemic lungat intectlons;
`lipophilic and accumulates in keratinous tissue
`IV = intravenous.
`
`t. Antltungof Agents
`
`1 .t Polyenes
`
`The most frequently used polyene macrolides
`are amphotericin-B and nystatin. These drugs act
`by binding to ergosterol in cell membranes (fig. 1),
`increasing permeability. disrupting metabolism
`and causing cell deathfi' Both amphotericin-B and
`nystatin have a broad spectrum of activity against
`most species of Candida and Aspergillus.
`Amphotericin-B has been available for more
`than 40 years and exists in a variety of formula-
`tions: however. because the oral bioavailability of
`amphotericin—B is less than 5%!“ the oral formu-
`
`lations are essentially topical agents for the treat~
`ment or prevention of oral or intestinal colonisa-
`tion. Intravenous formulations of amphotericinFB
`are used in the management of systemic fungal
`infections.
`
`Nystatin also has low oral bioavailability and is
`generally used only as a topical treatment for
`thrush or in preventing colonisation with Candida
`albicans in the gum”
`
`1.2 Allylomlnes
`
`The allylamine terbinafine inhibits squalenc
`epoxidasc (an enzyme involved in ergosterol syn’
`thesis; fig. 1), which results in ergosterol depletion.
`
`-: Ads International Limited All rights reserved.
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`Page 4 of 15
`
`

`

`gement of Fungal Infections
`
`epoxide
`
`Squalene
`
`7 mbrane disruption and cell death}BI Terbinafine
`. activity against dermatophytes. low activity
`‘*_ 'nst Aspergt'llus spp. and other filamentous
`f. a
`but limited activity against Candida spp. The
`_ g is registered for topical and oral treatment of
`: eous and nail dermatophyte infections”I and.
`‘ause terbinafine is lipophilic and keratino-
`r lic. it accumulates in sebum. hair and nails. Ter-
`
`afine has been used alone or in combination
`amphotericin-B or azoles for the treatment of
`sive fungal infectionsm' but no controlled
`I. dies have been published.
`
`v 1.3 Azoles
`
`HO
`
`Lanoatero!
`
`\
`
`H0
`
`Wmmymnwem’
`
`H0
`
`\
`
`Zymosterol
`
`. i
`
`Facosterol
`
`1
`
`IW
`
`Fig. 1. Ergosterol synthesis pathway and points of inhibition by
`antifungal agents.
`
`- The azole antifungals are synthetic compounds
`7'; inhibit the fungal cytochrome P450 (CYP)
`'-
`-demethylase (fig. l);ll ' 1 this results in a deple-
`3‘.- of ergosterol and a loss of membrane integrity
`6 activity. The azoles are divided into imidazoles
`Tn triazoles on the basis of their chemical struc-
`- e and clinical effectiveness.
`
`1.3.! Imidazotos
`
`'
`
`_ Miconazole has potent antifungal activity but is
`= ctive againstAspergillus spp.. and its insolubil-
`restricts its use. Ketoconazole has a spectrum
`activity similar to that of miconazole. When in-
`: need 20 years ago. ketoconazole was the first
`‘ ally absorbable antifungal azole (bioavailability
`
`: topical cream. Ketoconazole is primarily used for
`I
`-
`topical
`treatment of superficial yeast and
`rmatophyte infections.
`' Miconazole and ketoconazole have been largely
`pplanted by the triazoles in the treatment of
`s' rious fungal infections.
`
`1.3.2 Moles
`
`‘
`
`l
`
`ltraconazole and fluconazole are the only sys—
`'
`t‘mic triazole antifungal agents currently avail-
`ible. Itraconazole has a broad spectrum of antifun-
`“; activity against Candida spp.. Aspergiflus spp.
`iand dermatophytes: it accumulates in keratinous
`tissue. such as hair and nails, and is widely used
`for the treatment of fungal nail infections. In ad—
`dition. itraconazole is orally absorbed and accu-
`
`OMhtemflondLh-flad Mutantsresewed
`
`Drugs2m|1bl5tppll
`
`Page 5 of 15
`
`

`

`16
`Mats (‘3 Vfrweij
`__——————_u——u———-u—-—u—_-_—__
`
`mulates in organs that are frequent sites for sys-
`temic fungal infections (such as the spleen and
`lungs).“31 and can therefore be used to treat and
`prevent a variety of systemic fungal infections
`(see Boogaerts and Maertens “41). The bioavaila-
`bility and clinical efficacy of itraconazole for
`systemic infections have recently been improved
`with the development of oral solution and intrave-
`nous (lV) formulations (see De Beule and Van
`Gesteli'sl).“6'
`
`Fluconazoie has a narrower spectrum of anti-
`fungal activity than itraconazole;
`it
`is inactive
`against Aspergilius spp. and some species of Can-
`dida. Despite this. fluconazole is still used widely
`for the prophylaxis of systemic fungal infections
`and the treatment of confirmed systemic Candida
`infections in immunocompromised patients. Flu-
`conazole is also an effective treatment for crypto~
`coccal meningitis in patients with AIDSJ”I and is
`effective in preventing relapse when given as sec-
`ondary prophylaxisl'al Fluconazole has oral bio-
`availability of approximately 90% and can also be
`used to treat mucosal and cutaneous candidiasis.
`
`Because, like itraconazole. fluconazole accumu-
`
`lates in fingernails and toenails. it can also be used
`to treat onychomycosis.“9-3"'
`
`1.4 Other Agents
`
`Griseofulvin acts by binding to microtubular
`proteins and inhibiting fungal cell mitosis.
`
`Griseofulvin is effective only against dermato-
`phytes and is indicated for the treatment of derm-
`atophytoses of the skin. hair or nails when other
`treatments are considered inappropriate.
`Flucytosine is a synthetic fluorinated pyrimi—
`dine that disrupts DNA and RNA synthesis. It has
`a narrow spectrum of activity and is largely used in
`combination with amphotericin—B for the treatment
`of cryptococcal meningitis or deep candidiasislz”
`
`2. Treatment of Superficial
`Fungal Infections
`
`infections often produce
`fungal
`Superficial
`characteristic lesions. and a combination of clinical
`
`observation and laboratory investigation usually
`provides an accurate diagnosis.
`
`2.1 Dermoiophy’rosis
`
`Fungal infections of the skin. nails and hair are
`
`usually caused by dennatophytes. Tinea corporis,
`tinea cruris. tinea pedis and tinea manuum are man-
`
`aged with administration of topical imidazoles or
`allylamines for 2 to 4 weeks; generally, more than
`80% of patients are curedlzz'z‘” However, when the
`infections are extensive or when topical treatment
`
`fails. an oral antifungal agent is required. Treat-
`
`ment for 1 week with itraconazole capsules 200 to
`400 mgiday or for 2 to 4 weeks with terbinafine 250
`
`mg/day is usually effective.i25'3“' The choice of
`
`first-line treatment for tinea capitis is less well de-
`
`fined; oral itraconazole capsules or terbinafine may
`be preferred to tepical imidazoles. in a recent small
`trial. week-12 cure rates were 86% and 78% with
`
`respec-
`
`itraconazole capsules and terbinafine,
`tively.'3”
`Most cases of tinea unguium and other fungal
`infections of the nails (onychomycosis) can be
`treated effectively only with the oral administra-
`tion of itraconazole. terbinafine or to a lesser extent
`
`fiuconazoleJm Terbinafine 250 mg/day is usually
`administered for 6 or 12 weeks for the treatment of
`
`fingernail or toenail onychomycosis, respectively.
`These regimens provide mycological cure rates of
`88% in fingernails and 82% in toenails.[33'35]
`Therapeutic concentrations of itraconazole can
`be detected in the nail 6 to 9 months after therapy
`
`is stopped?“ This has led to the development of
`pulse therapy.
`in which itraconazole capsules
`400 mg/day are administered for only 1 week each
`month, repeated twice for fingernail onycho-
`mycosis and 3 times for toenail onychomycosis.
`The advantages of a pulse therapy regimen include
`reduced costs and improved complianceJ-‘Tl Com-
`parative trials of continuous terbinafine therapy
`and itraconazole pulse therapy have given contra-
`dictory resultsl33‘403
`
`r6 Adls Internationai timited. Ali rights reserved.
`
`omgsaticn;m.sunpl1
`
`Page 6 of 15
`
`

`

`3 : gement of Fungal Infections
`
`17
`
`_ 2.2 Superficial Condidiosis
`
`treat-
`infections require oral
`Candida nail
`n ntzlf” a 6-week course of itraconazole capsules
`II to 400 mg/day or 3 cycles of pulse therapy
`“ ch cycle consists of 1 week of drug therapy fol-
`;wed by 3 weeks with no therapy) with itra—
`'nazole capsules 400 mglday are effective (my-
`:ological and clinical cure rates of more than
`3 %).l41'43l Other superficial Candida infections,
`h as vaginal, penile and cutaneous candidiasis
`_Spond well to topical treatment with nystatin or
`: l imidazole, or oral treatment with itraconazole
`«a fluconazoie.
`
`Oral candidiasis in immunocompetent patients
`'_ an be controlled with topical imidazoles or a 2— to
`3 -week course of amphotericin-B oral suspension
`:r nystatin oral suspension. However, in neutro-
`n nic cancer patients and patients with HIV infec—
`tion, treatment with topical agents is associated
`with a high relapse rate and oral antifungals are
`referredJ‘Ml Oral fluconazole (tOO to 200 mg/day
`or 2 weeks) has proven efficacy in treating oral
`candidiasis (48% of patients mycologically cured;
`4% of patients clinically cured),l45] but flucona-
`zole-resistant candidiasis is frequently reported
`during prolonged exposure in patients with HIV
`infection or chronic mucocutaneous candidia-
`sis,l46'431 and fluconazole is ineffective against
`some species of Candida. Itraconazole capsules
`(200 mg/day for 2 to 4 weeks) are effective against
`oral and oesophageal candidiasis (40% of patients
`mycologically cured; 74% of patients clinically
`'cured),[491 but absorption of the capsule formula-
`‘tion can be variable in patients with HIV and
`IItiypochlorhydria. Itraconazole oral solution has
`lreliable absorption and greater bioavailability
`‘ than the capsule,[5°-5” and is at least as effective as
`’ fluconazole in immunocompromised patients with
`oral candidiasis (mycological cure rates of 88%
`. and 77% for itraconazole oral solution and flu-
`
`'conazole, respectively; clinical response rate of
`97% and 87% for itraconazole oral solution and
`
`fluconazole, respectively).[521 In addition, most pa-
`tients with fluconazole-refractory oral candidiasis
`
`respond to treatment with itraconazole oral solu-
`tion (200 mgfday for 2 weeks).l53'551
`
`3. Management of Systemic
`Fungal Infections
`
`Systemic fungal infections are life threatening
`and affect immunoeompromised people, such as
`patients with HIV, bone marrow transplant recipi—
`ents, patients with haematological malignancies
`and solid organ transplant recipients. Diagnosis of
`systemic fungal
`infections is difficult because
`symptoms are not specific and can be confused
`with those of bacterial infections. viral infections
`
`or the underlying condition, or with complications
`of treatment (see Garber' ' 1).
`
`Although diagnostic techniques for systemic
`fungal infections are improving, prophylaxis and
`empirical treatment continue to play a key role in
`the management of systemic fungal infections. The
`poor prognosis associated with systemic fungal in-
`fections means that chemoprophylaxis is fre-
`quently administered to patients at high risk and
`empirical therapy is initiated without proof of in-
`fection — usually when the patient has persistent
`fever of unknown origin that is unresponsive to
`broad spectrum antibiotics. Both approaches can
`result in the prolonged administration of antifungal
`agents to high-risk patient groups.
`
`3.1 Endemic Infections
`
`Most endemic mycoses are treated with amphe—
`tericin-B or itraconazole (table II). Ketoconazole
`
`may also be effective for treating immuno-
`competent patients with non—life-threatening
`histoplasmosis. blastomycosis or paracoccidioido—
`mycosisJ56] but fluconazole has relatively poor ef-
`ficacy against endemic mycoses.
`Itraconazole is recommended for the treatment
`
`of many endemic mycoses and as maintenance
`therapy in immunocompromised patients. Life-
`threatening histoplasmosis and blastomycosis may
`require intravenous treatment. such as with ampho-
`tericin—BJ57'53] However, oral itraconazole 100 to
`400 mg/day for at least 6 months is the usual
`
`© Adis International Limited. All rights reserved
`
`Drugs 2901;61 Suppl. I
`
`Page 7 of 15
`
`

`

`l8
`Mars 8 Verrueij
`
`Table II. First-choice therapies [Or endemic and other myooses
`
`Fungal infection
`Blastomycosis
`Lite-threatening and CNS
`Mild or moderate
`
`Histoplasmosis
`Life—threatening and CNS
`Mild or moderate
`
`Maintenance therapy in
`immunooompromised
`Histoplasma dubor'sr'r'
`intactan
`Paraceccidioidomycosis
`Coccidioidomycosis
`Lite-threatening
`
`Mild or moderate
`
`Maintenance therapy in
`immunocompromisad
`lmmunocompetent and
`non-meningeal
`lmmunooornpetent and
`meningeal
`
`Panicfliium memeffei
`
`Sporotrichosis
`Lymphocutaneous
`Wsoeral
`Severe disseminated
`Chromoblastomyoosis
`CNS = central nervous system.
`
`First-choice therapy
`
`Amphoten'cin-B (1 mg/kgiday)
`ltraeonazote (£00 mtg/day)
`
`Amphoterieln-B (1 mgfkg/day)
`ltraconazola (2200 mg/day)
`Itraconazole (400 mg/day)
`
`lttaconazole (100400 mgfday)
`
`ltraconazole (2 100 mg/day)
`
`Amphoten'cin-B {1 -1 .25
`"talks/day)
`Azoles (400 mglday}
`Azolas at recommended dose
`
`ltraoonazole (400 mgiday; >1
`year)
`Flueonazoie (2400 mg/day; lite)
`or itraconazole (400 mglday:
`lite)
`Amphotericln-B (20.6
`mglkg/dayl than ltmoonazole
`(2200 maiden
`
`ltraconazole (200 mglday)
`Itraoonazole (400 mglday)
`Amphotencin-B (1 mglkglday)
`Itraoonazole (100-200 mg/day)
`
`first-line treatment
`for
`Histopl‘asma duboisii.[56'
`Itraconazole capsules (2200 mglday for up to 6
`
`infections caused by
`
`months) are the treatment of choice for paracoc-
`
`cidioidomycosis and ketoconazole or amphoteri-
`cin-B are the best alternatives.l5°' The most effec-
`
`tive therapeutic strategy for coccidioidomycosis in
`immunocompetent hosts is unclear: amphotericin-
`
`B, itraconazole capsules. ketoconazole and flu—
`conazole have all been tested in clinical trials. with
`
`Similar results.'56-59'6” However, a recent compar-
`ison of itraconazolc capsules 400 mglday with
`
`fluconazole 400 mglday suggested that itracona-
`
`zole may be more effective in the treatment of
`
`progressive nonmeningeal coccidioidomycosis,
`particularly skeletal infectionsml In immuno-
`
`compromised patients, amphotcricin-B may be the
`first choice for treatment of coccidioidomycosis,
`although the potential benefit of itraconazole has
`not been tested.”"' In diffuse interstitial pneumo-
`nia, amphotericin-B is the most effective treat-
`ment. and in coccidioidal meningitis high dose
`fluconazole (400 to 1000 rag/day) has been recom-
`mendedJ‘m although itraconazole 400 mglday may
`be as effective)“
`
`In general. initial treatment with itraconazole
`capsules or amphotericin-B followed by itracon-
`azole capsules are the recommended treatments for
`other rare endemic mycoses ( table II).
`
`3.2 Aspergillosis and Deep Condidiosis
`
`The most frequently encountered systemic fun-
`gal infections of immunocompromised patients are
`those caused by species of Candida or Aspergr'llus.
`The various formulations of amphoten'cin-B and
`itraconazole are the most effective antifungal
`agents for the treatment and prevention of these
`systemic infections (table 111). Fluconazole is effec-
`tive only for the management of infections by sus—
`ceptible species of Candida, such as C. albicans,
`and C. parapsilosis.
`
`3.2. l Chemaprophylaxis
`Prophylaxis of systemic fungal infections is
`usually given when patients are considered to be at
`a particular risk of infection — for example. bone
`marrow transplant recipients.
`in addition. pre—
`emptive therapy is frequently given; this is anti-
`fungal prophylaxis in patients who have some evi-
`dence of infection but who do not meet the usual
`
`criteria for definitive diagnosis or for initiating em—
`pirical therapy.
`Because of its poor oral absorption, amphe-
`tericin-B is an ineffective prophylactic agent for
`systemic fungal infection. The use of low dose IV
`amphotericin-B (<1 mglkg/day) is associated with
`breakthrough infections,165~6"l and infusion-related
`adverse events and renal toxicity restrict the use of
`higher doses of amphotericin—B.
`The superior safety profiles of the triazole anti-
`fungals have made them the most widely used
`drugs in the prophylaxis of systemic fungal infec-
`
`*0 Ads lnterncrtlcnol Limited All rights reserved,
`
`Dmgszooi; at Supp“
`
`Page 8 of 15
`
`

`

`-
`
`.. : ement of Fungal Infections
`
`19
`
`'-
`
`_ Ill. Management options for systemic fungal infections
`
`w:
`"'__u ylaxisl‘
`
`{till treatmnl
`
`rmed candidiasis
`
`Options
`Itraconazole oral solution (5 mg/kg/day)
`Fluoonazole capsules (50-400 mg/day)
`Conventional amphotericin-B (0.6-1 mg/kg/day for 14 days or until resolution oi symptoms)
`Amphotartcin-B-Iiposomal (3 mgfkg/day for 14 days or until resolution of symptoms)
`ABLG (5 mglkg/day for 14 days or until resolution of symptoms)
`ABCD (4 mg/kg/day for 14 days or until resolution of symptoms)
`IV itraoonazole (400 mglday for 2 days followed by 200 mg/day for 14 days or until resolution of
`symptoms)
`IV fluoonazole (400 mgi'day) tor 3—7 days followed by capsules (400 mg/day until resolution of
`symptoms)°
`Conventional amphoterioin—B (0.6«1 mglkg/day until resolution of symptoms)
`AELC (5 mg/kglday until resolution of symptoms)
`IV itraconazole (400 mg/day until resolution of symptoms)‘3
`Oral itraconazole (400 mglday tor 14 days or more)
`Conventional amphotericin-B (1-1.5 mg/kglday for at least 14 days or until recovery of
`granulocytes and resolution of symptoms)
`Amphotericin-El-Iiposomal (3 mgfkg/day for at least 14 days or until recovery of granuiocy‘tes and
`resolution of symptoms)
`ABLC (5 mgfkglday for at least 14- days or until recovery of granulocytes and resolution of
`symptoms)
`ABCD (4 mgfkgr'day ior at least 14 days or until recovery of granulocytes and resolution of
`symptoms)
`1V itraconazole (400 mg/day for 2 days lollowed by 200 mglday for at least 14 days or until
`recovery ot granulocytes and resolution of symptoms)
`Value only established in selected patient groups (bone marrow transplant patients. high risk liver transplant patients. selected high risk
`neutropenic patients with haematological malignancy, and those with previously documented Invasive Aspergillus or other mould
`infection who are undergoing further courses of chemotherapy).
`- No clinical data.
`
`‘
`
`‘
`‘
`
`rrned aspergillosis
`
`'34.
`;
`
`I Only for infections by Candida spp. shown to be susceptible to fluoonazole.
`.2 LC = amphotericin-B-lipid—complex: ABCD = amphotericin—B—ooltoidal dispersion; IV = intravenous.
`
`_
`
`ons. Prophylaxis often requires long term anti-
`-'7'
`I gal administration and the ease of use of oral
`rmulations makes them a preferred option. How-
`. or, some patients at high risk have severely im-
`fe aired swallowing or are unconscious or intubatcd
`d can only be given intravenous agents.
`The high oral bioavailability of fluconazolc and
`ts availability in intravenous and oral formula-
`ons have led to the widespread use of this agent.
`' uconazolc has been shown to reduce the inci-
`
`ence of systemic C. albicans infections.l‘57-63] but
`‘t may be less effective in some high-risk patient
`groups, such as patients with acute leukaemia
`Jmudergoing remission-induction therapy or inten-
`.sive rescue therapy.l69-70] The most
`important
`'Weakness of fluconazole as a prophylactic agent is
`
`its narrow spectrum of activity; in some trials the
`
`predominance of Aspergillus infections in flu—
`conazole-trsatcd patients has highlighted this
`weaknessmJ Similarly, fluconazole does not offer
`protection against non—albicans Candida infec-
`tions; a concern surrounding the prophylactic use
`of fluconazolc is
`the potential
`increase in
`fluconazolc-rcsistant Candida spp. and increased
`colonisation by C. krusei and C. glabratal72'75]
`The broad spectrum of activity and good safety
`profile of itraconazolc make it an attractive choice
`for chemoprophylaxis. The capsule formulation is
`successful in preventing systemic fungal infec-
`tionsl75‘73] and at a dosage of 200 rug/day is as ef-
`fcctive as fluconazole (100 mgl’day).[7"l The ab—
`sorption of the itraconazole capsule formulation
`
`may be variable in patients with damage to the
`intestinal epithelium or with reduced gastric acid—
`
`© Adis Intornotlonol Umrled. All rlghts reserved.
`
`Drugs 2001:61 Suppl.
`
`1
`
`Page 9 of 15
`
`

`

`20
`Ma's Er Venom]
`W
`
`
`
`
`
`ity.“‘”"“ll An itraconazole oral solution. with its en-
`hanced bioavailability, has overcome the limita-
`tions of the capsule formulation and is effective in
`the prophylaxis of systemic fungal infections in
`neutropenic patientsm‘flsl In a placebo-controlled
`trial, itraconazole oral solution reduced the number
`of cases of invasive candidiasis but had no effect
`
`on the incidencc of invasive aspergillosisJW How-
`ever, in a comparative trial with oral fluconazole.
`itraconazole oral solution reduced the number of
`
`cases of aspergillosis.'37'
`Clearly, many patients at risk of systemic fungal
`infections are receiving co—medications. Because
`the azole antifungals are metabolised by CYP3A.
`they can interact with other drugs metabolised by
`this enzyme. In solid organ transplant or bone mar-
`row transplant recipients, the interaction between
`azoles and cyclosporin is the most significantJas-SL”
`but elevated plasma concentrations of cyclosporin
`can be managed by routine monitoring and reduc-
`ing the dosage as necessary. In patients with HIV
`infection, itraconazole may interact with protease
`inhibitors (by inhibiting CYP3A)[9OJ and flucona—
`zole may interact with the HIV reverse trans«
`criptase inhibitor zidovudine (by inhibiting
`glucuronidation)Jag-"132‘ As with the co-adminis-
`[ration of cyclosporin. blood concentration moni-
`toring and dosage reduction may be advisable
`when azoles and some anti-HIV drugs are used
`concurrently. In patients with HIV. the HIV prote-
`ase inhibitor saquinavir has low bioavailability,
`and it has been suggested that the addition of
`itraconazole may increase saquinavir plasma con-
`centrations and ultimately improve anti-HIV effi-
`cacy.'93l
`
`3.2.2 Empirical Hemman
`
`Empirical treatment is usually initiated in im-
`munocompromised patients with persistent fever
`of unknown origin (4 to 7 days) that is unrespon-
`sive to broad spectrum antibiotics or when pulmo-
`nary infiltrates or cavities are detected by com-
`puted tomography (CT) scan.
`
`Amphotericin-B has been the first-choice treat-
`ment for systemic fungal infections for several
`years. A significant benefit (reduced death rate
`
`from fungal infection and a decrease in clinically
`documented infection) is seen in patients receiving
`IV amphotericin-li’..["4i The broad spectrum of ac-
`tivity of amphotericin-B has been the key to its
`success in empirical therapy. but the use of higher
`doses — which could be more effective — is pre-
`vented by infusion-related adverse events (nausea.
`fever and chills) and renal toxicity.
`The triazole antifungal agents are the best alter-
`native to amphoteriein-B for empirical therapy.
`However, there have been no large-scale clinical
`trials comparing trlazoles with amphotericin-B for
`empirical
`therapy. Both fluconazole and im-
`conazole capsules have shown equivalence to am-
`photericin~B in small—scale clinical trials,195-9“ al-
`though fluconazole is useful only in the treatment
`of confirmed deep candidiasis. and even then only
`when the isolate is shown to be susceptible to
`fluconazole. Confirmed aspergillosis has been
`treated with success with high doses of IV ampho-
`tericin-Bm-“l or oral itraconazole.l99"m] Acombi-
`
`nation