SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC INFECTIONS

AMPHOTERICIN B (fungicidal; antifungal agent w/ the broadest spectrum of action)

SOURCE Streptomyces nodosus
CHEMISTRY - amphoteric polyene macrolide (polyene = containing many double bonds; macrolide = containing a large
lactone ring of 12 or more atoms)
- active against C. albicans, Cryptococcus neoformans; the organisms causing endemic mycoses, including
Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis; and the pathogenic molds,
such as Aspergillus fumigatus and the agents of mucormycosis.
FORMULATIONS 1) amphotericin B + sodium deoxycholate – colloidal suspension formulation (IV injection) bcs ampho B is
insoluble in H20
2) Fungizone – conventional formulation; as micelles
3) AmBisome, Amphotec, Abelcet – lipid formulations; as spheres, disks, and ribbons, respectively
Note: Lipid forms have lower toxicity thus higher doses can be used
PCOKINETICS - poorly absorbed from the GIT
- oral formulation is effective only for local treatment (e.g. fungi w/in the lumen of the tract)
- IV infusion drug is >90% protein-bound; half-life is ~15 days
- widely distributed; 2-3% reaches CSF
- drug is mostly metabolized; excreted slowly in urine
- no dose adjustment is required in ptx w/ hepatic impairment, renal impairment, and dialysis
PCODYNAMICS -
MOA Forms pores in fungal membranes (Loss of intracellular contents through pores is fungicidal)
RESISTANCE Candida lusitaniae and Pseudallescheria boydii are resistant
CLINICAL USES alternative TX for fungal CNS infections (intrathecal), those that have not responded with other agents
systemic fungal infections (slow IV infusion)
all-life threatening mycotic infections
TX against Cryptoccocus, Coccidioides, Histoplasma, Aspergillus, Blastomyces (CCHAB)
initial induction therapy for chronic therapy or prevention of relapse for immune suppressed patients,
those with severe fungal pneumonia, severe cryptococcal meningitis, histoplasmosis or coccidioidomycosis
(w/ is followed by maintenance therapy w/ azoles)
mycotic corneal cancers, keratitis (topical drops; direct subconjunctival injection)
fungal arthritis (adjunctive local joint injection)
candiduria (bladder irrigation w/ no significant systemic toxicity
Localized and systemic candidemia
ADVERSE INFUSION-RELATED TOXICITIES CUMULATIVE TOXICITIES
EFFECTS  fever, chills, muscle spasms, vomiting,  Nephrotoxicity
headache, and hypotension o renal damage/renal impairment – most significant
Tips To Prevent: o decreased renal perfusion (prerenal renal failure;
 slow the infusion rate or decreasing the reversible)
daily dose o renal tubular injury and dysfunction (irreversible)
 Premedication with antipyretics, o damaged renal tubular cells
antihistamines, meperidine, or  results to anemia due to reduced
corticosteroids erythropoietin production
 administer a test dose of 1 mg IV (serve o renal tubular acidosis (common manifestation)
as a guide to an initial dosing regimen o severe K and Mg wasting (common manifestation)
and premedication strategy) o sodium loading
 Administer normal saline infusions w/ daily
doses of amphotericin B.
 Neurotoxicity (from intrathecal administration)
o seizures
o chemical arachnoiditis
 Abnormalities of liver function tests
 FLUCYTOSINE (5-FC)
SOURCE Discovered through searching for novel antineoplastic agents
CHEMISTRY - water-soluble pyrimidine analog related to the chemotherapeutic agent 5-fluorouracil (5-FU)
- has narrower spectrum than Ampho B; only active against C neoformans, some Candida sp, and the
dematiaceous molds that cause chromoblastomycosis.
FORMULATIONS - PO
PCOKINETICS - well absorbed; poorly protein bound; penetrates well to all body tissues including the CSF
- eliminated via kidneys; toxicity occurs in renal insufficiency and in ptx w/ AIDS
- drug can be removed by hemodialysis
MOA
RESISTANCE
CLINICAL USES rarely used as single agent to avoid secondary resistance and because it acts on synergism w/ other agents
fluconazole-resistant candidal urinary tract infections (monotherapy)
cryptoccous and chromoblastomycosis infections
+ Amphoteric B: cryptococcal meningitis
+ Itraconizole: chromoblastomycosis
ADVERSE Note: A/E are most likely due to its toxic metabolite: Fluorouracil (a toxic antineoplastic compound). The use
EFFECTS of drug concentration measurements may be helpful in reducing the incidence of toxic reactions,
 Bone marrow toxicity/Myelosupression (most common)
o w/ anemia, leukopenia, and thrombocytopenia
 Derangement of liver enzymes (less common)
 Toxic enterocolitis

AZOLES (synthetic compounds)

Classified according to the # of nitrogen atoms in the five-membered azole ring
1) Imidazoles: ketoconazole, miconazole, and clotrimazole
2) Triazoles: itraconazole, fluconazole, voriconazole, isavuconazole, and posaconazole. Others are currently under investigation
Ketoconazole (first oral azole)
PCOKINETICS - greater propensity to inhibit mammalian cytochrome P450 enzymes
- less/poorly selective for fungal P450 than are the newer azoles.
PCODYNAMICS - Interferes with steroid hormone synthesis and phase I drug metabolism
CLINICAL USES - has fallen out of clinical use; no longer recommended for the treatment of fungal nail or skin infections
Itraconazole
CHEMISTRY - active against Aspergillus Sp, Candida, Cryptococcus, Blastomycosis, Coccidioidomycosis,, And
Histoplasmosis
FORMULATIONS - PO (liquid and capsules) and IV; 100-400 mg/d
- as liquid: formulated w/ cyclodextrin to enhance solubility and BA
PCOKINETICS - absorption is increased by food and by low gastric pH
- inhibits P450 enzymes to a lesser degree than ketoconazole
- effectiveness can be limited by reduced bioavailability
- penetrates poorly into CSF/CNS
PCODYNAMICS - reduced BA of itraconazole when taken with rifamycins (rifampin, rifabutin, rifapentine)
CLINICAL USES azole of choice for TX of disease due to the dimorphic fungi Histoplasma, Blastomyces, and Sporothrix
used extensively in the TX of dermatophytoses and onychomycosis
has been replaced by voriconazole as the azole of choice for aspergillosis
ADVERSE - low toxicity
EFFECTS
Fluconazole
CHEMISTRY no activity against Aspergillus or other filamentous fungi.
FORMULATIONS - PO and IV; 100-800 mg/d
PCOKINETICS - highly water-soluble; high oral BA
- better GIT tolerance
- good cerebrospinal fluid penetration
- has the least effect of all the azoles on hepatic microsomal enzymes thus less drug interactions
- has the widest therapeutic index of the azoles
RESISTANCE Emergence of fluconazole-resistant fungi
CLINICAL USES azole of choice in the TX and secondary prophylaxis of cryptococcal meningitis
equivalent to amphotericin B in TX of candidemia in ICU patients with normal white blood cell counts
(echinocandins are still superior for this indication)
agent most commonly used for the TX of mucocutaneous candidiasis
as prophylaxis in reducing fungal disease in bone marrow transplant recipients and AIDS patients
ADVERSE
EFFECTS
Voriconazole
CHEMISTRY - similar spectrum w/ itraconazole
- excellent activity against Candida sp (including some fluconazole-resistant species such as Candida krusei)
and the dimorphic fungi
FORMULATIONS - PO and IV; 400 mg/d
PCOKINETICS - well-absorbed orally; BA exceeding 90%,
- less protein binding than itraconazole
- inhibitor of CYP3A4 enzymes
- less toxic than amphotericin B
- Therapeutic trough levels should be between 1 and 5 mcg/mL.
PCODYNAMICS - dose reduction needed under CYP3A4 (cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors)
CLINICAL USES TX of choice for invasive aspergillosis and some environmental molds (Iatrogenic Fungal Meningitis)
ADVERSE  rash
EFFECTS  elevated hepatic enzymes
 photosensitivity dermatitis (via chronic PO therapy)
 visual disturbances (via IV; occur immediately after a dose and resolve within 30 minutes
o blurring
o changes in color vision or brightness;
Posaconazole (broadest-spectrum member of the azole family)
CHEMISTRY - Active against most species of Candida and Aspergillus
- first azole with significant activity against
- the agents of mucormycosis
FORMULATIONS PO (liquid and sustained acting tablet form; higher BA) and IV; 800 mg/d, divided into 2 or 4 doses.
PCOKINETICS - Absorption is improved when taken with meals high in fat
- High tissue levels, low blood levels
- Measurement of posaconazole levels is recommended in patients with serious invasive fungal
- infections (especially mold infections); steady-state posaconazole
- levels should be between 0.5 and 1.5 mcg/mL
PCODYNAMICS Drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine
CLINICAL USES for salvage therapy in invasive aspergillosis
as prophylaxis of fungal infections during induction chemotherapy for leukemia
for allogeneic bone marrow transplant patients with graft-versus host disease.
ADVERSE
EFFECTS
Isavuconazole (Isavuconazonium Sulfate)
SOURCE prodrug of the newest triazole, isavuconazole
CHEMISTRY antifungal spectrum similar to that of posaconazole.
FORMULATIONS PO (capsules) and IV; 2-day loading dose of 372 mg administered every 8 hours followed by single 372-mg
daily dose.
PCOKINETICS - 186 mg of the water-soluble prodrug is equivalent to 100 mg of isavuconazole
- High BA
- Food does not impact absorption
- better tolerated than voriconazole
PCODYNAMICS Coadministration with strong 3A4 inhibitors (eg, ritonavir) or inducers (eg, rifampin) is not recommended.
CLINICAL USES Currently licensed for the TX of invasive aspergillosis and invasive mucormycosis
ADVERSE
EFFECTS
 ECHINOCANDINS (newest class)
Caspofungin, Micafungin, and Anidulafungin
SOURCE
CHEMISTRY - large cyclic peptides linked to a long-chain fatty acid
- active against Candida and Aspergillus, but not C neoformans or the agents of zygomycosis and
mucormycosis.
FORMULATIONS - IV only
PCOKINETICS CASPOFUNGIN MICAFUNGIN ANIDULAFUNGIN
o water soluble o water soluble o water soluble
o highly protein bound o highly protein bound o highly protein bound
o excreted via kidneys and GIT o excreted via kidneys and GIT o excreted via kidneys and GIT
o half-life: 9-11 hrs o half-life: 11-15 hrs o half-life: 24-48 hrs
PCODYNAMICS - Caspofungin + cyclosporine: elevated liver enzymes
- Micafungin: increases levels of nifedipine, cyclosporine, and sirolimus
MOA Prevent fungal cell wall synthesis, disrupt fungal cell wall and causes cell death by inhibiting the synthesis of
β(1–3)-glucan
RESISTANCE Candida glabrata resistance emergence
CLINICAL USES CASPOFUNGIN MICAFUNGIN ANIDULAFUNGIN
disseminated and mucocutaneous candidiasis esophageal candidiasis
mucocutaneous candidal (esophageal candidiasis) invasive candidiasis
infections candidemia candidemia.
empiric antifungal therapy prophylaxis of candida/fungal
during febrile neutropenia infections in bone marrow
(replaced ampho B) transplant patients.
salvage therapy for invasive
aspergillosis in ptx who have
failed to respond to
amphotericin B
ADVERSE  extremely well tolerated
EFFECTS  minor gastrointestinal side effects
 flushing
 increase histamine release (due to Anidulafungin)

ORAL SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS

GRISEOFULVIN
SOURCE - derived from a species of penicillium
CHEMISTRY - fungistatic; keratophilic
- very insoluble
FORMULATIONS - microcrystalline PO form; 1 g/d
PCOKINETICS - absorption is improved w/ fatty foods
- must be administered for
- 2–6 weeks for skin and hair infections to allow the replacement
- of infected keratin by the resistant structures
PCODYNAMICS Drug interactions w/ warfarin and phenobarbital
MOA deposited in newly forming skin where it binds to keratin, protecting/preventing the skin from new infection
CLINICAL USES systemic treatment of dermatophytosis (must be administered for 2–6 weeks for skin and hair infections
to allow the replacement of infected keratin by the resistant structures
largely replaced by newer antifungal medications such as itraconazole and terbinafine.
ADVERSE  allergic syndrome much like serum sickness, serious skin reactions,
EFFECTS  a lupus-like syndrome, hepatotoxicity
 TERBINAFINE
SOURCE - synthetic allylamine
CHEMISTRY - fungicidal; keratophilic
FORMULATIONS - PO; 250 mg/d
MOA - interferes with ergosterol biosynthesis by inhibiting the fungal enzyme squalene epoxidase which leads to
the accumulation of the sterol squalene, toxic to the fungi.
CLINICAL USES treatment of dermatophytoses, especially onychomycosis (more effective than griseofulvin or
itraconazole)
ADVERSE  GIT upset, headache, hepatotoxicity (rare)
EFFECTS

TOPICAL ANTIFUNGAL THERAPY

NYSTATIN
SOURCE - polyene macrolide much like amphotericin B
CHEMISTRY - active against most Candida sp
FORMULATIONS - Topical only (creams, ointments, suppositories, and other forms)
- too toxic for parenteral
- oral form is limited by the unpleasant taste
CLINICAL USES for suppression of local candidal infections
oropharyngeal thrush
vaginal candidiasis
intertriginous candidal infections

TOPICAL AZOLES
Clotrimazole, Miconazole (most commonly used)
Others: Ketoconazole
FORMULATIONS vulvovaginal candidiasis
AND CLINICAL oral thrush (Oral clotrimazole troches, pleasant-tasting alternative to nystatin)
USES dermatophytic infections, including tinea corporis, tinea pedis, and tinea cruris (creams)
seborrheic dermatitis and pityriasis versicolor (topical Ketoconazole and shampoo)
ADVERSE  rare
EFFECTS

TOPICAL ALLYLAMINES
Terbinafine and Naftifine
CLINICAL USES treatment of tinea cruris and tinea corporis