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Echinocandins: a Promising New Antifungal Group G Educational Forum Echinocandins: A promising new antifungal group G. K. Randhawa, G. Sharma Department of ABSTRACT Pharmacology, Echinocandins are a new option for fungal infections. They are fungicidal and less toxic to the host Government Medical β College, Amritsar, by virtue of their novel mechanism of action. They are -1, 3-glucan synthase inhibitors. FDA, USA Punjab, India. has approved caspofungin for treatment of invasive aspergillosis in patients who fail to respond or are unable to tolerate other antifungals. Two other agents are in phase III clinical trials – micafungin Received: 31.3.2003 and anidulafungin. Caspofungin among echinocandins has been studied vastly and offers apparent Revised: 4.8.2003 exciting advantages of a broad spectrum of activity including strains of fungi resistant to other Accepted: 29.9.2003 antifungal agents, tolerability profile, with no nephrotoxicity and hepatotoxicity as compared to azole and macrolide antifungals. It may be effective in AIDS-related candidal esophagitis, oropha- Correspondence to: ryngeal candidiasis, fungal pneumonia and nonmeningeal coccidioidomycosis. Clinical trials are G. K. Randhawa required to ascertain their safety in special groups—pediatric, pregnant and nursing mothers. 338-‘D’ Block, Echinocandins provide an exciting option for combination therapy with other antifungals in fulmi- Ranjit Avenue, Amritsar - 143001, India. nant fungal infections. E-mail: [email protected] KEY WORDS: Caspofungin, glucan synthase inhibitor, fungal infections. Introduction Cell wall-acting agents are a new class of antifungals with a novel mechanism of action and are inherently selective and The incidence of severe, invasive and opportunistic fungal fungicidal in nature. Three classes of such compounds, tar- infections in immunocompromised patients like those treated geted respectively to β-1, 3-glucan synthase (echinocandins- with immunosuppressive drugs, intensive chemotherapy, in a derivative of pneumocandin B0), chitin synthase (nikkomycins) organ transplant recipients, AIDS patients and very low birth and mannoproteins (pradimicins/benanomicins), were ex- weight infants, is increasing at an alarming rate.1,2 Mortality plored for clinical development. Amongst them, echinocandins among infected patients may be as high as 75-100%, present- (caspofungin acetate, micafungin and anidulafungin) have ing an enormous challenge for healthcare providers.3 The most emerged as potentially clinically useful entities.8 common fungal pathogens are Candida and Aspergillus spp.4 Recent epidemiological trends indicate a shift towards infec- Diagnostic procedures tions with Aspergillus spp., non-albicans Candida spp. and previously uncommon fungi with decreased sensitivity to an- Evolving new diagnostic procedures for fungal infections tifungal agents.1,5- 7 would be helpful in early diagnosis and prevention of disease, There has been a dramatic increase in the armamentarium hence better and timely management of fungal infections with for fungal infections in the past one decade. Antifungal drugs decreased mortality. The clinical diagnosis is difficult based for serious infections are either fungistatic (fluconazole, upon symptoms, which are non-specific and similar to those itraconazole, i.e. azoles) and vulnerable to resistance or fun- of bacterial and viral infections. Previously used methods such gicidal (amphotericin B - polyene macrolide) but toxic to the as direct microscopic examination of clinical samples and se- host. A newer option, echinocandins are fungicidal and are rological tests have limited success. Improvements in diag- less toxic to the host by virtue of their novel mechanism of nostic procedures like high-resolution computed tomography,9 action. Antifungal agents with different mechanisms of action polymerase chain reaction10 and enzyme-linked immuno- and different adverse effect profiles have opened up new av- sorbent assay11 for invasive pulmonary aspergillosis have lim- enues for combination therapy to combat potentially life-threat- ited definitive prognostic value. A standardized method for ening diseases. testing the in vitro susceptibility of yeasts (NCCLS- National Targets for action of antifungal agents are given in Table 1. Committee for Clinical Laboratory Standards- the M27A pro- Indian J Pharmacol | April 2004 | Vol 36 | Issue 2 | 65-71 65 Randhawa GK, et al. Table 1 Targets for action of antifungal agents Target Specific target Antifungal group Antifungal agents 1. Cell wall Mannoprotein Pradimicin/benanomicin BMS-181184 β-glucan synthase Echinocandin Caspofungin (CAS) Micafungin (MICA) Anidulafungin (ANIDU) Chitin synthase – Nikkomycin 2. Cell membrane Ergosterol Polyene antibiotic Amphotericin B (AMB) Azole derivatives Clotrimazole Ketoconazole Miconazole Fluconazole (FLUC) Itraconazole (ITRA) Voriconazole Posiconazole Ravuconazole Allylamines/thiocarbamates Terbinafine Naftifine Fluoropyrimidine Flucytosine (FC) 3. Cytoplasm Protein synthesis Aminoacyl tRNA synthetase inhibitors: EF-3 inhibitors – 4. Nucleus DNA – Pentamidine tocol)12 and filamentous fungi13 to current antifungal agents azoles) that exert their effect on the fungal cell membrane, by Broth Dilution method has been developed. Other methods echinocandins block the synthesis of β (1,3)-d-glucan, a include the use of fluorescent dyes like 5, (6)-carboxyflourescein homopolysaccharide component of the cell wall in many patho- diacetate (CFDA) and bis-(1, 3-dibutylbarbituric acid) genic fungi.21 The rope-like glucan fibrils and chitin impart trimethine oxonol (DiBAC) to stain dead and live mycotic cells strength and shape to the cell wall and play an important role for in vitro testing.14 Diagnostic strategies to detect circulat- in cell division and cell growth.22,23 This process has no coun- ing antigens and polymerase chain reaction based detection terpart in mammalian eukryotic cells. CAS causes in vitro con- systems have been explored to improve identification prior to centration-dependent cell death i.e., fungicidal, in yeasts and the progressive advanced disease.15 The definitive diagnosis dimorphic fungi such as Candida albicans. Its effect on As- of invasive aspergillosis is based on showing the hyphal inva- pergillus fumigatus is less well understood, possibly by killing sion in tissue specimens together with a positive culture for the cells at the active centers for new cell wall synthesis within Aspergillus species from the same specimen. For early diag- A. fumigatus hyphae when they are exposed to CAS. The mini- nosis of aspergillosis, detection of circulating fungal antigens mal inhibitory concentrations (MIC) and minimal fungicidal and DNA seems to be a promising, rapid and sensitive diag- concentrations (MFC) for echinocandins are low for a broad nostic tool.16 spectrum of fungi. H N Caspofungin acetate (MK-991, formerly L-743, 872) 2 NH OH O O It is a glucan synthase inhibitor and is the first of a new H O N class of semi-synthetic, water-soluble lipopeptide antifungals. H NH CAS is approved for the treatment of invasive aspergillosis in H N N O H C patients who fail to respond or are unable to tolerate other 2 H N 3 O OH CH CH antifungal drugs. This is the indication due to which fast-track 3 3 H O O CH3 approval was granted by the Food and Drug Administration NH (FDA) in the USA in 2001.17 It may also be effective in AIDS- H N O OH 18 N related candidal esophagitis, oropharyngeal candidiasis, fun- H O gal pneumonia19 and nonmeningeal coccidioidomycosis.20 O Echinocandins are cyclic hexapeptides. The chemical struc- OH ture of CAS is given in Figure 1. Mechanism of action H O CASPOFUNGIN Unlike currently available agents (polyenes, pyrimidines, Figure 1: Chemical structure of CAS 66 Indian J Pharmacol | April 2004 | Vol 36 | Issue 2 | 65-71 Echinocandins Spectrum of activity Adverse effects CAS has a broad spectrum of antifungal activity both in The most commonly reported adverse effects with CAS are vitro and in vivo. It is active against Aspergillus spp. like A. histamine-type reactions like fever and rash, infusion-related fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans reactions including phlebitis, transient elevations in liver and Candida spp. (the most common cause of nosocomial transaminase levels,30 headache, nausea and anemia. Facial fungal infections) like C. albicans, C. glabrata, C. krusei and flushing has occurred during infusion. In animals, it has been C. tropicalis, including non-albicans species and isolates found to be embryotoxic. Pulmonary infiltrates and resistant to other drugs. In animals, it also has activity hypercalcemia are two serious drug-related adverse events against the cyst form of Pneumocystis carinii.24 The drug reported.26 In a study of 623 patients, no serious clinical or has little or no activity against Cryptococcus neoformans25 laboratory drug-related adverse event was noted.30 Compara- or Mucor spp. tively, CAS has been related with significantly fewer drug-re- In an animal model of coccidioidal meningitis (Coccidioides lated adverse events than AMB, hence better tolerated.24, 31 immitis), it was found that CAS might have a role in the treat- ment of progressive nonmeningeal coccidioidomycosis.20 Comparative studies with other antifungals (Table 2) Pharmacokinetics In vitro studies: In a study, the activities of FLUC, ITRA, AMB and CAS were compared against 178 blood stream Can- In humans, CAS is not absorbed from the gastrointestinal dida spp. isolates from cancer patients. CAS was found to be tract, therefore
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