Echinocandins: A promising new antifungal group

Transcription

1 Educational Forum Echinocandins: A promising new antifungal group G. K. Randhawa, G. Sharma Department of Pharmacology, Government Medical College, Amritsar, Punjab, India. Received: Revised: Accepted: Correspondence to: G. K. Randhawa 338- D Block, Ranjit Avenue, Amritsar , India. gkkullar@rediffmail.com ABSTRACT Echinocandins are a new option for fungal infections. They are fungicidal and less toxic to the host by virtue of their novel mechanism of action. They are β-1, 3-glucan synthase inhibitors. FDA, USA 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 and anidulafungin. Caspofungin among echinocandins has been studied vastly and offers apparent exciting advantages of a broad spectrum of activity including strains of fungi resistant to other 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, oropharyngeal candidiasis, fungal pneumonia and nonmeningeal coccidioidomycosis. Clinical trials are required to ascertain their safety in special groups pediatric, pregnant and nursing mothers. Echinocandins provide an exciting option for combination therapy with other antifungals in fulminant fungal infections. KEY WRDS: Caspofungin, glucan synthase inhibitor, fungal infections. Introduction The incidence of severe, invasive and opportunistic fungal infections in immunocompromised patients like those treated with immunosuppressive drugs, intensive chemotherapy, in organ transplant recipients, AIDS patients and very low birth weight infants, is increasing at an alarming rate. 1,2 Mortality among infected patients may be as high as %, presenting an enormous challenge for healthcare providers. 3 The most common fungal pathogens are Candida and Aspergillus spp. 4 Recent epidemiological trends indicate a shift towards infections with Aspergillus spp., non-albicans Candida spp. and previously uncommon fungi with decreased sensitivity to antifungal agents. 1,5-7 There has been a dramatic increase in the armamentarium for fungal infections in the past one decade. Antifungal drugs for serious infections are either fungistatic (fluconazole, itraconazole, i.e. azoles) and vulnerable to resistance or fungicidal (amphotericin B - polyene macrolide) but toxic to the host. A newer option, echinocandins are fungicidal and are less toxic to the host by virtue of their novel mechanism of action. Antifungal agents with different mechanisms of action and different adverse effect profiles have opened up new avenues for combination therapy to combat potentially life-threatening diseases. Targets for action of antifungal agents are given in Table 1. Cell wall-acting agents are a new class of antifungals with a novel mechanism of action and are inherently selective and fungicidal in nature. Three classes of such compounds, targeted respectively to β-1, 3-glucan synthase (echinocandinsa derivative of pneumocandin B 0 ), chitin synthase (nikkomycins) and mannoproteins (pradimicins/benanomicins), were explored for clinical development. Amongst them, echinocandins (caspofungin acetate, micafungin and anidulafungin) have emerged as potentially clinically useful entities. 8 Diagnostic procedures Evolving new diagnostic procedures for fungal infections would be helpful in early diagnosis and prevention of disease, hence better and timely management of fungal infections with decreased mortality. The clinical diagnosis is difficult based upon symptoms, which are non-specific and similar to those of bacterial and viral infections. Previously used methods such as direct microscopic examination of clinical samples and serological tests have limited success. Improvements in diagnostic procedures like high-resolution computed tomography, 9 polymerase chain reaction 10 and enzyme-linked immunosorbent assay 11 for invasive pulmonary aspergillosis have limited definitive prognostic value. A standardized method for testing the in vitro susceptibility of yeasts (NCCLS- National Committee for Clinical Laboratory Standards- the M27A pro- 65

2 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 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 fungi 13 to current antifungal agents by Broth Dilution method has been developed. ther methods include the use of fluorescent dyes like 5, (6)-carboxyflourescein diacetate (CFDA) and bis-(1, 3-dibutylbarbituric acid) trimethine oxonol (DiBAC) to stain dead and live mycotic cells for in vitro testing. 14 Diagnostic strategies to detect circulating antigens and polymerase chain reaction based detection systems have been explored to improve identification prior to the progressive advanced disease. 15 The definitive diagnosis of invasive aspergillosis is based on showing the hyphal invasion in tissue specimens together with a positive culture for Aspergillus species from the same specimen. For early diagnosis of aspergillosis, detection of circulating fungal antigens and DNA seems to be a promising, rapid and sensitive diagnostic tool. 16 azoles) that exert their effect on the fungal cell membrane, echinocandins block the synthesis of β (1,3)-d-glucan, a homopolysaccharide component of the cell wall in many pathogenic fungi. 21 The rope-like glucan fibrils and chitin impart strength and shape to the cell wall and play an important role in cell division and cell growth. 22,23 This process has no counterpart in mammalian eukryotic cells. CAS causes in vitro concentration-dependent cell death i.e., fungicidal, in yeasts and dimorphic fungi such as Candida albicans. Its effect on Aspergillus fumigatus is less well understood, possibly by killing the cells at the active centers for new cell wall synthesis within A. fumigatus hyphae when they are exposed to CAS. The minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) for echinocandins are low for a broad spectrum of fungi. Caspofungin acetate (MK-991, formerly L-743, 872) It is a glucan synthase inhibitor and is the first of a new class of semi-synthetic, water-soluble lipopeptide antifungals. CAS is approved for the treatment of invasive aspergillosis in patients who fail to respond or are unable to tolerate other antifungal drugs. This is the indication due to which fast-track approval was granted by the Food and Drug Administration (FDA) in the USA in It may also be effective in AIDSrelated candidal esophagitis, oropharyngeal candidiasis, 18 fungal pneumonia 19 and nonmeningeal coccidioidomycosis. 20 Echinocandins are cyclic hexapeptides. The chemical structure of CAS is given in Figure 1. N H 2 H 2 N H H H N NH N H N H NH N H H N H NH CH 3 H 3 C H H CH 3 CH 3 Mechanism of action Unlike currently available agents (polyenes, pyrimidines, H CASPFUNGIN Figure 1: Chemical structure of CAS 66

3 Echinocandins Spectrum of activity CAS has a broad spectrum of antifungal activity both in vitro and in vivo. It is active against Aspergillus spp. like A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans and Candida spp. (the most common cause of nosocomial fungal infections) like C. albicans, C. glabrata, C. krusei and C. tropicalis, including non-albicans species and isolates resistant to other drugs. In animals, it also has activity against the cyst form of Pneumocystis carinii. 24 The drug has little or no activity against Cryptococcus neoformans 25 or Mucor spp. In an animal model of coccidioidal meningitis (Coccidioides immitis), it was found that CAS might have a role in the treatment of progressive nonmeningeal coccidioidomycosis. 20 Pharmacokinetics In humans, CAS is not absorbed from the gastrointestinal tract, therefore it is not available for oral administration. The proposed susceptibility breakpoint for CAS against Candida spp. is a MIC of 1 µg/ml. Plasma concentration at 1 and 24 hours is mg/l and 1.19 mg/l with an area under the plasma concentration curve of mg/l.h. It has a volume of distribution of 9.67 L, is extensively bound to albumin (97%), has a plasma elimination half-life of 9 to 11 hours and is metabolized by peptide hydrolysis and N-acetylation to inactive metabolites in the liver. 26 It is not metabolized by the CYP450 enzyme system. 19 Hepatic metabolism is the primary route of excretion with kidneys eliminating less than 2% of the unchanged drug. Hepatotoxicity is not observed at therapeutic concentrations used in humans but was seen at substantially higher doses. In elderly volunteers (>65 years), there was a moderate increase in plasma concentrations after a single dose of 70 mg when compared with healthy (<45 years) volunteers, thereby suggesting that there might not be any need to adjust dosage in elderly patients. Its dosage need not be adjusted in renal insufficiency and mild hepatic disease, though use of CAS in severe hepatic disease has not been studied. 26 The exposure of the small intestine, lung and spleen to CAS was similar to that of plasma, while exposure of the heart, thigh and brain was lower than that of plasma. 27 When combined with other antifungal agents, CAS produces a synergistic or additive effect against a variety of clinically important fungi, though it needs further evaluation. 28 Efficacy CAS is as effective as AMB for the treatment of invasive candidiasis and more specifically, candidemia. In a doubleblind trial in 224 patients, the efficacy of CAS was similar to that of AMB with successful outcomes in 73.4% of the patients treated with CAS and in 61.7% of those treated with AMB. CAS was superior, with a favorable response in 80.7% of patients, as compared with 64.9% of those who received AMB. CAS was as effective as AMB in patients who had candidemia (favorable response in 71.7% and 62.8% of patients, respectively). 29 Adverse effects The most commonly reported adverse effects with CAS are histamine-type reactions like fever and rash, infusion-related reactions including phlebitis, transient elevations in liver transaminase levels, 30 headache, nausea and anemia. Facial flushing has occurred during infusion. In animals, it has been found to be embryotoxic. Pulmonary infiltrates and hypercalcemia are two serious drug-related adverse events reported. 26 In a study of 623 patients, no serious clinical or laboratory drug-related adverse event was noted. 30 Comparatively, CAS has been related with significantly fewer drug-related adverse events than AMB, hence better 24, 31 tolerated. Comparative studies with other antifungals (Table 2) In vitro studies: In a study, the activities of FLUC, ITRA, AMB and CAS were compared against 178 blood stream Candida spp. isolates from cancer patients. CAS was found to be the most active agent (MIC mg/l) against C. albicans, C. glabrata and C. tropicalis. It also showed substantial activity against azole-susceptible and azole-resistant Candida. 32 In another study, the activities of FLUC, AMB and CAS against biofilms were compared by the time-kill method. CAS displayed the most effective pharmacokinetic profile with 99% killing, while FLUC was ineffective against C. albicans biofilms, and killing of biofilm cells was suboptimal at therapeutic concentrations of AMB. 33 The activities of CAS and ANIDU were evaluated alone and in combination with FLUC using time-kill methods against isolates of Candida albicans, C. glabrata, C. tropicalis, C. krusei and Cryptococcus neoformans in one study. Combinations of FLUC and CAS or ANIDU showed indifferent results but also did not produce any antagonistic activity. 34 In one study CAS and ANIDU were compared with ITRA, FLUC, AMB and FC against 400 bloodstream isolates of Candida spp. obtained from >30 different medical centers. Both CAS and ANIDU were very active against all Candida spp. isolates (MIC 90, 0.25 and 1 µg/ml, respectively). CAS was 2 to 256-fold more active than ITRA, FLUC, AMB (except against C. parapsilosis) and FC (except against C. glabrata and C. parapsilosis). ANIDU was comparable to CAS, but was 4-fold less active against C. tropicalis and C. parapsilosis. All the isolates for which FLUC and ITRA had elevated MICs ( 64 and 1 µgm/ml, respectively) were inhibited by 0.5 µg/ml of CAS and ANIDU. These results suggest that both CAS and ANIDU possess promising antifungal activity. 35 In a study the in vitro activity of ANIDU, CAS, ITRA, AMB and FC was investigated against 51 clinical isolates of filamentous fungi, including A. flavus (10), A. fumigatus (12), Fusarium spp. (13), Rhizopus spp. (6), Pseudallescheria boydii (5) and one isolate each of Acremonium spp., A. niger, A. terreus, Paecilomyces spp. and Trichoderma spp. ANIDU was 2 to 4-fold more active than CAS against A. flavus, A. fumigatus and Trichoderma spp. Both ANIDU and CAS were considerably more active (MIC 90 of µg/ml) than ITRA, AMB and FC against Aspergillus spp., but were less active than ITRA and AMB against Rhizopus spp. CAS was more active than 67

4 Randhawa GK, et al. Table 2 Comparison of caspofungin with other antifungal agents Studies CAS compared with various antifungal agents Results In vitro studies 1. Roling et al, 2002 CAS and ANIDU alone / in combination with FLUC Indifferent but not antagonistic against Candida and Cryptococcus neoformans 2. Laverdiere et al, 2002 FLUC, ITRA, AMB CAS most active against C. albicans, C. glabrata, C. tropicalis Active against azole-sensitive and azole-resistant strains 3. Ramage et al, 2002 FLUC, AMB Against C. albicans biofilms CAS most effective FLUC ineffective AMB suboptimal effect 4. Marco et al, 1998 CAS and ANIDU with ITRA, FLUC, AMB, FC CAS and ANIDU more active against Candida spp. than other agents 5. Pfaller et al, 1998 CAS and ANIDU with ITRA, AMB, FC CAS and ANIDU showed promising activity against Aspergillus & other filamentous fungi spp. In vivo studies 1. Mora-Duarte et al, 2002 With AMB in invasive candidiasis (against A. fumigatus, Similar effects in patients of candidemia A. flavus, A. niger, A. terreus) Fewer ADRs with CAS No antagonism between CAS and AMB Some synergistic / additive effect between CAS and AMB 2. Villaneuva et al, 2002 With FLUC in candidal esophagitis in HIV patients CAS as effective as FLUC CAS better tolerated than FLUC 3. Villaneuva et al, 2001 With AMB in candidal esophagitis CAS as effective as AMB CAS better tolerated than AMB ANIDU or ITRA against Acremonium spp., Paecilomyces spp. and P. boydii. Therefore, ANIDU and CAS showed promising activity against Aspergillus spp. and other species of filamentous fungi. 36 In vivo studies: In a double-blind trial involving 224 patients, CAS and AMB deoxycholate were compared for the primary treatment of invasive candidiasis. 29 A modified intention-to-treat analysis showed that the efficacy of CAS and AMB was similar with successful outcomes in 73.4% and 61.7% respectively. CAS was as effective as AMB in patients who had candidemia with a favorable response in 71.7% and 62.8% of patients, respectively. There were significantly fewer drug-related adverse events with CAS than with AMB. No antagonism between them was seen against A. fumigatus, A. flavus, A. niger and A. terreus in vitro, although some synergistic additive activity was observed. 29 A double-blind randomized, multicentric trial was conducted to assess the efficacy, safety and tolerability of CAS and AMB in adults with symptomatic Candida esophagitis. By using modified intenton-to-treat analysis, endoscopically verified clinical success was achieved in 74% and 89% of patients receiving CAS 50 and 70 mg/day, respectively and in 63% of patients receiving AMB 0.5 mg/kg/day. Therapy was stopped due to drug-related adverse events in 24% of patients on AMB and in 4% and 7%, of patients who received CAS 50 and 70 mg/day respectively. CAS appears to have similar efficacy and better tolerability than AMB for the treatment of esophageal candidiasis. 37 In a double-blind randomized trial, the efficacy and safety of CAS (50 mg) was compared with FLUC (200 mg, i.v.) in adult patients with candida esophagitis. Eighty-seven per cent patients in this modified intention-to-treat analysis had HIV infection (median CD4 count of 30 cells/mm). C. albicans was the predominant isolate in this study. Favorable response rates were seen in 81% patients with CAS and in 85% patients with FLUC. By the fifth day of treatment, symptoms resolved in >50% patients with both agents. Therapy was discontinued in 1 patient (receiving FLUC) due to a drug-related adverse event. Symptoms recurred 4 weeks after stopping the drugs in 28% patients given CAS and in 17% patients given FLUC (P = 0.19). 38 Pre-clinical and clinical studies show that combinations of echinocandin with azoles and AMB do not produce antagonistic effects, rather may produce synergistic effects against pathogenic fungi The usefulness of such combinations is emerging in invasive aspergillosis management. 42 Therefore, combinations of these agents may warrant future clinical evaluation. Drug interactions CAS is not metabolized by the CYP450 enzyme and due to its different clearance mechanism it interacts minimally with other drugs. Co-administration with cyclosporine increased its plasma levels by 35% and caused transient liver transaminase abnormalities. Concurrent treatment with efavirenz, nelfinavir, phenytoin, dexamethasone, rifampicin and carbamazepine may require increasing dosage of CAS. It decreases serum levels of tacrolimus by about 20-25% when the two are co-administered. It does not interact with AMB or 68

5 Echinocandins mycophenolate mofetil. No interactions have been reported with oral ITRA (200 mg/day for 14 days). 26 Resistance A genetic study in the yeast model of Saccharomyces cerevisiae has shown that mutations in FKS1 and FKS2 genes result in CAS resistance. The SBE2 cdna plasmid conferred galactose-dependent CAS resistance when transformed back into the wild-type S. cerevisiae. The SBE2 deletion mutant was hypersensitive to CAS. Therefore, over expression of SBE2p under the regulated control of GAL1 promoter may result in CAS resistance in S. cerevisiae. This transport pathway may provide insight into the tolerance/ lack of sensitivity to CAS by some pathogenic fungi. 43 Fungal melanins might protect C. neoformans and H. capsulatum from the effects of AMB and CAS. 44 Dosage The recommended dosage of CAS in adults is 70 mg, i.v. on Day 1 followed by 50 mg/d given as a single dose over one hour with the duration of treatment depending on the severity of the patient s underlying condition and the clinical response. Dose adjustment based on age, sex, race or renal function does not appear to be necessary, although patients with moderate hepatic insufficiency should receive a lower maintenance dose. Moreover, it is an expensive agent costing $ 9,875 (about Rupees 4.5 lakhs) for an average treatment cycle (34 days) in a dosage of 50 mg daily. 17 Micafungin (FK-463; [MICA]) It is a new lipopeptide echinocandin with a broad-spectrum in vitro and in vivo antifungal activity, against both Aspergillus and Candida species. The mechanism of action is similar to CAS. MICA exhibits potent activity against Aspergillus species. It is also active against the dematiaceous fungi Cladosporium trichoides, Exophiala spinifera, Fonsecaea pedrosoi, and Exophiala dermatitidis except for certain clinical isolates. However, it had no activity against Fusarium solani, Pseudallescheria boydii, and the zygomycetes Absidia corymbifera, Cunninghamella elegans, Rhizopus oryzae and Rhizopus microsporus var. rhizopodiformis. Hence, MICA has potential utility for the treatment of infections caused by the Candida and Aspergillus species and dematiaceous fungi. 45 Pharmacokinetics After administration of a single (0.5 and 2 mg/kg, i.v.) dose of MICA to rabbits, the mean peak plasma drug concentrations were 7.62 and 16.8 µg/ml respectively, the area under the concentration-time curve from 0 to 24 hours ranged from 5.66 to µg x h/ml, the apparent volume of distribution at steady state ranged from to L/kg and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in the pharmacokinetic parameters and no accumulation were noted after multiple dosing. Thirty minutes after the last of eight daily doses, mean tissue MICA concentrations were highest in the lungs (2.26 to µg/g), liver (2.05 to 8.82 µg/g), spleen (1.87 to 9.05 µg/g) and kidney (1.40 to 6.12 µg/g). While MICA was not detectable in the cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 µg/g. Therapeutic drug concentrations in plasma and tissues can be achieved at 0.5 to 2 mg/kg dosage of MICA at common sites of invasive fungal infections. 46 Safety and efficacy In one study, MICA was well tolerated by the mice and was much more effective than AMB or FLUC against an AMB and FLUC-resistant C. tropicalis specimen at a dose of 2-10 mg/ kg body weight. 47 MICA appears to be a promising agent for invasive fungal infections but requires further clinical evaluation. It is in phase III clinical trials. Anidulafungin (LY303366; [ANIDU]) It is a new echinocandin with promising broad-spectrum, antifungal activity in vitro and in vivo with a mechanism of action similar to CAS. Spectrum of activity It exhibited prominent activity against Candida species including C. glabrata and C. Krusei but showed little activity against Cryptococcus neoformans. 25 Promising activity of ANIDU against Aspergillus spp. and other species of filamentous fungi has also been seen clinically. 36 The activity of ANIDU in vitro was significantly superior (P <0.05) to that of ITRA and FLUC against C. albicans, C. tropicalis, C. glabrata and C. krusei, but was less against C. famata and C. parapsilosis. 48 Efficacy In one study, there was no relationship between FLUC and ANIDU MICs for C. albicans or non-albicans species. For all isolates, geometric mean (GM) MIC values (in mg/l) were: ANIDU , FLUC -8.72, FC , AMB C. parapsilosis and C. guilliermondii were found to be significantly less susceptible to ANIDU than all other species (P 0.05). For all isolates, GM MFC values (in mg/l) were: ANIDU and AMB The in vitro activities of ANIDU, ITRA and AMB were assessed against 60 Aspergillus isolates, including isolates of A. fumigatus (35), A. terreus (8), A. flavus (8), A. niger (8) and A. nidulans (1). MFCs were 0.018, and mg/l for ANIDU, ITRA and AMB, respectively. ANIDU was fungicidal in 86.7% isolates (98% killing). In comparison, ITRA and AMB were fungicidal for 35% and 70% of isolates respectively (99.99% killing). 50 In a temporarily neutropenic murine model of invasive aspergillosis against AMB-susceptible (AMB-S) and AMB-resistant (AMB-R) A. fumigatus isolate based on in vivo response, 4 doses (1, 2.5, 10, and 25 mg/kg of body weight) of ANIDU were compared with AMB (0.5 to 5 mg/kg). AMB at 0.5 mg/kg and ANIDU at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AMB-S or 69

6 Randhawa GK, et al. AMB-R isolates. AMB at other dosages yielded a 70 to 100% survival rate for mice infected with AMB-S and 10 to 30% survival rate for mice infected with AMB-R (P = 0.01 to 0.04 compared with AMB-S). Against both isolates, ANIDU at 2.5, 10 and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as AMB for AMB-S, but superior to AMB for AMB-R (P < 0.03 to ). For AMB-R, ANIDU at 10 and 25 mg/kg/day was superior to AMB at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003) and for AMB- S, AMB at 5 mg/kg/day and at 5 mg/kg in 4 doses was more effective than all 4 regimens of ANIDU in reducing renal culture counts (P = 0.01 to ). ANIDU appears to be effective against AMB-susceptible and -resistant A. fumigatus infection in this model. 51 Therefore, ANIDU might have efficacy similar to CAS, FLUC, FC, ITRA and AMB. 35,36 Combinations of FLUC and CAS or ANIDU showed indifferent results but also did not produce any antagonistic activity. 34 Thus, by virtue of its novel mechanism of action, it can be tried in combination with other antifungal agents for severe fungal infections. ANIDU is in phase III clinical trials and needs more clinical evaluation on efficacy, safety and tolerability factors. Current status CAS among echinocandins has been studied vastly and offers apparent exciting advantages of a broad spectrum of activity including strains of fungi resistant to other antifungal agents, tolerability profile, with almost no nephrotoxicity and hepatotoxicity. Although additional studies are needed, CAS appears to be a promising agent for the treatment of patients with difficult-to-treat or life-threatening fungal infections and is FDA approved. Clinical trials are required to ascertain the safety of echinocandins in special groups pediatric, pregnant and nursing mothers. ANIDU and MICA are in phase III clinical trials. Echinocandins thus provide an exciting option for combination therapy with other antifungal agents in fulminant fungal infections. References 1. Groll AH, Shah PM, Mentzel C, Schneider M, Just-Nuebling G, Huebner K. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996;33: Denning DW, Evans EGV, Kibbler CC, Richardson MD, Roberts MM, Rogers TR, et al. Guidelines for the investigation of invasive fungal infections in hematological malignancy and solid organ transplantation. British Society for Medical Mycology. Eur J Clin Microbiol Infect Dis 1997;16: Meyers JD. Fungal infections in bone marrow transplant patients. Semin ncol 1990;17: Arathoon EG. Clinical efficacy of echinocandin antifungals. Curr pin Infect Dis 2001;14: Viscoli C, Girmenia C, Marinus A, Collette L, Martino P, Vandercam B, et al. Candidemia in cancer patients: A prospective, multicentre surveillance study by the Invasive Fungal Infection Group (IFIG) of the European rganization for Research and Treatment of Cancer (ERTC). Clin Infect Dis 1999;28: Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillous infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997;175: Groll AH, Walsh TJ. Uncommon oppurtunistic fungi: New nosocomial threats. Clin Microbiol Infect 2001;7: Georgopapadakou NH. Update on antifungals targeted to the cell wall: focus on beta-1,3-glucan synthase inhibitors. Expert pin Investig Drugs 2001;10: Cailot D, Casasnovas, Bernard A, Couaillier JF, Durand C, Cuisenier B, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin ncol 1997;15: Einsele H, Hebart H, Roller G, Loffler J, Rothenhofer I, Muller CA, et al. Detection and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol 1997;35: Maertens J, Verhaegen J, Demuynck H, Brock P, Verhoef G, Vandenberghe P, et al. Autopsy controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme linked immunosorbent assay for hematological patients at risk for invasive Aspergillosis. J Clin Microbiol 1999;37: NCCLS. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard. NCCLS document M27A. NCCLS Wayne, PA; NCCLS. Proposed reference method for broth dilution antifungal susceptibility testing of filamentous fungi. NCCLS document M28-P. NCCLS, Wayne, PA; Bowman JC, Hicks PS, Kurtz MB, Rosen H, Schmatz DM, Liberator PA, et al. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother 2002;46: Pound MW, Drew RH, Perfect JR. Recent advances in the epidemiology, prevention, diagnosis, and treatment of fungal pneumonia. Curr pin Infect Dis 2002;15: Perea S, Patterson TF. Invasive Aspergillus infections in hematologic malignancy patients. Semin Respir Infect 2002;17: Abramowicz M, Zuccotti G, Rizack MA, Goodstein D, Faucard A, editors. The Medical Letter. Caspofungin (Cancidas) for Aspergillosis Vol 43. p Stone EA, Fung HB, Kirschenbaum HL. Caspofungin: An echinocandin antifungal agent. Clin Ther 2002;24: Groll AH, Walsh TJ. Anti-fungal chemotherapy: Advances and perspectives. Swiss Med Wkly 2002;132: Deresinski SC. Coccidioidomycosis: Efficacy of new agents and future prospects. Curr pin Infect Dis 2001;14: Pacetti SA, Gelone SP. Caspofungin acetate for treatment of invasive fungal infections. Ann Pharmacother 2003;37: Denning DW. Echinocandins and Pneumocandins a new anti fungal class with a novel mode of action. J Antimicrob Chemother 1997;40: Kurtz MB, Douglas CM. Lipopeptide inhibitors of fungal glucan synthase. J Med Vet Mycol 1997;35: Morrison VA. The role of caspofungin and the echinocandins in the antifungal armamentarium. Curr pin Investig Drugs 2002;3: Krishnarao TV, Galgiani JN. Comparison of the in vitro activities of the echinocandin LY303366, the pneumocandin MK-0991 and fluconazole against Candida species and Cryptococcus neoformans. Antimicrob Agents Chemother 1997;41: Keating GM, Jarvis B. Caspofungin. Drugs 2001;61: Hajdu R, Thompson R, Sundelof JG, Pelak BA, Bouffard FA, Dropinski JF, et al. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743, 872). Antimicrob Agents Chemother 1997;41: Leather H, Wingard J. Caspofungin - a viewpoint. Drugs 2001;61: Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347: Sable CA, Nguyen BY, Chodakewitz JA, DiNubile MJ. Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transpl Infect Dis 2002;4: Kartsonis N, DiNubile MJ, Bartizal K, Hicks PS, Ryan D, Sable CA. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J Acquir Immune Defic Syndr 2002;31: Laverdiere M, Restieri C, Habel F. Evaluation of the in vitro activity of caspofungin against bloodstream isolates of Candida species from cancer patients: comparison of E test and NCCLS reference methods. Int J Antimicrob Agents 2002;20: Ramage G, VandeWalle K, Bachmann SP, Wickes BL, Lopez-Ribot JL. In vitro pharmacodynamic properties of three antifungal agents against preformed Candida albicans biofilms determined by time-kill studies. Antimicrob Agents 70

7 Echinocandins Chemother 2002;46: Roling EE, Klepser ME, Wasson A, Lewis RE, Ernst EJ, Pfaller MA. Antifungal activities of fluconazole, caspofungin (MK0991), and anidulafungin (LY ) alone and in combination against Candida spp. and Crytococcus neoformans via time-kill methods. Diagn Microbiol Infect Dis 2002;43: Marco F, Pfaller MA, Messer SA, Jones RN. Activity of MK-0991 (L-743, 872), a new echinocandin, compared with those of LY and four other antifungal agents tested against blood stream isolates of Candida spp. Diagn Microbiol Infect Dis 1998;32: Pfaller MA, Marco F, Messer SA, Jones RN. In vitro activity of two echinocandin derivatives, LY and MK-0991 (L-743, 792), against clinical isolates of Aspergillus, Fusarium, Rhizopus, and other filamentous fungi. Diagn Microbiol Infect Dis 1998;30: Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001;33: Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 2002;113: Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrob Agents Chemother 2001;45: Chiou CG, Groll AH, Walsh TJ. New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. ncologist 2000;5: De Pauw BE, Donnelly JP, Verweij PE, Meis JFGM. Current management of fungal infections in immunocompromised patients and polyene lipid complexes for treatment of invasive fungal infection. J Infect Dis Antimicrob Agents 1998;15: Rubin MA, Carrol KC, Cahill BC. Caspofungin in combination with Itraconazole for the treatment of invasive aspergillosis in humans. Clin Infect Dis 2002;34: sherov N, May GS, Albert ND, Kontoyiannis DP. verexpression of Sbe2p, a Golgi protein, results in resistance to caspofungin in Saccharomyces cerevisiae. Antimicrob Agents Chemother 2002;46: van Duin D, Casadevall A, Nosanchuk JD. Melanization of Cryptococcus neoformans and Histoplasma capsulatum reduces their susceptibilities to amphotericin B and caspofungin. Antimicrob Agents Chemother 2002;46: Nakai T, Uno J, tomo K, Ikeda F, Tawara S, Goto T, et al. In vitro activity of FK463, a novel lipopeptide antifungal agent, against a variety of clinically important moulds. Chemotherapy 2002;48: Groll AH, Mickiene D, Petraitis V, Petraitiene R, Ibrahim KH, Piscitelli SC, et al. Compartmental pharmacokinetics and tissue distribution of the antifungal echinocandin lipopeptide micafungin (FK463) in rabbits. Antimicrob Agents Chemother 2001;45: Warn PA, Sharp A, Morrissey G, Denning DW. In vivo activity of micafungin in a persistently neutropenic murine model of disseminated infection caused by Candida tropicalis. J Antimicrob Chemother 2002;50: Arevalo MP, Carrillo-Munoz AJ, Salgado J, Cardenes D, Brio S, Quindos G, et al. Antifungal activity of the echinocandin anidulafungin (VER002, LY ) against yeast pathogens: A comparative study with M27-A microdilution method. J Antimicrob Chemother 2003;51: Moore CB, akley KL, Denning DW. In vitro activity of a new echinocandin, LY303366, and comparison with fluconazole, flucytosine and amphotericin B against Candida species. Clin Microbiol Infect 2001;7: akley KL, Moore CB, Denning DW. In vitro activity of the echinocandin antifungal agent LY303, 366 in comparison with itraconazole and amphotericin B against Aspergillus spp. Antimicrob Agents Chemother 1998;42: Verweij PE, akley KL, Morrissey J, Morrissey G, Denning DW. Efficacy of LY against amphotericin B-susceptible and -resistant Aspergillus fumigatus in a murine model of invasive aspergillosis. Antimicrob Agents Chemother 1998;42: TH ANNUAL CNFERENCE INDIAN PHARMACLGICAL SCIETY Date : 14th-16th January, 2005 Venue : Science City, Kolkata rganized by: rganizing Vice-Chairperson: West Bengal Branch S. K. Bandopadhyay Indian Pharmacological Society Head Department of Pharmacology, IPGME&R, Kolkata Secretariat: Department of Pharmacology, rganizing Secretary: Institute of Postgraduate Medical T. K. Mondal Education & Research (IPGME&R), Reader & Head Department of Pharmacology, 244B Acharya J. C. Bose Road, West Bengal University of Animal& Kolkata Fisheries Sciences, ipgmer_2004@yahoo.com Kolkata