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-

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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 treatment 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 it is not available for oral administration. the most active agent (MIC90 0.19-0.5 mg/l) against C. albi- The proposed susceptibility breakpoint for CAS against Can- cans, C. glabrata and C. tropicalis. It also showed substantial dida spp. is a MIC of ≤1 µg/mL. Plasma concentration at 1 activity against azole-susceptible and azole-resistant Can- and 24 hours is 10.45 mg/L and 1.19 mg/L with an area un- dida.32 der the plasma concentration curve of 104.79 mg/L.h. It has In another study, the activities of FLUC, AMB and CAS a volume of distribution of 9.67 L, is extensively bound to against biofilms were compared by the time-kill method. CAS albumin (97%), has a plasma elimination half-life of 9 to 11 displayed the most effective pharmacokinetic profile with hours and is metabolized by peptide hydrolysis and N-acetyla- ≥ 99% killing, while FLUC was ineffective against C. albicans tion to inactive metabolites in the liver.26 It is not metabo- biofilms, and killing of biofilm cells was suboptimal at thera- lized by the CYP450 enzyme system.19 Hepatic metabolism peutic concentrations of AMB.33 is the primary route of excretion with kidneys eliminating The activities of CAS and ANIDU were evaluated alone and less than 2% of the unchanged drug. Hepatotoxicity is not in combination with FLUC using time-kill methods against iso- observed at therapeutic concentrations used in humans but lates of Candida albicans, C. glabrata, C. tropicalis, C. krusei was seen at substantially higher doses. In elderly volunteers and Cryptococcus neoformans in one study. Combinations of (>65 years), there was a moderate increase in plasma con- FLUC and CAS or ANIDU showed indifferent results but also centrations after a single dose of 70 mg when compared with did not produce any antagonistic activity.34 healthy (<45 years) volunteers, thereby suggesting that there In one study CAS and ANIDU were compared with ITRA, might not be any need to adjust dosage in elderly patients. FLUC, AMB and FC against 400 bloodstream isolates of Can- Its dosage need not be adjusted in renal insufficiency and dida spp. obtained from >30 different medical centers. Both mild hepatic disease, though use of CAS in severe hepatic CAS and ANIDU were very active against all Candida spp. iso- 26 µ disease has not been studied. The exposure of the small lates (MIC90, 0.25 and 1 g/mL, respectively). CAS was 2 to intestine, lung and spleen to CAS was similar to that of 256-fold more active than ITRA, FLUC, AMB (except against C. plasma, while exposure of the heart, thigh and brain was parapsilosis) and FC (except against C. glabrata and C. lower than that of plasma.27 When combined with other anti- parapsilosis). ANIDU was comparable to CAS, but was 4-fold fungal agents, CAS produces a synergistic or additive effect less active against C. tropicalis and C. parapsilosis. All the against a variety of clinically important fungi, though it needs isolates for which FLUC and ITRA had elevated MICs (≥ 64 and further evaluation.28 ≥1 µgm/mL, respectively) were inhibited by ≤ 0.5 µg/mL of CAS and ANIDU. These results suggest that both CAS and Efficacy ANIDU possess promising antifungal activity.35 In a study the in vitro activity of ANIDU, CAS, ITRA, AMB CAS is as effective as AMB for the treatment of invasive and FC was investigated against 51 clinical isolates of candidiasis and more specifically, candidemia. In a double- filamentous fungi, including A. flavus (10), A. fumigatus (12), blind trial in 224 patients, the efficacy of CAS was similar to Fusarium spp. (13), Rhizopus spp. (6), Pseudallescheria boydii that of AMB with successful outcomes in 73.4% of the pa- (5) and one isolate each of Acremonium spp., A. niger, A. tients treated with CAS and in 61.7% of those treated with terreus, Paecilomyces spp. and Trichoderma spp. ANIDU was AMB. CAS was superior, with a favorable response in 80.7% 2 to 4-fold more active than CAS against A. flavus, A. fumigatus of patients, as compared with 64.9% of those who received and Trichoderma spp. Both ANIDU and CAS were consider- µ AMB. CAS was as effective as AMB in patients who had ably more active (MIC90 of 0.03-0.12 g/mL) than ITRA, AMB candidemia (favorable response in 71.7% and 62.8% of pa- and FC against Aspergillus spp., but were less active than ITRA tients, respectively).29 and AMB against Rhizopus spp. CAS was more active than

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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. adult patients with candida esophagitis. Eighty-seven per cent and P. boydii. Therefore, ANIDU and CAS showed promising patients in this modified intention-to-treat analysis had HIV activity against Aspergillus spp. and other species of infection (median CD4 count of 30 cells/mm). C. albicans was filamentous fungi.36 the predominant isolate in this study. Favorable response rates In vivo studies: In a double-blind trial involving 224 pa- were seen in 81% patients with CAS and in 85% patients with tients, CAS and AMB deoxycholate were compared for the pri- FLUC. By the fifth day of treatment, symptoms resolved in mary treatment of invasive candidiasis.29 A modified inten- >50% patients with both agents. Therapy was discontinued in tion-to-treat analysis showed that the efficacy of CAS and AMB 1 patient (receiving FLUC) due to a drug-related adverse event. was similar with successful outcomes in 73.4% and 61.7% Symptoms recurred 4 weeks after stopping the drugs in 28% respectively. CAS was as effective as AMB in patients who had patients given CAS and in 17% patients given FLUC (P = candidemia with a favorable response in 71.7% and 62.8% of 0.19).38 patients, respectively. There were significantly fewer drug-re- Pre-clinical and clinical studies show that combinations of lated adverse events with CAS than with AMB. No antagonism echinocandin with azoles and AMB do not produce antagonis- between them was seen against A. fumigatus, A. flavus, A. tic effects, rather may produce synergistic effects against niger and A. terreus in vitro, although some synergistic addi- pathogenic fungi.39-41 The usefulness of such combinations is tive activity was observed.29 emerging in invasive aspergillosis management.42 Therefore, A double-blind randomized, multicentric trial was con- combinations of these agents may warrant future clinical evalu- ducted to assess the efficacy, safety and tolerability of CAS ation. and AMB in adults with symptomatic Candida esophagitis. By using modified intenton-to-treat analysis, endoscopically veri- Drug interactions fied clinical success was achieved in 74% and 89% of patients receiving CAS 50 and 70 mg/day, respectively and in 63% of CAS is not metabolized by the CYP450 enzyme and due to patients receiving AMB 0.5 mg/kg/day. Therapy was stopped its different clearance mechanism it interacts minimally with due to drug-related adverse events in 24% of patients on AMB other drugs. Co-administration with cyclosporine increased and in 4% and 7%, of patients who received CAS 50 and 70 its plasma levels by 35% and caused transient liver transami- mg/day respectively. CAS appears to have similar efficacy and nase abnormalities. Concurrent treatment with efavirenz, better tolerability than AMB for the treatment of esophageal nelfinavir, phenytoin, dexamethasone, rifampicin and candidiasis.37 carbamazepine may require increasing dosage of CAS. It de- In a double-blind randomized trial, the efficacy and safety creases serum levels of tacrolimus by about 20-25% when the of CAS (50 mg) was compared with FLUC (200 mg, i.v.) in two are co-administered. It does not interact with AMB or

68 Indian J Pharmacol | April 2004 | Vol 36 | Issue 2 | 65-71 Echinocandins mycophenolate mofetil. No interactions have been reported centrations were highest in the lungs (2.26 to 11.76 µg/g), with oral ITRA (200 mg/day for 14 days).26 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 cer- Resistance ebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 µg/g. Therapeutic drug concentrations in plasma A genetic study in the yeast model of Saccharomyces and tissues can be achieved at 0.5 to 2 mg/kg dosage of MICA cerevisiae has shown that mutations in FKS1 and FKS2 genes at common sites of invasive fungal infections.46 result in CAS resistance. The SBE2 cDNA plasmid conferred galactose-dependent CAS resistance when transformed back Safety and efficacy into the wild-type S. cerevisiae. The SBE2 deletion mutant was hypersensitive to CAS. Therefore, over expression of SBE2p In one study, MICA was well tolerated by the mice and was under the regulated control of GAL1 promoter may result in much more effective than AMB or FLUC against an AMB and CAS resistance in S. cerevisiae. This transport pathway may FLUC-resistant C. tropicalis specimen at a dose of 2-10 mg/ provide insight into the tolerance/ lack of sensitivity to CAS kg body weight.47 by some pathogenic fungi.43 Fungal melanins might protect C. MICA appears to be a promising agent for invasive fungal neoformans and H. capsulatum from the effects of AMB and infections but requires further clinical evaluation. It is in phase CAS.44 III clinical trials.

Dosage Anidulafungin (LY303366; [ANIDU])

The recommended dosage of CAS in adults is 70 mg, i.v. It is a new echinocandin with promising broad-spectrum, on Day 1 followed by 50 mg/d given as a single dose over one antifungal activity in vitro and in vivo with a mechanism of hour with the duration of treatment depending on the severity action similar to CAS. of the patient’s underlying condition and the clinical response. Dose adjustment based on age, sex, race or renal function Spectrum of activity does not appear to be necessary, although patients with moderate hepatic insufficiency should receive a lower maintenance It exhibited prominent activity against Candida species dose. Moreover, it is an expensive agent costing $ 9,875 (about including C. glabrata and C. Krusei but showed little activity Rupees 4.5 lakhs) for an average treatment cycle (34 days) in against Cryptococcus neoformans.25 Promising activity of a dosage of 50 mg daily.17 ANIDU against Aspergillus spp. and other species of filamentous fungi has also been seen clinically.36 The activity Micafungin (FK-463; [MICA]) of ANIDU in vitro was significantly superior (P <0.05) to that of ITRA and FLUC against C. albicans, C. tropicalis, C. glabrata It is a new lipopeptide echinocandin with a broad-spec- and C. krusei, but was less against C. famata and C. trum in vitro and in vivo antifungal activity, against both As- parapsilosis.48 pergillus and Candida species. The mechanism of action is similar to CAS. MICA exhibits potent activity against Aspergillus Efficacy species. It is also active against the dematiaceous fungi Cladosporium trichoides, Exophiala spinifera, Fonsecaea In one study, there was no relationship between FLUC and pedrosoi, and Exophiala dermatitidis except for certain clini- ANIDU MICs for C. albicans or non-albicans species. For all cal isolates. However, it had no activity against Fusarium solani, isolates, geometric mean (GM) MIC values (in mg/L) were: Pseudallescheria boydii, and the zygomycetes Absidia ANIDU -0.011, FLUC -8.72, FC -0.393, AMB -0.046. C. corymbifera, Cunninghamella elegans, Rhizopus oryzae and parapsilosis and C. guilliermondii were found to be significantly Rhizopus microsporus var. rhizopodiformis. Hence, MICA has less susceptible to ANIDU than all other species (P ≥ 0.05). potential utility for the treatment of infections caused by the For all isolates, GM MFC values (in mg/L) were: ANIDU 0.032 Candida and Aspergillus species and dematiaceous fungi.45 and AMB 0.143.49 The in vitro activities of ANIDU, ITRA and AMB were assessed against 60 Aspergillus isolates, including Pharmacokinetics isolates of A. fumigatus (35), A. terreus (8), A. flavus (8), A. niger (8) and A. nidulans (1). MFCs were 0.018, 19.76 and After administration of a single (0.5 and 2 mg/kg, i.v.) dose 12.64 mg/L for ANIDU, ITRA and AMB, respectively. ANIDU of MICA to rabbits, the mean peak plasma drug concentra- was fungicidal in 86.7% isolates (98% killing). In comparison, tions were 7.62 and 16.8 µg/ml respectively, the area under ITRA and AMB were fungicidal for 35% and 70% of isolates the concentration-time curve from 0 to 24 hours ranged from respectively (99.99% killing).50 In a temporarily neutropenic 5.66 to 21.79 µg x h/ml, the apparent volume of distribution murine model of invasive aspergillosis against AMB-suscepti- at steady state ranged from 0.296 to 0.343 L/kg and the elimi- ble (AMB-S) and AMB-resistant (AMB-R) A. fumigatus isolate nation half-life ranged from 2.97 to 3.20 h, respectively. No based on in vivo response, 4 doses (1, 2.5, 10, and 25 mg/kg significant changes in the pharmacokinetic parameters and of body weight) of ANIDU were compared with AMB (0.5 to 5 no accumulation were noted after multiple dosing. Thirty min- mg/kg). AMB at 0.5 mg/kg and ANIDU at 1 mg/kg yielded 10 utes after the last of eight daily doses, mean tissue MICA con- to 20% survival rates for mice infected with either AMB-S or

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AMB-R isolates. AMB at other dosages yielded a 70 to 100% 8. Georgopapadakou NH. Update on antifungals targeted to the cell wall: focus survival rate for mice infected with AMB-S and 10 to 30% sur- on beta-1,3-glucan synthase inhibitors. Expert Opin Investig Drugs 2001;10: vival rate for mice infected with AMB-R (P = 0.01 to 0.04 269-80. 9. Cailot D, Casasnovas O, Bernard A, Couaillier JF, Durand C, Cuisenier B, compared with AMB-S). Against both isolates, ANIDU at 2.5, et al. Improved management of invasive pulmonary aspergillosis in neutro- 10 and 25 mg/kg produced a survival rate of 70 to 80%, which penic patients using early thoracic computed tomographic scan and surgery. J was as effective as AMB for AMB-S, but superior to AMB for Clin Oncol 1997;15:139-47. AMB-R (P < 0.03 to 0.0006). For AMB-R, ANIDU at 10 and 25 10. Einsele H, Hebart H, Roller G, Loffler J, Rothenhofer I, Muller CA, et al. Detec- mg/kg/day was superior to AMB at 2 and 5 mg/kg/day in re- tion and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol 1997;35:1353-60. ducing tissue colony counts (P = 0.01 to 0.003) and for AMB- 11. Maertens J, Verhaegen J, Demuynck H, Brock P, Verhoef G, Vandenberghe P, S, AMB at 5 mg/kg/day and at 5 mg/kg in 4 doses was more et al. Autopsy controlled prospective evaluation of serial screening for circulat- effective than all 4 regimens of ANIDU in reducing renal cul- ing galactomannan by a sandwich enzyme linked immunosorbent assay for ture counts (P = 0.01 to 0.0001). ANIDU appears to be effec- hematological patients at risk for invasive Aspergillosis. J Clin Microbiol 1999;37: tive against AMB-susceptible and -resistant A. fumigatus in- 3223-8. 12. NCCLS. Reference method for broth dilution antifungal susceptibility testing fection in this model.51 of yeasts; approved standard. NCCLS document M27A. NCCLS Wayne, Therefore, ANIDU might have efficacy similar to CAS, FLUC, PA; 1997. FC, ITRA and AMB.35,36 Combinations of FLUC and CAS or 13. NCCLS. Proposed reference method for broth dilution antifungal susceptibility ANIDU showed indifferent results but also did not produce any testing of filamentous fungi. NCCLS document M28-P. NCCLS, Wayne, PA; 1998. antagonistic activity.34 Thus, by virtue of its novel mechanism 14. Bowman JC, Hicks PS, Kurtz MB, Rosen H, Schmatz DM, Liberator PA, et al. of action, it can be tried in combination with other antifungal The antifungal echinocandin caspofungin acetate kills growing cells of Aspergil- lus fumigatus in vitro. Antimicrob Agents Chemother 2002;46:3001-12. agents for severe fungal infections. ANIDU is in phase III clini- 15. Pound MW, Drew RH, Perfect JR. Recent advances in the epidemiology, pre- cal trials and needs more clinical evaluation on efficacy, safety vention, diagnosis, and treatment of fungal pneumonia. 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Efficacy of Candidemia in cancer patients: A prospective, multicentre surveillance study caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. by the Invasive Fungal Infection Group (IFIG) of the European Organization J Acquir Immune Defic Syndr 2002;31:183-7. for Research and Treatment of Cancer (EORTC). Clin Infect Dis 1999;28: 32. Laverdiere M, Restieri C, Habel F. Evaluation of the in vitro activity of 1071-9. caspofungin against bloodstream isolates of Candida species from cancer 6. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillous patients: comparison of E test and NCCLS reference methods. Int J Antimicrob infections in a large cohort of patients undergoing bone marrow transplanta- Agents 2002;20:468-71. tion. J Infect Dis 1997;175:1459-66. 33. Ramage G, VandeWalle K, Bachmann SP, Wickes BL, Lopez-Ribot JL. In vitro 7. Groll AH, Walsh TJ. 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Chemother 2002;46:3634-6. 43. Osherov N, May GS, Albert ND, Kontoyiannis DP. Overexpression of Sbe2p, a 34. Roling EE, Klepser ME, Wasson A, Lewis RE, Ernst EJ, Pfaller MA. Antifungal Golgi protein, results in resistance to caspofungin in Saccharomyces cerevisiae. activities of fluconazole, caspofungin (MK0991), and anidulafungin (LY 303366) Antimicrob Agents Chemother 2002;46:2462-9. alone and in combination against Candida spp. and Crytococcus neoformans 44. van Duin D, Casadevall A, Nosanchuk JD. Melanization of Cryptococcus via time-kill methods. Diagn Microbiol Infect Dis 2002;43:13-7. neoformans and Histoplasma capsulatum reduces their susceptibilities to 35. Marco F, Pfaller MA, Messer SA, Jones RN. Activity of MK-0991 (L-743, 872), amphotericin B and caspofungin. Antimicrob Agents Chemother 2002;46: a new echinocandin, compared with those of LY303366 and four other antifun- 3394-400. gal agents tested against blood stream isolates of Candida spp. Diagn Microbiol 45. Nakai T, Uno J, Otomo K, Ikeda F, Tawara S, Goto T, et al. In vitro activity of Infect Dis 1998;32:33-7. FK463, a novel lipopeptide antifungal agent, against a variety of clinically im- 36. Pfaller MA, Marco F, Messer SA, Jones RN. In vitro activity of two echinocandin portant moulds. Chemotherapy 2002;48:78-81. derivatives, LY303366 and MK-0991 (L-743, 792), against clinical isolates of 46. Groll AH, Mickiene D, Petraitis V, Petraitiene R, Ibrahim KH, Piscitelli SC, et al. Aspergillus, Fusarium, Rhizopus, and other filamentous fungi. Diagn Microbiol Compartmental pharmacokinetics and tissue distribution of the antifungal Infect Dis 1998;30:251-5. echinocandin lipopeptide micafungin (FK463) in rabbits. Antimicrob Agents 37. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A Chemother 2001;45:3322-7. randomized double-blind study of caspofungin versus amphotericin for the treat- 47. Warn PA, Sharp A, Morrissey G, Denning DW. In vivo activity of micafungin in ment of candidal esophagitis. Clin Infect Dis 2001;33:1529-35. a persistently neutropenic murine model of disseminated infection caused by 38. Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci Candida tropicalis. J Antimicrob Chemother 2002;50:1071-4. RJ, et al. A randomized double-blind study of caspofungin versus fluconazole 48. Arevalo MP, Carrillo-Munoz AJ, Salgado J, Cardenes D, Brio S, Quindos G, for the treatment of esophageal candidiasis. Am J Med 2002;113:294-9. et al. Antifungal activity of the echinocandin anidulafungin (VER002, LY- 303366) 39. Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro susceptibility testing against yeast pathogens: A comparative study with M27-A microdilution method. methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrob J Antimicrob Chemother 2003;51:163-6. Agents Chemother 2001;45:327-30. 49. Moore CB, Oakley KL, Denning DW. In vitro activity of a new echinocandin, 40. Chiou CG, Groll AH, Walsh TJ. New drugs and novel targets for treatment of LY303366, and comparison with fluconazole, flucytosine and amphotericin B invasive fungal infections in patients with cancer. Oncologist 2000;5:120-35. against Candida species. Clin Microbiol Infect 2001;7:11-6. 41. De Pauw BE, Donnelly JP, Verweij PE, Meis JFGM. Current management of 50. Oakley KL, Moore CB, Denning DW. In vitro activity of the echinocandin antifungal infections in immunocompromised patients and polyene lipid complexes fungal agent LY303, 366 in comparison with itraconazole and amphotericin B for treatment of invasive fungal infection. J Infect Dis Antimicrob Agents against Aspergillus spp. Antimicrob Agents Chemother 1998;42:2726-30. 1998;15:85-96. 51. Verweij PE, Oakley KL, Morrissey J, Morrissey G, Denning DW. Efficacy of 42. Rubin MA, Carrol KC, Cahill BC. Caspofungin in combination with Itraconazole LY303366 against amphotericin B-susceptible and -resistant Aspergillus for the treatment of invasive aspergillosis in humans. Clin Infect Dis fumigatus in a murine model of invasive aspergillosis. Antimicrob Agents 2002;34:1160-1. Chemother 1998;42:873-8.

37TH ANNUAL CONFERENCE INDIAN PHARMACOLOGICAL SOCIETY

Date : 14th-16th January, 2005 Venue : Science City, Kolkata

Organized by: Organizing Vice-Chairperson: West Bengal Branch S. K. Bandopadhyay Indian Pharmacological Society Head–Department of Pharmacology, IPGME&R, Kolkata - 700020. Secretariat: Department of Pharmacology, Organizing 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 - 700020. Fisheries Sciences, E-mail: [email protected] Kolkata - 700037.

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