Slide 1 Invasive Fungal Infections Slides 2–7

CANCIDAS® (Kaspofungina, MSD) w infekcjach grzybiczych Najnowsze dane klinicze
Slide 1 Invasive Fungal Infections Slides 2–7 Mechanism of Action of Current Antifungal Agents Slides 8–15 In Vitro Activity of Caspofungin Slides 16–18 Clinical Trials of Caspofungin Slides 19–73 Other Information on Caspofungin Slides 74–82 Bibliography Slides 83–88 ® Zastrzeżona nazwa handlowa Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.

Inwazyjne Infekcje Grzybicze
Slide 2 Invasive Fungal Infections Slides 2–7 Introduction Slide 3 Invasive Fungal Infections Are a Growing Problem: Focus on Aspergillosis Slide 4 Invasive Fungal Infections Are a Growing Problem: Focus on Candidiasis Slide 5 Invasive Fungal Infections: Patients at High Risk Slide 6 Invasive Fungal Infections: Current Treatment Options Slide 7

Badania kliniczne w zakażeniach Aspergillus i Candida
Wprowadzenie Slide 3 In this presentation, we will review current treatment options for invasive fungal infections and present a clinical update on caspofungin—the first of a new class of antifungal agents, the glucan synthesis inhibitors, also called the echinocandins.

Grzybice inwazyjne stanowią coraz większy problem: Aspergilloza
Częstość infekcji grzybiczych dramatycznie rośnie Wzrost ilości chorych z zaburzoną odpornością Wzrost liczby inwazyjnych procedur medycznych Aspergillus jest drugim najczęstszym grzybiczym patogenem po Candida U pacjentów z zaburzeniami odporności dochodzi do 90% śmiertelności Slide 4 The incidence of fungal infections has risen dramatically in the past two decades in large part because of an increased number of immunocompromised patients and increased invasive procedures.1-3 More aggressive chemotherapy Increase in solid-organ transplantation Increased use of vascular catheters Aspergillus is the second most common fungal pathogen after Candida.4 The mortality associated with invasive Aspergillus infections is high, up to 90% in the most severely immunocompromised patients despite treatment.5,6 Diagnosis is problematic.4,7 Delays in diagnosis and treatment are associated with increased mortality.3,7 Na podstawie Andriole VT J Antimicrob Chemother 1999;44:151–162; Groll AH i wsp. Adv Pharmacol 1998;44:343–500; Denning DW Clin Infect Dis 1998;26:781–805; Andriole VT Curr Clin Top Infect Dis 1998;18:19–36; Lin S-J i wsp. Clin Infect Dis 2001;32:358–366; Paterson DL, Singh N Medicine (Baltimore) 1999;78:123–138. References 1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. 2. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: Comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. 3. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26:781–805. 4. Andriole VT. Current and future therapy of invasive fungal infections. Curr Clin Top Infect Dis 1998;18:19–36. 5. Lin S-J, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: Systematic review of the literature. Clin Infect Dis 2001;32:358–366. 6. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore) 1999;78:123–138. 7. Harari S. Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients. Drugs 1999;58:621–631.

Grzybice inwazyjne stanowią coraz większy problem: Kandydoza
Wzrastająca liczba ciężkich infekcji Inwazyjne zakażenia Candida Są czwartą najczęstszą przyczyną posocznic w Stanach Zjednoczonych* Patogen l. przypadków Częstość (%) Slide 5 Koagulazoujemne staphylokoki Staphylococcus aureus Enterokoki Candida species Serious fungal infections are on the rise as shown by the increase of life-threatening infections due to invasive Candida.1,2 Per a 1983 nationwide survey of medical and surgical patients in the United States, the 9th most common cause of nosocomial bloodstream infections was the Candida species.3 In a 3-year (1995–1998) surveillance study of 49 hospitals across the United States, the high incidence of Candida infections places it as the 4th leading cause of nosocomial bloodstream infections.4 In this study, only coagulase-negative staphylococci, Staphylococcus aureus, and enterococci have higher rates of incidence.4 *W 3 letnim badaniu(1995–1998) w 49 szpitalach w Stanach Zjednoczonych. Na podstawie Edmond MB i wsp. Clin Infect Dis 1999;29:239–244; Andriole VT J Antimicrob Chemother 1999;44:151–162; Uzun O, Anaissie EJ Ann Oncol 2000;11:1517–1521. References 1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. 2. Uzun O, Anaissie EJ. Predictors of outcome in cancer patients with candidemia. Ann Oncol 2000;11:1517–1521. 3. Centers for Disease Control and Prevention. Nosocomial infection surveillance, Morb Mortal Wkly Rep 1984;33(2SS):9SS–21SS. 4. Edmond MB, Wallace SE, McClish DK i wsp.. Nosocomial bloodstream infections in United States hospitals: A three-year analysis. Clin Infect Dis 1999;29:239–244.

Inwazyjne grzybice: Pacjenci wysokiego ryzyka
Potencjalne czynniki ryzyka to: Bez neutropenii: Ostra niewydolność nerek Żywienie pozajelitowe Leki przeciw beztlenowcom Wcześniejsze użycie wankomycyny Stosowanie lipidów Niedawny zabieg operacyjny Utrzymywanie trójdrożnych cewników dożylnych Z neutropenią Nowotwory złośliwe Przeszczepy Antybiotykoterapia o szerokim spektrum Wcześniejsze użycie wankomycyny Zaburzenia odporności Zabiegi operacyjne Stosowanie cewników dożylnych Slide 6 The high incidence of invasive fungal infections has arisen primarily as a consequence of advanced medical treatment technologies, especially in gravely ill patients.1,2 Fungal invasion is prevalent1,2 When patients are immunosuppressed (e.g., neutropenic patients or solid-organ transplant recipients) When there is disruption of the gastrointestinal tract (e.g., surgery, trauma, or chemotherapy) If there is disruption of anatomical barriers (e.g., catheterization or mechanical ventilation) In circumstances in which normal microflora are disturbed (e.g., through use of broad-spectrum antibiotics) Awareness of risk factors for invasive fungal infection is key to identifying potential patient candidates for antifungal therapy.1,2 The multicenter National Epidemiology of Mycosis Survey (NEMIS) was the largest prospective study designed to determine risk factors for developing candidal bloodstream infections (CBSIs) among patients in surgical and neonatal intensive care units.1 Previous studies evaluating risk factors had several limitations, including the utilization of data from a single institution over a long time period, and not being prospective in design. In addition, few were focused on surgical intensive care unit populations.1 In NEMIS, independently associated risk factors for CBSIs included acute renal failure, parenteral nutrition, and prior surgery. Neutropenia was not an independent risk factor.1 National Epidemiology of Mycosis Survey (NEMIS) było prospektywnym, wieloośrodkowym badaniem przeprowadzonym w 6 ośrodkach w Stanach Zjednoczonych w latach 1993–1995 w celu oceny czynników ryzyka wystąpienia innfekcji krwi grzybami Candida (CBSIs) w grupie pacjentów przebywających w chirurgicznych i neonatologicznych oddziałach intensywnej terapii >48 h. Wsród 4276 pacjentów, stwierdzono 42 tego typu infekcje.. Na podstawie Blumberg HM i wsp., and the NEMIS Study Group Clin Infect Dis 2001;33:177–186; Garber G Drugs 2001; 61(suppl 1):1–12. References 1. Blumberg HM, Jarvis WR, Soucie JM i wsp. and the NEMIS Study Group. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: The NEMIS prospective multicenter study. Clin Infect Dis 2001;33:177–186. 2. Garber G. An overview of fungal infections. Drugs 2001;61(suppl 1):1–12.

Inwazyjne grzybice: Obecne możliwości leczenia
Amphoterycyna B „Złoty standard” skuteczności Szeroki wachlarz ostrych i przewlekłych objawów ubocznych w tym nefrotoksyczność, także przy postaciach lipidowych Azole Starsze: Niewystarczająca skuteczność w infekcjach Aspergillus Nowsze triazole: Kliniczna skuteczność w infekcjach Aspergillus Wzrastająca oporność w kandydozach spowodowanych gatunkami non-albicans Liczne interakcje lekowe związane z cytochromem P450 Slide 7 Current options for the treatment of invasive fungal infections can be limited by efficacy and/or tolerability concerns. Amphotericin B, long considered the “gold standard” for efficacy, can produce a wide variety of acute and chronic side effects, including nephrotoxicity.1,2 Lipid formulations of the agent, including liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloid dispersion, while less nephrotoxic than the original formulation, do not completely avoid the risk of renal insufficiency.1-4 Azole antifungal agents, while less toxic than amphotericin B, are less dependably effective in relevant invasive infections. Older agents, including fluconazole and itraconazole, have demonstrated inconsistent clinical efficacy in Aspergillus infections,5,6 while newer agents such as voriconazole are more useful in this setting.7 In candidal infections, increasing resistance to older agents and cross- resistance to newer triazoles has been observed, particularly in infections caused by non-albicans species.8,9 Moreover, both older and newer azoles are associated with cytochrome P450 (CPY450)-mediated, potentially clinically relevant drug-drug interactions. 9,10 Therefore, a critical need remains for effective and well tolerated drugs with limited drug interactions for the treatment of serious fungal infections.9 Na podstawie Deray G J Antimicrob Chemother 2002;49(suppl S1):37–41; Cannon JP, Garey KW, Danziger LH Pharmacotherapy 2001;21(9):1107–1114; White MH i wsp. Clin Infect Dis 1998;27(2):296–302; Walsh TJ i wsp. Antimicrob Agents Chemother 2001;45(12):3487–3496; Andriole VT J Antimicrob Chemother 1999;44:151–162; Groll AH i wsp. Adv Pharmacol 1998;44:343– 500; Denning DW i wsp. Clin Infect Dis 2002;34:563–571; Bates DW i wsp. Clin Infect Dis 2001;32:686–693; Graybill JR Int J Clin Pract 2001;55:633–638; Groll AH, Walsh TJ Swiss Med Wkly 2002;132:303–311. References 1. Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother 2002;49(suppl S1):37–41. 2. Cannon JP, Garey KW, Danziger LH. A prospective and retrospective analysis of the nephrotoxicity and efficacy of lipid-based amphotericin B formulations. Pharmacotherapy 2001;21(9):1107–1114. 3. White MH, Bowden RA, Sandler ES i wsp.. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998;27(2):296–302. 4. Walsh TJ, Goodman JL, Pappas P i wsp.. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: Maximum tolerated dose study. Antimicrob Agents Chemother 2001;45(12):3487–3496. 5. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. 6. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: A comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44: 343–500. 7. Denning DW, Ribaud P, Milpied N i wsp.. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002;34:563–571. 8. Bates DW, Su L, Yu DT i wsp.. The mortality and costs of acute renal failure associated with amphotericin therapy. Clin Infect Dis 2001;32:686–693. 9. Graybill JR. The echinocandins, first novel class of antifungals in two decades: Will they live up to their promise? Int J Clin Pract 2001;55:633–638. 10. Groll AH, Walsh TJ. Antifungal chemotherapy: Advances and perspectives. Swiss Med Wkly 2002;132:303–311.

Mechanizmy działania współczesnych leków przeciwgrzybiczych
Slide 8 Mechanism of Action of Current Antifungal Agents Slides 8–15 Amphotericin B Slide 9 Azoles Slide 10 Caspofungin Slide 11 Caspofungin (continued) Slide 12 Sites of Action of Selected Antifungal Agents Slide 13 Mechanisms of Action of Current Therapies and Implications for Efficacy Slide 14 Mechanisms of Action of Current Therapies and Implications for Tolerability Slide 15

Mechanizm działania: Amphoterycyna B
Łączy się z ergosterolem błony komórkowej grzybów powodując zmiany jej przepuszczalnośći i wypływ elementów komórkowych na zewnątrz komórki Komórki ssaków również zawierają sterole w błonach komórkowych Sugeruje się, że ten niszczący mechanizm działania nie omija komórek ludzkich Slide 9 Amphotericin B acts by binding to sterols, such as ergosterol, in fungal cell membranes, thereby increasing the permeability of the cell membrane.1,2 Pores are formed in the membrane through which cytoplasmic contents leak.3 The resulting loss of intracellular potassium and other molecules causes impaired fungal viability and, ultimately, cell death.3,4 Amphotericin B also binds to other sterols, such as cholesterol in human cells, which can result in poor tolerability.2,4,5 Na podstawie Fungizone® Intravenous Package Insert. Apothecon® (A Bristol-Myers Squibb Company), April 1998; Stevens DA, Bennett JE. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459; Andriole VT J Antimicrob Chemother 1999;44:151–162. References 1. Harari S. Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients. Drugs 1999;58:621–631. 2. Fungizone® Intravenous [package insert]. Princeton, NJ, USA: Apothecon® (A Bristol-Myers Squibb Company), April 1998. 3. Stevens DA, Bennett JE. Antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459. 4. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: Comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. 5. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162.

Mechanizm działania: Azole
Hamują CYP450 3A zależną C14-alfa-demetylazę powodując Zmniejszenie zawartości ergosterolu Nagromadzenie toksycznych steroli Zniszczenie błony cytoplazmatycznej Slide 10 Like amphotericin B, azoles act at the level of the fungal cell membrane.1-3 Azoles inhibit fungal CYP450 3A–dependent C14-alpha- demethylase, which is responsible for the synthesis of ergosterol in the fungal cell membrane.1,2,4 The resulting ergosterol depletion and accumulation of toxic sterols directly damage the cytoplasmic membrane, resulting in fungistatic activity.1,2,4,5 Additionally, since azoles are inhibitors of the CYP450 system, they have many drug-drug interactions, such as with immunosuppressive agents.1,6,7 CYP450=cytochrome P-450 Na podstawie Harari S Drugs 1999;58:621–631; Stevens DA, Bennett JE. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459; Andriole VT J Antimicrob Chemother 1999;44:151–162; Andriole VT Curr Clin Top Infect Dis 1998;18:19–36. References 1. Harari S. Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients. Drugs 1999;58:621–631. 2. Stevens DA, Bennett JE. Antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459. 3. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. 4. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. 5. Andriole VT. Current and future therapy of invasive fungal infections. Curr Clin Top Infect Dis 1998;18:19–36. 6. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: Comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. 7. Sporanox® Injection [package insert]. Raritan, NJ, USA: Ortho Biotech Inc., January 2000.

Mechanizm działania: Kaspofungina
Kaspofungina jest pierwszym lekiem nowej klasy, inhibitorów syntezy glikanu, zwanych również echinokandynami Inhibitory syntezy glikanu mają unikatowy mechanizm działania, który zapewnia skuteczność i bezpieczeństwo Slide 11 The development of new antifungal agents has been guided by an increased understanding of the pathways involved in fungal cell growth and reproduction.1 The fungal cell wall is composed of a complex of proteins and polycarbohydrates, including glucan, which provides a strong and rigid framework. The cell wall counters the osmotic forces that would otherwise result in cell lysis.2 For these reasons, the cell wall has been a logical focus of new drug investigations. Caspofungin is the first in the new class of glucan synthesis inhibitors, also called the echinocandins, that target the fungal cell wall.2,3 This mechanism of action is unique and differs from that of both amphotericin B and the azoles, in that the target is the cell wall rather than the cell membrane.4-6 Na podstawie Marco F i wsp. Diagn Microbiol Infect Dis 1998;31:33–37; Groll AH i wsp. Adv Pharmacol 1998;44:343–500; Graybill JR i wsp. Antimicrob Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Curr Opin Infect Dis 1997;10:449–458. References 1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. 2. Tkacz JS. Glucan biosynthesis in fungi and its inhibition. In: Sutcliff JA, Georgopapadaku NH, eds. Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992:495–523. 3. Marco F, Pfaller MA, Messer SA i wsp.. 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;31:33–37. 4. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: Comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. 5. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41:1775–1777. 6. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458.

Mechanizm działania: Kaspofungina (c.d.)
Beta (1,3)-D-glikan jest podstawą spójności ściany komórkowej wielu grzybów,w tym Aspergillus i Candida spp. Kaspofungina wybiórczo hamuje syntezę beta (1-3)-D-glikanu, uszkadzając w ten sposób integralność ściany komórkowej W rezultacie ściana komórkowa staje się przepuszczalna i pod nieobecność czynników osmotycznych, dochodzi do lizy komórki Synteza Beta (1-3)-D-glikanu nie zachodzi w komórkach ludzkich Slide 12 Caspofungin acts by specifically inhibiting the synthesis of beta (1,3)-D-glucan, which is an integral component of the cell wall of many fungi, including Aspergillus and Candida species.1 Disruption of the cell-wall structure by caspofungin leads to osmotic instability and, ultimately, lysis of the fungal cell.1,2 In contrast to amphotericin B and azoles, caspofungin targets substances in the fungal cell wall rather than the cell membrane.1,3,4 This novel mechanism of action may have particular value in the treatment of infections due to resistant fungal strains.2,3 Both amphotericin B and the azoles must traverse the cell wall to act in the cell membrane.5 Na podstawie Groll AH, Walsh TJ Curr Opin Infect Dis 1997;10:449–458; Tkacz JS. In: Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992:495–523. References 1. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. 2. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: Comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. 3. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41:1775–1777. 4. Tkacz JS. Glucan biosynthesis in fungi and its inhibition. In: Sutcliff JA, Georgopapadaku NH, eds. Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992:495–523. 5. Franzot SP, Casadevall A. Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro. Antimicrob Agents Chemother 1997;41(2):331–336.

Miejsce uchwytu niektórych leków przeciwgrzybiczych
Błona komórkowa Polieny Azole Slide 13 Ściana komórkowa Inhibitory syntezy glikanu (echinokandyny) Currently available antifungal agents can be classified by their site of action in fungal cells,1 which can have important implications for both efficacy and tolerability. Available agents include the polyenes, nucleoside analogs, and the azoles.1 These agents are not ideal because amphotericin B treatment is associated with severe side effects, and nucleoside analogs and azole possess a fungistatic rather than fungicial action.2 These classes are limited by lack of selective toxicity for fungal cells, that is, their therapeutic target is not exclusive to the fungal cell.2 For this reason, new antifungals— glucan synthesis inhibitors, also called echinocandins—that target the cell wall (not found in mammalian cells) are an important focus of current research which have the potential to provide a superior efficacy and safety profile versus current agents.2-5 Na podstawie Andriole VT J Antimicrob Chemother 1999;44:151–162; Graybill JR i wsp. Antimicrob Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Expert Opin Invest Drugs 2001;10(8):1545–1558. References 1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. 2. Debono M, Gordee RS. Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol 1994;48: 471–497. 3. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41(8):1775–1777. 4. Marco F, Pfaller MA, Messer SA i wsp.. 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;31:33–37. 5. Groll AH, Walsh TJ. Caspofungin: Pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Invest Drugs 2001;10(8):1545–1558.

Mechanizm działania współczesnych leków i ich wpływ na skuteczność
Punkt uchwytu działanie Implikacje kliniczne Amphoterycyna B Błona Łączenie z ergosterolem – śmierć komórki Silna aktywność o szerokim spektrum Azole Hamowanie enzymów CYP450 odpowiedzialnych za syntezę ergosterolu; zniszczenie błony cytoplazmatycznej Aktywność w spektrum o różnej sile Kaspofungina Ściana Hamuje syntezę glikanu, niszczy ścianę komórkową Szerokie spektrum, potencjalne możliwości w leczeniu skojarzonym Slide 14 The action of amphotericin B on sterols in the fungal cell membrane provides potent, broad-spectrum fungicidal activity that has earned this drug its place as first-line therapy for most severe fungal infections.1,2 The action of azole antifungals on ergosterol in the fungal cell membrane also produces antifungal activity. However, azoles only offer fungistatic activity, and potency and spectrum vary among available compounds.1,3 In contrast to amphotericin B and azoles, caspofungin targets substances in the fungal cell wall rather than the cell membrane.4,5 This novel mechanism of action may have particular value in the treatment of resistant fungal strains.5 Moreover, caspofungin has the potential to deliver additive effects when used in combination with amphotericin B or azoles.5,6 Both amphotericin B and the azoles must traverse the cell wall to act in the cell membrane. The ability to enhance these agents’ activity may be attributable to inhibition of cell-wall synthesis, by which caspofungin increases access of the other drugs to their respective targets, as shown in an in vitro study of these drugs against Cryptococcus neoformans.6 Na podstawie Andriole VT J Antimicrob Chemother 1999;44:151–162; Stevens DA, Bennett JE. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone, 2000:448–459; Graybill JR i wsp. Antimicrob Agents Chemother 1997;41:1775–1777; Franzot SP, Casadevall A Antimicrob Agents Chemother 1997;41(2):331–336. References 1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. 2. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: Comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. 3. Stevens DA, Bennett JE. Antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459. 4. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. 5. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41:1775–1777. 6. Franzot SP, Casadevall A. Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro. Antimicrob Agents Chemother 1997;41(2):331–336.

Mechanizmy działania współczesnych leków i ich wpływ na tolerancję
Aktywność amfoterycyny B w stosunku do komórkek grzybów i ludzi może być przyczyną poważnej toksyczności w tym nefrotoksyczności Słabszy efekt działania w komórkach ludzi niż grzybów powoduje dobrą tolerancję azoli i triazoli Wyjątkowy, wybiórczy mechanizm działania kaspofunginy odpowiada za niewielką toksyczność leku Slide 15 In addition to ergosterol, amphotericin B binds to other sterols, including cholesterol, that are present in human cells. Its activity in host cells is believed to underlie the formidable toxicities observed with amphotericin B, including nephrotoxicity.1-3 Azoles also affect sterols, but with less activity in human cells than in fungal cells. The superior tolerability of azoles to that of amphotericin B may be explained by these lesser effects.1,4 Additionally, since azoles are inhibitors of the CYP450 system, they have many drug-drug interactions, such as with immunosuppressive agents.5 Caspofungin acts specifically on targets not found in human cells— beta (1,3)-D-glucan in the fungal cell wall.6 Therefore, caspofungin has a low potential for the mechanism- based toxicities seen with amphotericin B.7,8 Na podstawie Groll AH i wsp. Adv Pharmacol 1998;44:343–500; Sawaya BP i wsp. J Am Soc Nephrol 1995;6:154–164; Tkacz JS In: Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992:495–523; Marco F i wsp. Diagn Microbiol Infect Dis 1998;31:33–37. References 1. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: Comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. 2. Sawaya BP, Briggs JP, Schnermann J. Amphotericin B nephrotoxicity: The adverse consequences of altered membrane properties. J Am Soc Nephrol 1995;6:154–164. 3. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41:1775–1777. 4. Stevens DA, Bennett JE. Antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459. 5. Sporanox® Injection [package insert]. Raritan, NJ, USA: Ortho Biotech Inc., January 2000. 6. Tkacz JS. Glucan biosynthesis in fungi and its inhibition. In: Sutcliff JA, Georgopapadaku NH, eds. Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992:495–523. 7. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. 8. Marco F, Pfaller MA, Messer SA i wsp.. 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;31:33–37.

Aktywność Kaspofunginy In Vitro
Slide 16 In Vitro Activity of Caspofungin Slides 16–18 Spectrum of in vitro Activity Against Aspergillus spp. Slide 17 Spectrum of in vitro Activity Against Candida spp. Slide 18

Kaspofungina: zakres działania in vitro obejmuje Aspergillus spp.
Potencjalne działanie in vitro obejmuje wiele grzybów strzępkowych i drożdżaków, w tym Aspergillus spp. Aspergillus fumigatus Aspergillus flavus Aspergillus niger Aspergillus nidulans Aspergillus terreus Aspergillus candidus Slide 17 Caspofungin has demonstrated potent in vitro activity against fungal species such as Aspergillus.1 Susceptibility testing was performed according to a modification of the National Committee for Clinical Laboratory Standards method M38-A (for Aspergillus species). Standardized susceptibility-testing methods for beta (1,3)-D-glucan synthesis inhibitors have not been established.* Na podstawie Groll AH, Walsh TJ Curr Opin Infect Dis 1997;10:449–458. *Results of susceptibility studies do not necessarily correlate with clinical outcome. Reference 1. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458.

Kaspofungina : zakres działania in vitro obejmuje Candida spp.
Candida albicans Candida dubliniensis Candida glabrata Candida guilliermondii Candida kefyr Candida krusei Candida lipolytica Candida lusitaniae Candida parapsilosis Candida rugosa Candida tropicalis Slide 18 Kaspofungina jest aktywna w stosunku do szczepów Candida z pierwotną lub wtórną opornością na fluconazol, amfoterycynę B lub flucytozynę z uwagi inny mechanizm działania Caspofungin has demonstrated potent in vitro activity against Candida species.1,* Susceptibility testing was performed according to a modification of the National Committee for Clinical Laboratory Standards method M27-A (for Candida species).2 Standardized susceptibility-testing methods for beta (1,3)-D-glucan synthesis inhibitors have not been established.* *Results of susceptibility studies do not necessarily correlate with clinical outcome. Reference 1. Groll AH, Walsh TJ. Antifungal chemotherapy: Advances and perspectives. Swiss Med Wkly 2002;132:303–311.

Kaspofungina - Badania kliniczne
Slide 19 Clinical Trials of Caspofungin Slides 19–73 Empirical Therapy (Protocol 026) Objective Slide 20 Study Design Slide 21 Patient Population Slide 22 Primary Endpoint Slide 23 Efficacy and Safety Hypotheses Slide 24 Baseline Characteristics of Patients Slide 25 Response Rates vs. Liposomal Amphotericin B (MITT) Slide 26 Successful Outcome of Baseline Infections—Overall (MITT) Slide 27 Successful Outcome of Baseline Infections—Aspergillus and Candida Infections (MITT) Slide 28 Breakthrough Infections (MITT) Slide 29 Survival (MITT) Slide 30 Discontinuations Due to Lack of Efficacy or Toxicity (MITT) Slide 31 Mortality Slide 32 Adverse Events Slide 33 Drug-Related AEs Slide 34 Summary and Conclusions Slide 35 Invasive Aspergillosis (Protocol 019) Study Design Slide 36 Study Design (cont’d) Slide 37 Endpoints Slide 38 Baseline Characteristics of Patients Slide 39 Favorable Clinical Response at the End of Therapy Slide 40 Favorable Clinical Response 4 Weeks Post-Therapy Slide 41 Safety Profile (Clinical AEs) Slide 42 Safety Profile (Systemic Infusion-Related AEs) Slide 43 Safety Profile (Laboratory AE) Slide 44 Summary and Conclusions Slide 45 Invasive Aspergillosis (Protocol 028/029) Study Design Slide 46 Patient Characteristics (N=214) Slide 47 Favorable Overall Clinical Response Slide 48 Favorable Clinical Response After 7 Days of Therapy Slide 49 Invasive Candidiasis (Protocol 014) Species of Candida Most Commonly Isolated in Bloodstream Infections Slide 50 Mortality Associated with Candidemia Slide 51 Candidemia in Neutropenic Patients with Cancer: Clinical Characteristics Slide 52 Candidemia in Non-Neutropenic Patients with Cancer: Clinical Characteristics Slide 53 Objective Slide 54 Design Slide 55 Design (cont’d) Slide 56 Efficacy Evaluation: Study Definitions Slide 57 Efficacy Endpoints Slide 58 Efficacy vs. Amphotericin B (MITT Analysis) Slide 59 Efficacy vs. Amphotericin B (Evaluable Patients Analysis Slide 60 Efficacy vs. Amphotericin B in Patients with Candidemia (MITT) Slide 61 Time to First Negative Blood Culture Slide 62 Failure or Relapse Rates (MITT Analysis) Slide 63 Mortality Assessment Slide 64 Safety Profile of Caspofungin vs. Amphotericin B Slide 65 Summary and Conclusions Slide 66 Esophageal/Oropharyngeal Candidiasis Protocols 003, 004, and Objectives Slide 67 Study Design (Protocols 003 and 004) Slide 68 Study Design (Protocol 020) Slide 69 Clinical Tolerability Compared to Fluconazole Slide 70 Drug-Related Laboratory AE Profile Compared to Fluconazole Slide 71 Increase in Serum Creatinine Compared to Amphotericin B Slide 72 Summary and Conclusions Slide 73 Kaspofungina - Badania kliniczne

Terapia empiryczna (Protokół 026) Cel
Porównać odsetek pacjentów z gorączką i neutropenią, którzy pozytywnie odpowiedzieli na leczenie kaspofunginą lub liposomalną amfoterycycną B Slide 20 Despite advances during the last decade in the supportive care of neutropenic patients with cancer, invasive fungal infections continue to be a major cause of morbidity and mortality in these patients because of alterations of normal host defenses.1,2 The single most important predisposing factor to infection in these patients is neutropenia, which impairs the immune response.1 Fever, without the usual signs and symptoms of localized infection, is often the only presenting sign of infection.1 Among patients with neutropenia, fungal infections are most commonly due to Candida spp. and Aspergillus spp.2 Invasive candidiasis in this group is most frequently caused by C. albicans, followed by C. tropicalis, C. glabrata, and C. parapsilosis; infections due to C. krusei are less frequent, and those due to C. lusitaniae, C. dubliniensis, or C. guilliermondii are rare.2 Invasive aspergillosis, among the most serious infectious complications in neutropenic patients, is most commonly caused by A. fumigatus, A. terreus, A. flavus, and A. niger.2 Because early definitive diagnosis of invasive fungal infections in patients with febrile neutropenia is difficult, empirical administration of antifungal agents has become common practice in neutropenic patients with persistent fever despite empirical antibacterial therapy.2,3 Most experts recommend that antifungal therapy be initiated 5 to 7 days after the start of the antibacterial therapy, and be continued until clinical, microbiological, and radiologic evidence indicates that the infection is resolved.1 Recently, a clinical study was conducted in 1111 patients with persistent fever and neutropenia to compare the proportions of patients with a favorable overall response in groups receiving caspofungin versus liposomal amphotericin B.4 Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: References 1. Barber FD. Management of fever in neutropenic patients with cancer. Nurs Clin North Am 2001;36(4):631–644. 2. Donowitz GR, Maki DG, Crnich i wsp.. Infections in the neutropenic patient—new views of an old problem. Hematology 2001;113–139. 3. Kern WV. Risk assessment and risk-based therapeutic strategies in febrile neutropenia. Curr Opin Infect Dis 2001;14(4):415–422. 4. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Rodzaj badania
Wieloośrodkowe, randomizowane, z podwójnie ślepą próbą. Kaspofungina 50 mg/dobę (po 70 mg 1dnia) lub L-AMB 3 mg/kg/dobę Komisja Bezpieczeństwa Danych i Monitoringu kontrolowała zbieranie danych Dodatkowy Komitet do oceny infekcji grzybiczej podstawowej i wtórnej Slide 21 Protocol 026 was a double-blind, randomized, multicenter study.1 Patients (16 years and older) were randomized to receive either caspofungin (70 mg on day 1 and 50 mg/day thereafter) plus a placebo to liposomal amphotericin B (L-AMB), or L-AMB (3 mg/kg per day) plus a placebo to caspofungin.1 Caspofungin or matching placebo was given as a single daily dose infused intravenously over approximately one hour, and L-AMB was given as a single daily dose infused intravenously over approximately two hours.1 An independent Data Safety and Monitoring Board was appointed to monitor the data as they accumulated during the study.1 Because definitive diagnosis of fungal infections is often not possible, a blinded Adjudication Committee consisting of three outside experts reviewed all cases of suspected baseline and breakthrough fungal infections. The Blinded Adjudication Committee classified each case as “possible,” “probable,” or “proven,” determined the timing of the infection, the causative pathogen, and the response to therapy for baseline infections.1 L-AMB=liposomalna amfoterycyna B Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Populacja chorych
Kryteria włączenia: Wiek >16 lat Chemioterapia ostrej białaczki, chłoniaka lub innych nowotworów złośliwych lub przeszczep szpiku albo komórek pnia Neutropenia (ANC <500 µl) przez 4 dni >4 poprzedzające dni antybiotykoterapii Gorączka (>38.0ºC) Kryteria wykluczenia: Niewłaściwie leczona infekcja bakteryjna Nieprawidłowe wyniki badań laboratoryjnych Pozajelitowo stosowana amfoterycyna B w ciągu 10 dni poprzedzających badanie Spodziewane przeżycie <5 dni lub w skali Karnofsky’ego <30 Wspólne podawanie rifampicyny, cyklosporyny A lub ogólnego leczenia p-grzybiczego Slide 22 The protocol specified that eligible patients would be at least 16 years of age and have had:1 Chemotherapy for leukemia, lymphoma, or other cancers OR bone marrow or peripheral-blood stem-cell transplantation Neutropenia (ANC <500 µl) for at least 4 days At least 4 days of prior systemic antibacterial therapy Fever (>38.0ºC) Patients were excluded from enrollment if they had:1 An inadequately treated bacterial infection Abnormal laboratory values Platelet count <5000/µl International normalized ratio >1.6 Bilirubin >3 the upper limit of normal (ULN) Aspartate transaminase (AST) or alanine transaminase (ALT) >5 ULN Alkaline phosphatase >3 ULN Parenteral amphotericin B within 10 days prior to study treatment Expected survival of <5 days or Karnofsky score <30 Concomitant rifampin, cyclosporin A, or systemic antifungal therapy Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Spełnienie wszystkich poniższych kryteriów:
Terapia empiryczna (Protokół 026) Pierwszoplanowy punkt końcowy Spełnienie wszystkich poniższych kryteriów: Skuteczne leczenie podstawowej infekcji Brak infekcji wtórnej w trakcie lub w ciągu 7 dni po zakończeniu leczenia Przeżycie 7 dni po leczeniu Brak konieczności przerwania leczenia z powodu działań niepożądanych Ustąpienie gorączki na 48 godzin w trakcie okresu neutropenii Slide 23 A successful treatment outcome was defined as fulfillment of all the following criteria: successful treatment of any baseline fungal infection, if present; absence of breakthrough fungal infections during the administration of study drug or up to 7 days after completion of treatment; survival for 7 days after completion of study drug; absence of premature discontinuation of the study drug because of study drug-related toxicity or lack of efficacy; and resolution of fever for 48 hours during the period of neutropenia. If one or more of these five criteria were not met, the patient was classified as having an unsuccessful outcome.1 Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Reakcji związanych z infuzją Działań niepożądanych związanych z lekiem
Terapia empiryczna (Protokół 026) Skuteczność i bezpieczeństwo Założenie pierwszoplanowe: Kaspofungina nie będzie gorsza od L-AMB w ocenie pierwszoplanowego punktu końcowego Bezpieczeństwo: Kaspofungina nie będzie gorsza od L-AMB w częstości występowania Nefrotoksyczności (podwojenie wartości kreatyniny w surowicy lub wzrost o 1.0 mg/dl jeśli była podwyższona na początku – pierwszoplanowa ocena bezpieczeństwa) Reakcji związanych z infuzją Działań niepożądanych związanych z lekiem Przerwania terapii z powodu działań niepożądanych Slide 24 Upon enrollment and before randomization, patients were stratified to either a high-risk or a low-risk stratum. Patients at high risk had undergone allogeneic bone marrow or peripheral stem-cell transplantation and/or had received chemotherapy for a relapse of acute leukemia.1 Patients were also stratified according to whether or not they had received prophylactic antifungal treatment since their most recent chemotherapy regimen.1 The primary efficacy hypothesis was that in this population of patients with persistent fever and neutropenia, the proportion of patients with a successful treatment outcome in the caspofungin group would be non-inferior to that in the L-AMB group.1 The definition of non-inferiority used in the statistical analysis was that the 95.2% CI for the difference in favorable overall response rates between the treatment groups must include 0 and the lower limit must be no less than –10%.1 For the test of non-inferiority with respect to nephrotoxicity, the lower limit of the 2-sided 95% CI for the difference between groups must be 0 and the upper limit must not exceed 5%.1 The primary safety hypothesis was that caspofungin would be non- inferior to L-AMB with respect to frequency of1 Nephrotoxicity (doubling in serum creatinine or increase by 1.0 mg/dl if serum creatinine is elevated at entry—primary safety endpoint) Infusion-related adverse events (AEs) Drug-related AEs Discontinuations due to drug-related AEs Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Charakterystyka pacjentów
% Kaspofungina L-AMB (n=564) (n=547) Mężczyźni, % Średni wiek w latach 51 (17–83) 49 (16–83) Choroba podstawowa Ostra białaczka szpikowa (%) Ostra białaczka limfoblastyczna(%) Non-Hodgkin’s chłoniaki (%) Wysokie ryzyko(%) Allogeniczny HSCT (%) Wznowa ostrej białaczki(%) Profilaktyka p-grzybicza(%) ANC <100/µl (%) Czas leczenia Średni/mediana (skrajności) 13/11 (1–90) 12.5/10 (1–90) Slide 25 The majority of patients enrolled in the study were men.1 The median age was 50 years overall, ranging from 16 to 83 years.1 The most common primary conditions were acute myelogenous leukemia, acute lymphocytic leukemia, and non-Hodgkin’s lymphoma.1 The numbers of patients categorized as high risk due to allogeneic hematopoietic stem-cell transplant (HSCT) were similar in the two treatment groups; i.e., 6.6% in the caspofungin group and 7.5% in the L-AMB group.1 A numerically larger proportion of patients in the caspofungin group versus the L-AMB group were considered high risk on the basis of relapsed acute leukemia (20.0% and 15.4%, respectively).1 The proportion of patients who received antifungal prophylaxis prior to study entry was similar in the two treatment groups.1 Most patients entered the study severely neutropenic, with an ANC <100 cells/µl.1 The duration of therapy was similar in the groups, ranging from 1 to 90 days.1 Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

(MITT*) Modified Intention To Treat
Terapia empiryczna (Protokół 026) Odsetek pozytywnych odpowiedzi (MITT*) Modified Intention To Treat Całkowicie pozytywna odpowiedź Wyleczenie podstawowej infekcji Brak wtórnej infekcji grzybiczej Przeżycie 7 dni follow - up Slide 26 Brak przerwań terapii The estimated difference in response rates (the primary composite endpoint) between the two treatment groups was 0.2%, with a 95.2% CI of (–5.6, 6.0). The CI contains 0 and the lower limit is above – 10%, indicating that caspofungin is non-inferior to L-AMB as empirical therapy in patients with persistent fever and neutropenia.1 The treatment-by-stratum interaction test indicated that the difference in response rates between the two treatment groups was consistent across strata defined by risk and antifungal prophylaxis.1 Of the individual endpoints contained in the composite endpoint: Success in baseline infection showed a clear difference in response rates (a 25.9% difference in favor of caspofungin) due to the consistently higher response rates for both Aspergillus and Candida infections in the caspofungin versus the L-AMB group.1 However, because of the small number of patients with a baseline infection (27 patients in each group), this difference must be viewed with caution.1 Absence of breakthrough fungal infections occurred in a slightly (<0.9%) higher proportion of patients in the L-AMB group.1 Resolution of fever occurred in a slightly higher proportion of patients (0.2%) in the L-AMB group.1 The proportion of patients who survived for at least 7 days after completion of therapy was higher in the caspofungin versus the L-AMB group. The 95% CI for this difference is (0.0, 6.8), indicating that the survival rates do not reach a statistical advantage for the caspofungin group.1 The proportion of patients who did not discontinue therapy prematurely was higher in the caspofungin versus the L-AMB group. The 95% CI for this difference (0.3, 8.1) lies completely above 0, indicating that a higher proportion of patients receiving caspofungin versus L-AMB completed therapy or had a non- endpoint discontinuation. This difference was seen regardless of risk stratum or use of antifungal prophylaxis.1 Ustąpienie gorączki –10 –5 5 10 15 25 60 Różnica w %  lepszy AmBisome lepsza Kaspofungina  *MITT – Modified Intention to Treat Analysis - ocenie poddano wszystkich pacjentów którzy otrzymali przynajmniej 1 dawkę leku. Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: MITT – Modified Intention to Treeat Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Skuteczne wyleczenie podstawowej infekcji (MITT)
Kaspofungina (n=27) 52 Slide 27 L-AMB (n=27) 26 Patients with known, documented invasive fungal infections were excluded from Protocol 026.1 Therefore, patients included in the analysis of successful outcome of baseline infections may have had a suspected infection present at study entry, but confirmatory information did not become positive until after study entry.1 Approximately 5% of each treatment group (27 patients in each group) had baseline infections.1 Successful outcomes were observed in a higher proportion of patients in the caspofungin group (52%) than that in the L-AMB group (26%). However, due to the small number of patients with baseline infections in this study, any apparent difference between treatment groups must be viewed with caution.1 The most common baseline infections were due to Aspergillus species (12 infections per group; the most common diagnosis was Aspergillus pneumonia) and Candida species (12 infections per group; the most common diagnosis was fungemia). Other pathogens included Ascomycetes, Fusarium, non-specified mold, and Zygomycetes.1 Response rates were higher in the caspofungin group versus the L-AMB group for baseline infections due to both mold and yeast pathogens.1 10 20 30 40 50 60 % pacjentów Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Skuteczne wyleczenie podstawowej infekcji — Aspergillus lub Candida (MITT) Infekcje Aspergillus Kaspofungina (n=12) 42 L-AMB (n=12) 8 5 10 15 20 25 30 35 40 45 Slide 28 Infekcje Candida For infections due to Aspergillus, which occurred in 12 patients in each treatment group, successful outcomes were observed in 42% of patients in the caspofungin group versus 8% of patients in the L- AMB group.1 For infections due to Candida, which also occurred in 12 patients in each treatment group, successful outcomes were observed in 67% of patients in the caspofungin group versus 42% of patients in the L-AMB group.1 Kaspofungina (n=12) 67 L-AMB (n=12) 42 10 20 30 40 50 60 70 80 % pacjentów Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Infekcje wtórne (nadkażenia) (MITT)
Kaspofungina L-AMB (n=556) (n=539) Wszyscy pacjenci z wtórną inf. grzybiczą 29 23 Aspergillus spp. 10 9 Candida spp Inne* Slide 29 Overall, 30 breakthrough infections were reported in 29 patients in the caspofungin group, and 24 breakthrough infections were reported in 23 patients in the L-AMB group.1 The most common breakthrough infections in both groups were due to Candida species, and the most common diagnoses were chronic disseminated candidiasis (13) and fungemia (12). The second most common breakthrough infections were due to Aspergillus species, and the most common diagnosis was pneumonia (12).1 Chronic disseminated candidiasis was more commonly observed as a breakthrough infection than as a baseline infection in both groups. 1 Overall, by pathogen, the breakthrough infections were well balanced between the two treatment groups.1 *Basidomycetes, Fusarium, Zygomycetes Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Przeżycie (MITT)
100 90 80 70 p=0.044 60 50 Przeżycia % 40 Slide 30 30 20 The percentages of patients who survived for at least 7 days after completion of therapy were 93% in the caspofungin group and 89% in the L-AMB group.1 Kaplan-Meier estimates were used to display survival through day 63 after initiation of therapy. Throughout this period of follow-up, the proportion of patients who survived was consistently higher in the caspofungin group than in the L-AMB group (log-rank chi- square test, p=0.044).1 Kaspofungina (n=556) L-AMB (n=539) 10 7 14 21 28 35 42 49 56 63 Dzień badania Kaspofungina n= L-AMB n= Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Przerwanie leczenia z powodu braku skuteczności lub z powodu działań niepożądanych (MITT) Kaspofungina (n=556) 10.3 Slide 31 L-AMB (n=539) 14.5 A lower proportion of patients receiving caspofungin (10.3%) versus patients receiving L-AMB (14.5%) discontinued therapy due to lack of efficacy or toxicity.1 The rates of successful completion of therapy or non-endpoint discontinuation, without premature discontinuation due to toxicity or lack of efficacy, were consistently higher among patients receiving caspofungin regardless of risk stratum or use of antifungal prophylaxis.1 2 4 6 8 10 12 14 16 % pacjentów Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Śmiertelność
Liczba (%) zgonów Kaspofungina L-AMB u pacjentów z (n=556) (n=539) Podstawową infekcją 3/27 12/27 (11.1%) (44.4%) Wtórną infekcją 10/29 9/23 (34.5%) (39.1%) Slide 32 Because mortality rates are substantial in patients with febrile neutropenia, due to fungal and other infections, as well as underlying malignancy and its noninfectious complications, the trial investigators examined mortality from a variety of perspectives, including rates in patients with documented fungal infections.1 The proportion of patients with a baseline infection who died was substantially lower in the caspofungin group (3 deaths; 11.1%) than in the L-AMB group (12 deaths; 44.4%). The excess mortality in the L-AMB group was due to clinical AEs involving many different body systems, with the largest differences between groups due to fatal bacterial infections, fungal infections, and nonspecific sepsis syndromes.1 The proportion of patients with breakthrough infections who died was similar in the caspofungin group (10 deaths; 34.5%) versus the L-AMB group (9 deaths; 39.1%).1 Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Działania niepożądane
lepsza Kaspofungina lepsza L-AMB Nefrotoksyczność Związane z infuzją Slide 33 Związane z lekiem działania niepożądane The main tolerability hypothesis for Protocol 026 was that the incidence of nephrotoxicity (defined as a doubling of serum creatinine or an increase in creatinine by 1 mg/dl if the creatinine was elevated at study entry) during IV therapy would be no greater in the caspofungin group than in the L-AMB group. The analysis of nephrotoxicity included only patients with normal renal function (creatinine clearance >30 ml/min) at baseline. This hypothesis was validated: the incidence of nephrotoxicity was 8.9% lower in the caspofungin group, with a 95% CI completely below 0 (–12.0, – 5.9), indicating that the risk of nephrotoxicity was lower with caspofungin than with L-AMB.1 Another tolerability hypothesis was that caspofungin would be non- inferior to L-AMB with respect to infusion-related AEs (systemic symptoms such as fever, chills, headache, nausea, vomiting, tachycardia, or tachypnea) with an onset during or within one hour after drug infusion. This hypothesis was validated: the incidence of infusion-related events in the caspofungin group was 16.4% lower than that in the L-AMB group (p<0.001), with a 95% CI completely below 0 (–22.2, –10.7), indicating that such events were less likely to occur in patients who received caspofungin (35.1%) than in patients who received L-AMB (51.6%).1 The incidence of drug-related clinical AEs was 12.6% lower in the caspofungin group (47%) than in the L-AMB group (59.6) (p<0.001), with a 95% CI completely below 0 (–18.4, –6.8).1 The incidence of discontinuations due to a serious drug-related clinical AE was significantly lower in the caspofungin group than in the L-AMB group (p=0.015).1 Przerwanie leczenia wskutek działań niepożądanych związanych z lekiem –30 –20 –10 10 Różnica w % *Możliwe, prawdopodobne lub na pewno związane z lekiem, wg badających Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Kaspofungina powodowała znacząco mniej p value
Terapia empiryczna (Protokół 026) Działania niepożądane związane z lekiem Kaspofungina powodowała znacząco mniej p value Działań niepożądanych związanych z lekiem <0.001 Przerwań leczenia z powodu dz.niepożądanych 0.015 Dz. niepożądanych laboratoratoryjnych <0.001 Przerwań leczenia z powodu laboratoryjnych działań niepożądanych 0.010 Slide 34 Patients receiving caspofungin experienced significantly fewer drug-related AEs (p<0.001), discontinuations due to serious drug- related clinical AEs (p=0.015), drug-related laboratory AEs (p<0.001), and discontinuations due to drug-related laboratory AEs (p=0.01).1 Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

Terapia empiryczna (Protokół 026) Podsumowanie i wnioski
Kaspofungina była równie skuteczna co L-AMB w empirycznej terapii podejrzenia infekcji grzybiczej u gorączkujących pacjentów z neutropenią Kaspofungina wykazała przewagę nad L-AMB w Leczeniu infekcji podstawowej Ilości przedwczesnych przerwań terapii Kaspofungina wpływała korzystnie na przeżycie 7-dniowe oraz w przebiegu podstawowej infekcji grzybiczej (p<0.01) Kaspofungina i L-AMB były porównywalne w Ilości wtórnych infekcji ustępowaniu gorączki Kaspofungina była lepiej tolerowana niż L-AMB w odniesieniu do Nefrotoksyczności Działań niepożądanych związanych z infuzją Działań niepożądanych związanych z lekiem Przerwania terapii wskutek działań niepożądanych związanych z lekiem Slide 35 Protocol 026 demonstrated that caspofungin was as effective as L-AMB as empirical therapy of suspected fungal infections in febrile neutropenic patients.1 Caspofungin provided benetifs versus L-AMB with respect to outcome of baseline fungal infections and the proportion of patients who did not discontinue treatment prematurely due to toxicity or lack of efficacy.1 Caspofungin also improved survival, assessed by several methods; i.e., survival to 7 days post-therapy and survival by Kaplan-Meier estimates (p=0.044).1 The proportion of patients who experienced breakthrough infections and the proportion of patients whose fever resolved with therapy was similar in the caspofungin and L-AMB treatment groups.1 Overall, caspofungin was better tolerated than L-AMB with respect to nephrotoxicity, infusion-related events, drug-related AEs, and discontinuations due to drug-related AEs.1 Na podstawie Walsh T.J. i wsp. „Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia” NEJM 2004; 351; 14: Reference 1. Data on file, MSD ________.

CANCIDAS® Inne informacje
Slide 36 Other Information on Caspofungin Slides 74-82 Safety Profile Across Multiple Clinical Studies Slide 75 Caspofungin vs. Amphotericin B Label-to-Label Comparison of Dosing Slide 76 Dosing and Administration Slide 77 Indications Slide 78 Contraindications Slide 79 Precautions Slide 80 Drug-Drug Interactions Slide 81 Summary Slide 82

Profil bezpieczeństwa we wszystkich badaniach klinicznych
Oceniony u 1440 pacjentów 394 pacjentów w badaniach I fazy Większość pacjentów z infekcją Candida miało poważne schorzenia podstawowe w tym hematologiczne lub inne złośliwe nowotwory, była po dużych zabiegach operacyjnych lub z HIV W badanich klinicznych wśród pacjentów z kandydozą przełyku lub/i jamy ustnej i gardła, kaspofungina (n=83) wykazała profil bezpieczeństwa porównywalny z flukonazolem (n=94) W badanich klinicznych wśród pacjentów z inwazyjną kandydozą, kaspofungina (n=114) wykazała lepszy profil tolerancji niż amfoterycyna B (n=125) W otwartym, nieporównawczym badaniu u chorych z aspergilozą (n=69), kaspofungina podtrzymała korzystny profil Slide 37 1440 patients who received single or multiple doses of caspofungin have been evaluated for clinical and laboratory AEs. 564 patients had febrile neutropenia, 125 patients had invasive candidiasis, 285 had esophageal and/or oropharyngeal candidiasis, and 72 patients had invasive aspergillosis. The remaining 394 patients were enrolled in Phase I studies. Most of the patients with Candida infections had serious underlying conditions, including hematologic or other malignancy, recent major surgery, or HIV, which necessitated multiple concomitant medications. Patients with invasive aspergillosis often had serious predisposing conditions such as bone-marrow or peripheral stem-cell transplants, hematologic malignancies, solid tumors or organ transplants, which necessitated multiple concomitant medications. In the invasive candidiasis study, the incidence of drug-related clinical AEs was lower in the caspofungin-treated group (28.9%) versus 58.4% of the amphotericin B patients. In terms of the urogenital system, 0.9% of caspofungin patients versus 5.6% of amphotericin B patients developed renal insufficiency and no caspofungin patients versus 5.6% of amphotericin B patients showed acute renal insufficiency. Also, the proportion of patients who experienced an infusion-related AE was lower in the caspofungin group (20.2%) than in the amphotericin B group (48.8%). Throughout the trials, for all indications, caspofungin maintained a favorable safety/tolerability profile.

Kaspofungina / Amfoterycyna B Porównanie dawkowania
Dawki Dawki Dzień 1 Po 1 dniu 0.25 mg/kg do 1.5 mg/kg*** 70 mg/dobę* 50 mg/dobę 1-godzinna infuzja Nie potrzebna premedykacja 2- 6 godzinna infuzja Slide 38 Nie konieczna modyfikacja dawki Konieczna modyfikacja dawki W niewydolności nerek W średniego stopnia niewydolności wątroby (5- 6 stopnia w skali Child-Pugh)** W wieku podeszłym W oparciu o stan kliniczny i chorobę podstawową Caspofungin is easy to administer compared with amphotericin B. On the first day of therapy, patients with invasive aspergillosis should receive a 70 mg loading dose of caspofungin; thereafter, they should receive a 50 mg daily dose. For patients with esophageal and/or oropharyngeal candidiasis, 50 mg/day should be administered from day 1.1 Weight-based dosing is required for amphotericin B.1 Caspofungin should be infused over 1 hour, whereas amphotericin B requires 2 to 6 hours to infuse. Additionally, no premedication is necessary before administering caspofungin.1 Caspofungin does not require any dosage adjustment in patients with renal insufficiency or mild hepatic insufficiency (Child-Pugh score 5 to 6), or in the elderly. Dosages of amphotericin B must be adjusted based on the disease state and the patient’s underlying condition.2 For patients with invasive aspergillosis and moderate hepatic insufficiency (Child-Pugh score 7 to 9), an adjustment of the daily dose to 35 mg is recommended after the initial 70 mg loading dose. For patients with esophageal and/or oropharyngeal candidiasis and moderate hepatic insufficiency, a daily dose of 35 mg is recommended with no loading dose. There is no clinical experience in patients with severe hepatic insufficiency (Child- Pugh score >9). *U pacjentów z inwazyjną aspergillozą, gorączkujących i z neutropenią; dla pacjentów z kandydozą jamy ustnej, gardła i przełyku mg/day ** U pacjentów z inwazyjną aspergillozą, zaostrzoną niewydolnością wątroby (Child-Pugh 7 -9), zaleca się zmniejszenie dawki dobowej do 35 mg. po dawce nasycającej 70 mg. Dla pacjentów z kandydozą przełyku, jamy ustnej i gardła i zaostrzonej niewydolności wątroby zalecana jest dawka 35 mg bez dawki nasycającej. Brak doświadczeń klinicznych u chorych z ciężką niewydolnością wątroby (Child-Pugh >9). ***Optymalna dawka nie jest znana Na podstawie informacji o leku Fungizone®. Reference 1. Fungizone® Intravenous [package insert]. Princeton, NJ, USA: Apothecon® (A Bristol-Myers Squibb Company), April 1998.

Kaspofungina była tolerowana do 162 dni terapii w badaniu klinicznym*
Dawkowanie i podawanie leku Kaspofungina była tolerowana do 162 dni terapii w badaniu klinicznym* Czas trwania leczenia zależy od: Ciężkości choroby podstawowej Stanu immunosuppresji Odpowiedzi klinicznej Slide 39 In the aspergillosis study (Protocol 019), the mean duration of therapy was 33.7 days, with a range of 1 to 162 days of therapy. Although there is no information to demonstrate an increase in efficacy with higher doses, available data suggest that an increase in dosage to 70 mg daily may be considered in patients without evidence of clinical response in whom caspofungin has been well tolerated. Recommended durations of therapy are as follows: Empirical Therapy: Should be continued until resolution of neutropenia. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. Invasive Candidiasis: Duration of treatment should be dictated by the patient’s clinical and microbiologic response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Patients who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia. Invasive Aspergillosis: Duration of treatment should be based on the patient’s underlying disease, recovery from immunosuppression, and clinical response. *69 pacjentów otrzymywało od 1 do 162 dni leczenia

Inwazyjna kandydoza, w tym kandydemia u pacjentów z neutropenią i bez
Wskazania Empiryczne leczenie podejrzenia infekcji grzybiczej u pacjentów z neutropenią i gorączką Inwazyjna kandydoza, w tym kandydemia u pacjentów z neutropenią i bez Inwazyjna aspergilloza u pacjentów opornych lub nietolerujących standardowych terapii Slide 40 Caspofungin has received a new first-line indication for empirical therapy for presumed fungal infections in febrile neutropenic patients. Caspofungin is indicated for invasive candidiasis, including candidemia, in neutropenic and non-neutropenic patients. Caspofungin is indicated for invasive aspergillosis in patients who are refractory to or intolerant of other therapies. Caspofungin is also indicated for the first-line parenteral treatment of esophageal and/or oropharyngeal candidiasis.

Przeciwwskazania Kaspofungina jest przeciwwskazana u pacjentów nadwrażliwych na jakikolwiek składnik produktu Slide 41 Caspofungin is contraindicated in patients with hypersensitivity to any component of this product.

Uwagi Kaspofungina powinna być używana ostrożnie w następujących grupach pacjentów: Kobiety ciężarne kaspofungina nie powinna być stosowana bez bezwględnej potrzeby Matki karmiące Kobiety otrzymujące kaspofunginę nie powinny karmić piersią Pacjenci z niewydolnością wątroby Średniego stopnia (Child-Pugh 5 - 6), bez modyfikacji dawki Z zaostrzoną niewydolnością wątroby (Child-Pugh 7 -9), po 70 mg dawki nasycającej, zaleca się 35 mg/dobę Brak klinicznych doświadczeń u pacjentów z ciężką niewydolnością wątroby (Child-Pugh >9) Dzieci Nie ustalano skuteczności i tolerancji u dzieci Nie zaleca się stosowania poniżej 18 roku życia Slide 42 Caspofungin should be used with caution in the following patient groups Pregnant women: There are no well-controlled studies with pregnant women. Caspofungin should not be used in pregnancy unless clearly necessary. Nursing mothers: It is not known whether caspofungin is excreted in human milk. Women receiving caspofungin should not breast-feed. Patients with hepatic insufficiency For patients with a Child-Pugh score of 5 to 6 (mild hepatic insufficiency), no dosage adjustment is needed. For patients with a Child-Pugh score of 7 to 9 (moderate hepatic insufficiency), a 35 mg daily dose of caspofungin is recommended after the initial 70 mg dose. There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9) Children: Tolerability and efficacy in pediatric patients have not been established. Use in patients under 18 years of age is not recommended.

Kaspofungina nie jest inhibitorem jakiegokolwiek enzymu układu CYP450
Interakcje lekowe Kaspofungina nie jest inhibitorem jakiegokolwiek enzymu układu CYP450 Kaspofungina nie wykazuje interakcji z lekami zapobiegającymi odzrzucaniu przeszczepu: mykofenolat lekami p-grzybiczymi: amfoterycyna B, itrakonazol Wspólne użycie z cyklosporyną nie jest zalecane dopóki nie zostanie dokładnie zbadane w długotrwałej terapii Slide 43 Studies in vitro show that caspofungin is not an inhibitor of any enzyme in the CYP450 system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for CYP450 enzymes. Concomitant use with cyclosporine is not recommended until multiple-dose use in patients is studied. In one clinical study, three of four subjects who received caspofungin 70 mg on days 1 through 10 and cyclosporine (two 3 mg/kg doses administered 12 hours apart on day 10) developed transient elevations of ALT* on day 11 that were two to three times the ULN. In a separate panel of subjects within the same study, two of eight patients who received caspofungin 35 mg daily for 3 days and cyclosporine (two 3 mg/kg doses administered 12 hours apart on day 1) had smaller increases in ALT (slightly above the ULN) on day 2. In both groups, elevations in AST** paralleled ALT elevations, but were of lesser magnitude. *ALT = alanine aminotransferase **AST = aspartate aminotransferase

Specyficzny mechanizm działania
Podsumowanie Specyficzny mechanizm działania Pierwszy nowej klasy inhibitor syntezy beta (1-3)-D-glikanu Wysoka skuteczność i tolerancja Obecnie zalecany w leczeniu inwazyjnej aspergillozy* Slide 44 Caspofungin is the first in a new class of beta (1,3)-D-glucan synthesis inhibitors (echinocandins). Selective mechanism of action compromises the integrity of the fungal cells, not human cells.1 This selective mechanism of action of caspofungin offers both efficacy and tolerability, providing a new option for treating serious fungal infections.1-3 *U pacjentów opornych lub nie tolerujących innych terapii Na podstawie Graybill JR i wsp. Antimicrob Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Curr Opin Infect Dis 1997; 10:449–458; Onishi J i wsp. Antimicrob Agents Chemother 2000;44:368–377. References 1. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41:1775–1777. 2. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. 3. Onishi J, Meinz M, Thompson J i wsp.. Discovery of novel antifungal (1,3)-β-D-glucan synthase inhibitors. Antimicrob Agents Chemother 2000;44:368–377.

w terapii przecigrzybiczej
Cancidas® - wyznacza nowe standardy w terapii przecigrzybiczej Silne działanie przeciwgrzybicze w leczeniu: empirycznym gorączki neutropenicznej inwazyjnej kandydozy* inwazyjnej aspergilozy** Profil bezpieczeństwa porównywalny z flukonazolem Przełomowy mechanizm działania na ścianę komórki grzyba Dawkowanie 1 raz na dobę Slide 45 Caspofungin is the first in a new class of beta (1,3)-D-glucan synthesis inhibitors (echinocandins). Selective mechanism of action compromises the integrity of the fungal cells, not human cells.1 This selective mechanism of action of caspofungin offers both efficacy and tolerability, providing a new option for treating serious fungal infections.1-3 * u pacjentów dorosłych * U pacjentów ** u pacjentów dorosłych inwazyjnej aspergilozy opornej na terapię. Leczenie inwazyjnej aspergilozy u pacjentów dorosłych nietolerujących terapii amfoterycyną B, preparatami lipidowymi amfoterycyny B i (lub) itrakonazolem. . References 1. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41:1775–1777. 2. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. 3. Onishi J, Meinz M, Thompson J i wsp.. Discovery of novel antifungal (1,3)-β-D-glucan synthase inhibitors. Antimicrob Agents Chemother 2000;44:368–377.

Caspofungin is the first in a new class of beta (1,3)-D-glucan synthesis inhibitors (echinocandins). Selective mechanism of action compromises the integrity of the fungal cells, not human cells.1 This selective mechanism of action of caspofungin offers both efficacy and tolerability, providing a new option for treating serious fungal infections.1-3 References 1. Graybill JR, Najvar LK, Luther MF i wsp.. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41:1775–1777. 2. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. 3. Onishi J, Meinz M, Thompson J i wsp.. Discovery of novel antifungal (1,3)-β-D-glucan synthase inhibitors. Antimicrob Agents Chemother 2000;44:368–377.

Piśmiennictwo Anaissie EJ, Rex JH, Uzun O i wsp.. Predictors of adverse outcome in cancer patients with candidemia. Am J Med 1998;104:238–245. Andriole VT. Current and future therapy of invasive fungal infections. Curr Clin Top Infect Dis 1998;18:19–36. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. Arathoon EG, Gotuzzo E, Noriega LM i wsp.. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother 2002;46:451–457. Barber FD. Management of fever in neutropenic patients with cancer. Nurs Clin North Am 2001;36(4):631–644. Bates DW, Su L, Yu DT i wsp.. Mortality and costs of acute renal failure associated with amphotericin therapy. Clin Infect Dis 2001;32:686–693. Berrouane YF, Herwaldt LA, Pfaller MA. Trends in antifungal use and epidemiology of nosocomial yeast infections in a university hospital. J Clin Microbiol 1999;37(3):531–537. Blumberg HM, Jarvis WR, Soucie JM i wsp.. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: The NEMIS prospective multicenter study. Clin Infect Dis 2001;33:177–186. Cannon JP, Garey KW, Danziger LH. A prospective and retrospective analysis of the nephrotoxicity and efficacy of lipid-based amphotericin B formulations. Pharmacotherapy 2001;21(9):1107–1114. Carroll K, Jeppson K, Reading J i wsp.. Factors influencing outcome in hospitalized patients with candidemia. Infect Dis Clin Pract 1993;2:268–271. Slide 47 Anaissie EJ, Rex JH, Uzun O i wsp.. Predictors of adverse outcome in cancer patients with candidemia. Am J Med 1998;104:238–245. Andriole VT. Current and future therapy of invasive fungal infections. Curr Clin Top Infect Dis 1998;18:19–36. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162. Arathoon EG, Gotuzzo E, Noriega LM i wsp.. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother 2002;46:451–457. Barber FD. Management of fever in neutropenic patients with cancer. Nurs Clin North Am 2001;36(4):631–644. Bates DW, Su L, Yu DT i wsp.. Mortality and costs of acute renal failure associated with amphotericin therapy. Clin Infect Dis 2001;32:686–693. Berrouane YF, Herwaldt LA, Pfaller MA. Trends in antifungal use and epidemiology of nosocomial yeast infections in a university hospital. J Clin Microbiol 1999;37(3):531–537. Blumberg HM, Jarvis WR, Soucie JM i wsp.. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: The NEMIS prospective multicenter study. Clin Infect Dis 2001;33:177–186. Cannon JP, Garey KW, Danziger LH. A prospective and retrospective analysis of the nephrotoxicity and efficacy of lipid-based amphotericin B formulations. Pharmacotherapy 2001;21(9):1107–1114. Carroll K, Jeppson K, Reading J i wsp.. Factors influencing outcome in hospitalized patients with candidemia. Infect Dis Clin Pract 1993;2:268–271.

Piśmiennictwo Data on file, MSD_________.
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Piśmiennictwo Georgopapadakou NH, Walsh TJ. Human mycoses: Drugs and targets for emerging pathogens. Science 1994;264:371–373. Graybill JR, Najvar LK, Luther MF, Fothergill AW. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;1775–1777. Graybill JR. The echinocandins, first novel class of antifungals in two decades: Will they live up to their promise? Int J Clin Pract 2001;55:633–638. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: A comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. Groll AH, Walsh TJ. Caspofungin: Pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Invest Drugs 2001;10(8):1545–1558. Groll AH, Walsh TJ. Antifungal chemotherapy: Advances and perspectives. Swiss Med Wkly 2002;132: 303–311. Harari S. Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients. Drugs 1999;58(4):621–631. Harvey RL, Myers JP. Nosocomial fungemia in a large community teaching hospital. Arch Intern Med 1987;147:2117–2120. Jarvis WR, White JW, Munn VP i wsp.. Nosocomial infection surveillance, MMWR CDC Surveill Summ 1984;33(2SS):9SS–21SS. Slide 49 Georgopapadakou NH, Walsh TJ. Human mycoses: Drugs and targets for emerging pathogens. Science 1994;264:371–373. Graybill JR, Najvar LK, Luther MF, Fothergill AW. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;1775–1777. Graybill JR. The echinocandins, first novel class of antifungals in two decades: Will they live up to their promise? Int J Clin Pract 2001;55:633–638. Groll AH, Walsh TJ. Potential new antifungal agents. Curr Opin Infect Dis 1997;10:449–458. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: A comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343–500. Groll AH, Walsh TJ. Caspofungin: Pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Invest Drugs 2001;10(8):1545–1558. Groll AH, Walsh TJ. Antifungal chemotherapy: Advances and perspectives. Swiss Med Wkly 2002;132:303–311. Harari S. Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients. Drugs 1999;58(4):621–631. Harvey RL, Myers JP. Nosocomial fungemia in a large community teaching hospital. Arch Intern Med 1987;147:2117–2120. Jarvis WR, White JW, Munn VP i wsp.. Nosocomial infection surveillance, MMWR CDC Surveill Summ 1984;33(2SS):9SS–21SS.

Piśmiennictwo Kartsonis NA. Caspofungin Development Program. Presented at the 12th European Congress of Clinical Microbiology and Infectious Disease. Milan, Italy, April 24–27, 2002. Kern WV. Risk assessment and risk-based therapeutic strategies in febrile neutropenia. Curr Opin Infect Dis 2001;14(4):415–422. Komshian SV, Uwaydah AK, Sobel JD i wsp.. Fungemia caused by Candida species and Torulopsis glabrata in the hospitalized patient: Frequency, characteristics and evaluation factors influencing outcome. Rev Infect Dis 1989;11(3):379–390. Lin S, Schranz J, Teutsch S. Aspergillosis case-fatality rate: Systematic review of the literature. Clin Infect Dis 2001;32:358–366. Maertens J, Raad I, Petrikkos G i wsp.. Update of the multicenter, noncomparative study of caspofungin (CAS) in adults with invasive aspergillosis (IA) refractory (R) or intolerant (I) to other antifungal agents: An analysis of 90 patients. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif, September Poster M-868. Marco F, Pfaller MA, Messer SA i wsp.. 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;31:33–37. Mora-Duarte J, Betts R, Rotstein C i wsp.. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2000;347:2020–2029. Nguyen MH, Peacock JE, Tanner DC i wsp.. Therapeutic approaches in patients with candidemia. Ann Oncol 2000;11:1517–1521. Slide 50 Kartsonis NA. Caspofungin Development Program. Presented at the 12th European Congress of Clinical Microbiology and Infectious Disease, Milan, Italy, April 24–27, 2002. Kern WV. Risk assessment and risk-based therapeutic strategies in febrile neutropenia. Curr Opin Infect Dis 2001;14(4):415–422. Komshian SV, Uwaydah AK, Sobel JD i wsp.. Fungemia caused by Candida species and Torulopsis glabrata in the hospitalized patient: Frequency, characteristics and evaluation factors influencing outcome. Rev Infect Dis 1989;11(3):379–390. Lin S, Schranz J, Teutsch S. Aspergillosis case-fatality rate: Systematic review of the literature. Clin Infect Dis 2001;32:358–366. Maertens J, Raad I, Petrikkos G i wsp.. Update of the multicenter, noncomparative study of caspofungin (CAS) in adults with invasive aspergillosis (IA) refractory (R) or intolerant (I) to other antifungal agents: An analysis of 90 patients. Presented at 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif, September Poster M-868. Marco F, Pfaller MA, Messer SA i wsp.. 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;31:33–37. Mora-Duarte J, Betts R, Rotstein C i wsp.. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2000;347:2020–2029. Nguyen MH, Peacock JE, Tanner DC i wsp.. Therapeutic approaches in patients with candidemia. Ann Oncol 2000;11:1517–1521.

Piśmiennictwo Onishi J, Meinz M, Thompson J i wsp.. Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 2000;44(2):368–377. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore) 1999;78(2): 123–138. Perfect J. Paper presented at the 12th European Congress of Clinical Microbiology and Infectious Disease. Milan, Italy, April 24–27, 2002. Pfaller MA, Jones RN, Doern GV i wsp.. Bloodstream infections due to Candida species: SENTRY antimicrobial surveillance program in North American and Latin America, 1997– Antimicrob Agents Chemother 2000;44(3):747–751. Rex JH, Walsh TJ, Sobel JD i wsp.. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000;30:662–678. Sawaya BP, Briggs JP, Schenermann J. Amphotericin B nephrotoxicity: The adverse consequences of altered membrane properties. J Am Soc Nephrol 1995;6:154–164. Sporanox® Injection [package insert]. Raritan, NJ, USA: Ortho Biotech Inc., January 2000. Stedman TL. Stedman’s Medical Dictionary. 26th ed. Philadelphia: Lippincott, Williams & Wilkins, 2000. Stevens DA, Bennett JE. Antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459. Stone EA, Fung HB, Kirschenbaum HL. Caspofungin: An echinocandin antifungal agent. Clin Ther 2002;24(3):351–377. Slide 51 Onishi J, Meinz M, Thompson J i wsp.. Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 2000;44(2):368–377. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore) 1999;78(2):123–138. Perfect J. Paper presented at the 12th European Congress of Clinical Microbiology and Infectious Disease, Milan, Italy, April 24–27, 2002. Pfaller MA, Jones RN, Doern GV i wsp.. Bloodstream infections due to Candida species: SENTRY antimicrobial surveillance program in North American and Latin America, 1997– Antimicrob Agents Chemother 2000;44(3):747–751. Rex JH, Walsh TJ, Sobel JD i wsp.. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000;30:662–678. Sawaya BP, Briggs JP, Schenermann J. Amphotericin B nephrotoxicity: The adverse consequences of altered membrane properties. J Am Soc Nephrol 1995;6:154–164. Sporanox® Injection [package insert]. Raritan, NJ, USA: Ortho Biotech Inc., January 2000. Stedman TL. Stedman’s Medical Dictionary. 26th ed. Philadelphia: Lippincott, Williams & Wilkins, 2000. Stevens DA, Bennett JE. Antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459. Stone EA, Fung HB, Kirschenbaum HL. Caspofungin: An echinocandin antifungal agent. Clin Ther 2002;24(3):351–377.

Piśmiennictwo Tkacz JS. Glucan biosynthesis in fungi and its inhibition. In: Sutcliff JA, Georgopapadaku NH, eds. Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992;495–523. Uzun O, Anaissie EJ. Predictors of outcome in cancer patients with candidemia. Ann Oncol 2000;11: 1517–1521. Villanueva A, Arathoon EG, Gotuzzo E i wsp.. A randomized double-blind study of caspofungin versus amphotericin B for the treatment of candidal esophagitis. Clin Infect Dis 2001;33:1529–1535. Villanueva A, Gotuzzo E, Arathoon EG i wsp.. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 2002;113:294–299. Walsh TJ, Goodman JL, Pappas P i wsp.. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: Maximum tolerated dose study. Antimicrob Agents Chemother 2001;45(12):3487–3496. White MH, Bowden RA, Sandler ES i wsp.. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998;27(2):296–302. Slide 52 Tkacz JS. Glucan biosynthesis in fungi and its inhibition. In: Sutcliff JA, Georgopapadaku NH, eds. Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992;495–523. Uzun O, Anaissie EJ. Predictors of outcome in cancer patients with candidemia. Ann Oncol 2000;11:1517–1521. Villanueva A, Arathoon EG, Gotuzzo E i wsp.. A randomized double-blind study of caspofungin versus amphotericin B for the treatment of candidal esophagitis. Clin Infect Dis 2001;33:1529–1535. Villanueva A, Gotuzzo E, Arathoon EG i wsp.. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 2002;113:294–299. Walsh TJ, Goodman JL, Pappas P i wsp.. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: Maximum tolerated dose study. Antimicrob Agents Chemother 2001;45(12):3487–3496. White MH, Bowden RA, Sandler ES i wsp.. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998;27(2):296–302.

CANCIDAS® – najnowsze dane kliniczne
Przed zastosowaniem należy zapoznać się z pełną informacją o leku Merck nie zaleca użycia jakiegokolwiek produktu w inny sposób, niż opisano to w informacjach o lekach Slide 53 Before prescribing, please consult the manufacturers’ prescribing information. Merck does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved CAN 2004-W-6281-SS Printed in USA VISIT US ON THE WORLD WIDE WEB at MSD Polska Sp. z o.o. ul. Chłodna 51, Warszawa, tel. (+48-22) , fax (+48-22) ® Zastrzeżona nazwa handlowa Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. © Zastrzeżone prawa autorskie MSD Polska Sp. z o.o CAN SS

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