Advances in antifungal prophylaxis and empiric therapy in patients with hematologic malignancies: Review article

Transplant Infectious Disease

Volumn 11, Issue 6, 2009, Pages 480-490

  Murali, S ^a   Langston, A ^a  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Antifungal prophylaxis; Hematologic malignancies; Invasive fungal infections; Risk factors

Indexed keywords

AMPHOTERICIN B; AMPHOTERICIN B DEOXYCHOLATE; AMPHOTERICIN B LIPID COMPLEX; ANIDULAFUNGIN; ANTINEOPLASTIC AGENT; ARABINOSE; CASPOFUNGIN; CORTICOSTEROID; CYCLOSPORIN; ECHINOCANDIN; FLUCONAZOLE; ITRACONAZOLE; MICAFUNGIN; PLACEBO; POSACONAZOLE; TACROLIMUS; VORICONAZOLE;

ACUTE GRANULOCYTIC LEUKEMIA; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; ANTIFUNGAL ACTIVITY; ASPERGILLOSIS; CANDIDIASIS; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; DRUG MEGADOSE; FUNGAL COLONIZATION; FUSARIOSIS; GRAFT VERSUS HOST REACTION; HEMATOLOGIC MALIGNANCY; HUMAN; INFECTION RISK; MORBIDITY; MYCOSIS; MYELODYSPLASTIC SYNDROME; NEPHROTOXICITY; NEUTROPENIA; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REVIEW; RISK ASSESSMENT; VISUAL HALLUCINATION;

ANTIBIOTIC PROPHYLAXIS; ANTIFUNGAL AGENTS; ASPERGILLOSIS; CANDIDIASIS; HEMATOLOGIC NEOPLASMS; HUMANS; MYCOSES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RISK FACTORS;

EID: 71149119746     PISSN: 13982273     EISSN: 13993062     Source Type: Journal    
DOI: 10.1111/j.1399-3062.2009.00441.x     Document Type: Review

References (95)

1. Rousey SR, Russler S, Gottlieb M, Ash RC. Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation. Am J Med 1991 91 (5) : 484 492.
2. Winston DJ. Prophylaxis and treatment of infection in the bone marrow transplant recipient. Curr Clin Top Infect Dis 1993 13 : 293 321.
3. Marr KA, Seidel K, White TC, Bowden RA. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000 181 (1) : 309 316.
4. Afessa B, Peters SG. Major complications following hematopoietic stem cell transplantation. Semin Respir Crit Care Med 2006 27 (3) : 297 309.
5. Segal BH, Almyroudis NG, Battiwalla M, et al. Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts. Clin Infect Dis 2007 44 (3) : 402 409.
6. Rotstein C. Empiric antifungal therapy in neutropenic cancer patients. Curr Infect Dis Rep 2006 8 (1) : 7 13.
7. Mahfouz T, Anaissie E. Prevention of fungal infections in the immunocompromised host. Curr Opin Investig Drugs 2003 4 (8) : 974 990.
8. Prentice HG, Kibbler CC, Prentice AG. Towards a targeted, risk-based, antifungal strategy in neutropenic patients. Br J Haematol 2000 110 (2) : 273 284.
9. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002 100 (13) : 4358 4366.
10. Krcmery V, Barnes AJ. Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect 2002 50 (4) : 243 260.
11. Cernicka J, Subik J. Resistance mechanisms in fluconazole-resistant Candida albicans isolates from vaginal candidiasis. Int J Antimicrob Agents 2006 27 (5) : 403 408.
12. Chryssanthou E, Cherif H, Petrini B, Kalin M, Bjorkholm M. Surveillance of triazole susceptibility of colonizing yeasts in patients with haematological malignancies. Scand J Infect Dis 2004 36 (11-12) : 855 859.
13. Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006 91 (8) : 1068 1075.
14. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997 175 (6) : 1459 1466.
15. Bohme A, Karthaus M. Systemic fungal infections in patients with hematologic malignancies: indications and limitations of the antifungal armamentarium. Chemotherapy 1999 45 (5) : 315 324.
16. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002 34 (7) : 909 917. (Pubitemid 34229758)
17. Morgan J, Wannemuehler KA, Marr KA, et al. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol 2005 43 : S49 S58.
18. Tricot G, Joosten E, Boogaerts MA, Vande PJ, Cauwenbergh G. Ketoconazole vs. itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of two nonrandomized studies. Rev Infect Dis 1987 9 : S94 S99.
19. Menichetti F, Del Favero A, Martino P, et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B. Ann Intern Med 1994 120 (11) : 913 918.
20. Chandrasekar PH, Gatny CM. The effect of fluconazole prophylaxis on fungal colonization in neutropenic cancer patients. Bone Marrow Transplantation Team. J Antimicrob Chemother 1994 33 (2) : 309 318.
21. Alberti C, Bouakline A, Ribaud P, et al. Relationship between environmental fungal contamination and the incidence of invasive aspergillosis in haematology patients. J Hosp Infect 2001 48 (3) : 198 206.
22. Kruger WH, Zollner B, Kaulfers PM, Zander AR. Effective protection of allogeneic stem cell recipients against Aspergillosis by HEPA air filtration during a period of construction - a prospective survey. J Hematother Stem Cell Res 2003 12 (3) : 301 307.
23. Bow EJ, Loewen R, Cheang MS, Schacter B. Invasive fungal disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenetic role of the antileukemic regimen. Clin Infect Dis 1995 21 (2) : 361 369.
24. Bow EJ. Infection risk and cancer chemotherapy: the impact of the chemotherapeutic regimen in patients with lymphoma and solid tissue malignancies. J Antimicrob Chemother 1998 41 : 1 5.
25. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007 356 (4) : 335 347.
26. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007 356 (4) : 348 359.
27. Philpott-Howard J. Prevention of fungal infections in hematology patients. Infect Control Hosp Epidemiol 1996 17 (8) : 545 551.
28. Nucci M, Anaissie EJ, Queiroz-Telles F, et al. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer 2003 98 (2) : 315 319.
29. McLintock LA, Jordanides NE, Allan EK, et al. The use of a risk group stratification in the management of invasive fungal infection: a prospective validation. Br J Haematol 2004 124 (3) : 403 404.
30. Powles R, Mehta J, Kulkarni S, et al. Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000 355 (9211) : 1231 1237.
31. Storek J, Dawson MA, Storer B, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001 97 (11) : 3380 3389.
32. Miyakoshi S, Kusumi E, Matsumura T, et al. Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases. Biol Blood Marrow Transplant 2007 13 (7) : 771 777.
33. Saavedra S, Sanz GF, Jarque I, et al. Early infections in adult patients undergoing unrelated donor cord blood transplantation. Bone Marrow Transplant 2002 30 (12) : 937 943.
34. Leather HL, Wingard JR. New strategies of antifungal therapy in hematopoietic stem cell transplant recipients and patients with hematological malignancies. Blood Rev 2006 20 : 267 287.
35. Scotter JM, Campbell P, Anderson TP, Murdoch DR, Chambers ST, Patton WN. Comparison of PCR-ELISA and galactomannan detection for the diagnosis of invasive aspergillosis. Pathology 2005 37 (3) : 246 253.
36. Spiess B, Seifarth W, Hummel M, et al. DNA microarray-based detection and identification of fungal pathogens in clinical samples from neutropenic patients. J Clin Microbiol 2007 45 (11) : 3743 3753.
37. Adam O, Auperin A, Wilquin F, Bourhis JH, Gachot B, Chachaty E. Treatment with piperacillin-tazobactam and false-positive Aspergillus galactomannan antigen test results for patients with hematological malignancies. Clin Infect Dis 2004 38 (6) : 917 920.
38. Obayashi T, Yoshida M, Mori T, et al. Plasma (1->3)-beta-d-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 1995 345 (8941) : 17 20.
39. Obayashi T, Yoshida M, Tamura H, Aketagawa J, Tanaka S, Kawai T. Determination of plasma (1->3)-beta-d-glucan: a new diagnostic aid to deep mycosis. J Med Vet Mycol 1992 30 (4) : 275 280.
40. Pickering JW, Sant HW, Bowles CA, Roberts WL, Woods GL. Evaluation of a (1->3)-beta-d-glucan assay for diagnosis of invasive fungal infections. J Clin Microbiol 2005 43 (12) : 5957 5962.
41. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 2005 41 (9) : 1242 1250.
42. Perfect JR, Klotman ME, Gilbert CC, et al. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis 1992 165 (5) : 891 897.
43. Tollemar J, Ringden O, Andersson S, Sundberg B, Ljungman P, Tyden G. Randomized double-blind study of liposomal amphotericin B (Ambisome) prophylaxis of invasive fungal infections in bone marrow transplant recipients. Bone Marrow Transplant 1993 12 (6) : 577 582. (Pubitemid 24020989)
44. Riley DK, Pavia AT, Beatty PG, et al. The prophylactic use of low-dose amphotericin B in bone marrow transplant patients. Am J Med 1994 97 (6) : 509 514.
45. Kelsey SM, Goldman JM, McCann S, et al. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study. Bone Marrow Transplant 1999 23 (2) : 163 168.
46. Timmers GJ, Zweegman S, Simoons-Smit AM, van Loenen AC, Touw D, Huijgens PC. Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients: data of a prematurely stopped clinical trial. Bone Marrow Transplant 2000 25 (8) : 879 884.
47. Mattiuzzi GN, Estey E, Raad I, et al. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction: chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer 2003 97 (2) : 450 456.
48. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992 326 (13) : 845 851.
49. Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, double-blind, multicenter trial. Ann Intern Med 1993 7 (118) : 495 503.
50. Bodey GP, Anaissie EJ, Elting LS, Estey E, O'Brien S, Kantarjian H. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. Cancer 1994 73 (8) : 2099 2106.
51. Annaloro C, Oriani A, Tagliaferri E, et al. Efficacy of different prophylactic antifungal regimens in bone marrow transplantation. Haematologica 1995 80 (6) : 512 517.
52. Schaffner A, Schaffner M. Effect of prophylactic fluconazole on the frequency of fungal infections, amphotericin B use, and health care costs in patients undergoing intensive chemotherapy for hematologic neoplasias. J Infect Dis 1995 172 (4) : 1035 1041.
53. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation - a prospective, randomized, double-blind study. J Infect Dis 1995 171 (6) : 1545 1552.
54. Marr KA, Seidel K, Slavin MA, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 2000 96 (6) : 2055 2061.
55. Kern W, Behre G, Rudolf T, et al. Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia: results of a prospective randomized phase III study. Cancer 1998 83 (2) : 291 301.
56. Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999 28 (2) : 331 340.
57. Takatsuka H, Takemoto Y, Okamoto T, et al. Fluconazole versus amphotericin B for the prevention of fungal infection in neutropenic patients with hematologic malignancy. Drugs Exp Clin Res 1999 25 (4) : 193 200.
58. Wolff SN, Fay J, Stevens D, et al. Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group. Bone Marrow Transplant 2000 25 (8) : 853 859.
59. Morgenstern GR, Prentice AG, Prentice HG, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. Br J Haematol 1999 105 (4) : 901 911.
60. Huijgens PC, Simoons-Smit AM, van Loenen AC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J Clin Pathol 1999 52 (5) : 376 380.
61. Harousseau JL, Dekker AW, Stamatoullas-Bastard A, et al. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrob Agents Chemother 2000 44 (7) : 1887 1893.
62. Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 2003 138 (9) : 705 713.
63. Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004 103 (4) : 1527 1533.
64. Glasmacher A, Cornely O, Ullmann AJ, et al. An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia. J Antimicrob Chemother 2006 57 (2) : 317 325.
65. Oren I, Rowe JM, Sprecher H, et al. A prospective randomized trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2006 38 (2) : 127 134.
66. van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004 39 (10) : 1407 1416.
67. Vehreschild JJ, Bohme A, Buchheidt D, et al. A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML). J Infect 2007 55 (5) : 445 449.
68. Kanda Y, Yamamoto R, Chizuka A, et al. Prophylactic action of oral fluconazole against fungal infection in neutropenic patients: a meta-analysis of 16 randomized, controlled trials. Cancer 2000 89 (7) : 1611 1625.
69. Bow EJ, Laverdiere M, Lussier N, Rotstein C, Cheang MS, Ioannou S. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Cancer 2002 94 (12) : 3230 3246.
70. Glasmacher A, Prentice A, Gorschluter M, et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J Clin Oncol 2003 21 (24) : 4615 4626.
71. Vardakas KZ, Michalopoulos A, Falagas ME. Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta-analysis of randomised-controlled trials. Br J Haematol 2005 131 (1) : 22 28.
72. Prentice AG, Glasmacher A, Djulbegovic B. In meta-analysis itraconazole is superior to fluconazole for prophylaxis of systemic fungal infection in the treatment of haematological malignancy. Br J Haematol 2006 132 (5) : 656 658.
73. Robenshtok E, Gafter-Gvili A, Goldberg E, et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 2007 25 (34) : 5471 5489.
74. Laverdiere M, Rotstein C, Bow EJ, et al. Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. J Antimicrob Chemother 2000 46 (6) : 1001 1008.
75. Kintzel PE, Rollins CJ, Yee WJ, List AF. Low itraconazole serum concentrations following administration of itraconazole suspension to critically ill allogeneic bone marrow transplant recipients. Ann Pharmacother 1995 29 (2) : 140 143.
76. Mattiuzzi GN, Alvarado G, Giles FJ, et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother 2006 50 (1) : 143 147.
77. Ellis M, Frampton C, Joseph J, et al. An open study of the comparative efficacy and safety of caspofungin and liposomal amphotericin B in treating invasive fungal infections or febrile neutropenia in patients with haematological malignancy. J Med Microbiol 2006 55 (Part 10) : 1357 1365.
78. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007 356 (24) : 2472 2482.
79. Cohen-Wolkowiez M, Benjamin DK Jr., Steinbach WJ, Smith PB. Anidulafungin: a new echinocandin for the treatment of fungal infections. Drugs Today 2006 42 (8) : 533 544.
80. Benjamin DK Jr, Driscoll T, Seibel NL, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother 2006 50 (2) : 632 638.
81. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002 347 (6) : 408 415. (Pubitemid 34851833)
82. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002 346 (4) : 225 234. (Pubitemid 34438861)
83. Cherif H, Kalin M, Bjorkholm M. Antifungal therapy in patients with hematological malignancies: how to avoid overtreatment? Eur J Haematol 2006 77 (4) : 288 292.
84. Ullmann AJ, Heussel CP, Cornely OA. Voriconazole versus liposomal amphotericin B for empirical antifungal therapy. N Engl J Med 2002 346 (22) : 1745 1747.
85. Siwek GT, Pfaller MA, Polgreen PM, et al. Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis. Diagn Microbiol Infect Dis 2006 55 (3) : 209 212.
86. Cordonnier C, Maury S, Pautas C, et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant 2004 33 (9) : 943 948.
87. Wingard JR, Carter SL, Walsh TJ, et al. Results of a randomized, double-blind trial of fluconazole (FLU) vs. voriconazole (VORI) for the prevention of invasive fungal infections (IF) in 600 allogeneic blood and marrow transplant (BMT) patients. Blood (ASH Annual Meeting Abstracts) 2007 110 (11) : 163.
88. Trifilio S, Singhal S, Williams S, et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant 2007 40 (5) : 451 456.
89. Trifilio SM, Bennett CL, Yarnold PR, et al. Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy. Bone Marrow Transplant 2007 39 (7) : 425 429.
90. Sansone-Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S, Mant TG. Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus. Pharmacotherapy 2007 27 (6) : 825 834.
91. Chandrasekar P, Ljungman PT. Antifungal therapy strategies in hematopoietic stem-cell transplant recipients: early treatment options for improving outcomes. Transplantation 2008 86 (2) : 183 191.
92. Braedel S, Radsak M, Einsele H, et al. Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4. Br J Haematol 2004 125 (3) : 392 399.
93. Bochud PY, Chien JW, Marr KA, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008 359 (17) : 1766 1777.
94. Netea MG, Gow NA, Munro CA, et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 2006 116 (6) : 1642 1650.
95. Shoham S, Huang C, Chen JM, Golenbock DT, Levitz SM. Toll-like receptor 4 mediates intracellular signaling without TNF-alpha release in response to Cryptococcus neoformans polysaccharide capsule. J Immunol 2001 166 (7) : 4620 4626.