• 1

    Booz MK, 1972. The management of hydatid disease of bone and joint. J Bone Joint Surg Br 54 :698–709.

  • 2

    Fraiji EK Jr, DH C, 1997. Echinococcosis. Pathology of Infectious Diseases. Stamford, CT: Appleton & Lange.

  • 3

    Schaefer JW, Khan MY, 1991. Echinococcosis (hydatid disease): lessons from experience with 59 patients. Rev Infect Dis 13 :243–247.

  • 4

    Akhan O, Gumus B, Akinci D, Karcaaltincaba M, Ozmen M, 2007. Diagnosis and percutaneous treatment of soft-tissue hydatid cysts. Cardiovasc Intervent Radiol 30 :419–425.

    • Search Google Scholar
    • Export Citation
  • 5

    Junghanss T, da Silva AM, Horton J, Chiodini PL, Brunetti E, 2008. Clinical management of cystic echinococcosis: state of the art, problems, and perspectives. Am J Trop Med Hyg 79 :301–311.

    • Search Google Scholar
    • Export Citation
  • 6

    Moro P, Schantz PM, 2009. Echinococcosis: a review. Int J Infect Dis 13 :125–133.

  • 7

    Todorov T, Vutova K, Mechkov G, Petkov D, Nedelkov G, Tonchev Z, 1990. Evaluation of response to chemotherapy of human cystic echinococcosis. Br J Radiol 63 :523–531.

    • Search Google Scholar
    • Export Citation
  • 8

    Wen H, New RR, Craig PS, 1993. Diagnosis and treatment of human hydatidosis. Br J Clin Pharmacol 35 :565–574.

  • 9

    Teggi A, Lastilla MG, De Rosa F, 1993. Therapy of human hydatid disease with mebendazole and albendazole. Antimicrob Agents Chemother 37 :1679–1684.

    • Search Google Scholar
    • Export Citation
  • 10

    Horton RJ, 1997. Albendazole in treatment of human cystic echinococcosis: 12 years of experience. Acta Trop 64 :79–93.

  • 11

    Moro PL, Gonzalez AE, Gilman RH, 2000. Cystic Hydatid Disease. Hunter GW, Strickland GT, Magill AJ, eds. Hunter’s tropical medicine and emerging infectious diseases. Philadelphia: W.B. Saunders, 866–871.

  • 12

    Jung H, Hurtado M, Sanchez M, Medina MT, Sotelo J, 1992. Clinical pharmacokinetics of albendazole in patients with brain cysticercosis. J Clin Pharmacol 32 :28–31.

    • Search Google Scholar
    • Export Citation
  • 13

    Saimot AG, Meulemans A, Cremieux AC, Giovanangeli MD, Hay JM, Delaitre B, Coulaud JP, 1983. Albendazole as a potential treatment for human hydatidosis. Lancet 2 :652–656.

    • Search Google Scholar
    • Export Citation
  • 14

    Morris DL, Chinnery JB, Georgiou G, Stamatakis G, Golematis B, 1987. Penetration of albendazole sulphoxide into hydatid cysts. Gut 28 :75–80.

    • Search Google Scholar
    • Export Citation
  • 15

    Cobo F, Yarnoz C, Sesma B, Fraile P, Aizcorbe M, Trujillo R, Diaz-de-Liano A, Ciga MA, 1998. Albendazole plus praziquantel versus albendazole alone as a pre-operative treatment in intra-abdominal hydatisosis caused by Echinococcus granulosus. Trop Med Int Health 3 :462–466.

    • Search Google Scholar
    • Export Citation
  • 16

    Wilson JF, Rausch RL, McMahon BJ, Schantz PM, 1992. Parasiticidal effect of chemotherapy in alveolar hydatid disease: review of experience with mebendazole and albendazole in Alaskan Eskimos. Clin Infect Dis 15 :234–249.

    • Search Google Scholar
    • Export Citation
  • 17

    Schantz PM, 1999. Echinococcosis. Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases. New York: Churchill Livingstone, 1005–1025.

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Intra-Cystic Drug Concentration of Albendazole Sulphoxide in Patients with Echinococcus granulosus Cysts

Mesküre CapanDepartment of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Gesellschaft, Infektiologie, St. Pölten, Austria

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Sebastian KeltnerDepartment of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Gesellschaft, Infektiologie, St. Pölten, Austria

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Florian ThalhammerDepartment of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Gesellschaft, Infektiologie, St. Pölten, Austria

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Stefan WinklerDepartment of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Gesellschaft, Infektiologie, St. Pölten, Austria

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Walter JägerDepartment of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Gesellschaft, Infektiologie, St. Pölten, Austria

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Markus ZeitlingerDepartment of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Gesellschaft, Infektiologie, St. Pölten, Austria

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Michael RamharterDepartment of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Vienna, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Gesellschaft, Infektiologie, St. Pölten, Austria

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Albendazole therapy—alone or in combination with surgery—remains the standard of care for human echinococcosis depending on the stage of disease. However, only limited data are available on target site concentrations in liver cysts and data for non-liver cysts are lacking. We report on intra-cystic concentrations of the biologically active metabolite albendazole sulphoxide in non-liver cysts indicating a relative intra-cystic drug concentration of 48–156% compared with plasma levels. These data are evidence for a satisfactory penetration of albendazole sulphoxide into Echinococcus cysts localized in other organs than the liver and underline the usefulness of albendazole therapy for this indication.

Echinococcosis is caused by the ingestion of eggs of the dog tapeworm or fox tapeworm belonging to the genus Echinococcus. E. granulosus causes considerable human morbidity and mortality, with the highest prevalence in rural areas because of close co-habitation of humans, animal intermediate hosts, and final hosts. Oncospheres migrate after ingestion to different organs and form cysts most commonly located in the liver (60–70%) and lungs (20%). Other localizations of cysts, including the kidney, spleen, muscles, bone, pancreas, central nervous system, and soft tissue, have been described but are less common.13

Treatment recommendations for E. granulosus cysts include long-term therapy with albendazole alone or in combination with praziquantel, percutaneous drainage, and surgical removal of the lesions.46 Albendazole is a benzimidazole derivative and is highly active against echinococcal protoscolices. However, the in vivo therapeutic response is limited by its low and erratic bioavailability.710 Nevertheless albendazole is the most commonly used drug for pre- and post-operative anthelminthic treatment and continued suppressive therapy of inoperable hydatid cysts. 11 On the background of its variable absorption, the penetration of albendazole and its active metabolite albendazole sulphoxide into cysts is of major importance for adequate in vivo activity. Whereas limited data are available for Echinococcus cysts of the liver, little is known about the intra-cystic concentrations of albendazole in patients treated for echinococcal cysts located in other organs than the liver. In this study, we aimed to assess the ability of albendazole and its active metabolite albendazole sulphoxide to penetrate into E. granulosus cysts of two patients with non-liver cysts.

A 60-year-old women of Turkish origin (Patient A) residing in Austria for > 5 years was diagnosed with a painless tumor on the left thigh, which became noticeable after voluntary weight loss of 25 kg. The second patient (Patient B), a 30-year-old Turkish citizen, presented at the hospital with progressive cough, night sweats, and dyspnea. Inflammation markers were increased in both patients, with C-reactive protein at 8.7 and 2.4 mg/dL for Patients A and B, respectively (normal range, < 1 mg/dL). Marked eosinophilia was recorded (550 and 3,020/μL blood for Patients A and B, respectively) in differential blood count, and serologic investigation by enzyme-linked immunosorbent assay and Western blot confirmed the diagnosis of E. granulosus infection. Computer tomography and magnetic resonance imaging showed a cystic lesion in the proximal Musculus satorius of 7.5 cm diameter in Patient A. Patient B had a distinctive pleural effusion on the right side of the lung with transgression of the diaphragm. Following current treatment recommendations, patients were prescribed 400 mg albendazole to be taken twice daily with a fatty meal for 5 and 4 days before surgical removal, respectively. 12 Histologic examination of cyst tissues confirmed diagnosis by visualization of typical protoscolices. Patients continued anthelminthic treatment for 1 month after surgery and had no signs of recurrence of Echinococcus cysts.

Venous blood samples for drug analysis were taken in the morning of surgery before albendazole intake and during the intervention. Undiluted cyst fluid was obtained during operation and was subsequently stored at −80°C until further analysis. Concentrations of albendazole and albendazole sulphoxide in plasma and cyst fluid were measured by a validated high-performance liquid chromatographic (HPLC) method using an “UltiMate 3000” system (Dionex, Sunnyvale, CA). Separation of albendazole sulphoxide was carried out using a Hypersil BDS-C18 column (Thermo Fisher Scientific, Waltham, MA) with an acetic acid/methanol mobile phase. The limit of quantification for albendazole and albendazole sulphoxide was 0.063 and 0.072 μg/mL, respectively. Coefficients of accuracy and precision for both compounds were < 8%.

HPLC measurement showed that, in all clinical samples, albendazole was below the limit of detection. However, albenda zole sulphoxide—the active metabolite—was quantified in pre-operative and intra-operative samples in the range of 0.10 and 1.3 μg/mL in plasma. Furthermore, the analysis of cystic fluid samples also showed albendazole sulphoxide concentrations of 0.16 and 0.6 μg/mL, indicating a relative intra-cystic drug concentration of 48% and 156% compared with plasma, respectively (Table 1).

These data show—besides the known variability of plasma concentrations—good tissue penetration of albendazole sulphoxide into echinococcal cysts, with ~50% variation compared with plasma drug concentrations. In general, plasma concentrations of albendazole A previous report indicated maximum plasma levels for albendazole sulphoxide in the range of 0.45–2.96 μg/mL and intra-cystic drug concentrations between 0.06 and 0.42 μg/mL. 12,13 Morris and others 14 reported an ~20% intra-cystic concentration of albendazole sulphoxide in patients treated with 10 mg/kg albendazole for 1 month before surgery. Although these data are in line with our results for plasma drug concentrations, the relative intra-cystic drug concentration of albendazole sulphoxide was significantly higher in our patients. Interestingly, in a previous study, praziquantel, another anthelminthic drug with activity against tapeworms, led to a considerable increase in albendazole plasma levels. 15 In that report, the activity against protoscolices was significantly higher in patients treated with a combination of albendazole and praziquantel.

Thus far, most data on target site drug concentrations derive from echinococcal cysts of the liver and information on intra-cystic drug penetration for other organs are scarce. Despite the limited number of patients in this study, our data indicate that drug penetration in cysts located in the pleural cavity and the skeletal muscle is comparable or potentially higher compared with previous data on liver cysts.

Albendazole has been used for the treatment of human echinococcosis since the 1980s and—depending on the stage of the disease—continuous long-term albendazole therapy shows cure rates between 30% and 80%. Although the oral bioavailability of albendazole is characterized by significant variation, intra-cystic drug penetration seems less variable and comparable to plasma drug levels. Although many questions about the optimal medical treatment of echinococcosis remain, the use of albendazole has been shown to allow safer manipulation of liver cysts during surgery, thus minimizing the chance of secondary recurrence. Based on our data, this may similarly be true for cysts localized in other organs. 16,17 Further data on anthelminthic combination therapy and the development of novel anthelminthic drugs with improved oral bioavailability are desirable to further improve the management of echinococcosis.

Table 1

Albendazole sulphoxide (μg/mL) and relative intra-cystic drug concentration

Table 1

*

Address correspondence to Michael Ramharter, Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria. E-mail: michael.ramharter@meduniwien.ac.at

Authors’ addresses: Mesküre Capan, Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; and Institute of Tropical Medicine, University of Tübingen, Wilhelmstraße 27, 72074 Tübingen, Germany. Sebastian Keltner, Florian Thalhammer, and Stefan Winkler, Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Walter Jäger, Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria. Markus Zeitlinger, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Michael Ramharter, Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; Institute of Tropical Medicine, University of Tübingen, Wilhelmstraße 27, 72074 Tübingen, Germany; and Karl Landsteiner Gesellschaft, Infektiologie, Julius Raab Promenade 7 3100 St. Pölten, Austria.

Financial support: This work was supported by a grant of the independent Karl Landsteiner Gesellschaft, Austria.

REFERENCES

  • 1

    Booz MK, 1972. The management of hydatid disease of bone and joint. J Bone Joint Surg Br 54 :698–709.

  • 2

    Fraiji EK Jr, DH C, 1997. Echinococcosis. Pathology of Infectious Diseases. Stamford, CT: Appleton & Lange.

  • 3

    Schaefer JW, Khan MY, 1991. Echinococcosis (hydatid disease): lessons from experience with 59 patients. Rev Infect Dis 13 :243–247.

  • 4

    Akhan O, Gumus B, Akinci D, Karcaaltincaba M, Ozmen M, 2007. Diagnosis and percutaneous treatment of soft-tissue hydatid cysts. Cardiovasc Intervent Radiol 30 :419–425.

    • Search Google Scholar
    • Export Citation
  • 5

    Junghanss T, da Silva AM, Horton J, Chiodini PL, Brunetti E, 2008. Clinical management of cystic echinococcosis: state of the art, problems, and perspectives. Am J Trop Med Hyg 79 :301–311.

    • Search Google Scholar
    • Export Citation
  • 6

    Moro P, Schantz PM, 2009. Echinococcosis: a review. Int J Infect Dis 13 :125–133.

  • 7

    Todorov T, Vutova K, Mechkov G, Petkov D, Nedelkov G, Tonchev Z, 1990. Evaluation of response to chemotherapy of human cystic echinococcosis. Br J Radiol 63 :523–531.

    • Search Google Scholar
    • Export Citation
  • 8

    Wen H, New RR, Craig PS, 1993. Diagnosis and treatment of human hydatidosis. Br J Clin Pharmacol 35 :565–574.

  • 9

    Teggi A, Lastilla MG, De Rosa F, 1993. Therapy of human hydatid disease with mebendazole and albendazole. Antimicrob Agents Chemother 37 :1679–1684.

    • Search Google Scholar
    • Export Citation
  • 10

    Horton RJ, 1997. Albendazole in treatment of human cystic echinococcosis: 12 years of experience. Acta Trop 64 :79–93.

  • 11

    Moro PL, Gonzalez AE, Gilman RH, 2000. Cystic Hydatid Disease. Hunter GW, Strickland GT, Magill AJ, eds. Hunter’s tropical medicine and emerging infectious diseases. Philadelphia: W.B. Saunders, 866–871.

  • 12

    Jung H, Hurtado M, Sanchez M, Medina MT, Sotelo J, 1992. Clinical pharmacokinetics of albendazole in patients with brain cysticercosis. J Clin Pharmacol 32 :28–31.

    • Search Google Scholar
    • Export Citation
  • 13

    Saimot AG, Meulemans A, Cremieux AC, Giovanangeli MD, Hay JM, Delaitre B, Coulaud JP, 1983. Albendazole as a potential treatment for human hydatidosis. Lancet 2 :652–656.

    • Search Google Scholar
    • Export Citation
  • 14

    Morris DL, Chinnery JB, Georgiou G, Stamatakis G, Golematis B, 1987. Penetration of albendazole sulphoxide into hydatid cysts. Gut 28 :75–80.

    • Search Google Scholar
    • Export Citation
  • 15

    Cobo F, Yarnoz C, Sesma B, Fraile P, Aizcorbe M, Trujillo R, Diaz-de-Liano A, Ciga MA, 1998. Albendazole plus praziquantel versus albendazole alone as a pre-operative treatment in intra-abdominal hydatisosis caused by Echinococcus granulosus. Trop Med Int Health 3 :462–466.

    • Search Google Scholar
    • Export Citation
  • 16

    Wilson JF, Rausch RL, McMahon BJ, Schantz PM, 1992. Parasiticidal effect of chemotherapy in alveolar hydatid disease: review of experience with mebendazole and albendazole in Alaskan Eskimos. Clin Infect Dis 15 :234–249.

    • Search Google Scholar
    • Export Citation
  • 17

    Schantz PM, 1999. Echinococcosis. Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases. New York: Churchill Livingstone, 1005–1025.

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