• 1

    Cheng AC, Currie BJ, 2005. Melioidosis: epidemiology, patho-physiology, and management. Clin Microbiol Rev 18 :383–416.

  • 2

    Peacock SJ, 2006. Melioidosis. Curr Opin Infect Dis 19 :421–428.

  • 3

    Centers for Disease Control and Prevention, 2004. Laboratory exposure to Burkholderia pseudomallei—Los Angeles, California, 2003. MMWR Morb Mortal Wkly Rep 53 :988–990.

    • Search Google Scholar
    • Export Citation
  • 4

    Gilbert D, Moellering R, Eliopolous G, Sande M, 2006. The Sanford Guide to Antimicrobial Therapy 2006. Sperryville, VA: Antimicrobial Therapy.

  • 5

    Arzola JM, Hawley JS, Oakman C, Mora RV, 2007. A case of prostatitis due to Burkholderia pseudomallei. Nat Clin Pract Urol 4 :111–114.

    • Search Google Scholar
    • Export Citation
  • 6

    Lee YL, Lee SS, Tsai HC, Chen YS, Wann SR, Kao CH, Liu YC, 2006. Pyogenic liver abscess caused by Burkholderia pseudomallei in Taiwan. J Formos Med Assoc 105 :689–693.

    • Search Google Scholar
    • Export Citation
  • 7

    White NJ, 2003. Melioidosis. Lancet 361 :1715–1722.

  • 8

    Suputtamongkol Y, Rajchanuwong A, Chaowagul W, Dance DA, Smith MD, Wuthiekanun V, Walsh AL, Pukrittayakamee S, White NJ, 1994. Ceftazidime vs. amoxicillin/clavulanate in the treatment of severe melioidosis. Clin Infect Dis 19 :846–853.

    • Search Google Scholar
    • Export Citation
  • 9

    Dance DA, Wuthiekanun V, Chaowagul W, White NJ, 1989. The activity of amoxycillin/clavulanic acid against Pseudomonas pseudomallei. J Antimicrob Chemother 24 :1012–1014.

    • Search Google Scholar
    • Export Citation
  • 10

    Chierakul W, Wangboonskul J, Singtoroj T, Pongtavornpinyo W, Short JM, Maharjan B, Wuthiekanun V, Dance DA, Teparrukkul P, Lindegardh N, Peacock SJ, Day NP, Chaowagul W, White NJ, 2006. Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis. J Antimicrob Chemother 58 :1215–1220.

    • Search Google Scholar
    • Export Citation
  • 11

    Rajchanuvong A, Chaowagul W, Suputtamongkol Y, Smith MD, Dance DAB, White NJ, 1995. A prospective comparison of co-amoxiclav and the combination of chloramphenicol, doxycycline, and co-trimoxazole for the oral maintenance treatment of melioidosis. Trans R Soc Trop Med Hyg 89 :546–549.

    • Search Google Scholar
    • Export Citation
  • 12

    Limmathurotsakul D, Chaowagul W, Chierakul W, Stepniewska K, Maharjan B, Wuthiekanun V, White NJ, Day NP, Peacock SJ, 2006. Risk factors for recurrent melioidosis in northeast Thailand. Clin Infect Dis 43 :979–986.

    • Search Google Scholar
    • Export Citation
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Consensus Guidelines for Dosing of Amoxicillin-Clavulanate in Melioidosis

Allen C. ChengMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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Wirongrong ChierakulMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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Wipada ChaowagulMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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Ploenchan ChetchotisakdMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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Direk LimmathurotsakulMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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David A. B. DanceMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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Sharon J. PeacockMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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Bart J. CurrieMenzies School of Health Research, Charles Darwin University, Darwin, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Department of Medicine, Srinagarind Hospital, Khon Kaen Universty, Khon Kaen, Thailand; Health Protection Agency South West, United Kingdom; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Royal Darwin Hospital, Darwin, Australia

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Melioidosis is an infectious disease endemic to northern Australia and Southeast Asia. In response to clinical confusion regarding the appropriate dose of amoxicillin-clavulanate, we have developed guidelines for the appropriate dosing of this second-line agent. For eradication therapy for melioidosis, we recommend 20/5 mg/kg orally, three times daily.

INTRODUCTION

Melioidosis is an infectious disease caused by Burkholderia pseudomallei, endemic to northern Australia and Southeast Asia. B. pseudomallei is regarded as a potential bioweapon and imported cases of melioidosis are not infrequently reported in travelers returning from endemic areas. As researchers and clinicians treating substantial numbers of patients with melioidosis in Australia and Thailand, we have been made aware of confusion regarding dosing of amoxicillin-clavulanate used in the management of melioidosis. This is particularly true in light of conflicting pharmacokinetic data and a range of combination formulations containing ratios of amoxicillin:clavulanate (A:C) of between 2:1 and 16:1.

METHODS

We became aware of misquoted dosing recommendations in our own recent reviews of melioidosis,1,2 other guidelines that have not provided dosing recommendations3 or provided incorrect dosing recommendations,4 and multiple recent case reports where an incorrect dose of amoxicillin-clavulanate was administered for melioidosis.5,6 A correspondence was conducted among researchers and clinicians who are active in clinical research and who treat or have treated significant numbers of patients with melioidosis in the endemic areas. Dosing recommendations were reached by consensus and were based on the available pharmacokinetic evidence, clinical trials, and clinical experience with this agent.

RESULTS

First-line treatment recommendations suggest an intravenous intensive course of ceftazidime or a carbapenem followed by a prolonged oral eradication course of cotrimoxazole (commonly used in Australia) or cotrimoxazole with doxycycline (commonly used in Thailand).7 However, amoxicillin-clavulanate is still used as a second-line agent in eradication treatment of melioidosis, particularly for patients with sulfonamide allergy, those who are intolerant of cotrimoxazole (particularly with neutropenia or gastrointestinal intolerance), in pregnant patients (where cotrimoxazole is relatively contraindicated) and in children (where doxycycline is contraindicated).

For intravenous intensive phase therapy, amoxicillin-clavulanate at a dose of 20/5 mg/kg 4-hourly is an alternative to ceftazidime or carbapenems for less severe cases where this agent is available.8,9 However intravenous amoxicillin-clavulanate is associated with higher rates of treatment failure,8 and there are few indications for this agent if first-line agents are available.

For eradication treatment of melioidosis, we recommend that oral amoxicillin-clavulanate (coamoxiclav) should be used at a dose of 20/5 mg/kg three times a day. For adult patients < 60 kg, a dose of 1000/250 mg three times daily is suggested. In regions where coamoxiclav is only available in fixed 2:1 combinations, we use 500 mg/250 mg three times daily with additional amoxicillin (500 mg three times daily). For patients > 60 kg, we use a maximum dose of 1500/375 mg three times daily. We do not recommend twice daily regimens or formulations containing A:C ratios of > 4:1 (such as “Duo Forte” or “XR” formulations) because of inadequate clavulanate.10 Oral eradication treatment should be continued for 12–20 weeks.

CONCLUSION

These recommendations are based on our extensive clinical experience with this agent, but there is also substantial evidence suggesting that coamoxiclav is associated with higher relapse rates when compared with cotrimoxazole-based regimens for oral eradication-phase treatment.11,12 These studies also reinforce the need to monitor patients carefully for gastrointestinal intolerance to ensure compliance. Checkerboard susceptibility testing suggests that clavulanate is key to the antimicrobial action of the combination, leading to the suggestion that more frequent oral dosing (6- or 4-hourly) may provide more optimal serum concentrations.10 However, the efficacy and tolerability of such regimens are as yet unknown. Ongoing research is examining the efficacy of simpler primary eradication regimens such as cotrimoxazole alone. Work is required in defining the optimal PK/PD relationships for antibiotics used to manage melioidosis.

*

Address correspondence to Bart J. Currie, Menzies School of Health Research, PO Box 41096, Casuarina NT 0811. E-mail: bart@menzies.edu.au

These Guidelines were developed as a consensus amongst a group of clinicians with extensive experience of treating melioidosis in the endemic regions of Thailand and Australia.

Authors’ addresses: Allen C. Cheng, Department of Medicine, University of Melbourne, c/- 9th floor, Royal Melbourne Hospital, Parkville VIC 3052, Australia, E-mail: allen.cheng@menzies.edu.au. Wirongrong Chierakul, Direk Limmathurotsakul, and Sharon J. Peacock, Faculty of Tropical Medicine, Mahidol University, Rajvithi Road, Bangkok, E-mails: kae@tropmedres.ac, direk@tropmedres.ac, and Sharon@tropmedres.ac. Wipada Chaowagul, Sappasithiprasong Hospital, Sappasit Road, Ubon Ratchathani, E-mail: vipada_1@yahoo.com. Ploenchan Chetchotisakd, Department of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, E-mail: ploencha@kku.ac.th. David A. B. Dance, Health Protection Agency South West, Tamar Science Park, 1 Davy Road, Derriford, Plymouth PL6 8BX, E-mail: david.dance@phnt.swest.nhs.uk.

Financial support: AC is supported by a NHMRC postdoctoral fellowship and SJP is supported by a Wellcome Trust Career Development Award.

REFERENCES

  • 1

    Cheng AC, Currie BJ, 2005. Melioidosis: epidemiology, patho-physiology, and management. Clin Microbiol Rev 18 :383–416.

  • 2

    Peacock SJ, 2006. Melioidosis. Curr Opin Infect Dis 19 :421–428.

  • 3

    Centers for Disease Control and Prevention, 2004. Laboratory exposure to Burkholderia pseudomallei—Los Angeles, California, 2003. MMWR Morb Mortal Wkly Rep 53 :988–990.

    • Search Google Scholar
    • Export Citation
  • 4

    Gilbert D, Moellering R, Eliopolous G, Sande M, 2006. The Sanford Guide to Antimicrobial Therapy 2006. Sperryville, VA: Antimicrobial Therapy.

  • 5

    Arzola JM, Hawley JS, Oakman C, Mora RV, 2007. A case of prostatitis due to Burkholderia pseudomallei. Nat Clin Pract Urol 4 :111–114.

    • Search Google Scholar
    • Export Citation
  • 6

    Lee YL, Lee SS, Tsai HC, Chen YS, Wann SR, Kao CH, Liu YC, 2006. Pyogenic liver abscess caused by Burkholderia pseudomallei in Taiwan. J Formos Med Assoc 105 :689–693.

    • Search Google Scholar
    • Export Citation
  • 7

    White NJ, 2003. Melioidosis. Lancet 361 :1715–1722.

  • 8

    Suputtamongkol Y, Rajchanuwong A, Chaowagul W, Dance DA, Smith MD, Wuthiekanun V, Walsh AL, Pukrittayakamee S, White NJ, 1994. Ceftazidime vs. amoxicillin/clavulanate in the treatment of severe melioidosis. Clin Infect Dis 19 :846–853.

    • Search Google Scholar
    • Export Citation
  • 9

    Dance DA, Wuthiekanun V, Chaowagul W, White NJ, 1989. The activity of amoxycillin/clavulanic acid against Pseudomonas pseudomallei. J Antimicrob Chemother 24 :1012–1014.

    • Search Google Scholar
    • Export Citation
  • 10

    Chierakul W, Wangboonskul J, Singtoroj T, Pongtavornpinyo W, Short JM, Maharjan B, Wuthiekanun V, Dance DA, Teparrukkul P, Lindegardh N, Peacock SJ, Day NP, Chaowagul W, White NJ, 2006. Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis. J Antimicrob Chemother 58 :1215–1220.

    • Search Google Scholar
    • Export Citation
  • 11

    Rajchanuvong A, Chaowagul W, Suputtamongkol Y, Smith MD, Dance DAB, White NJ, 1995. A prospective comparison of co-amoxiclav and the combination of chloramphenicol, doxycycline, and co-trimoxazole for the oral maintenance treatment of melioidosis. Trans R Soc Trop Med Hyg 89 :546–549.

    • Search Google Scholar
    • Export Citation
  • 12

    Limmathurotsakul D, Chaowagul W, Chierakul W, Stepniewska K, Maharjan B, Wuthiekanun V, White NJ, Day NP, Peacock SJ, 2006. Risk factors for recurrent melioidosis in northeast Thailand. Clin Infect Dis 43 :979–986.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Bart J. Currie, Menzies School of Health Research, PO Box 41096, Casuarina NT 0811. E-mail: bart@menzies.edu.au
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