• View in gallery
    Figure 1.

    Case 1: (1A) computer tomography (CT) of the brain with contrast June 2005 showing hypodensity in the right frontal lobe; (1B) CT with contrast August 2005 showing ring-enhancing lesion with surrounding edema in right frontoparietal lobe; (1C) CT with contrast February 2006 showing lesion in right frontal lobe with surrounding edema. Case 2: (2A) CT with contrast July 2005, reported as normal; (2B) CT with contrast October 2005 showing epidural collection in right frontal lobe area with surrounding edema; (2C) CT with contrast May 2006 showing resolution of previous abnormalities. Case 3: (3A) mass in parietal area of skull (consent and permission to use the photograph was obtained from the patient); (3B) skull x-ray showing punch-out lesions; (3C) CT without contrast showing cystic mass at right parietal scalp area and epidural abscess with evidence of bone involvement.

  • 1

    Chaowagul W, White NJ, Dance DA, Wattanagoon Y, Naigowit P, Davis TM, Looareesuwan S, Pitakwatchara N, 1989. Melioidosis: a major cause of community-acquired septicemia in northeastern Thailand. J Infect Dis 159 :890–899.

    • Search Google Scholar
    • Export Citation
  • 2

    Currie BJ, Fisher DA, Howard DM, Burrow JN, Selvanayagam S, Snelling PL, Anstey NM, Mayo MJ, 2000. The epidemiology of melioidosis in Australia and Papua New Guinea. Acta Trop 74 :121–127.

    • Search Google Scholar
    • Export Citation
  • 3

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

  • 4

    Currie BJ, Fisher DA, Howard DM, Burrow JN, 2000. Neurological melioidosis. Acta Trop 74 :145–151.

  • 5

    Chadwick DR, Ang B, Sitoh YY, Lee CC, 2002. Cerebral melioidosis in Singapore: a review of five cases. Trans R Soc Trop Med Hyg 96 :72–76.

    • Search Google Scholar
    • Export Citation
  • 6

    Lee MK, Chua CT, 1986. Brain abscess due to Pseudomonas pseudomallei. Aust NZ J Med 16 :75–77.

  • 7

    Wuthiekanun V, Peacock SJ, 2006. Management of melioidosis. Expert Rev Anti Infect Ther 4 :445–455.

  • 8

    Lutsar I, Friedland IR, 2000. Pharmacokinetics and pharmacodynamics of cephalosporins in cerebrospinal fluid. Clin Pharmacokinet 39 :335–343.

    • Search Google Scholar
    • Export Citation
  • 9

    Klugman KP, Dagan R, 1995. Carbapenem treatment of meningitis. Scand J Infect Dis Suppl 96 :45–48.

  • 10

    Chierakul W, Anunnatsiri S, Short JM, Maharjan B, Mootsikapun P, Simpson AJ, Limmathurotsakul D, Cheng AC, Stepniewska K, Newton PN, Chaowagul W, White NJ, Peacock SJ, Day NP, Chetchotisakd P, 2005. Two randomized controlled trials of ceftazidime alone versus ceftazidime in combination with trimethoprim–sulfamethoxazole for the treatment of severe melioidosis. Clin Infect Dis 41 :1105–1113.

    • Search Google Scholar
    • Export Citation
  • 11

    Friedrich H, Hansel G, 1977. [An investigation into the levels of a trimethoprim–sulphamethoxazole combination in the ventricular fluid of neurosurgical patients (authors’ transl.)]. Acta Neurochir (Wien) 37 :271–280.

    • Search Google Scholar
    • Export Citation
  • 12

    Andersson H, Alestig K, 1976. The penetration of doxycycline into CSF. Scand J Infect Dis Suppl 17–19.

  • 13

    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
  • 14

    Bakken JS, Bruun JN, Gaustad P, Tasker TC, 1986. Penetration of amoxicillin and potassium clavulanate into the cerebrospinal fluid of patients with inflamed meninges. Antimicrob Agents Chemother 30 :481–484.

    • Search Google Scholar
    • Export Citation
  • 15

    Dance DA, Wuthiekanun V, Chaowagul W, White NJ, 1989. The antimicrobial susceptibility of Pseudomonas pseudomallei. Emergence of resistance in vitro and during treatment. J Antimicrob Chemother 24 :295–309.

    • Search Google Scholar
    • Export Citation
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Variable Presentation of Neurological Melioidosis in Northeast Thailand

Direk LimmathurotsakulMahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Medicine and Department of Neurosurgery, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom

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Wipada ChaowagulMahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Medicine and Department of Neurosurgery, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom

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Prawatwong WongsrikaewMahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Medicine and Department of Neurosurgery, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom

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Arhtitpong NarmwongMahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Medicine and Department of Neurosurgery, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom

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Nicholas P. DayMahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Medicine and Department of Neurosurgery, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom

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Sharon J. PeacockMahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Medicine and Department of Neurosurgery, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom

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We describe three instructive cases of neurologic melioidosis that demonstrate the variable nature of clinical manifestations and disease pathology. The appropriate duration and choice of parenteral and oral antimicrobial therapy for neurologic melioidosis are also discussed.

INTRODUCTION

Melioidosis, the infection caused by Burkholderia pseudomallei, is most commonly reported from Northeast Thailand and Northern Australia.1,2 Manifestations of disease are extremely broad-ranging.3 A specific syndrome of meningoencephalitis with flaccid paraparesis or peripheral motor weakness occurs in 5% of cases in Northern Australia, and cerebral abscess is occasionally reported.46 We prospectively evaluated 191 melioidosis cases presenting to Sappasithiprasong Hospital, Ubon Ratchathani, Northeast Thailand, during 2005 to define the frequency and manifestations of neurologic melioidosis in this setting. Three adult cases were defined with variable presenting features and disease pathology. These cases provide a framework for the discussion of appropriate antimicrobial therapy of neurologic melioidosis.

CASE REPORTS

Patient 1, a 68-year-old male rice farmer with a history of chronic kidney disease associated with renal calculi and a left lithotomy 2 years previously, presented with a 7-day history of fever. Parenteral ceftriaxone was prescribed for suspected acute pyelonephritis, but on day 3 he developed a left hemiparesis (grade I) with a left upper motor neuron facial palsy; his Glasgow coma score (GCS) was 14. A random plasma glucose was 25 mmol/L. Three blood cultures were negative. Throat swab and urine were culture-negative for B. pseudomallei. Computer tomography (CT) showed hypodensity in the right frontal lobe area (Figure 1–1A). He was treated for acute pyelonephritis, acute ischemic stroke, and a new diagnosis of diabetes mellitus. Parenteral ceftazidime was given for 9 days, during which his fever settled and the motor weakness improved (grade IV). He was discharged with a 10-day course of oral amoxicillin–clavulanic acid (amoxicillin 2 g/day and clavulanic acid 500 mg/day). One month after discharge, he was re-admitted with headache, confusion, and worsening hemiparesis (grade II). Repeat CT showed a large ring-enhancing lesion with surrounding edema in the right frontoparietal lobe (Figure 1–1B). A cranial burr hole was made, and 30 mL of pus was aspirated, which on culture grew B. pseudomallei with a typical susceptibility pattern (susceptible to ceftazidime, meropenem, trimethoprim-sulfamethoxazole, doxycycline, and amoxicillin–clavulanic acid). He was treated with meropenem for 2 weeks followed by ceftazidime for 6 weeks; no oral antimicrobials were prescribed. He made a full neurologic recovery and remained well for 5 months, after which he presented with recurrent hemiparesis (grade IV). CT showed a ring-enhancing lesion in the right frontal lobe with surrounding edema (Figure 1–1C). He was treated with ceftazidime for 3 months, followed by a 1-year course of oral eradicative treatment with trimethoprim–sulfamethoxazole (80 mg/400 mg, 6 tablets/day; body weight 55 kg). He has since regained full neurologic function.

Patient 2, a 51-year-old female rice farmer with a history of diabetes mellitus and chronic kidney disease associated with a right nephrectomy 10 years previously, presented with a 6-day history of fever and two generalized tonic–clonic convulsions. Neurologic examination on admission was normal with a GCS of 15. A blood culture grew B. pseudomallei with typical susceptibility pattern. CT was reported to be normal (Figure 1–2A). She was treated with ceftazidime for 14 days, followed on discharge by trimethoprim-sulfamethoxazole (80 mg/400 mg, 6 tablets/day) plus doxycycline (100 mg, 2 tablets/day). At follow-up clinic 1 month later, she complained of nausea, vomiting, and anorexia. Oral antimicrobials were changed to amoxicillin–clavulanic acid (amoxicillin 3 g/day and clavulanic acid 750 mg/day). Two months subsequent to this, she developed a progressive left hemiparesis (grade I) over a period of 1 week and had four generalized seizures. CT showed an epidural collection in the right frontal lobe area with surrounding edema (Figure 1–2B). Blood and urine cultures were negative; she was treated with ceftazidime for 2 weeks followed by meropenem for 2 weeks. Follow-up CT showed no improvement. Craniotomy was performed, and 5 mL of pus obtained from the epidural space was culture-positive for B. pseudomallei with a typical antimicrobial susceptibility pattern. Ceftazidime was continued for a further 5 weeks before switching to oral trimethoprim–sulfamethoxazole (80 mg/400 mg, 8 tablets/day; body weight 64 kg). She completed 20 weeks of oral treatment and regained full neurologic function. Repeat CT showed almost complete resolution of the abnormalities (Figure 1–2C). B. pseudomallei obtained from the first and second episodes had an identical banding pattern on pulsed-field gel electrophoresis (data not shown).

Patient 3, a 45-year-old female rice farmer with a history of diabetes mellitus, presented with a splenic abscess. She was treated for suspected melioidosis with parenteral amoxicillin–clavulanic acid for 9 days followed by oral amoxicillin–clavulanic acid for 4 months (amoxicillin 3 g/day and clavulanic acid 750 mg/day), and trimethoprim–sulfamethoxazole (80 mg/400 mg, 4 tablets/day; body weight 35 kg) for a month after the development of a rash. Follow-up abdominal ultrasound showed complete resolution of the splenic lesion. Eleven months after the first admission, she presented with a 1-month history of fever, chills, and a progressively enlarging skull mass. On examination, there was an 8-cm soft fluctuant parietal skull mass (Figure 1–3A). No neurologic deficit was present. Blood cultures were negative, but urine culture grew B. pseudomallei. Skull x-ray revealed two “punched-out” bone lesions in the affected area (Figure 1–3B). CT showed a cystic lesion in the scalp and an epidural abscess with bone changes consistent with osteomyelitis (Figure 1–3C). Ceftazidime was commenced 4 days prior to a craniotomy, during which the infectious process was found to involve the scalp muscle, bone, and epidural space. Craniectomy was performed, and 30 mL of yellowish pus was evacuated, which was culture-negative. Ceftazidime was continued for 16 days, followed by oral trimethoprim–sulfamethoxazole (80 mg/400 mg, 6 tablets/day; body weight 35 kg) for 20 weeks.

DISCUSSION

Patients presenting with fever together with seizures and/or a neurologic deficit in melioidosis-endemic regions should be investigated by brain CT. The initial scan, however, may show few or no abnormalities in cases of melioidosis with cerebral involvement. Individuals with suspected melioidosis affecting any site should have cultures of blood, urine, throat swab, respiratory secretions, pus, or swabs from skin lesions as available. Patient 3 demonstrates the utility of culturing from disseminated sites, because urine culture alone was positive in this case. On the basis of this study, 1.5% of melioidosis patients in Thailand appear to have neurologic melioidosis with intracranial involvement, while the syndrome of meningoencephalitis was not found.

Antimicrobial therapy for melioidosis generally requires parenteral therapy for 10–14 days, followed by oral antimicrobials for 12–20 weeks. Recommended drugs are ceftazidime or a carbapenem drug for parenteral therapy, followed by trimethoprim–sulfamethoxazole with or without doxycycline for oral eradication therapy.7 Therapy for intracerebral melioidosis requires special consideration because not all drugs used for the treatment of melioidosis achieve therapeutic concentrations in the brain. Ceftazidime or a carbapenem are appropriate because they both achieve high levels in CSF.8,9 The addition of parenteral trimethoprim–sulfamethoxazole to ceftazidime is not associated with a survival advantage in the treatment of melioidosis in general,10 but dual therapy should be considered for the treatment of neurologic infection in view of its excellent CNS penetration.11 Doxycycline concentrations in CSF are not higher than their minimal inhibitory concentration (MIC) to B. pseudomallei12 but may be important for the treatment of extracerebral sites. We recommend parenteral treatment of neurologic melioidosis for a minimum of 4 weeks, followed by oral eradication therapy for a minimum of 6 months. This mirrors treatment recommendations at the Royal Darwin Hospital in Northern Australia (Professor Bart Currie, personal communication). Choice and duration of oral eradicative treatment are determinants of relapse.13 Amoxicillin–clavulanic acid has been shown to be associated with a higher rate of relapse, but the combination remains an alternative oral agent in Thailand.3,13 This is not an acceptable option, however, for treatment of neurologic melioidosis because the concentration of amoxicillin–clavulanic acid in CSF is < 10% relative to blood,14 which falls below the MIC for B. pseudomallei.15 Patient 2 had relapse while being treated with amoxicillin–clavulanic acid, and patient 3 had relapse 5 months after completing 20 weeks of oral treatment, 16 weeks of which was with amoxicillin–clavulanic acid. Options for treatment of patients with intolerance to trimethoprim–sulfamethoxazole or infected with strains resistant to trimethoprim–sulfamethoxazole are limited. Prolonged parenteral therapy is impossible in resource-poor regions, where probably the best option is chloramphenicol plus doxycycline.

Figure 1.
Figure 1.

Case 1: (1A) computer tomography (CT) of the brain with contrast June 2005 showing hypodensity in the right frontal lobe; (1B) CT with contrast August 2005 showing ring-enhancing lesion with surrounding edema in right frontoparietal lobe; (1C) CT with contrast February 2006 showing lesion in right frontal lobe with surrounding edema. Case 2: (2A) CT with contrast July 2005, reported as normal; (2B) CT with contrast October 2005 showing epidural collection in right frontal lobe area with surrounding edema; (2C) CT with contrast May 2006 showing resolution of previous abnormalities. Case 3: (3A) mass in parietal area of skull (consent and permission to use the photograph was obtained from the patient); (3B) skull x-ray showing punch-out lesions; (3C) CT without contrast showing cystic mass at right parietal scalp area and epidural abscess with evidence of bone involvement.

Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.118

*

Address correspondence to Direk Limmathurotsakul, Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand. E-mail: direk@tropmedres.ac

Authors’ addresses: Direk Limmathurotsakul, Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand, Telephone: +66 2 354 1395, Fax: +66 2 354 9169, E-mail: direk@tropmedres.ac. Wipada Chaowagul, Prawatwong Wongsrikaew, and Arhtitpong Narmwong, Sappasithiprasong Hospital, Ubon Ratchathani Hospital, Ubon Ratchathani, Thailand, 34000. Nicholas P. Day and Sharon J. Peacock, Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, U.K.

Acknowledgments: The authors thank the director of Sappasithiprasong Hospital, together with the medical and nursing staff of the Medical and out-patient department; the staff of the Wellcome Trust–Oxford University–Mahidol University Tropical Medicine Research Program; Vanaporn Wuthiekanun, Gumphol Wongsuvan, Aunchalee Thanwisai, and Narisara Chantratita for laboratory data, including genotyping; and Nongluk Getchalarat and Jintana Suwannapruk for their technical assistance.

Financial support: This study was funded by the Wellcome Trust.

Disclosure: No conflicts of interest are reported by any author.

REFERENCES

  • 1

    Chaowagul W, White NJ, Dance DA, Wattanagoon Y, Naigowit P, Davis TM, Looareesuwan S, Pitakwatchara N, 1989. Melioidosis: a major cause of community-acquired septicemia in northeastern Thailand. J Infect Dis 159 :890–899.

    • Search Google Scholar
    • Export Citation
  • 2

    Currie BJ, Fisher DA, Howard DM, Burrow JN, Selvanayagam S, Snelling PL, Anstey NM, Mayo MJ, 2000. The epidemiology of melioidosis in Australia and Papua New Guinea. Acta Trop 74 :121–127.

    • Search Google Scholar
    • Export Citation
  • 3

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

  • 4

    Currie BJ, Fisher DA, Howard DM, Burrow JN, 2000. Neurological melioidosis. Acta Trop 74 :145–151.

  • 5

    Chadwick DR, Ang B, Sitoh YY, Lee CC, 2002. Cerebral melioidosis in Singapore: a review of five cases. Trans R Soc Trop Med Hyg 96 :72–76.

    • Search Google Scholar
    • Export Citation
  • 6

    Lee MK, Chua CT, 1986. Brain abscess due to Pseudomonas pseudomallei. Aust NZ J Med 16 :75–77.

  • 7

    Wuthiekanun V, Peacock SJ, 2006. Management of melioidosis. Expert Rev Anti Infect Ther 4 :445–455.

  • 8

    Lutsar I, Friedland IR, 2000. Pharmacokinetics and pharmacodynamics of cephalosporins in cerebrospinal fluid. Clin Pharmacokinet 39 :335–343.

    • Search Google Scholar
    • Export Citation
  • 9

    Klugman KP, Dagan R, 1995. Carbapenem treatment of meningitis. Scand J Infect Dis Suppl 96 :45–48.

  • 10

    Chierakul W, Anunnatsiri S, Short JM, Maharjan B, Mootsikapun P, Simpson AJ, Limmathurotsakul D, Cheng AC, Stepniewska K, Newton PN, Chaowagul W, White NJ, Peacock SJ, Day NP, Chetchotisakd P, 2005. Two randomized controlled trials of ceftazidime alone versus ceftazidime in combination with trimethoprim–sulfamethoxazole for the treatment of severe melioidosis. Clin Infect Dis 41 :1105–1113.

    • Search Google Scholar
    • Export Citation
  • 11

    Friedrich H, Hansel G, 1977. [An investigation into the levels of a trimethoprim–sulphamethoxazole combination in the ventricular fluid of neurosurgical patients (authors’ transl.)]. Acta Neurochir (Wien) 37 :271–280.

    • Search Google Scholar
    • Export Citation
  • 12

    Andersson H, Alestig K, 1976. The penetration of doxycycline into CSF. Scand J Infect Dis Suppl 17–19.

  • 13

    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
  • 14

    Bakken JS, Bruun JN, Gaustad P, Tasker TC, 1986. Penetration of amoxicillin and potassium clavulanate into the cerebrospinal fluid of patients with inflamed meninges. Antimicrob Agents Chemother 30 :481–484.

    • Search Google Scholar
    • Export Citation
  • 15

    Dance DA, Wuthiekanun V, Chaowagul W, White NJ, 1989. The antimicrobial susceptibility of Pseudomonas pseudomallei. Emergence of resistance in vitro and during treatment. J Antimicrob Chemother 24 :295–309.

    • Search Google Scholar
    • Export Citation
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