Melioidosis Therapy
Abstract & Commentary
By Philip R. Fischer, MD, DTMH
Dr. Fischer is a Professor of Pediatrics, Division of General Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN.
Dr. Fischer reports no financial relationships relevant to this field of study.
Synopsis: Melioidosis is a soil-related infection of south Asia and northern Australia that is caused by Burkholderia pseudomallei. It commonly causes pneumonia and bacteremia but can infect the central nervous system, bones, eyes, and heart. Treatment involves one to two weeks of intensive intravenous ceftazidime (alternatively either meropenem or imipenem) in combination with 20 or more weeks of oral therapy. Dosage details for this disease have recently been clarified.
Source: Cheng AC, et. al. Consensus guidelines for dosing of amoxicillin-clavulanate in melioidosis. Am J Trop Med Hyg2008;78:208-209.
Melioidosis is frequently fatal, often undiagnosed, and difficult to treat. It seems to be spreading beyond its regional foci in northern Australia and south Asia, and can affect travelers. Unfortunately it has been proposed as a potential weapon of bioterrorism. What could be worse? Published treatment regimens are sometimes misunderstood and improperly followed.
Thus, clinical and research experts with extensive experience in both the study and treatment of melioidosis convened discussions to clarify the dosing of amoxicillin-clavulanate in melioidosis treatment. It is recommended that when amoxicillin-clavulanate is used for the second phase (eradication) treatment of melioidosis, an individual dose of 20 mg amoxicillin and 5 mg clavulanate per kg body weight should be given three times daily for at least 20 weeks.
Commentary
Melioidosis is a life-threatening illness caused by Burkholderia pseudomallei. While associated with the disease for nearly 100 years, the Gram-negative etiologic microbe has been previously identified in both the Bacillus and Pseudomonas genuses. Illness is most often seen in northern Australia and southeast Asia (roughly 20 degrees south to 20 degrees north latitude) or in travelers who have visited those regions. The organisms are most commonly associated with soil.1 Infection has been linked to seasonal monsoons2 as well as to the December 2004 Asian tsunami.3
Risk factors for developing melioidosis include type II diabetes2 with about half of melioidosis patients having diabetes. A history of significant soil exposure is frequent in infected individuals as are both male gender and aboriginality (in Australia) - likely because of their links to soil exposure. Renal disease and chronic lung disease are also risk factors, and travelers with cystic fibrosis seem to be at significant risk of infection.1
Inhalation and direct inoculation seem to be the most common routes of contact with the infecting organisms, but ingestion can also occur. Larger infecting doses seem to be associated with more severe disease.1
Pneumonia is the most common presentation and bacteremia is identified in about half of tested patients.1 Presentation with genitourinary infection, including prostatic abscesses, is relatively common in Australia while about one-third of melioidosis patients in Thailand are children with suppurative parotitis. Brain stem encephalitis with paralysis is seen in a few percent of patients.1,4 Localized bone and joint infection,5 corneal ulcers, and cardiac infection are less common presentations.1
Long incubation periods, for up to 62 years and late recurrences (13% of patients during the 10 years after the initial illness) of infection are possible.3 Thus, neither the lack of a recent travel history nor the history of seemingly-effective previous treatment precludes a diagnosis of melioidosis. Mortality is high ~19% (Australia) to 50% (Thailand).3
The diagnosis of melioidosis is dependent on clinical suspicion, and many cases likely go unrecognized.2 The diagnosis is confirmed by culturing B. pseudomallei from blood or other body fluids. The organisms have varying antibiotic resistances, so susceptibility testing is useful. Typically, however, B. pseudomallei is susceptible to ceftazidime, trimethoprim-sulfamethoxazole, doxycycline, meropenem, and amoxicillin-clavulanate. Azithromycin, ertapenem, and other antibiotics are less useful.1, 6
Quick cures are not possible. Specific antimicrobialtreatment must be associated with aggressive supportive care, and outcomes are often most dependent on the technological support and therapeutic skill in the treating center. Antibiotic treatment is divided into two stages. A half dozen randomized controlled trials support the use of intensive initiation therapy with intravenous ceftazidime (40-50 mg/kg/dose every six to eight hours) in combination with trimethoprim (8 mg/kg/dose up to 320 mg/dose orally twice daily) - sulfamethoxazole (40 mg/kg/dose up to 1600 mg/dose orally twice daily). An alternative intravenous agent would be either meropenem or imipenem, but not ertapenem. This intensive initiation phase should continue for seven to 14 days.1
Ongoing eradication treatment should continue for at least an additional 20 weeks. This may be performed with either doxycycline (2 mg/kg/dose orally twice daily) or trimethoprim (5 mg/kg/dose orally twice daily) - sulfamethoxazole (25 mg/kg/dose orally twice daily), or amoxicillin (20 mg/kg/dose orally three times daily) - clavulanate (5 mg/kg/dose orally three times daily).
What else can be learned from this recent publication? First, the paper reminds us of the means by which treatment recommendations should be formulated. Suggestions for therapy should be based on clear evidence, preferably from randomized, controlled, blinded studies. This evidence, especially when contradictory, inconclusive, or limited, should be interpreted by academic and clinical experts with experience in the details of management.
A second lesson from this paper is that authors writing for international audiences should be perfectly clear in their treatment recommendations. Similarly, readers of the literature should be careful to understand what the authors meant, rather than how people in other settings night interpret the authors' words. The problem with several recent publications had been that Australian and Asian dosage recommendations ("mg/kg three times daily" written with the assumption that these quantities would be divided by three for each dose) were interpreted differently (as if the larger dose was to be given repeatedly three times each day).
A third lesson, especially when dealing with infections that are only rarely seen in travelers' home countries, is to remember to use the dose that is supported by evidence for the particular indication. Amoxicillin--clavulanate is used for several different types of infections, and the product comes in several "convenient" fixed preparations. Prescribers should be careful to use an appropriate preparation to give the desired amount of each component of the treatment.
References:
- Cheng AC, Currie BJ. Melioidosis: epidemiology, pathophysiology, and management. Clin Microbiol Rev 2005;18:383-416.
- Vidyalakshmi K, et al. Melioidosis: an under-diagnosed entity in western coastal India: a clinico-microbiological analysis. Indian J Med Microbiol 2007;25:245-248.
- Peacock SJ. Melioidosis. Curr Opin Infect Dis 2006;19:421-428.
- Muthusamy KA, Waran V, Puthucheary SD. Spectra of central nervous system melioidosis. J Clin Neurosci 2007;14:1213-1215.
- Jain VK, et al. Melioidosis: a review of orthopedic manifestations, clinical features, diagnosis and management. Ind J Med Sci 2007;61:580-590.
- Karunakara R., Puthucheary SD. Burkholderia pseudomallei: in vitro susceptibility to some new and old antimicrobials. Scand J Infect Dis 2007;39:858-861.
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