Melioidosis: refining management of a tropical time bomb
Authors: Dale A Fisher, Patrick N A Harris
Journal: The Lancet (2013)

Melioidosis, dubbed the Vietnamese time bomb1Time MagazineDiseases: Viet nam's time bomb.Time. Feb 10, 1967; (accessed Oct 23, 2013).http://content.time.com/time/magazine/article/0,9171,840848,00.htmlGoogle Scholar after reports of lengthy disease latency in war veterans, is caused by Burkholderia pseudomallei and manifests as acute, subacute, or chronic disease. Bacteraemic disease especially when associated with pneumonia is the most lethal form, especially if associated with septic shock, but infection with or without abscess formation can occur in any organ system. Although most presentations occur soon after exposure, the organism's ability to evade host immune mechanisms and to survive and multiply in phagocytes2Jones AL Beveridge TJ Woods DE Intracellular survival of Burkholderia pseudomallei.Infect Immun. 1996; 64: 782-790PubMed Google Scholar gives rise to latency—latency of up to 62 years has been reported.3Ngauy V Lemeshev Y Sadkowski L Crawford G Cutaneous melioidosis in a man who was taken as a prisoner of war by the Japanese during World War II.J Clin Microbiol. 2005; 43: 970-972Crossref PubMed Scopus (198) Google Scholar Seroprevalence rates vary widely but are highest in northeast Thailand, where most children show evidence of exposure.4Wuthiekanun V Chierakul W Langa S et al.Development of antibodies to Burkholderia pseudomallei during childhood in melioidosis-endemic northeast Thailand.Am J Trop Med Hyg. 2006; 74: 1074-1075PubMed Google Scholar It remains unclear how many of those with serological evidence of exposure harbour latent B pseudomallei with the potential for subsequent activation. Several risk factors cause some people to have an increased risk of melioidosis, with diabetes being the most common.5Wiersinga WJ Currie BJ Peacock SJ Melioidosis.N Engl J Med. 2012; 367: 1035-1044Crossref PubMed Scopus (589) Google Scholar For those with culture-confirmed melioidosis, treatment recommendations include an initial intensive intravenous course of at least 10 days with ceftazidime or a carbapenem.5Wiersinga WJ Currie BJ Peacock SJ Melioidosis.N Engl J Med. 2012; 367: 1035-1044Crossref PubMed Scopus (589) Google Scholar This course is followed by a so-called oral eradication phase of at least 3 months. The initial clinical response might indicate a need to modify the duration of the intensive phase, but the optimum antibiotic regimen and duration for eradication are uncertain. Recurrent melioidosis was noted in 13% of patients treated in Australia,6Currie BJ Fisher DA Anstey NM Jacups SP Melioidosis: acute and chronic disease, relapse and re-activation.Trans R Soc Trop Med Hyg. 2000; 94: 301-304Summary Full Text PDF PubMed Scopus (199) Google Scholar but its prevalence has fallen over the past decade, possibly attributed to improved compliance, choice, and dosing of antibiotic regimens.7Currie BJ Ward L Cheng AC The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study.PLoS Negl Trop Dis. 2010; 4: e900Crossref PubMed Scopus (522) Google Scholar Higher rates of recurrence in Thailand have been associated with inadequate duration of treatment.8Limmathurotsakul D Chaowagul W Chierakul W et al.Risk factors for recurrent melioidosis in northeast Thailand.Clin Infect Dis. 2006; 43: 979-986Crossref PubMed Scopus (105) Google Scholar In The Lancet, Ploenchan Chetchotisakd and colleagues present findings from the MERTH trial,9Chetchotisakd P Chierakul W Chaowagul W et al.Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trial.Lancet. 2013; (published online Nov 25.)http://dx.doi.org/10.1016/S0140-6736(13)61951-0PubMed Google Scholar in which they enrolled 626 patients with melioidosis, randomly allocating them to receive trimethoprim-sulfamethoxazole alone (the recommended regimen in Australia) or trimethoprim-sulfamethoxazole plus doxycycline (the recommended regimen in Thailand). During follow-up, they recorded no between-group difference in the occurrence of culture-positive recurrent cases (16 in the single-drug group, 21 in the combination group; hazard ratio 0·81, 95% CI 0·42–1·55), suggesting non-inferiority of the single-drug treatment (p=0·01). Furthermore, toxicity was higher in the combination group. The study's power calculations probably did not take into account the high rate of re-infection by a different genotype from the initial infection, rather than true relapse. Of recurrences with paired isolate typing undertaken (29 [78%] of 37 patients with culture-confirmed recurrent melioidosis), 15 (52%) were due to a different genotype, which is much higher than previous reports—in a study of 921 patients in which detailed typing was used to characterise paired isolates from relapse cases, 26% were shown to be new infections.10Maharjan B Chantratita N Vesaratchavest M et al.Recurrent melioidosis in patients in northeast Thailand is frequently due to reinfection rather than relapse.J Clin Microbiol. 2005; 43: 6032-6034Crossref PubMed Scopus (75) Google Scholar It is tempting to postulate that at least some of these re-infections were actually recurrence from an original polyclonal infection, but the pronounced difference in median time to re-presentation of 7 months (for relapse) versus 29 months (for reinfection) suggests otherwise. Previous work has also shown polyclonal infection to be a rare occurrence, happening in only 1·5% of patients.11Limmathurotsakul D Wuthiekanun V Chantratita N et al.Simultaneous infection with more than one strain of Burkholderia pseudomallei is uncommon in human melioidosis.J Clin Microbiol. 2007; 45: 3830-3832Crossref PubMed Scopus (21) Google Scholar Despite this unexpected finding, even a subgroup analysis of same-genotype relapses lends support to the investigators' conclusions. MERTH had a treatment duration longer than generally recommended—20 weeks. Advocates of combination antibiotics for 3 months might therefore remain unconvinced without further research clarifying the optimum duration. However, several points support the study's findings. Doxycycline might antagonise the effects of trimethoprim-sulfamethoxazole in vitro.12Dance DA Wuthiekanun V Chaowagul W White NJ Interactions in vitro between agents used to treat melioidosis.J Antimicrob Chemother. 1989; 24: 311-316Crossref PubMed Scopus (30) Google Scholar Also, doxycycline monotherapy is associated with high rates of relapse.13Chaowagul W Simpson AJ Suputtamongkol Y Smith MD Angus BJ White NJ A comparison of chloramphenicol, trimethoprim-sulfamethoxazole, and doxycycline with doxycycline alone as maintenance therapy for melioidosis.Clin Infect Dis. 1999; 29: 375-380Crossref PubMed Scopus (76) Google Scholar For many years, single-drug treatment with trimethoprim-sulfamethoxazole has been used effectively as eradication treatment in Australia.6Currie BJ Fisher DA Anstey NM Jacups SP Melioidosis: acute and chronic disease, relapse and re-activation.Trans R Soc Trop Med Hyg. 2000; 94: 301-304Summary Full Text PDF PubMed Scopus (199) Google Scholar In view of the extended duration of eradication treatment necessary, compliance might be hampered by adverse events as reported in the combination treatment group in this trial. Patients in this group had a 40% rate of switching to second-line regimens due to adverse events. B pseudomallei is an environmental saprophyte found in the soil and fresh surface water of tropical regions. Clinical trials in such settings are often difficult, meaning that conditions of treatment are necessarily real-world. Melioidosis endemicity has been reported in dozens of tropical regions and cases are also imported to non-tropical areas, but numbers are generally small. Adequately powered clinical trials can be done only in highly endemic areas such as Thailand, with support from international organisations experienced in clinical trials. It is a disease of major public health importance in northeast Thailand, and is possibly the third most common cause of death due to an infection after HIV and tuberculosis, accounting for roughly 20% of community-acquired bacteraemia.5Wiersinga WJ Currie BJ Peacock SJ Melioidosis.N Engl J Med. 2012; 367: 1035-1044Crossref PubMed Scopus (589) Google Scholar The findings of MERTH should prompt a change in standard recommendations for the eradication treatment phase of melioidosis toward trimethoprim-sulfamethoxazole alone. However, many questions about optimum doses and duration remain, with some even suggesting that an extended intravenous phase might decrease the rate of relapse. Because B pseudomallei has such complex interactions with host immunity resulting in latency, diverse presentations, and high risk of disease relapse, future treatment guidelines might be equally complex and possibly stratified, related to disease site and severity, as well as host factors and initial treatment response. We declare that we have no conflicts of interest. Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trialOur findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline for the oral phase of melioidosis treatment, and is preferable on the basis of safety and tolerance by patients. Full-Text PDF Open Access