CLINICAL MICROBIOLOGY REVIEWS, Apr. 2005, p. 383–416 0893-8512/05/$08.00ϩ0 doi:10.1128/CMR.18.2.383–416.

2005 Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Vol. 18, No. 2

Melioidosis: Epidemiology, Pathophysiology, and Management
Allen C. Cheng1,2 and Bart J. Currie1,2,3*
Menzies School of Health Research, Charles Darwin University,1 Northern Territory Clinical School, Flinders University,2 and Department of Medicine, Royal Darwin Hospital,3 Darwin, Australia INTRODUCTION .......................................................................................................................................................384 Background and History........................................................................................................................................384 EPIDEMIOLOGY .......................................................................................................................................................384 Melioidosis in the Australia-Pacific Region........................................................................................................384 Distribution of Melioidosis in Asia ......................................................................................................................385 Thailand ...............................................................................................................................................................385 PDR Laos .............................................................................................................................................................386 Vietnam ................................................................................................................................................................386 Malaysia and Indonesia.....................................................................................................................................386 Singapore .............................................................................................................................................................387 China, Hong Kong Special Administrative Region, and Taiwan .................................................................387 Other parts of Asia.............................................................................................................................................387 Areas outside Asia ..................................................................................................................................................389 Animals and Melioidosis .......................................................................................................................................389 BACTERIOLOGY AND PATHOGENESIS.............................................................................................................389 General Bacteriology ..............................................................................................................................................389 Environmental Microbiology and Epidemiology ................................................................................................389 Bacterial Virulence Factors ...................................................................................................................................390 Secretory antigens...............................................................................................................................................390 Cell-associated antigens.....................................................................................................................................391 Molecular Epidemiology ........................................................................................................................................392 Genome Sequence of B. pseudomallei and Comparison with That of B. mallei ..............................................392 Role of Host Immune Responses..........................................................................................................................393 Innate immunity..................................................................................................................................................393 Role of macrophages in immunity....................................................................................................................393 Role of T cells in immunity ...............................................................................................................................394 Antibody responses .............................................................................................................................................394 Other host factors...............................................................................................................................................394 Prospects for Vaccine .............................................................................................................................................394 CLINICAL FEATURES .............................................................................................................................................395 Risk Factors.............................................................................................................................................................395 Clinical Syndromes.................................................................................................................................................396 Modes of Acquisition and Incubation Period .....................................................................................................397 Melioidosis as a Potential Bioweapon .................................................................................................................398 DIAGNOSIS AND MANAGEMENT OF MELIOIDOSIS ....................................................................................399 Diagnosis..................................................................................................................................................................399 Culture-based methods ......................................................................................................................................400 Antigen detection ................................................................................................................................................400 Antibody detection ..............................................................................................................................................400 Molecular methods .............................................................................................................................................401 Antibiotic Resistance ..............................................................................................................................................401 Antibiotic Treatment ..............................................................................................................................................403 Management of Sepsis Syndrome.........................................................................................................................405 CONCLUSIONS .........................................................................................................................................................406 ACKNOWLEDGMENTS ...........................................................................................................................................406 REFERENCES ............................................................................................................................................................406

* Corresponding author. Mailing address: Menzies School of Health Research, P.O. Box 41096, Casuarina, NT 0811, Darwin, Australia. Phone: 61 8 8922 8196. Fax: 61 8 8927 5187. E-mail: bart@menzies .edu.au. 383

384

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CLIN. MICROBIOL. REV.

INTRODUCTION Background and History The pathologist Alfred Whitmore and his assistant C. S. Krishnaswami first described melioidosis as a “glanders-like” disease among morphia addicts in Rangoon, Burma, in 1911 (474, 475). They recognized a new organism that fulfilled Koch’s postulates for causation of disease. This bacterium, which could be isolated from autopsy specimens on peptone agar and potato slopes, could be distinguished from the organism causing glanders by its relatively rapid growth, its motility, and the lack of the Strauss reaction when it was injected into guinea pigs. Based on these characteristics, “. . . sufficiently peculiar to distinguish it from all pathogenic bacteria previously known to us” (475), they correctly surmised that this new bacterium was closely related to that which caused glanders, a finding that has only recently been confirmed by molecular studies (170, 197, 313). This disease, now termed melioidosis, was named from the Greek “melis” (distemper of asses) and “eidos” (resemblance) by Stanton and Fletcher in 1932 (405). During the last century this gram-negative environmental bacterium has been variously known as Bacillus pseudomallei, Bacillus whitmorii (or Bacille de Whitmore), Malleomyces pseudomallei, Pseudomonas pseudomallei, and, since 1992, Burkholderia pseudomallei (496). In the latter half of the 20th century, melioidosis emerged as an infectious disease of major public health importance in southeast Asia and northern Australia. In Ubon Ratchathani, Thailand, B. pseudomallei accounts for up to approximately 20% of community-acquired bacteremias (74). At the Royal Darwin Hospital, Australia, it has been the most common cause of fatal community-acquired bacteremic pneumonia (112, 147). Largely due to clinical trials in Thailand, significant improvements have been made in defining the optimal antibiotic therapy for melioidosis. However, the choice of antibiotic regimen has not been shown to have an impact on mortality within the first 48 h of admission (473), and severe melioidosis in Thailand is still associated with a case fatality rate of approximately 50% (472). In Australia, the mortality rate is still significant and approaches 20% among all patients with melioidosis (111).

disease are currently noted, did not record cases until 1947 and 1950, respectively (130, 358). Other anomalies that may be related to incomplete ascertainment include a high serological prevalence (7%) of melioidosis in returning American troops stationed in Vietnam (97) but a low rate of disease in the indigenous population (324, 453). In addition, the high prevalence of melioidosis in the Issan region of northeastern Thailand contrasts with the low prevalence in the People’s Democratic Republic of Laos (PDR Laos) to the east of the Mekong River and in Cambodia further south (9, 68, 329). A caveat to this paradox is the uncertainty associated with the seropositivity rates in southeast Asia, which may represent exposure to the less pathogenic Burkholderia thailandensis (472). The worldwide distribution of B. thailandensis is yet to be clearly defined, but it is clear that it comprises the most common soil isolates in northeast Thailand (437); it has not been found in Australia (108). Melioidosis in the Australia-Pacific Region Melioidosis was first recognized within Australia from an outbreak in sheep in 1949 in Winton, northern Queensland (101). The first human case described was in a diabetic who died from septicemic melioidosis in Townsville in 1950 (358), and the first case reported from the Northern Territory occurred in 1960 (102). This apparently late emergence of such an important infectious disease in northern Australia led to suggestions that B. pseudomallei may have colonized Australia from southeast Asia (157), although the molecular diversity of isolates contrasts with foci in areas where the organism is not endemic (107). Although the area where melioidosis is endemic has generally been regarded as restricted to the latitudes 20oS and 20oN in southeast Asia and northern Asia (266), large outbreaks have occurred outside this area in Australia, including the first case in Winton (22oS) and 159 cases of melioidosis in pigs over 3 years in the Burnett River region (25.5oS), which were attributed to a contaminated water supply (237). Autochthonous cases have also occurred outside this area in southwest Western Australia (107, 171), the Brisbane River Valley in Queensland (27oS) (236, 374), Alice Springs, and Mackay. The distribution of endemic cases in 2001 and 2002 and previously reported foci outside of the area of endemicity is shown in Fig. 2. Epidemiological studies have defined an annual incidence rate in the Top End of the Northern Territory as 16.5 per 100,000 between 1989 and 1999 (112), with rates as high as 41.7 per 100,000 in 1998, which were associated with two severe weather events and high annual rainfall (114). There have been few other population-based rates described previously for Australia, but in a geographically restricted area within the Torres Strait in northern Queensland in the 2000 to 2002 seasons (151), a rate of 40 cases per 100,000 was documented. In contrast to many other countries where the disease is endemic, in Australia most patients are from remote locations but are transported to referral hospitals in the Top End region of the Northern Territory, the Kimberley region of Western Australia, and far north Queensland and the Torres Strait for management.

EPIDEMIOLOGY Melioidosis is regarded as endemic to southeast Asia and northern Australia, corresponding approximately to the tropical latitudes between 20°N and 20°S. The worldwide epidemiology of melioidosis has been comprehensively reviewed by David Dance (118, 130); data from those and other, more recent reports are summarized in Table 1 and Fig. 1. Writing over 10 years ago, Dance (130) noted that published case reports and series are likely to represent only the “tip of the iceberg,” as culture facilities are not available in most of the rural tropics where the infection is likely to be prevalent. This is also evident in the apparent changing epidemiology of the infection; despite Krishnaswami documenting melioidosis in 5% of all autopsy deaths in 1917, the only reported cases from Burma since 1945 have been in travelers (205, 268, 472). Similarly, Thailand and Australia, where the highest rates of

VOL. 18, 2005 TABLE 1. Worldwide distribution of melioidosis based on reported cases
Level of evidence Country (reference[s])

MELIOIDOSIS

385

Endemic; multiple case series described ........................................ Northern Australia (24, 111), Thailand (74, 267), Singapore (191, 272, 424), Malaysia (345), Burma (475), Vietnam (97, 204) Possibly endemic; multiple cases, significant numbers of ........... Southern China (499, 501), Hong Kong Special Administrative Region (170, exported cases 397, 398), Brunei (130), PDR Laos (329; P. Newton, personal communication), Cambodia (9, 68), Taiwan (40, 205, 262–264) Epidemic; limited outbreak .............................................................. Aruba (Netherland Antilles) (421), France (130), Brisbane River Valley (Queensland, Australia) (236, 374) Sporadic case reports ........................................................................ Asia India (43, 44, 122, 224, 231, 348), Indonesia (39, 120, 341, 370), Bangladesh (122, 201, 239, 300, 414), Japan (16), Philippines (120), Pakistan (122), Sri Lanka (452) Americas and Caribbean Guadeloupe (327), Martinique (320), Puerto Rico (94, 146), Equador (45), Panama (296), El Salvador (45, 130), Haiti (130), Brazil (301, 378), Costa Rica and Colombia (O. Dance, personal communication), Venezuela (M. C. Redondo, Abstr. 11th Int. Conf. Infect. Dis. abstr. 58.026, 2004) Pacific Guam (302), Fiji (100; B. J. Currie and M. Lowe, unpublished data), Papua New Guinea (112, 132, 240, 362, 469), New Caledonia (S. Hello, personal communication) Africa and Middle East Iran (131, 339), Uganda (130), Sierra Leone (130), The Gambia (130), Madagascar (130), Kenya (49) Unconfirmed identification, uncertain travel history, or ............. Asia-Pacific serological evidence only Korea (130), Hawaii (323), East Timor (P. Armstrong, personal communication) Europe Spain (130), Germany (130) Africa and Middle East United Arab Emirates (118), Saudi Arabia (118), Egypt (130), South Africa (451), Turkey (130), Egypt (130), Niger (153), Burkina Faso (Upper Volta) (130) Americas Mexico (35), United States (38, 150, 164, 228, 295) Isolates from environment only ....................................................... Italy (504), Peru (130), Co ˆte d’Ivoire (130), Reunion Island (130), Haiti (130)

Environmental sampling has revealed widespread isolation of samples from soil, mud, and pooled surface water in northern Australia, including Queensland (427), around Darwin (58, 299), and remote communities in the Northern Territory and Western Australia (107, 215). Two outbreaks have been linked to contamination of the drinking water supply, where disease control measures, such as cleaning of the water supply and pipes, led to a cessation of the outbreaks (115, 212, 213). Although serological tests have been demonstrated to have poor sensitivity and specificity in clinical situations, seroprevalance is likely to reflect background exposure to B. pseudomallei on a population basis. Serosurveys of populations in northern Australia have demonstrated relatively low rates of seropositivity compared to the rates seen in northeastern Thailand. This was reflected in a study in Queensland, where seropositivity in urban populations (up to 5%) was lower than that in patients residing in rural locations or in patients of Aboriginal or South Pacific origin (up to 10%) (24), which were similar to those found in the primarily indigenous population of Arnhem Land in the Northern Territory (12.8%) (112).

These seroprevalences contrast with the much higher rates in immigrants from southeast Asia to Queensland (29%) (24). At least six cases of melioidosis have been reported from Port Moresby in Papua New Guinea (104, 132, 260, 362), as has one additional case in an ex-serviceman living in Brisbane (240), for whom the place of exposure was not clear. Small serological surveys in the Port Moresby region have not demonstrated antibodies to B. pseudomallei (33, 362). However, a series of clinical cases in Balimo, Western Province, has led to the suggestion that melioidosis may occur elsewhere in the country (112, 469). Distribution of Melioidosis in Asia Thailand. The high rates documented in northern Australia compare to the annual incidence of 4.4 cases per 100,000 in Ubon Ratchathani province in northeast Thailand (417). Other centers in northeast Thailand, such as Khon Kaen, Nakhon Ratchasima, Buri Ram, and Udon Thani, also see large numbers of patients. In a national survey, 30 of the 125 hos-

Cases have continued to be observed in returning servicemen for up to 29 years following exposure (93. and most recently. relatively few cases have been reported in adjacent Laos (329). 3. pseudomallei from soil isolates in the Vientiane region (494a). REV.100. may also account for the much higher rates of seropositivity seen in Thailand (230). the annual number of isolates was over 1. pseudomallei were made by Vaucel in Hanoi and Chambon in Saigon (now Ho Chi Minh City) (67. with the patchy distribution of B. However. 130). although it is likely to be found elsewhere in the country. Newton. Vietnam. FIG. Results from this survey and the locations of hospitals reporting large numbers of cases in Thailand are shown in Fig. recent attempts at systematic surveillance have not found significant proportions of B. In Thailand. which had previously been recognized as B. With the large numbers of French and later American troops based in Vietnam. Stanton and Fletcher noted animal cases at the Institute of Medical Research of the Federated Malay States as far back as 1913. Outside of Vientiane. 393). pseudomallei. thailandensis. despite recovery of B. and the first descriptions of the saprophytic niche of B. pseudomallei in the environment associated with clinical cases. Puthucheary et al. Melioidosis was first noted in what is now southern Vietnam by Pons and Advier (336). matches rates of clinical B. may account for the variation in disease throughout the country (437). MICROBIOL. Despite the fact that the highest rates in Thailand have been documented in the northeast Issan region. Mahosot Hospital in Vientiane recognized a handful of cases each year. pseudomallei to B. Malaysia and Indonesia. pseudomallei is widely distributed in soil and. constituting 2% of blood culture isolates at this referral center between 2000 and 2002 (P. Worldwide distribution of melioidosis. the ratio of B. A serosurvey conducted in Malaysia in 1964 to 1966 revealed a 7. pitals did not have microbiological facilities. 489). 285). which is highest in the northeast. this probably represents a conservative estimate of the number of cases of melioidosis in Thailand (267). thailandensis found in soil.386 CHENG AND CURRIE CLIN. 306. B. with exposure to environmental B. pseudomallei and access to modern clinical and laboratory services. less virulent strains of Burkholderia spp. microbiological facilities are limited and the epidemiology is undefined. 492). large numbers of cases were described from the 1940s to the 1970s (130). However. These findings and the possibility of the existence of other. PDR Laos. as have sporadic cases in Vietnamese emigrants and returned travelers to other countries (192. pseudomallei isolation throughout Thailand (267. 173. Cases from both peninsular and east Malaysia have continued to be described. more particularly. This may be analogous to the situation in Papua New Guinea. and during 1994 to 1995. 1. the rate of the closely related but less virulent B. personal communication). pseudomallei in blood culture isolates or soil around Ho Chi Minh City (324). in pooled surface water such as in rice paddies (154. compared to the areas of endemicity of northern Australia (24).3% seropositivity (indi- . reviewed 50 septicemic cases of melioidosis in 1992 at a single referral center in Kuala Lumpur and noted a total of 85 cases from June 1976 to June 1991 (346). and they published reports of these and subsequent human and animal cases in 1932 (404).

Unusually. Regional variation in incidence rate in northern Australia based on data for notifiable diseases in 2001 and 2002 (80). an annual rate of 1. 483). 205. Serosurveys have consistently demonstrated a low rate of seropositivity in Singapore (0. a high rate of ceftazidime resistance (57%) was observed (501). On mainland China. P. Sporadic cases of melioidosis from Indonesia have been reported in the Dutch literature for many years (39. B.. 225. 348). Small numbers of cases of locally acquired melioidosis have been observed in Hong Kong (397. Hong Kong Special Administrative Region.2% in the general population and 1. 2005 MELIOIDOSIS 387 FIG. 337 cases) being culture-confirmed cases (191). 2. Abstr. and the United States (370). 292. 283).VOL. 121). rect hemagglutination assay [IHA] titers of Ͼ1:40). in addition to more recent cases exported to Australia (177) the United Kingdom (120). An ongoing outbreak in marine mammals in an ocean park has been described (193). 398. suggesting poor ascertainment . pseudomallei (44). In Singapore. 501). have been described (40. Other parts of Asia. a case series and several sporadic cases. mostly autochthonous. In Taiwan. 223. Lim. During early 2004. with an unusually higher case-fatality rate (40%). when 104 patients were reported (41). and a seroprevalence of 14% was demonstrated by IHA in a tuberculosis sanatorium (396). Multiple cases have been reported from disparate regions of India but have been largely restricted to a few large medical centers. pseudomallei from surface water appears to be less common than it was in the 1960s (425) and less common than it is in other countries in the region. 272). More recently. 231.2% of soil and water specimens in Hainan Island and adjoining coastal provinces as far north as 25°N (500). 262–264. pseudomallei has been isolated from 4. which were attributed to abnormally heavy rains and flooding (O. presumably where identification is possible (87. some of these. 3. a seasonal pattern or an association with rainfall has not been noted in Singapore. 4th World Melioidosis Congr. and Taiwan. with the majority (89%. including an apparent outbreak of a bubonic plague-like illness attributed to B. higher numbers have been noted since 1998. have been disputed (43. 395). Previous autochthonous cases outside the area of endemicity are indicated by stars. Cases in travelers returning to Europe from the Indian subcontinent have been reported. Isolation of B. 57 cases have been reported. as confirmed by human cases and seroprevalences (IHA titers of Ͼ1:40) of up to 34% in farmers in the region (499. with the highest rates in recruits from Kedah (peninsular Malaysia) and Sabah (east Malaysia) (412). except in immigrants from Thailand or Malaysia (191. 440. China. The case-fatality rate for patients with severe melioidosis otherwise appears in line with those in more developed countries (69). Singapore. abstr. melioidosis has been a notifiable disease since 1989. 18. In the seven isolates from culture-positive cases tested.6% in construction workers). in contrast to the case for most other series (191). 2004).7 cases of melioidosis was documented between 1989 and 1996.

.388 CHENG AND CURRIE CLIN. MICROBIOL. Provinces with highest numbers of isolates are highlighted. pseudomallei from clinical specimens (per 1. 3.000 specimens) in Thai hospitals based on a hospital survey in 1995 (267). Regional variation in rates of isolation of B. FIG. REV.

Chantratita. but in semisolid media this finding is less reliable (154). 239. referred to as “l’affaire du jardin des plantes. is being prospectively investigated in Thailand (N. and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud (53. and kangaroos (156.5 for up to 70 days) (133). pigs. Serological studies in East Timor suggest exposure to B. requiring an awareness of this disease by clinicians worldwide (65. distorted by the magnitude of immigration from those countries. 401). pseudomallei. 370). 122. pseudomallei in the Americas. Animals and Melioidosis A wide variety of animal species have been shown to be susceptible to melioidosis. 458). 277. further studies have demonstrated highest yields from moist soils and pooled surface water (306.” was thought to be due to either the importation of horses from Iran or an infected panda donated by Mao Tse-Tung (130. Although few cases in Sri Lanka have been described (452). 252. and a wide temperature range (24o to 32°C) and dehydration (soil water content of Ͻ10% for up to 70 days) (77. BACTERIOLOGY AND PATHOGENESIS General Bacteriology B. goats. 18. personal communication). with mostly smooth colonies initially and dry or wrinkled colonies on further incubation. Although the disease was reported in up to 10% of autopsy deaths in Rangoon. and captive marine animals (193). 228). Subsequent molecular studies have been conflicting (495). and rats and guinea pigs (474). thailandensis by its ability to assimilate arabinose (271. 112. horses. and the Middle East (118. The association between surface water and melioidosis is supported by the strong association with monsoonal rains (74. 113. 373. However. including inbred mouse strains (456). Areas outside Asia Most cases reported outside southeast Asia are from travelers to areas of endemicity. including small-colony variants. pseudomallei is visualized as a gram-negative bacillus with bipolar staining and is vacuolated and slender and has rounded ends. cats. The saprophytic nature of B.VOL. sheep. including west and east Africa. 300). 472). The clinical significance of the various colony types. One case from within the country has been described (414). Some early studies implicated the aerosolization of dry dusts as a route of acquisition for American servicemen in Vietnam. A variety of animals have been used in experimental models. pseudomallei (200). 130). 2005 MELIOIDOSIS 389 of cases locally (122. water buffalo. The finding that higher rainfall is significantly associated with sepsis and pneumonia suggests that environmental conditions during the monsoonal season . 112. antiseptic and detergent solutions (161. Whitmore distinguished it from Burkholderia mallei by its motility on a hanging drop. 426. 237. personal communication]). Central and South America. pseudomallei but with atypical characteristics that were felt to put this identification in doubt (130). Human and animal cases have been imported from Bangladesh. 326. one serosurvey revealed a seroprevalence of 7% in a rural rice-growing area near Vellore (231). alpacas (220a). 436. On culture. Epizoontic outbreaks have also been reported among imported animals from areas of endemicity. and dogs (277). However. Burma. 122. 492). Sporadic cases of melioidosis in travelers returning from Bangladesh have also been reported (122. or are disputed (164). 434) but not exposure to UV light (434). 430). 429). koalas (253). it is often described as having a “safety pin” appearance. 413. Armstrong. personal communication). 266) and with occupational and recreational exposure to surface water and mud (74. including camels. Most recently. 266). In addition. pseudomallei. based on the high incidence in helicopter crews (204). the organism demonstrates differing colonial morphology. with phylogenetic analysis placing this isolate in a distinct group apart from both B. 390). goats. 205. Pakistan. Wuthiekanun. Much debate has focused on the question of indigenous B. a report described a case that was believed to have been acquired in that country (326). the susceptible BALB/c and more resistant C57BL/6 inbred mouse strains have been used extensively in studies of host responses to B. pseudomallei was first recognized in 1955 in French Indochina (67). had poorly documented travel histories (38. pseudomallei is a resilient organism that is capable of surviving hostile environmental conditions. A cluster of infections is sheep. cattle. chickens (457). particularly with flooding of rice paddies and planting at the commencement of the monsoonal season (417). This outbreak. since 1945 the only cases reported were one in a Dutch traveler (268) and a second possible exported case in a Taiwanese traveler (205). and pigs living on Aruba (Dutch Antilles) was attributed to B. In North America. and the Philippines (120. in the original series. India. It is oxidase positive and can be distinguished from the closely related but less pathogenic B. which was identified by the authors as B. Cattle. 277). sporadic autochthonous cases have been reported throughout the world. but no culture-confirmed cases have been reported (P. acidic environments (pH 4. thailandensis and B. It is likely that harsh environmental conditions may confer a selective advantage for the growth of B. Birds are also considered to be relatively resistant to melioidosis (258). including a series of three patients presenting with septic arthritis following travel to Syhet (201). Possibly the most intensely studied organism was the “Oklahoma isolate” from a soil-contaminated wound infection following a farming accident (295). although cases have been reported (428. including prolonged nutrient deficiency (493) (of durations of up to 10 years [V. the Caribbean. pseudomallei in 1957 (421). pseudomallei (170). Cases imported into the United Kingdom probably reflect the prevalence of melioidosis within the countries of origin. Indonesia. deers. early reported cases were associated with travel (150). An outbreak in a Paris zoo in the 1970s resulted in the spread to other zoos and equestrian clubs throughout France and to the deaths of at least two humans and a number of animals. 431). Environmental Microbiology and Epidemiology B.

unpublished data). lecithinase. including nutrient deficiency. cepacia bacteria to emerge following horizontal transmission of genetic elements (199). REV. it is believed that biofilm formation is stimulated by bacterial quorum-sensing mediators such as N-acylhomoserine lactones (468). pseudomallei in the environment may include physical factors such as rainfall. Movement of the bacterium towards one pole of the cell occurs by means of continuous actin polymerization into a “comet-tail” formation similar to that observed with other pathogens such as Listeria (48. pseudomallei is also well adapted to its many hosts. Many. has also been implicated in other outbreaks in Australia (115. other vegetation. lipases. Bacterial Virulence Factors Like many saprophytic organisms. the finding that the relationship between the density of bacteremia and mortality is similar in melioidosis and other gram-negative bacteremias . and extremes of temperature. were isolated from a potable water source and the environment. early work has defined putative signaling pathways in B. disinfectant and antiseptic solutions (including detergents and chlorine). It is resistant to complement lysosomal defensins and cationic peptidases and can survive within many eukaryotic cell lines. 413. 234. In particular. 237). and a siderophore. 410). Although cleared. a process described for other pathogens such as Legionella pneumophila (217). rather than soil. a process described for other pathogens such as L. Levy and T. Subsequent studies suggested that B. superoxide dismutase. Inglis. However. pseudomallei produces a glycocalyx polysaccharide capsule that is probably an important virulence determinant (407). a sampling study of the site of an aborted attempt to grow rice in the Northern Territory at Fogg Dam failed to recover B. Valede and Y. 410). Altered phenotypes such as slow-growing small-colony variants can be observed on primary plates from clinical specimens (V. including proteases (261. producing proteases. Sampling studies in Australia have suggested that bacterial counts increase to a depth of 60 to 90 cm (427. UV radiation. phospholipase C (246). and hemolysin. but the finding that dry. or lecithinase.000 ppm (202). Australia. cepacia may be a hazard to human health. As Burkholderia cepacia can degrade toxic compounds in pesticides and is active against many soilborne pathogens. as discussed above (217). Factors that may influence the distribution of B. irrigated areas have been shown to be favored by the organism in Malaysia and Thailand (306. remains uncertain. and temperature. There has been some interest in the interaction between species in the Burkholderia genus (99. Song. personal communication). and the use of fertilizers. moist clay soils seem to be favored by the organism (427). abstr 30 and 31. pneumophila. numerous insertion sequences within B.. shallower soils may be culture negative yet PCR positive has led to the suggestion that the organism may persist in a viable but nonculturable state (58). This suggests that unusual mechanisms may mediate the survival of B. and transposable genetic elements in B. Secretory antigens. pseudomallei and the parasite Acanthamoeba sp. D. personal communication) or can be induced by passaging in vivo or in vitro and are also associated with significant antibiotic resistance. Contamination of drinking water supplies. Transposon mutations in the general secretory pathway. MICROBIOL. chemical factors such as soil composition. sensitive techniques using flow cytometry do demonstrate the possible presence of viable bacteria in small numbers despite free chlorine concentrations of up to 1. pseudomallei within the body. perioxidase. lechithinase. cepacia. Direct cell-to-cell spread is thought to occur by the induction of these cellular protrusions and fusion of cell membranes to form multinucleated giant cells (184. The implications of global climate change for the epidemiology of melioidosis are as yet unknown (103). have a higher rate of disease (343). pseudomallei in vitro (A. a cytotoxic exolipid. Wuthiekanun. The role of secreted antigens is unclear. resulting in a failure to secrete protease. B. 2004). However. 376). These variants may subsequently revert spontaneously to their normal morphology and antibiotic susceptibility (188). such as the “globi” observed within macrophages and giant cells in autopsy specimens (477). resulting in significant antibiotic resistance (461). pseudomallei may infect Acanthamoeba trophozoites by coiling phagocytosis. pseudomallei. cepacia. 234. with the potential for more virulent B. unpublished data). including for some strains sequences identical to B. In a Western Australia outbreak. The presence of chlorinators does not affect community rates of melioidosis in areas of endemicity (82). including professional phagocytes such as neutrophils and macrophages (472). or “slime”) allows for the formation of microcolonies in a protective environment in which the organism is phenotypically altered. such as B. both B. Ultrastructural studies using electron microscopy have shown multiplication within the vacuoles of phagocytes following internalization and subsequent endosome lysis (185). acid and alkali pH. pseudomallei is a resilient bacterium that can survive in a variety of hostile condi- tions. This justifies concerns that widespread agricultural use of B.390 CHENG AND CURRIE CLIN. When Acanthamoeba trophozoites are infected with B. B. these are not found in the Top End region of Australia. which have also been observed in human tissue (477). pseudomallei insertion sequences (284). 492). Thomas. 492). and lipase (26) are probably secreted via the general secretory pathway (type II secretion system) (137). Chlorination of the water supply was associated with the termination of one of these outbreaks and appears to be effective against B. pseudomallei (B. However. lipase. Abstr. do not appear to result in an attenuation of virulence in an animal model (53). The significance of this interaction and those with plant-associated organisms as a reservoir for persistent environmental contamination is being assessed (A. In other bacteria. catalase. there has been interest in its use as a crop biological control agent (199). 4th World Melioidosis Congr. exposure to many antibiotics. may be associated with inhalation rather than inoculation as the primary mode of acquisition (113). pseudomallei that may be virulence factors (E. B. and populations residing on these soil types in Darwin. humidity. 167). The significance of other mutant forms of the organism. and recent soil disturbances such as excavation and plowing (215). hemolysins. such as cell wall-deficient L-forms that can be induced only in vitro by passage through rabbit alveolar cells (241). pseudomallei (61) have been identified. Currie. bacterial escape from vacuoles is mediated by coiling phagocytosis. This capsule (biofilm.

4th World Melioidosis Congr. However. However. passive immunization against an exopolysaccharide provided protection against high-dose challenge in a mouse model (227). A largely unexplored area has been the role of iron metabolism in determining virulence. such as Staphylococcus aureus. 487). It is known that a siderophore. 363). lipopolysaccharide (LPS) (formerly O-PS II) (195). In addition. pseudomallei in humans and animals (304). 503). Flagellin proteins may be important in pathogenesis. thailandensis (233. such as Vibrio parahaemolyticus. less virulent B. 388). appear to be associated with increased rates of melioidosis (286. pseudomallei to attach to and invade epithelial cell lines appears to be growth phase and temperature dependent. or Burkholderia secretion apparatus). such as hemosiderosis and thalassemia. pseudomallei is supported by the finding of homology between the SPI-1 pathogenicity island of Salmonella enterica (Inv/Spa/Prg) and TTSS3 of B. Reckseilder-Zenteno. pseudomallei and is efficient at acquiring iron at acidic pH (498). Outer membrane proteins. 389). pseudomallei challenge (52). 2004). pseudomallei and is a virulence determinant. This presumed function in B. and 17 kDa. and flagellin proteins (75. immune system evasion (347). 328). flagellinspecific antiserum passively protected diabetic infant rats against B. This siderophore is regulated by the fur gene. which can affect otherwise healthy individuals and where virulence factors such as Panton-Valentine leukocidin correlate with severe disseminated disease. 37. CPS I (previously thought to represent a component of LPS and known as O-PS I) is found only in B. However. infection of these hosts is accidental and is not likely to provide an evolutionary advantage for an otherwise environmental organism. malleobactin. which demonstrate a susceptibility to alternative complement pathway (139. pseudomallei in a mouse model appears to be attenuated by iron-enriched media (441). pseudomallei generally has low diseasecausing potential in healthy hosts despite its ubiquity in the environment. Antibodies to LPS have been shown to be protective against severe disease in humans (75) and in animals (63). including BopE. is elaborated by B. fimC. retain their virulence (64). In addition. are activated under specific conditions to allow delivery of effector molecules to host cells in order to facilitate invasion and survival in phagosomes (162. 2005 MELIOIDOSIS 391 suggests that exotoxins do not play a significant role in determining outcome (472). 467). A number of genes for different CPSs. and strains with mutations in this antigen are less virulent than wild-type strains (28). In other organisms. Microarray studies have determined that growth of B. such as a protein tyrosine phosphatase. The ability of B. 356). thailandensis in the presence of arabinose results in downregulation of TTSS3 via the putative positive regulator bsaN. pseudomallei organisms with mutations in the Bsa and BopE system are also confined to the endosome and are unable to gain access to cell actin. and attachment to epithelial cells (3). TTSS in other organisms. and mutations involving the TTSS3 system (as opposed to TTSS1 and TTSS2) attenuate virulence in a hamster model (467). Although clinical conditions with iron overload. suggesting that this system is also important in mediating endosomal membrane lysis (410). A number of cell-associated antigens have been demonstrated to be immunogenic in patients with melioidosis. Capsular polysaccharide appears to provide protection within the phagosomal environment (342. Other cell-associated antigens include type I pili (encoded by fimA. Bacterial products secreted by this TTSS (termed Bsa. a number of type III secretion systems (TTSS) have been described (349). the mechanisms underlying this in vitro phenomenon and its clinical relevance are yet to be determined (60). Other outer membrane proteins. This stands in contrast to other organisms whose ecological niche is in humans and animals. The important role of LPS is supported by studies examining laboratoryinducted mutations in the gene coding for LPS. 486) and an attenuation in virulence in a mouse diabetes model (139. The virulence of B. B. thailandensis strains do not contain some TTSS (349). Antigenic differences in CPS or other surface proteins may account for the lack of epithelial attachment and pathogenicity of B. this may suggest that iron plays a more important role in pathogenesis than has been recognized. . 38. including capsular polysaccharide (CPS). such as Salmonella enterica. which also regulates superoxide dismutase and peroxidase (275). pilC. the 38-kDa peptidoglycan-associated protein appears to form aggregates and to function as a porin (174. 290. and other antigens with strong homology to the pilB. 31. with molecular masses of 70.VOL. Although bacteria do not contain the substrate tyrosine phosphate. However. Capsular polysaccharide appears to have a role in environmental protection (229). like infections with Vibrio and Salmonella spp. have also been identified and used in diagnostic tests. as strains with mutations of acpA. termed CPS I to IV. In addition B. CPS II is downregulated in vivo and is thought to be involved in environmental survival (S. 408. which parallels increased virulence (117). analogous enzymes in other bacteria such as Yersinia have alternative substrates that are believed to be important in signal transduction (229). 138. and fimD) and a putative type IV pilus complex. acid phosphatases do not appear to be a major virulence determinant. suggesting that the loss of the ability to assimilate arabinose is linked to the increased virulence of B. 18. and pilD products of Pseudomonas aeruginosa have been defined. have been defined (245). They also happen to allow the bacterium to avoid the host immune responses of humans and animals.. Cell-associated antigens. 410). have recently been described. However. It is important to note that these putative virulence factors are mechanisms developed (in evolutionary terms) by the organism to survive in its as-yet-unidentified ecological niche(s). are thought to result in cytoskeletal rearrangements facilitating host cell invasion (408). pseudomallei strains with mutations involving known putative TTSS3 effectors are not significantly attenuated (409. iron-restricted conditions result in the induction of siderophore production. Abstr. pseudomallei (349. This fact is reflected in the poor characterization of bacterial products as being truly virulent in animal studies and in the organism’s primary affinity for hosts with impaired immunity. conflicting results have been reported with nonmotile fliC mutants which were less virulent in BALB/c mice (96) but not in Syrian hamsters or diabetic mice (138). 24. abstr. resulting in loss of phosphatase activity. B.

REV. 180. Adapted from reference 197 with permission of the publisher. Comparisons of typing methods demonstrate that RAPD analysis and PFGE are more discriminatory than ribotyping (180. mallei A major recent advance has the completion of sequencing and the annotation of the genomes of both B. Multilocus sequence typing appears to have a discriminatory ability similar to that of PFGE (79. rfb. 441). accession numbers 006350 and 006351. B. that recurrent infection is usually due to relapse with the same strain rather than reinfection with a different strain (109. Furthermore. and ribotyping. collegenase Adhesins: surface proteins that may modulate host-cell interaction Fimbriae and pili: type I and IV pili and tad-type pili (including pil) a For details. 115. chemotaxis-associated proteins (including che) Secretion: type I. and bop) Surface components: lipopolysaccharide. pseudomallei may have differing virulence. B. Certain ribotypes appeared to be associated with a higher mortality or risk of relapse in one study (333). and the smaller tends to carry genes required for survival and virulence factors. 115). and D beta-lactamases (including oxa and penA). pseudomallei (313). pseudomallei. thailandensis was relatively avirulent led to a suggestion that different strains of B. based on allelic differences present at seven housekeeping genes. pseudomallei group. pseudomallei (clinical strain K92643) (197. There was stability in the levels of virulence within two of these clone types. and V secretion systems. and C (107. but many isolates in this study did not fall into defined groups (441). This suggests that introduction of B. This technique. both being distinct from B. More recently. This study confirmed the diversity seen in isolates worldwide and placed B. The genome of B. and potential surface polysaccharide biosynthesis (including waa.net/). thailandensis (170).17 Mb. and wcb) Exoproteins: phospholipase C (including plc). mallei does not contain any of these genomic islands. 448). identified by anomalies in GC content or dinucleotide signatures together with accompanying coding sequences resembling those of mobile genetic elements. pseudomallei genomea Survival Virulence Secondary metabolism: possible antibiotic. Gene deletion. pseudomallei. aminoglycoside acetyltransferase Intracellular stress: superoxide and nitric oxide detoxification enzymes (including sod) Motility and chemotaxis: flagellum system (including fli and flg). 140. Genome Sequence of B. see National Center for Biotechnology Information Genome Project. 170). III. metalloprotease A and other proteases (including mpr). a sequence-based successor to multilocus enzyme electrophoresis. Genes associated with survival and virulence identified in the B. multidrug efflux pumps (including amr). In contrast. A striking finding was the demonstration of genomic islands. Molecular typing of Australian isolates by PFGE and ribotyping have shown three clusters. Two other studies have suggested that clinical presentation or outcome may depend on the strain type. These are likely to represent DNA that has been recently horizontally acquired and are variably found in clinical and environmental strains of B. in contrast to clonal outbreaks in regions where the organism is not endemic (107). pseudomallei into these regions is not a recent event. 449). 216. These and other studies have demonstrated considerable diversity in isolates (333). respectively) that demonstrate functional partitioning (197). Molecular Epidemiology A variety of molecular tools have been used to infer genetic relatedness between isolates of B. A summary of some of the key genes identified is given in Table 2.392 CHENG AND CURRIE CLIN. II. A second small study (n ϭ 18) using multilocus enzyme electrophoresis and RAPD analysis suggested that soft tissue infections were restricted to one cluster and respiratory and neurological infections were seen in another cluster (317). 179. MICROBIOL. probably as a result of mammalian host restriction and a consequent reduction in selective pressure. suggesting that horizontal acquisition of DNA is not an important source of genetic variation as it is in B. capsular polysaccharide. Rather. is ideal for genetic analysis beyond the outbreak situation due to its re- producibility and the low rate of genetic change in the allelic sites and allows for comparisons between strains typed at different laboratories though an internet-based database (http: //www. The finding that the antigenically similar B. and that outbreaks of infection may be clonal (107. multilocus sequence typing. numerous . siderophore biosynthetic pathways (including fur) Drug resistance: Ambler class A. suggesting ancient origins that predate the transient land bridges between these regions in the Miocene period (79). The larger chromosome carries many genes required for cell metabolism and growth. 313). These have included pulsed-field gel electrophoresis (PFGE).mlst. mallei within this wider B.07 and 3. TABLE 2. pseudomallei. pseudomallei and Comparison with That of B. surfactant. including three type III secretion systems (including bsa. pseudomallei. Australian isolates appear to be clustered separately from those from the other countries of southeast Asia where the disease is endemic. is suggested by the absence of many of the genes required for environmental survival in B. B. has been developed for B. bip. pseudomallei is composed of two large chromosomes (of 4. termed A. The findings that the gene order is conserved on the larger chromosome and has a greater number of orthologous matches compared to other bacteria suggest that they may not have a common ancestry. These studies have demonstrated that environmental isolates can be identical to epidemiologically related human or animal strains (107. 180). random amplified polymorphic DNA (RAPD) analysis. mallei (strain ATCC 23344) and B.

little is known regarding the precise localization of latent intracellular B. thalassemia. resulting in phagocytosis. We have previously speculated that the intracellular niche of this organism and its interaction with hosts with specific co- . Reports of patients with chronic granulomatous disease (146. chronic renal failure (190. 175). although the alternative complement pathway is activated. Similar defects have been observed in association with high alcohol consumption (27. is an early and potent proinflammatory cytokine. 276. TNF-␣ is required for the containment of infection. cerebral malaria. representing a stable mutation in the TNF-␣ promoter (G3A substitution at base Ϫ308). 447). In addition. particularly patients with diabetes. (iii) the fact that although gamma interferon (IFN-␥) appears to be vital in resistance. It appears to be able to evade phagosome-lysosome fusion and destroy the phagosome membrane as soon as 15 min after ingestion (185). several points require explanation by any comprehensive model of pathogenesis: (i) the specific comorbidities present in patients susceptible to melioidosis. as well as their bactericidal activity. 40. 360). although there is some evidence that high-titer antibodies against LPS may be protective against severe infection. Similarly. the presence of TNF2 was associated with a statistically significant relative risk of melioidosis of 2. in one study. including those of the macrophage/ monocyte lineage (185. T cells. improvements in laboratory markers are seen following G-CSF use (186. mallei. However. 311. oxidative burst. 288. 168. 312. and (v) the site from which latent infection may reactivate. However. Macrophages exposed to B. Although this is assumed to play a role in the site of latent infection. 433). 226). B. 46. 422) support the role of neutrophils in resistance to melioidosis. the low levels of IFN-␤ production by macrophages may also mediate poor intracellular control by inducible nitric oxide synthase-dependent mechanisms (444). 2005 MELIOIDOSIS 393 insertion sequences and simple sequence repeats point to an alternative mechanism for genetic variability in B. Multiple studies of G-CSF in nonneutropenic animal models have demonstrated improvements in outcome (172. pseudomallei interactions have compared responses in patients with melioidosis and healthy controls. Innate immunity. High systemic levels are associated with septic shock. 47. They suggest that there is less early phagolysosome fusion in macrophages from melioidosis patients. particularly as human immunodeficiency virus (HIV) infection does not seem to be a risk factor for disease. 322. was increased by priming with IFN-␥. pseudomallei after early host-bacterium interaction and the bactericidal ability of macrophages. alcoholism. and multiple and single organ involvement.3 (318). resulting in higher intracellular bacterial concentrations (S. Abstr. and meningococcal purpura fulminans (249). The TNF2 allele. It is also associated with increased susceptibility to mucocutaneous leishmaniasis. Of further interest is the possibility of reversing these functional defects with granulocyte colony-stimulating factor (GCSF). abstr. 305. 18. septicemia. Role of Host Immune Responses Although many studies have observed and defined immune responses believed to be important in pathogenesis. 366). 312. 411. produced primarily by macrophages but also by B cells. 361). pseudomallei appears to be resistant to serum bactericidal components (220). 353). providing an explanation for the important role of this cytokine in mediating resistance (447). the responsiveness of these cells. Studies of the role of phagocytes in melioidosis have demonstrated conflicting results. In 109 of 123 Thai patients with melioidosis. ultrastructural studies of macrophage-B. (ii) the fact that repeated exposure. as relapse after apparently successful treatment and an extended incubation period after exposure suggest a dormant state similar to that seen in tuberculosis. (iv) the contributions of the various bacterial products to infection and. where high TNF-␣ levels were associated with mortality. and renal impairment. B. As mentioned above. pseudomallei appears to be able to survive and multiply within professional phagocytes. When the patients were matched to 74 seronegative controls. which is sufficient in some patients to provoke an antibody response to a highly conserved lipopolysaccharide antigen. the role of adaptive CD4-mediated immunity remains uncertain. The use of G-CSF has been associated with a fall in mortality in patients with septic shock due to B. 309. 325. pseudomallei can survive and multiply within professional phagocytes. 242. pseudomallei. 342). Phagocytosis was increased by the addition of specific antibodies and complement (148).VOL. and killing activity (30–32. TNF-␣. 289) but not all (354) studies. However. 310. including macrophage/monocyte and neutrophil cell lines (226. The comorbidities recognized as risk factors for melioidosis also may be operating by impairing neutrophil function. In human studies. lower levels and slower production of inducible nitric oxide synthase and tumor necrosis factor alpha (TNF-␣) were seen in a macrophage cell line compared to those after exposure to Escherichia coli and S. 183. and thalassemia (476). 287. 338. pseudomallei do not appear to respond in the same way as they do to other pathogens. This is consistent with functional studies demonstrating poor early bactericidal activity in most (149. Puthucheary. 195. 166. 207. 194.. including in patients with melioidosis. as might be expected for an intracellular bacterium. and fibroblasts. a clinical trial has commenced recently (84). phagocytosis. and patients with diabetic foot infection may benefit from the use of G-CSF (134. It is established that B. neutralization of TNF-␣ in a mouse model increased susceptibility to melioidosis (369). enterica serovar Typhi (446. Role of macrophages in immunity. is insufficient protection against infection. large multicenter clinical trials have failed to demonstrate benefits in pneumonia and severe sepsis. 2004). Diabetes mellitus has been demonstrated to result in impaired chemotaxis. possibly due to late administration of G-CSF in the course of the illness (85. 4th World Melioidosis Congr. the relative contributions of endotoxin and exotoxins to pathogenesis and evasion of the immune system (the finding that the relationship between bacterial counts in blood and mortality is similar to that with other gram-negative organisms suggests that exotoxins do not contribute directly to outcome). more specifically. it is resistant to the effects of the terminal complement membrane attack complex (149). 505). is associated with increased production of TNF-␣. the presence of TNF2 (present in 9% of the study population) was associated with an increased risk of death.

394 CHENG AND CURRIE CLIN. levels of mRNA for Th1 cytokines (IFN-␥. a key Th1 cytokine that stimulates phagocytosis. Similarly. However. A classic framework to view specific host responses is the type 1/type 2 dichotomy. there is evidence that anti-inflammatory Th2 responses are necessary to balance proinflammatory Th1 responses. C57BL mice are more resistant to Leishmania major and IL-10 gene knockout (IL-10Ϫ/Ϫ) mice are more resistant to Listeria monocytogenes. personal communication). 369). 480). as in melioidosis. the ratio of immunoglobulin G1 (IgG1) to IgG2 in humans (454) and mice (200) also suggests that a type 1 response may be adaptive. thailandensis is insufficient to provoke a protective response for primary infection or relapse. either as an immunoprotective agent or as a DNA vaccine adjuvant. pseudomallei components have been demonstrated to be immunogenic in patients with melioidosis. despite its prevalence in Thailand (92). the induction of adverse cytokine profiles. Other approaches that have been investigated include the use of DNA vaccines against the fliC flagellin structural gene . Antibody responses. This may suggest that the intensities of both pro. most puzzling is the absence of evidence to suggest that HIV infection is a risk factor for melioidosis. Antibodies could persist variably for over 3 years (454). Role of T cells in immunity. Type 1 responses are generally adaptive against intracellular pathogens. theoretical concerns focus on the possibility of DNA integration into host cells (although CpG itself does not contain a promoter). IL-12. 235). CD8ϩ T cells have been demonstrated to be a source of IFN-␥ early in the response to infection with B. and neutralization of IL-12 can be demonstrated to result in impaired IFN-␥ production (256) and increased susceptibility in mice (369). This process appears to be a “bystander” phenomenon mediated by IL-12 and IL-18 rather than engagement of the T-cell receptor. REV. pseudomallei. indicating that natural humoral immunity does not appear to be protective. particularly the IgG1 and IgG2 subtypes (86). In a mouse model. possibly by increasing bacterial phagocytosis by macrophages (445. Similarly. 290. 138. unexpectedly. More extensive cytokine characterization of Th1 and Th2 responses in mouse strains with differential susceptibility has now demonstrated a mixed pattern. 75. pseudomallei compared to BALB/c mice (200. Prospects for Vaccine A Canadian group has been exploring potential vaccination strategies. 227). A possible association between HLADRB1*1602 and severe melioidosis. thailandensis and B. Of these. Antibodies of all classes against a culture filtrate antigen were demonstrated in patients with prior melioidosis. J. does not appear to be a risk factor for infection. In addition. As discussed above. independent of possible confounders such as diabetes mellitus. Despite recent work demonstrating some protection in animal models following vaccination with B. including capsular polysaccharide and lipopolysaccharide (O-PS I and O-PS II) (195). It is likely that recognition of bacterial endotoxin or other bacterial components plays a significant role in adaptive and maladaptive responses in melioidosis. antibodies against the LPS component O-PS II and possible an exopolysaccharide and flagellin components have been demonstrated to be protective (52. it is unlikely that this strategy alone will provide sufficient protection. the antibody response resulting from repeated natural exposure to B. 210). Studies examining the role of polymorphisms in Toll-like receptor alleles and mannose-binding lectin genes and their correlation with the severity of disease are under way (W.and anti-inflammatory responses merely reflect the magnitude of the inflammatory insult. 328). can be demonstrated in patients with melioidosis and in ex vivo blood simulated with heat-killed B. pseudomallei (270). Evidently. such as with advanced HIV infection. thailandensis and other attenuated strains (209. Other studies have implicated effector cells as cytotoxic T lymphocytes and NK cells responding to IFN-␥ via the CXC chemokines IP-10 and Mig (257). given the extensive histories of exposure of patients to both B. MICROBIOL. In melioidosis. such as diabetes. and other cell wall proteins (386). and their resistance is attributed to their tendency to type 1 responses (403). severe sepsis may represent an unregulated Th1 response.120) for many years who presented with reactivation in association with staphylococcal endocarditis suggests that persistently high titers may define a group of patients that require close follow-up (355). These cells may act to induce apoptosis in infected cells via granzymes (GrA and GrB) (255). NK cells and. 259) and by the demonstration of the key role of IFN-␥. flagellin proteins (75. Wiersinga. the oxidative burst. pseudomallei. and the possibility of triggering autoimmune phenomena in susceptible patients (243). In septic patients. which have recently been reviewed (466). the sine qua non of Th1 polarization. The description of a patient with a persistently high IHA titer (Ͼ1:5. the disease may be present even with high antibody titers. The demonstration of a specific cell-mediated immune response in survivors of acute melioidosis suggests that this may be important in the long-term control and prevention of re- lapse (34. Severe impairment of specific cellular immunity. 256). and IL-12)and Th2 cytokines (IL-10) increased in both susceptible BALB/c and resistant C57BL/6 mice (443). A promising therapy is the use of the use of the bacterial genomic sequences in the form of unmethylated CpG oligodeoxynucleotide. IL-6. Although no significant adverse reactions have been noted in human studies to date. poor outcomes are associated with high levels of both IL-6 (a Th1 cytokine) and IL-10 (a Th2 cytokine) (382). and its correlation with the severity of illness in humans (59. CpG was shown to be strongly protective when administered prior to exposure to B. and the level was highest for IgG. morbidities. this appears to be supported by the demonstration that type 1 response-prone C57BL6 mice were relatively resistant to B. Other host factors. many B. as with other septic states. in which cell-mediated responses are usually inversely proportional to the levels of antibody response. placing susceptibility genes between the HLA-Cw and HLA-DQ loci of the HLA-B58 haplotype (141). suggest that the innate immune response plays a prime role in the control of this organism (111). pseudomallei. but this has not been borne out by other studies. The relatively minor role of specific immunity relative to innate immunity in this infection may explain the capacity of this organism for latency as well as the lack of protection against disease despite repeated exposure to the organism. However. pseudomallei and B. was described (145). and intracellular bacterial killing (368.

........... 13....... linking the capsular and O-PS lipopolysaccharide antigens to exotoxin A of Pseudomonas aeruginosa............... Subsequent studies have attributed the inhibitory effect to a preservative used with insulin (384).6 to 2... A population-based study in Australia defined adjusted relative risks of 4. 299)....3 to 4....... 299.........0 (2...... The observation that case clusters are associated with sudden..3 (415.. 417)............. 299) Male gender .Reports from travelers to areas of endemicity (122............. 114......... mallei or B....... also associated with immunosuppressives (29....................1. which is known to be important in the pathogenesis of melioidosis (226)..... 299.........All series in Australia......... in particular..3 (114) Splenectomy . 417) Soil/water exposure ............ but many have implicated the effect of these comorbidities on neutrophil function (111................ febrile neutropenia............. case-control and population-based studies in Australia and Thailand give estimated relative risk of 5.2 (415.... 417) Chronic granulomatous disease................Between 37 and 60% of patients are diabetic.... points away from this as the mechanism of action (105. renal disease (renal failure and calculi) associated with increased risk of melioidosis (odds ratio....9 to 3..........1) for diabetics............. Currie....... and occupational exposure to surface water were all associated with an increased risk of melioidosis (415)........... unpublished data) Cystic fibrosis .. the high incidence of type 2 diabetes......1 (1......4 (1......Use of Piper methysticum root documented in 8% of Australian series (111) but not associated with pneumonia in case-control study (98) Chronic lung disease ..... 362.. rather than type 1 diabetes.....Subsequent to episode of melioidosis...... leprae may suggest common host susceptibility (56.2 to 4.......4 to 5........................... 415........... Malaysia.2 (114). M...1) for those aged Ն45 years........1 (111........ pseudomallei mutants............... Given the cost of such vaccines....Case report (189) Renal transplantation.... 334........ is being investigated in a horse model of glanders (53... and Singapore demonstrate male preponderance (114. 3............ postcyclonic rainfall in Australia has suggested that public health interventions may best be targeted after these events (80).Two case reports (146... A B. often related to thalassemia (196..... 89..... Attenuated strains would have to be demonstrated to be avirulent..0 (3.... 299.............. 2.. assumed to relate to exposure to soil or water (111........... 381).......... 372.4 to 18...........7 in case-control and population-based studies (111..................... case-control studies in Thailand estimate relative risk of 10...... Studies have examined risk factors in patients with melioidosis compared with septic and nonseptic hospital controls to estimate a relative risk...... Although it was suggested that insulin may have a direct effect on B.... or M.. In a Thai study..9 to 13.... 458) Porphyria cutanea tarda .. the usefulness of this advice has not been evaluated..... 198............Case reports (417) Hemosiderosis. The reason for these specific risk factors is not clear......... mallei candidate conjugate vaccine..... 54)... 4... tuberculosis...... Although protective footwear is often recommended for patients at high risk of melioidosis........ 191...................Rice farmers constitute 81% of patients in Thailand.. diabetes.....Conflicting evidence..9) (415.... 417) Thalassaemia ...... and the resource-constrained regions in which such a vaccine might be used... mainly type 2. with relative risk of 4........... 417) Dengue hemorrhagic fever............0) for males............. 417).Present in 27% of Australian patients (111).... 2005 TABLE 3.. thailandensis can cause clinical infection has important implication for vaccine research (271). likely to be an adverse event in response to medication (160) and the use of attenuated B................. and 3.... pseudomallei would find use outside military settings..... 464) Aboriginality.. it is unlikely that a vaccine for B......... 398......... excessive alcohol use documented in 39% of Australian patients............5) for those with chronic lung disease.................................. relative risk in case-control study estimated at 3.... 363).........8) for those with chronic renal disease.. a case report suggesting that even araϩ B.. 417)......... 114.. the uncertain duration of protection........... thalassemia................ 2........Case reports of patients with infection with atypical mycobacteria.... the relatively low incidence of the disease...............0) for Aboriginal Australians.... 464) Aplastic anaemia..........Case reports (286..... 95..2 (2... CLINICAL FEATURES Risk Factors A number of risk factors for developing melioidosis have been defined in several studies and are summarized in Table 3... one unreported case of pulmonary hemosiderosis secondary to mitral valve disease (B...Patients with renal impairment or failure comprise 10% of Australian series (111) with relative risk of 3........ with relative risk of 2.. 18....... 2..........Five of 18 pediatric patients in Thailand (334) Neutropaenia............... Thailand.......... 417) Excessive alcohol consumption..... 114..........2 to 5..... 415......... less prevalent in Thai patients (12%) (417) Kava use .. Clinical risk factors for melioidosis Risk factor Level of evidence MELIOIDOSIS 395 Diabetes mellitus ..... heavy.......... pseudomallei (487)..VOL.Case report. 417...... have a high incidence of melioidosis. steroid-containing herbal remedies documented in up to 10% of Thai patients (415) Glucose-6-phosphatase deficiency .... .....................Case reports........1 to 6...6) for those with excess alcohol consumption.......................3 (3..... renal disease (defined as renal calculi or renal failure)...1 (9.... with up to 60% of patients having preexisting or newly diagnosed type 2 diabetes (111............␣-Thalassemia trait common in Thailand (44%) but disease less common (8%)...... 417) Renal disease .Population-based study in Australia estimates relative risk of 2... 422) Mycobacterial disease .... patient also diabetic (224) Systemic lupus erythematosis or steroid use.Case studies...Case reports only (273..7 to 8... Patients with diabetes mellitus...

362. reports of patients with hemosiderosis suggest that impairment of phagocytic cells may be important (286. Despite cell-mediated immunity being implicated as a mechanism of resistance to melioidosis (34. with prostatic abscesses occurring in 18% of males. Bacteremic cases only. In the Australian series. 438. Variation in clinical pattern of melioidosis worldwide % of patients in: Clinical presentation Royal Darwin Hospital series (1989–1999. 321). Mycobacterium terrae. Case reports of melioidosis and previous or subsequent mycobacterial infection (Mycobacterium tuberculosis. 417). Acute suppurative parotiditis accounts for up to 40% of pediatric cases but only small numbers of adult cases in Thailand (119. d NR. which have been well described (55.3 2 5 3 NR NR 58 38–61 23 8 13 NR NR NR NR NR NR 4 NR 51 30 100b 68 Culture-confirmed cases only. in contrast to a rate of 30 to 40% in Thai children (119). characterized by brain stem encephalitis and flaccid paralysis. early reports implicating inhalation in helicopter crews based in Vietnam (204) and the presence of a marked association of the rates of pneu- monia with rainfall (113) suggest that inhalation may be more important than had been previously appreciated. based on cases of pneumonia arising following a history of inoculation and the finding that radiographic assessment of pneumonia often lags behind the patient’s clinical status. and the distinct but uncommon encephalomyelitis syndrome seen in tropical Australia. infection with HIV does not appear to be a major risk factor (92). Srinagarind Hospital (1978 to 1985). MICROBIOL. not recorded. this includes steroid-containing herbal remedies (“yaa chud”) in Thailand. the use of which was documented in up to 10% of Thai patients (415). Cultures of cerebrospinal fluid were positive in only one of seven cases. Nakorn Ratchsima (1983 to 1985). Similarly. the absence of suppurative parotitis in Australia. n ϭ 252) (111) Singapore series (1989–1996. However. and Nontaburi (1983 to 1985). Encephalomyelitis. The use of steroids is associated with an increased risk of melioidosis. Summary of reported cases presented in 1985 from Khon Kaen Hospital (1982 to 1985). Neurological involvement has also been observed in animals (252. 235). Small numbers of children with a similar syndrome have been recognized in Thailand (365). n ϭ 331)a (191) Kuala Lumpur series (1976–1991. Ubon Ratchathani (1982 to 1985). It may be bilateral in 10% of patients and may be complicated by rupture or permanent facial nerve palsy. 459). It is conventionally thought that lung involvement arises after hematogenous spread following inoculation. 422). n ϭ 63)b (74) Pneumonia or pleural effusion Genitourinary infection Skin or soft tissue infection Neurological melioidosis or brain abscess Splenic abscess Liver abscess Other intra-abdominal Prostatic abscess Parotid abscess Bone or joint Pericardial effusion No clinical focus Septic shock Bacteremia Mortality a b c 58 19 17 4 4 2 3 18 (of males) 0 4 1 10 20 46 19 NRd NR NR NR NR NR NR NR NR NR NR NR NR 43 39 58 10 24 6 2 4 4 NR NR 12 2 NR 16 100b 65 45 7 13 3 2 7 5 0. 258. with monocytic pleocytosis the most common finding (488). 62. Primary meningitis has been observed in Thailand (365) but more often results from ruptured cerebral abscesses (472). pneumonia is the most common presentation of melioidosis and is involved in approximately half of all cases. n ϭ 50)b (346) CLIN. . such as facial sinuses (66) or orbital cellulitis (365). or Mycobacterium leprae) may reflect a common host susceptibility to these intracellular pathogens (56. Important clinical differences have been seen between patients in Australia and Thailand (Table 4): the high incidence of genitourinary infection in Australia. REV. is seen in 4% of melioidosis presentations in northern Australia and is associated with considerable morbidity and mortality (110). It has been reported only once in Australia (151).396 CHENG AND CURRIE TABLE 4. Infectious Diseases Association of Thailand series (n ϭ 686)c (344) Sapprasithiprasong Hospital series (1986–1987. A number of case studies have noted an intriguing association with chronic granulomatous disease that may highlight the underrecognized role of neutrophil defects in pathogenesis (146. Clinical Syndromes In all series. This should be distinguished from more focal suppurative infections involving the central nervous system. Some of these may represent direct spread from contiguous sites. It seems to arise in patients with no defined risk factors and is generally associated with a good prognosis. 89. 66. 332. chronic obstructive pulmonary disease and the consumption of kava and alcohol have also been implicated (111). 282). 363). Chulalongkorn Hospital Bangkok (1980 to 1985).

similar to necrotizing fasciitis from other organisms (465). soldiers in Vietnam. there was a wide variation in response. Inhalation was initially thought to be the primary mode of acquisition.000 hospitalized children and 4. Markers of organ dysfunction. Factors associated with a higher risk of relapse included poor adherence to therapy. pyopericardium is probably the most common manifestation. but myocardial abscesses (37) and endocarditis (344) have been reported. subconjunctival abscesses.7 compared to localized disease).5) (72. this was not specific to melioidosis. it is likely that these factors as well as the size of the inoculum are responsible for the pattern and severity of disease. 417). but in 1. Markers of inflammation such as C-reactive protein (CRP) are often used. in Australia. There also are differences in the dosing of TMP-SMX. the prevalence of prostatic infection (18% of male patients) mandates routine imaging. except that the systemic features of the illness may be more prominent. As with other infectious diseases. 419). aymptomatic carriage has been reported (426). elevations in CRP levels predicted relapse. However. based on studies of U. is likely to be an important factor. in addition to close follow-up.. and hypopyon were managed with topical and intravenous ceftazidime with good outcomes (385). variation in the host immune response. even in the absence of fever or leukocytosis (22). Treatment failure. the use of ampicillin-clavulanate or the four-drug conventional therapy in the intensive phase (relative risk of 2 compared to ceftazidime). Other ocular manifestations include orbital cellulitis with contiguous spread to the sinuses (478). In the majority of cases. Presentations may be rapidly progressive. Infections involving many other sites have been described. as discussed above. Bone and joint infections are uncommon and may be difficult to differentiate from other causes of infection. i. with a significant mortality even in patients with low procalcitonin levels (391). Corneal ulcers were described for a series of three Thai patients following corneal trauma. ingestion.e.524 healthy subjects) in Thailand. play an underappreciated role in determining the clinical manifestation of disease. This contrasts with other internal abscesses. including leukopenia (particularly lymphopenia). Infection with a different strain was demonstrated in between 4 and 7% of cases in Thailand and Australia (109. together with long courses of intravenous antibiotics (337). 109).VOL. has been defined in studies as fever for longer than 14 days or bacteremia for longer than 7 days (383). although the level of procalcitonin reflected the clinical severity of illness and the response to therapy. Persistently positive cultures from other sites and radiological abnormalities are not uncommon and do not necessarily portend a poorer prognosis (111. alanine aminotransferase. 2005 MELIOIDOSIS 397 The high proportion of patients with prostatic infection in Australia contrasts with the higher proportions of patients with liver and spleen abscesses seen in Thailand (455). hepatic dysfunction (raised aspartate aminotransferase. Surgical drainage is often required. improved compliance with this simple eradication regimen. Although the presence of regional variation in the pattern of disease (such as the relative absence of parotiditis in Australia) suggests that bacterial variation may be important. and metabolic derangements (hypoglycemia and acidosis).S. . In addition. raising the possibility that these strains are behaving more like B. 18. The clinical use of procalcitonin has also been assessed in Thailand. are recognized for B. particularly those with cystic fibrosis. and bilirubin levels). a small study demonstrated that CRP levels were elevated in 46 patients with melioidosis. 81. 140) and in one of five recurrent cases in Malaysia (448). are of prime importance in determining the pattern of disease. a review of the use of CRP levels in the larger Darwin prospective series has revealed cases with normal levels or mild elevations on admission with severe or fatal disease. the positive predictive value of a throat swab for clinical disease was 100% (230. and inoculation. There is a large body of evidence that suggests that host factors. mediastinal infection. such as near drownings. We believe that variations in the mode and magnitude of acquisition. In the Royal Darwin Hospital series. The state of asymptomatic carriage has been suggested (109). It occurs in 13 to 23% of cases and a median of 6 to 8 months (but up to many years) later (72. The response to therapy is often poor. Modes of Acquisition and Incubation Period Three modes of acquisition. with a mean duration of fever of 9 days documented. with long-term carriage without signs of overt disease have been described (458). 106). 111). are associated with a short incubation period. Situations likely to be associated with a high inoculum. and eradication therapy of less than 8 weeks (relative risk of 2. renal dysfunction (raised urea and creatinine levels). the use of doxycycline monotherapy or amoxicillin-clavuanate in the eradication phase. with drainage commonly required (106. that the CRP level responded within 2 days in patients with uncomplicated treatment courses. 494). and thyroid and scrotal abscesses (111). and variation in acquisition. severe disease (relative risk of 4. pseudomallei. on admission appear to predict mortality (74. In addition. molecular studies have failed to document this to date. with antibiotic therapy alone. Cardiac involvement is rare. cepacia in this group of patients.545 adults (1. and that persistent elevation in four patients was attributed to undiagnosed sites of infection or inadequate treatment. only 1 patient of Ͼ60 treated with trimethoprim-sulfamethoxazole (TMP-SMX) eradication relapsed (109). Variation in the clinical presentation and severity of melioidosis may be due to one or more of three factors: variation in bacterial strains (including the presence or absence of virulence factors). In Australia. even less than 24 h (262. inhalation. In goats.011 patients with melioidosis and 3. Relapse after apparently successful treatment is well described and is associated with a mortality similar to that for the initial episode. Extensive ulcers. particularly age and comorbidities. but the relative contributions of each are yet to be determined. 109). Occasional patients. including mycotic aneurysms. relapse is due to reactivation of the original infecting strain (demonstrated by restriction fragment length polymorphism or pulsed-field gel electrophoresis). including in relapse (83). a higher dose is given (8/40 mg/kg of body weight twice a day) than in Thailand (5/25 mg/kg twice a day). which may respond to medical therapy alone (111). Skin and soft tissue infections are a common manifestation of melioidosis and may be the source of systemic infection or result from hematogenous spread.

25% of patients gave a history of an inoculation injury prior to presentation. It is now believed that inoculation is the major mode of acquisition. 466). Reports of neonatal cases suggest perinatal transmission (181. Two laboratory-acquired cases have been described. In addition. Cases of reactivation associated with other illnesses. unpublished data). Malaria and seasonal dietary factors have also been proposed as triggers (417). no confirmed cases of sexual transmission are known to have occurred from these cases (Currie. 269). with increasing funding overseas for research into virulence factors and vaccine development (221. Melioidosis carries a potentially high mortality rate. Minor wounds to the feet of rice farmers are common during the planting and harvesting seasons. Work done in the 1950s (315) and more recently. where it was noted that helicopter crews seemed to have a high incidence of the disease (204). This and its long incubation period resulted in melioidosis acquiring the sobriquet “the Vietnamese time bomb” (204). with an Australian having microabscesses of the gastric wall with seeding of the peritoneum from a ruptured gastric ulcer (112). P. However. B. and transplacental spread has been documented in goats (277). an incubation period of 1 to 21 days has been defined (112). more likely in the monsoonal season with heavy rain and wind. we do not believe that ingestion plays an important role but rather believe that this simply represents a source of inoculation or inhalation. the feared epidemic failed to materialize. One study has demonstrated the value of prophylactic or immediate ciprofloxacin or doxycycline (for 5 days following exposure) in increasing the median lethal dose in an animal model of peritoneal inoculation (364). when farmers spend most of the working day wading in mud and surface water. intravenous use of illicit opiates was described as a risk factor. with 13% having symptoms exceeding 2 months at presentation (112). Ingestion has been suggested as a mode of infection (129. pseudomallei as a bioweapon is uncertain. Other countries with a military interest in B. It is believed that biological weapons research using B. More recently. has defined infectious doses via this mechanism in mice and other animals. unpublished data). in this subgroup of patients. The potential risk posed by B. highlighting the need for biosafety precautions (20. These findings have also been noted on occasion in humans.” In this story. but this has not been implicated since then (474). but this probably is not a significant factor in Australia. although contamination of potable water has been implicated as the point source in two outbreaks (115. 173). 212). Although outbreaks have been linked to contamination of drinking water. 240. although the extent of this effort and the possibility of engineered antibiotic resistant strains remain unknown (6. Possible epizoonotic human infections have been implicated in at least three cases in humans in Australia (277). Vertical transmission has been proven on only one occasion in humans (1). 399). such as staphylococcal endocarditis. no other cases are believed to have occurred outside the natural environment. both in a sibling of a child with cystic fibrosis (198) and a possible sexual transmission from a returned serviceman to his partner (294). It is also clear that more chronic presentations are not uncommon. Melioidosis as a Potential Bioweapon Almost a century before the “anthrax letters” incident in the United States. In animals. Two cases of suspected nosocomial infection were reported from Srinagarind Hospital in Thailand and were associated with contamination of chlorhexidine-cetramide (Savlon) (344). but these are obviously not applicable in Australia. 293). incubation periods of as long as 24 to 29 years in ex-servicemen who were in Papua New Guinea and Vietnam have been described (93. Other unusual modes of transmission include person to person. Reactivation of melioidosis following influenza infection has been described (285). this may not necessarily reflect ingestion as the primary mode of transmission. and one case has been attributed to culturepositive breast milk (351). one associated with sonication outside a safety hood (371) the other after organisms were spilled during centrifugation (176). REV. In the Darwin series. Holmes is sent a box designed to inoculate the recipient with “Tapanuli fever” on opening. but apart from laboratory accidents (176. as the influenza season comes after the melioidosis season (109). 377). and its causative agent has intrinsic antibiotic resistance . nonambulant patients with no history of exposure to soil or surface water (O. 204). Nonprimate animal models of inhalational melioidosis were defined in the 1950s (315). Although prostatic infection is common in Australia and sexual transmission has been suggested (470). 280. have been noted (355). 123). This is supported by the recent observation that a number of patients in Singapore who presented during a period of heavy rainfall were elderly. Inhalation or inoculation with a high bacterial load. inoculation at the time of a snake bite has also been described (74). Inoculation is characterized by infection with a longer incubation period and disease of a lesser severity. pseudomallei occurred in the former USSR. although sporadic cases have continued to surface in the United States from remote exposure (93. 344). 371). this route has been implicated by findings of infected gastrohepatic nodes in pigs (237). It is more likely that seasonal agricultural practices and exposure to surface water are more important determinants of the seasonal pattern of disease. Sir Arthur Conan-Doyle recognized the potential of this infectious agent as a potential bioweapon in his Sherlock Holmes story “The Dying Detective. the contribution of this route of infection is undefined. Nosocomial transmission to four animals that had attended a single veterinary practice was attributed to contamination of a multidose injectable solution (277). pseudomallei has been considered an important potential bioweapon. In the original description of melioidosis. driven by biodefense (221). is characterized by more severe infection and pneumonia.398 CHENG AND CURRIE CLIN. as well as more recently (221). pseudomallei included the United States and possibly Egypt (247. We believe that both inhalation and inoculation may be important in the acquisition of melioidosis. remote Australian community (161). MICROBIOL. Contaminated detergent has also been implicated in a cluster of cases in a small. The finding that periods of heavy rainfall are associated not only with higher numbers of cases but also pneumonic presentations and cases of increased severity may suggest a shift to inhalation during extreme weather events (113). Lim. and Tapanuli fever is thought by many to represent melioidosis (218.

weaponization has not been known to have been performed. pseudomallei from bodily fluids of patients remains the “gold standard” in diagnosis and requires the use of selective media for nonsterile specimens. mallei was believed to have been used in the First World War by the Central Powers to infect Russian horses with glanders on the eastern front. 377). deliberate infection of human prisoners of war and animals with B. Gram stain and other histopathological stains are not specific for the organism.7 94.8 75–80 86.9 64 72 80 85 86 79 100 88 87.1 100 100 100 100 75 92 34–82 79. immunofluorescence assay. Vietnam. few have been extensively tested in the field. Subsequently. immunoaffinity-purified antigen) Serum ELISA (IgM) Serum ELISA (various antigens) Serum ELISA (immunoaffinity-purified antigen) Serum ELISA (culture filtrate antigen) Serum DOT (culture filtrate antigen) Serum DOT (culture filtrate antigen) Serum DOT (culture filtrate antigen) Immunochromogenic card test (IgG) Immunochromogenic card test (IgM) Immunochromogenic card test (IgG) Immunochromogenic card test (IgM) Serum (Western blot) Serum (various antibody targets) Serum IFA (whole-cell antigen) Antigen detection Specimen immunofluoresence Serum ELISA (19. Although many of these rapid tests have been developed. acute-phase serum only) Serum ELISA (IgG. the former Soviet Union.8 83 81. and rapid culture techniques (Table 5). 2005 TABLE 5. the closely related bacterium B.9 93 68 91 100 99 99 97. In contrast.VOL. and a wide host range. A number of techniques have been employed to attempt to reduce the time required to achieve a diagnosis. DIAGNOSIS AND MANAGEMENT OF MELIOIDOSIS Diagnosis Isolation of B. acute-phase serum only) Serum ELISA (purified glycolipid antigen) Serum ELISA (IgG. and Egypt (5. monoclonal antibody latex agglutination. including antigen detection on specimens or on culture supernatant.5-kDa antigen) Direct specimen ELISA (MAb 5F8) Urine IFA Blood PCR (LPS1. and glanders possibly was used in the Afghanistan conflict between 1982 and 1984 (6).7 86 96 100 IFA. molecular techniques. DOT. LPS2) Blood PCR (16S rRNA) Blood PCR (various primers) Blood PCR (16S rRNA) Blood PCR Blood culture supernatant MAb-LA MAb-LA MAb-LA MAb-LA a Unknown (47) Thailand (150) Thailand (184) Thailand (101) Thailand (130) Thailand (148) Thailand (299) Australia (298) Australia (191) Australia (191) Australia (191) Japan.8 74–82 71. mallei was done at the Pinfang (China) Institute during the Second World War by the Japanese (247).7 67 47–100 100 100 99.3 99.1 88 77 79 67 70 23–59 45–63 73 82 75 81 95.2 90 69 90 80 91 56–95 314 142 15 386 375 479 490 319 25 25 25 330 142 142 386 375 479 386 375 479 319 319 490 490 386 386 291 462 14 10 136 375 178 251 144 352 13 335 335 143 99 96 98 96 91.2 97 64 85. with significant effect. and the susceptibility of immunocompetent individuals after inhalation is not clear. Sensitivities and specificities of diagnostic tests for melioidosis Test a MELIOIDOSIS 399 Study location (n) Sensitivity (%) Specificity (%) Reference Antibody detection Complement fixation test Serum IHA Serum IHA Serum IHA (purified antigens) Serum IHA Serum IHA Serum IHA Serum IHA Serum IHA (acute-phase serum only) Serum IFA (IgG.4 93 72 85. mallei was also undertaken in the United States. antibody detection. 18. Further development with B. DOT immunoassay.2 100 31–41 47 100 95. Thailand (416) Thailand (150) Thailand (150) Thailand (101) Thailand (130) Thailand (148) Thailand (101) Thailand (130) Thailand (148) Australia (298) Australia (298) Thailand (299) Thailand (299) Thailand (101) Thailand (101) India (22) Thailand (272) Thailand (147) Thailand (114) Thailand Thailand (130) Australia (52) Thailand Thailand (29) Thailand (7) Thailand (1. MAb-LA. 369) Thailand Thailand Thailand (88) Not recorded 71 77 46–94 61. However. . the disease does not spread from person to person.

pseudomallei in areas of endemicity (130).3 h. none are yet commercially available. 482). However. 163). the Vitek 1 system. Recovery from throat. urine. reflecting the density of bacteremia. Antibody detection. 230). as different thresholds are used for interpretation (between 1:10 and 1:160 in various studies) and the strains used to formulate the whole-cell antigen are not standardized. The use of a recently described B. is now commonly used (128). Antigen tests for exotoxin and cell components have shown reasonable sensitivity and specificity in studies.and 200-kDa proteins have been validated in a clinical context. 308). particularly in Thailand. latex agglutination. Furthermore. for exotoxin in culture supernatant (219) and a 40-kDa secreted protein (481. Efforts have been made to refine the antigen targets. B. In that study. A fluorescent urinary antigen system has been developed. antibodies against atypical LPS may not cross-react against the IHA antigens. pseudomallei. using the automatic BacT/Alert system. Peacock. may also be useful in identifying B. thailandensis strains. personal communication). where rates of background seropositivity may be up to 30 to 47% in various populations (238). IHA remains the most widely used test despite its poor sensitivity and specificity.7% (13). compared to 1:160 in Thailand) (265. and wound swabs was increased by the use of a selective broth (491). It was shown to agglutinate blood culture fluid positive for B. pseudomallei but are not currently commercially available (308. Australia. with a specificity of 99. rectal. a sensitivity of 81% and a specificity of 96% were defined (136). Background seropositivity appears to be less common in Australia. 462) are practical ways to identify B. except in immigrants from southeast Asia (24). It was first described in 1965 (208) and has been used extensively in serosurveys (19. but not IgM. correlated with mortality. The only test finding widespread use in Thailand currently is a monoclonal antibody latex agglutination test against the 200kDa protein that was evaluated in 12 centers in Thailand. 73. personal communication). Ashdown (17) tested his eponymous medium. The test was also highly specific and did not agglutinate araϩ B. pseudomallei early in life (12. a 30-kDa protein (335). neutral red. cepacia selective agar is currently being evaluated in Thailand (S. REV. Although a variety of antigen detection methods have been studied. Immunofluoresence. Culture-based methods. These findings have significant implications for laboratories in areas where the organism is not endemic and is only occasionally encountered. compared to 40. of these. urine. including LPS (143). pseudomallei reliably (278). thailandensis or B. Cultures of bone marrow have the same sensitivity as blood culture (124). Enterococcus faecalis (n ϭ 23). There are conflicting opinions as to the reliability of the API 20NE test panel. and Serratia marcescens (n ϭ 14) being the most common contaminants (17). but a subsequent evaluation gave poorer results (386). and 200kDa proteins. in 1979.8 h. 462). but only where specialized microscopy facilities are available. with colistin. thailandensis (387). and an exopolysaccharide (406). including refinement of a 30-kDa exotoxin and 19. where available. Antigen detection. and a further 4 strains gave indeterminate results (211). An older method is the complement fixation test (314). MICROBIOL. (n ϭ 73). Studies of the clinical performance of IHA are difficult to compare. The use of the IHA is problematic in areas of endemicity. with Klebsiella spp. but not the Vitek 2 system. and gentamicin (4 mg/liter). but most have not been field tested. cepacia (n ϭ 17). it is evident that the sensitivity of IHA is limited in patients with acute septic illnesses (15). and pus) is the most promising way to reduce the time to diagnosis in areas of endemicity. pseudomallei selective agar (BPSA) (203) and the more available B. Selective media have long been used for the isolation of B. pseudomallei was isolated in eight specimens. crystal violet. pseudomallei strains at a Western Australian laboratory were misidentified. appeared to identify B.5 h (380). a major component in the crude antigen used in the IHA. pseudomallei from cultures (307) as well as in distinguishing B.400 CHENG AND CURRIE CLIN. 61. 502). latex agglutination (13) and immunofluoresence (307. Immunofluoresence from direct specimen (including sputum. Colonial morphology on Ashdown medium and. pseudomallei from nonsterile fluids and environmental samples. latex agglutination for culture identification and direct immunofluoresence from direct specimens (such as sputum. depending on which organisms are used to prepare the IHA assay reagent (11). P. most commonly as Chromobacterium violaceum. on 8. with a sensitivity of 95%. n ϭ 42). The Vitek automated system is widely used. the Isolator lysis centrifugation had 81% sensitivity with a time to positivity of 39. and immunofluorescence are currently used clinically. in initial trials. B. The time to blood culture positivity.9% of those with a time to detection of Ͼ24 h. a result can be obtained within an hour. Although IgM antibodies should be more specific (21.7% of patients died if blood cultures became positive with 24 h. and monoclonal antibodies for cell wall components. containing tryptase soy agar with glycerol. However. and only IHA. presumably due to subclinical exposure to B. Compared with conventional broth-based blood culture (median time to positivity. An evaluation of this technique and potential improvements to even further simplify the methods is under way (V. ELISAs based on LPS and 30. 40-. field tests of IgM antibody detection have not reflected this promise (142). or pus) have been used in research labs in Thailand. including strains with atypical LPS patterns. but at the cost of reduced sensitivity. These include two enzyme-linked immu- nosorbent assays (ELISAs). there is some heterogeneity between strains in LPS. two studies have reported good results with this manual system (128). Alternative blood culture methods could decrease the time to obtain a positive culture. Wuthiekanun. pseudomallei from B. Reagents are based on antibodies to lipopolysaccharide and protein fractions of B. and the pour plate method had 61% sensitivity with a median time to positivity 45. A modified Ashdown medium. as with latex agglutination. as with the API 20E system (278). utilizing the broad antibiotic resistance of the organism (152. 62% of positive cultures were detected in the first 24 h and more than 90% were detected within 48 h (432). IgG. aeruginosa (n ϭ 57). another study found that 6 of 50 B. appears to be more sensitive (74 to 82%) and specific (75 to 80%) than the IHA but still lack the performance necessary .000 clinical specimens in Townsville.5-. the lower cutoff titer in Australia reflects this (1:40. Antigen tests have been developed for use on direct specimens or in blood culture supernatant. 238).

and D beta-lactamases have been identified (197). Methods that determine the MIC (ε-tests. and ceftriaxone (71. 100%.) may be moderately sensitive (79%) but more specific (90%) than IHA (490). These were associated with mutations in the blaA gene (439). unpublished data). Transposon mutation analysis has revealed that the . 420). B. rather than culture. or persisting over periods of 1 to 6 years in seven patients (454). In addition. with responses of IgG. A rapid immunochromogenic test (PanBio Ltd. Antibiotic Resistance B. 16S mRNA sequencing has long been used for the identification of bacterial species. 93%) and specificity (both assays. and a betalactamase specific for ceftazidime (169). chloramphenicol. and IgA to a culture filtrate antigen falling. the quinolones. They have been demonstrated to have little activity in the acute phase (473) and are bacteriostatic in vitro (36. Relapse attributable to resistance may occur with either oral or intravenous agents used in treatment (222. 126. seven genes encoding Ambler class A. 95%) reported were for comparison against IHA. However. the most important of these is the BushJacoby-Medeiros class 2e beta-lactamase BPS-1. Although a class C beta-lactamase was initially identified from the genome sequence (316). 435). 144. the clinical significance of this beta-lactamase is not yet known. and none have performed sufficiently well to replace the IHA (375). Ceftazidime. Acquired resistance to beta-lactam antibiotics while on treatment with a beta-lactam–beta-lactamase inhibitor combination or ceftazidime resulted from three distinct phenotypic changes: derepression of the chromosomal enzyme.. Nevertheless. Many tests based on molecular detection of B. Carbapenem antibiotics appear to be useful even for isolates exhibiting extended beta-lactamase activity (392). 386. pseudomallei against antibiotics is summarized in Table 6. rising. with disk diffusion methods probably overestimating the extent of resistance.VOL. Similar results were reported from the Northern Territory. 88. The use of primers to detect a region of the 16S RNA demonstrated a sensitivity of 100% but a low specificity in a small clinical study (178). persisted over 2 years in 20 of 23 patients (21). More recent studies are examining the role of a PCR for the type III secretion system (394) in clinical and environmental specimens (D. an insensitivity to inhibition by beta-lactamase inhibitors. rifamycins. Testing for TMP-SMX resistance is problematic. pseudomallei exhibits resistance to diverse groups of antibiotics. 126. 274). The significance of other in vitro phenomena such as postantibiotic effect (463) and results of time-kill studies (392) are not known but may confer a theoretical advantage to carbepenems. Primers targeting regions in the 23S rRNA. pseudomallei (484. Australia) for IgM and IgG appeared to perform well in a series of 121 patients. and ceftazidime resistance emerged on therapy in only one patient (222). pseudomallei is susceptible to kanamycin. which hydrolyzes most cephalosporins but is readily inhibited by clavulanate (91. OXA-42 and OXA-43. Recent work in Thailand suggested that the IgG immunochromogenic test (PanBio Ltd. However the high sensitivity (IgG. 222). 250. the carbapenem antibiotics (imipenem and meropenem). Acquired resistance to doxycycline has been observed when doxycycline has been used as monotherapy (222) and. may also be responsible for ceftazidime resistance in some isolates (316). Primary resistance to these agents was not observed in 170 isolates from the Darwin prospective study. broth microdilution. with TMP-SMX monotherapy (111. 352. 497). including third-generation cephalosporins. resistance rates appear to be higher in Thailand (281). IHA titers. Longitudinal studies of antibody titer have revealed an unpredictable response. its relative resistance to quinolones and macrolides limits therapeutic options for the treatment of melioidosis. 251. 18. The in vitro susceptibility of B. The oral antibiotic TMP-SMX. Ambler class A). Acquired resistance to ceftazidime while on therapy is an uncommon cause of treatment failure. mallei from B. pseudomallei have been described. with or without doxycycline and chloramphenicol. where the positive predictive value of a serological test is much higher. demonstrating a good correlation with IHA (159). and aminoglycosides. Other tests for detection of antibody have had similar results. However. 2005 MELIOIDOSIS 401 for clinical use (386). much less frequently. IgM. Overexpression of the class D beta-lactamases. Antibiotics with bacteriostatic activity do not appear to be clinically useful in the intensive phase. whereas IgM had poor specificity compared to culture (319). but few have been field tested. Brisbane. 485). Within the B. Primary resistance to chloramphenicol and doxycycline occurs infrequently (approximately 6%) (383. pseudomallei genome. a parallel study performed in Darwin demonstrated that IgG performed similarly to IHA. this and the positive predictive value remain to be validated prospectively. with the rationale of protection against the emergence of resistant strains during therapy and the improved intracellular penetration of TMP-SMX (111. this method has been used for phylogeny (50. in vitro studies suggest antagonism (127). or agar dilution) are recommended and demonstrate much lower rates of primary resistance (3 to 10%) (331). as a gold standard (116). 51) as well as clinical identification (458) of Burkholderia spp. but acquired resistance more frequently occurs with chloramphenicol (126). as well as other 16S mRNA-specific primers (165). the 16S RNA. 473). although this antibiotic is no longer used in the treatment of clinical melioidosis. reflecting total antibody levels. although clinical evidence is lacking. IgM. encoded by the gene blaA (or penA. and to a lesser degree amoxicillin-clavulanate remain the backbone of current initial treatment. these include the tetracyclines. it is likely that this represents a class B metallo-beta-lactamase (197). The use of combination therapy in the initial intensive phase is routine in the Northern Territory of Australia and in parts of Thailand. Sequencing of the groEL gene may also be useful but may not reliably differentiate B. the clinical significance of this is unknown. However. Molecular methods. B. a commercial test kit using standardized antigens would be useful for areas where the organism is not endemic. and the 16S and 23S RNA junction have been evaluated (58. as resistance to carbepenems remains uncommon (392). 497). 400). penicillins. Functionally. Similarly. Gal. Queensland. is used for the prolonged eradication phase.

232. 497 392 18.5 0. 392. NIH collection (51) Thailand (97) Various (63) Various (590) U. 497 182 155.06–16 1–4 2–8 0. 297. 232 497 23 23 76.625/3. Australia (197) U. 497 497 2–4 3. 222. 402.S.56 3.13–25 0.125–20/100 0. 76. 497 392 158 297.13 0. 182.25 6.56–Ͼ64 1/19–5/25 1. 222.5 1–50 8 16 4–32 2–6. 297 222. 346. 232.13–128 16–50 50–Ͼ64 12. 402 18. 497 232. of isolates) 50% 90% Range CLIN. 222. 232. 331.78–3. 76.S. 392. 76. 346. 182. 232.25 3. .56 2/28–Ͼ64 3.13–50 1–16 8–16 NR 0. 76.13–8 6. 155.25–16 0. National Institutes of Health. 232. 392 232.5 1 0.6–Ͼ200 297 18.13–8 1–16 32 42 8–64 0. MICROBIOL. 182.5–16 6. 76.S.39–0.13 0.402 CHENG AND CURRIE TABLE 6. 76.5 8–12.25–0. 402.5 NR 2 Ͼ64 Ͼ64 12.125–128 0. 222.13–Ͼ200 64 128 8–Ͼ128 NR 128 16–128 4–12.5 Ͼ64 1–3 0. d MICs vary with testing method.78–12. 76. In vitro activities of selected antibiotics against B. NR. Reference(s) Amikacin Amoxicillin Amoxicillin-clavulanate Ampicillin Ampicillin-sulbactam Azithromycin Azlocillin Aztreonam Biapenem Carbenicillin Carumonam Cefamandole Cefazolin Cefepime Cefixime Cefoperazone Cefoperazone-sulbactam Cefotaxime Cefoxitin Ceftazidime Ceftazidime Ceftriaxone Cefuroxime Cefuzonam Cephalexin Cephalothin Chloramphenicol Ciprofloxacin Cycloserine Doxycycline Enoxacin Erythromycin Fosfomycin Gentamicin Imipenem Kanamycin Lomefloxacin Meropenem Minocycline Moxalactam Nalidixic acid Neomycin Netilmicin Norfloxacin Novobiocin Ofloxacin Panipenem Piperacillin Piperacillin-tazobactam Rifampin Sulfamethoxazole Temafloxacin Tetracycline Ticarcillin Ticarcillin-clavulanate Trimethoprim TMP-SMXd Tosufloxacin a b c United Kingdom (12) Various (127) Various (406) Various (199) Thailand (199) United Kingdom collection (unknown) Australia (100) Various (423) Thailand (124) Canadian collection (20) Thailand.13 Ͼ64 Ͼ64 6.25–32 4–6. 497 402 76. 497 18.13–25 128 128 16–128 Ͼ200 Ͼ200 Ͼ200 32 64 0. 497 18.78–1 0. United Kingdom collection (211) Australia (100) Australia (100) Thailand (97) Thailand (199) Thailand. 497 182 497 222. 497 18. pseudomallei MIC (mg/liter)a Agent Source (no.56–25 Ͼ64 Ͼ64 1.S.3–16 64 Ͼ64 4–8 32–Ͼ64 8 Ͼ64 4 8–32 0. NIHc collection (51) Various (277) Thailand (97) U.25 6. 222.25–8 8–25 16–64 3. 402.25–128 1–Ͼ64 2–16 2–Ͼ256 0.25–256 2–8 16–Ͼ64 1. REV. 392. 76 23. 232 497 182 497 182.25 Ͼ64 Ͼ64 6. 232. NIH. 232.25–4 1. 346. 182.5–256 Ͼ64 Ͼ64 3.25 8–16 0.39–6. 76 18. 497 23 222 18.78–2 2–4 16–64 3.25 6.3–32 32–64 32–256 2/0.25–Ͼ256 0.25 50% and 90%.25–16 1 1 0. 402.5 2 8 NR 2–4 Ͼ64 0. 232. 232.25 3. Thailand (391) Thailand (97) Australia (100) Thailand (97) U. 497 497 23 497 182 297 18.78–1 0. 222.25–8 0.5 4 16 4 3. 232.12–8 8 32 1–32 6. not recorded. 346. 497 76. 402 232. United Kingdom collection (97) Thailand (97) Thailand (97) NRb Ͼ64 2–8 32–64 4 64 2 4–16 0.13 8 16 4–16 25 50 3. NIH collection (51) United Kingdom collection (12) Thailand. 497 76. 402 402 232 18 18.06–2 50–200 0. respectively. NIH collection (51) Thailand (97) Australia. 402 23 23 497 402 76 244 18. MICs at which 50 and 90% of isolates are inhibited.78–1 0.5–Ͼ512 0. 76. 402. 497 402. 497 182 76. Hong Kong (27) Malaysia (50) Various (324) Australia (100) Australian clinical (170) Various (887) Various (127) Various (127) Thailand (97) Australia (100) Australian clinical isolates (100) Various (409) Various (423) U.5–Ͼ64 3. NIH collection (51) Various (124) Thailand (124) Various (605) Thailand (199) Various (175) Various (97) Thailand (296) Various (175) Various (326) Thailand (199) Thailand.S.5–4 1–8 0.78–12.13–8 Ͼ64 1–4 4–8 32–Ͼ64 6.25–2 100 4–8 Ͼ64 Ͼ64 12.78–16 128–Ͼ256 256–Ͼ256 64–Ͼ256 4–16 4–16 1–Ͼ256 16–25 25–Ͼ64 1. 23. 76.5 0. 297.

There results were replicated in another Thai center. used synergy testing in Acanthamoeba trophozoites to guide antibiotic therapy in a patient failing treatment (214). Similarly. respectively. B. unpublished data Ceftazidime (120) vs chloramphenicol (100). Chaowagul.5 vs 47 47 vs 47 38 vs 36 21 vs 16 14 vs 18 No significant difference 14 10 days efflux system AmrAB-OprA (encoded by the gene amr [aminoglycoside-macrolide resistance]) confers resistance. unpublished data Amoxicillin-clavulanate (60/15) vs chloramphenicol (40). the clinical relevance of these findings is not known (460). These interventions were the subject of a systematic review (367). from 74 to 37%. Although successful in this case. pseudomallei in biofilm were shown to be ciprofloxacin-clarithromycin. of patients Relapse rate (%) 350 70 88 W. The only treatment to demonstrate a mortality benefit is ceftazidime. the BALB/c inbred mouse model has also been employed to determine candidate interventions. and TMP-SMX (10/50) Ceftazidime (100) and TMP-SMX (8/40) vs chloramphenicol (100). Survival curves suggested that the benefit was seen after 48 h. this system is a unique mechanism for high-level aminoglycoside resistance (303. Clinical trials of intensive-phase intravenous antibiotics in severe melioidosis No. and imipenemazithromycin. doxycycline (4). with similar caveats (340. and TMP-SMX (10/50) Azithromycin (8) and ciprofloxacin (8) vs doxycycline (4) and TMP-SMX (10/50) Doxycycline (4) and TMP-SMX (10/50) vs chloramphenicol (40). where a fall in mortality from 47 to 19% was observed in association with ceftazidime with TMP-SMX (400). with up to 200 times the MIC for the planktonic cells (800 ␮g of ceftazidime per ml and 8. doxycycline (4). doxycycline (4). pseudomallei was incubated on a silastic surface for 16 h. doxycycline (4). Antibiotic combinations active against B. Clinical trials of eradication-phase oral antibiotics in treatment of melioidosis Reference Regimen (dose. mg/kg/day) Duration (days) Enrolled Culture confirmed MELIOIDOSIS 403 Outcome measures (%) Treatment failure Mortality 473 400 419 383 423 90 W. mg/kg/day) Duration (wk) No. suggesting irreversible severe disease in those who died (473). Although efflux systems conferring macrolide resistance have been described. Antibiotic Treatment Six published randomized controlled trials and one unpublished randomized controlled trial have examined intensivephase interventions in severe melioidosis and are the basis of the ceftazidime-based regimens used currently (Table 7). Inglis et al. 486). In Thai adults. details are presented in Tables 9 and 10. this applicability of this remains uncertain. in a sequential open-label randomized trial of ceftazidime against chloramphenicol–doxycycline–TMP-SMX (known as conventional therapy) in severe disease. The recommended intensive and eradication antibiotic regimens used in Thailand and Australia differ significantly. and TMP-SMX (8/40) Ceftazidime (120) vs amoxicillin-clavulanate (120/40) Ceftazidime (120) vs imipenem (50) Ceftazidime (25) and co-trimoxazole (8/40) vs cefoperazone-sulbactam (100) and cotrimoxazole (8/40) Ceftazidime (100) and TMP-SMX (8/40) vs Cefoperazone-sulbactam (25/25) Ceftazidime (120) vs ceftazidime (120) and TMP-SMX (10/50) At least 7 10–14 At least 7 At least 10 161 136 379 296 84 219 449 34 vs 31 27 vs 34 106 vs 105 106 vs 108 20 vs 20 51 vs 51 118 vs 123 39 vs 51 41 vs 20 37 vs 74 18. and TMP-SMX (10/50) Doxycycline (4) vs chloramphenicol (40)..VOL. Khon Kaen. 2005 TABLE 7. 18. ciprofloxacin-azithromycin. The use of in vivo models to test antibiotic combinations remains a research tool. the group TABLE 8. and it is unlikely to gain widespread acceptance. the use of ceftazidime was associated with a 50% reduction in mortality. Chierakul et al.000 ␮g of TMP-SMX per ml) (461). More recent attention has focused on the role of biofilms in protecting bacteria against antibiotics. doxycycline (4). In one such study. of patients Reference Regimen (dose. For eradication-phase therapy (also pessimistically known as maintenance therapy). three published trials and one unpublished trial have examined the role of oral antibiotics in preventing relapse (Table 8). 442). Electron microscopy demonstrated that cells in biofilm were still viable after 24 h of exposure. In that study. and TMP-SMX (10/50) 20 vs 20 20 vs 20 12 vs 20 12–20 vs 12–20 49 vs 52 58 vs 58 36 vs 29 89 vs 91 16 vs 4 26 vs 1 22 vs 3 No significant differences .

Abstr 4th World Melioidosis Congr. Eradication-phase antibiotic regimens used for patients with normal renal function Regimen Royal Darwin Hospital (111) Other recommended (472) TMP-SMX at 8/40 mg/kg (up to 320/1. Second-line regimen for treatment failure with ceftazidime at Sapprasithiprasong Hospital. despite similar definitions of treatment failure. REV. tds. close followup and monitoring of adherence are important) (i) Chloramphenicol at 10 mg/kg orally four times a day for 8 weeks. Mortality was not different overall.5 mg/kg per h as a continuous infusion. studies since have failed to demonstrate improved outcomes with amoxicillin-clavulanate. and chloramphenicol (16 versus 4%). this may have been a potentially subjective endpoint in this open-label trial (383). reflecting in part the use of rapid diagnostics such as immunofluorescence. MICROBIOL. is likely to affect observed mortality rates. and longer (4 to 8 weeks) for deep-seated infection. or septic arthritis. This is supported by a retrospective review of meropenem use in Australia. Pharmacokinetic considerations dictate an increased frequency of dosing (every 4 h) to ensure adequate trough levels of clavulanic acid (125). Intensive-phase antibiotic regimens used for patients with normal renal function Regimen Royal Darwin Hospital (111) CLIN. three times a day. use of oral amoxicillin-clavulanate (with supplemental amoxicillin) was associated with a higher relapse rate than conventional treatment with TMP-SMX. . although this may be confounded by other factors (78). An important issue in these studies is the wide variation in the baseline mortality rate. will be of interest. Imipenem-cilistatin was compared with ceftazidime in a large trial. or imipenem. even with adjustment for known prognostic factors. only 50% of patients adhered to the full 20-week duration of therapy. ranging from 14 to 47% in ceftazidime-based arms. particularly in light of the incomplete carbapenem study. In one trial. the timing of enrollment. where a lower MIC. Ubon Ratchathani. with an interquartile range of 4. and this appeared to be the most important factor in determining relapse (350). (ii) ceftazidime at 19 mg/kg intravenously (bolus) followed by 3. this trial was terminated prior to planned enrollment due to the withdrawal of pharmaceutical company support. The systematic review highlighted the need for a severity-of-illness scoring system (367). where a lower mortality was seen in meropenem-treated patients with severe sepsis. doxycycline at 2 mg/kg orally twice a day for at least 20 weeks. A clinical trial of this agent in intensive therapy demonstrated a similar mortality but a higher treatment failure rate requiring a change in antibiotic regimen (25 versus 5%) (419). In maintenance therapy.600 mg) every 12 h and ceftazidime at 50 mg/kg (up to 2 g) intravenously every 6 h or (ii) meropenem at 25 mg/kg (up to 1 g) intravenously every 8 h and G-CSF (filgrastim) 300 ␮g intravenously for 10 days if patient has septic shock (duration of therapy at least 14 days. where no significant differences in mortality were demonstrated (S. Ceftazidime-based regimens have been used as the control arm for studies of the intensive phase. cefoperazone-sulbactam. osteomyelitis. Other recommended (472) (i) TMP-SMX at 8/40 mg/kg (up to 320/1.. that received conventional therapy had more severe disease. which may have partially accounted for the mortality difference observed.600 mg) every 12 h (duration of therapy at least 3–6 months. patients may be discharged for outpatient administration of ceftazidime if clinically stable) a b c (i) Ceftazidime at 40 mg/kg intravenously every 8 ha. particularly in regard to the treatment of severe sepsis.5 to 15 days (range TABLE 10. defevescence may take somewhat longer. Anunnatsiri. Second-line regimen for empiric treatment of melioidosis at Sapprasithiprasong Hospital. This may explain the high rate of treatment failure in the ceftazidime arm of this trial compared to the ceftazidime arm in the amoxicillin-clavulanate trial conducted at the same center (419). doxycycline. In addition. This is likely to represent differences in the severity of illness due to differences in inclusion criteria. or (iv) ampicillin-clavulanate at 20/4 mg/kg intravenously every 4 hc (duration of therapy at least 10 days or until clear clinical improvement) Without TMP-SMX. and TMP-SMX at 5/25 mg/kg orally twice a day for at least 20 weeksa or (ii) amoxicillin-clavulanate at 30/15 mg/kg orally tds for 20 weeks and amoxicillin at 30 mg/kg orally tds for 20 weeksb a b First-line regimen at Sapprasithiprasong Hospital. however. 2004). first-line regimen at Sapprasithiprasong Hospital.404 CHENG AND CURRIE TABLE 9. a more favorable time-kill profile. The use of imipenem was associated with lower rates of treatment failure in patients surviving for Ͼ48 h (20 versus 41%) than the use of ceftazidime. abstr 10. as a lower mortality is seen in patients who survive the first 24 to 48 h of admission. Intravenous amoxicillin-clavulanate is not available in Australia but is widely used in Thailand for the treatment of empirical sepsis and melioidosis. Future studies of meropenem against ceftazidime. (iii) imipenem at 20 mg/kg intravenously every 8 hb. however. Current studies include a trial of ceftazidime alone compared with ceftazidime with TMP-SMX. the median duration of fever following commencement of antibiotics was 9 days. and lower endotoxin release may be of theoretical advantage. Although in treatment of uncomplicated melioidosis it is usual for blood cultures to become negative within a few days. Second-line regimen for adults and first-line regimen for children (Ͻ14 years) and pregnant women at Sapprasithiprasong Hospital.

S. where a small but significant mortality benefit has been demonstrated. reflecting similar studies in other groups of patients with other infections (357). and poor standardization of markers of severity (367). Patients with a fatal outcome often had cultures that were persistently positive until death (111). 2004). 10 to 18% of surviving patients remained bacteremic after 4 days of treatment. A future trial comparing TMP-SMX alone with TMP-SMX and doxycycline is planned. pseudomallei when inoculated intraperitoneally. whether oral therapy without an initial intensive intravenous phase can be used for mild disease. A method to reduce the cost of antibiotics required for treatment using continuous infusions of ceftazidime was explored in a pharmacokinetic study. short-course (8-week) ciprofloxacin-azithromycin and longer-course (up to 20 weeks) quinolone monotherapy were also associated with high relapse rates of Ͼ20% (73. However. no attempt was made to control for severity of infection or time to administration of antibiotics. but whether it is active in vivo is debated.or postdose serum bactericidal and inhibitory titers did not appear to correlate with outcome in 195 adult patients. $100 per day. However. these two ideas deserve further examination. the observation that immunocompetent children with mild disease recover with incision and drainage only may suggest that some low-risk patients with limited disease may not even require antibiotic therapy (279). the latter is associated with high rates of adverse events (32% in this trial) that may limit adherence (70). In addition. Management of Sepsis Syndrome A detailed review of the management of sepsis is beyond the scope of this review and has been summarized in recent consensus guidelines (135). abstr. Abstr 4th World Melioidosis Congr. Activated protein C levels have been demonstrated to be low in severe melioidosis (254). In one study. Criticisms of trials identified included the failure to conceal allocation. pseudomallei and to other gram-negative organisms. Similarly. analogous to the case for deep-seated staphylococcal infections. 6. with infusers and antibiotics costing approximately U. prolonged intensive-phase antibiotics may be sufficient without the need for eradication therapy. In a retrospective review the initial use of ceftriaxone and cefotaxime was associated with a higher mortality than seen for patients treated empirically (71). A systematic Cochrane review published in 2001 did not identify any further unpublished clinical trials. doxycycline. In Thailand. Although its high cost makes it of little relevance to the majority of patients with severe melioidosis worldwide. and 8 to 21% of surviving patients were bacteremic after 7 days of imipenem or ceftazidime. in addition. 206). Ceftriaxone has borderline activity against B. We also speculate that. where relapse appears to be uncommon. However. 88). and none have included patients with melioidosis. Lower rates have been reported in Australia with TMP-SMX alone (111). and TMP-SMX) is commonly used. It supported the use of a ceftazidime. this technology is currently expensive. and the optimal regimens for children. A trial comparing the four-drug regimen with TMP-SMX and doxycycline has recently been completed in Thailand and suggests that TMP-SMX with doxycycline is associated with relapse rates equivalent to those with the four-drug regimen (W.. Sydney. Adherence to therapy (only 50% completed the 20-week course of therapy in the Thai study) is the most important factor predicting relapse. pseudomallei in vitro. personal communication). Stephens. Fewer studies examining eradication therapy have been performed. there is no evidence of any pathophysiological differences between patients with severe sepsis due to B. the failure to use an intentto-treat analysis. The clinical utility of measuring serum antibiotic levels by means of a bioassay was assessed in a Thai study (379). prophylactic ciprofloxacin or doxycycline was demonstrated to raise the median lethal dose of B. It should be noted that few of the interventions discussed are supported by evidence (Table 11). TMP-SMX would also be theoretically effective. and chloramphenicol. 18. Much recent interest has focused on the use of drotrecogin alfa (activated protein C) in severe sepsis (42). Although patients who survived had lower rates of bacteremia (50 to 63%) than nonsurvivors. reinforcing the necessity for adherence to therapy and the need to define a better-tolerated regimen. with a relapse rate of approximately 10% (350). These data support the use of elastomeric infusion devices (Baxter. While appearing radical. 2005 MELIOIDOSIS 405 of up to 39 days) (383). The use of high-dose ceftriaxone (2 g intravenously daily) for the empirical treatment of community-acquired sepsis is widespread in Australia and in Thailand. Although the prolonged use of eradication-phase antibiotics is currently the norm.or imipenem-containing intensive therapy phase followed by a long oral eradication phase. Chaowagul. Pre. but its use has not been assessed. P. doxycyline. A negative trial that did include patients with melioidosis . it has been used in a small number of patients at the Royal Darwin Hospital (D. similar to that seen with another study (10 to 11 days) (90). respectively (383). persistent cultures from sites other than blood do not necessarily portend a poorer prognosis (419). sputum cultures in uncomplicated pneumonia may take more than a week to become negative (111).VOL. Australia) through a peripherally inserted central catheter to complete intensive-phase antibiotic therapy for melioidosis in Australia (111. excluding staffing costs (206). In that study a bolus dose of 12 mg/kg intravenously followed by a constant infusion of 4 mg/kg/h was found to provide an adequate dose while allowing for a total lower dose to be delivered than with traditional 8-h bolus dosing (7). a duration of therapy of 8 weeks was associated with high rates of relapse (350. the four-drug regimen (chloramphenicol. It found little data available on the appropriate therapy for mild disease and for eradication therapy. Doxycycline alone for eradication therapy is associated with unacceptable rates of relapse (26%) and treatment failure (16%) compared with the conventional regimen of TMP-SMX. Animal models of prophylactic antibiotic regimens have been prompted by the potential for intentional release but may also be important when considering accidental laboratory exposure (364). Future issues yet to be addressed include the definition of the minimum duration and regimen required for eradication. 416). An analysis of this study suggested that the failure to complete at least 12 weeks of therapy remained the most important determinant of relapse.

.... H..Multiple large studies of heparin and/or mechanical devices in general intensive care unit populations (135) Stress ulcer prophylaxis . Dans... These include Nick White.. other smaller studies show conflicting results (135) Physiological-dose steroids. Ahmed................ earlier clinical identification.. B.... 6.... K.. Kenneth Alibek.. P. 1998... J. Alejandria. Wipada Chaowagul..406 CHENG AND CURRIE CLIN.. Cochrane Database Syst............... 1999.. Tim Inglis. Mantaring....... J.......... 0. 298).. ACKNOWLEDGMENTS We are grateful to our colleagues in this field for their generosity in sharing unpublished data and information from ongoing studies. TABLE 11. MICROBIOL..... 4..........64) (4)... including 36 patients with melioidosis (418)..... M...... N. N. Am.. Y....Y... 2001. U...... a platelet-activating factor receptor antagonist........ 7.S..... but this information is yet to be translated into accurate...... A..... Congress.... V.... pseudomallei remains to be seen. a clinical trial examining the role of insulin infusions for tight glycemic control would be of interest.. 361).... and increase intracellular concentrations of antibiotics (131.. Identification of virulence factors has been accelerated by the completion of genome sequencing of a strain of B... economy. Statement by Dr.Use of polyclonal immunoglobulin associated with mortality benefit in a meta-analysis (relative risk.. Alibek.. Abbink... M. Studies exploring the role of preventative measures. Chaowagul..... Pharmacokinetic- . L...... Susan Jacups. Alibek........ J.... is supported by an Australian National Health and Medical Research Council Training Scholarship. Narisara Anuntagool....... Mattie. W... M...... Despite improvements in antibiotic therapy. Smith. concerns about quality of the pooled studies Activated protein C. 3. Whether a vaccine could prevent infection or severe disease due to B. Tao... 2000. Terrorist and intelligence operations: potential impact on the U. Other studies have defined virulence factors that allow evasion of killing mechanisms by phagocytes and a possible role for cell-mediated immunity. Although exogenous administration of G-CSF has not been associated with improved outcomes in patients with pneumonia and/or severe sepsis in large clinical trials (310.Early goal-directed therapy (based on fluid and blood product infusions. Orendi. 60:90–93. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.. Acute Respiratory Distress Syndrome Network...S...C...Multiple large studies of proton pump inhibitors or histamine receptor antagonists (135) involved lexipafant. pseudomallei. 342:1301–1308.. Economic constraints may make vaccination an unrealistic option for many regions of endemicity.. G-CSF may reverse these defects (312)... J... Tharavichikul. Suputtamongkol.. practical...... N.... several confounding factors may at least partly account for this effect (84).Ventilation with lower tidal volumes (6 ml/kg) in patients with acute lung injury or acute respiratory distress syndrome associated with a fall in mortality (40 vs 31%) (2). and N........ apart from a close association with rainfall.Use of drotrecogin alfa in patients with severe sepsis associated with a fall in mortality in a large clinical trial (31 vs 25%) Limiting tidal volumes ..... M.. H. C. melioidosis may differ from infections due to other organisms because of the key role of neutrophils in patients with recognized risk factors for neutrophil defects.. Joint Economic Committee.. Nick Day. Vanaporn Wuthiekanun. Vicki Krause. Robert Norton. Omori.... Angus. act to counter inflammatory cytokines (187.. Intravenous immunoglobulin for treating sepsis and septic shock (Cochrane Review)... and David Dance.C....C.. Nagatake. REV........ Wuthiekanun..Use of sedation protocols associated with reduced length of stay and duration of ventilation (57) Polyclonal immunoglobulin..... The use of G-CSF in patients with septic shock due to melioidosis was associated with a large fall in mortality (from 95 to 10%). and A.. J.. F... Hyg..4 to 6. Given the prevalence of diabetes and acute hyperglycemia in patients with melioidosis and its putative role in inducing neutrophil dysfunction. B. no significant difference in mortality was observed in patients with severe sepsis.. Rev.. Paul Newton.... F..... K. D..... 471).. A...... Random House. D.. Don Woods. Med. CONCLUSIONS Melioidosis is a disease of public health importance in southeast Asia and northern Australia that has the potential for epidemic spread to areas where it is not endemic... REFERENCES 1.1 mmol/liter) by means of an insulin infusion associated with a fall in mortality in surgical intensive care patients in a clinical trial (8 vs 5%) (450) Sedation protocol . Biohazard. however... 2... Trop.. Intensive glycemic control has been associated with improved outcomes in surgical intensive care patients in Belgium (450)....Low-dose hydrocortisone and fludrocortisone in patients with relative adrenal insufficiency due to severe sepsis associated with a fall in mortality in a clinical trial (63 vs 53%) (8) Deep venous thrombosis prophylaxis .. Wirongrong Chierakul. Med.. Mother-to-child transmission of Burkholderia pseudomallei..... 2:CD001090. The presence of specific risk factors such as diabetes suggests that functional neutrophil defects are important in the patho- genesis of melioidosis. L...... and better management of severe sepsis are required to reduce the burden of this disease.. inotropes.. and J. Med.. A randomized.. 2000... A. White.. New York. and commercially available diagnostic tests. are yet to be elucidated.. de Beaufort.. and T.. and ventilation with invasive monitoring) associated with a fall in mortality in a clinical trial (31 vs 47%) (359) Insulin infusion . We are also grateful to the staff at Royal Darwin Hospital and Sappasithiprasong Hospital for supporting ongoing clinical research... H..... placebo-controlled trial is under way in Thailand... M... melioidosis is still associated with a significant mortality attributable to severe sepsis and its complications...... Enciso.... Gary Lum.. K.. In a randomized placebo-controlled trial in Thailand involving 131 patients... Engl.. Sharon Peacock. Washington... M.... Lansang.. 5.. Masaki. Attachment of Burkholderia pseudomallei to pharyngeal epithelial cells: a highly pathogenic bacteria with low attachment ability... Engl.. J.. 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