Burkholderia pseudomallei (Melioidosis) and B. mallei (Glanders)

There are several members of the genus Burkholderia (formerly Pseudomonas) but only three are considered significant human pathogens: B. pseudomallei, the cause of melioidosis; B. mallei, the cause of glanders; and B. cepacia, a cause of opportunistic lung infection in cystic fibrosis patients (discussed elsewhere). Melioidosis is an infection caused by the motile, an opportunistic, aerobic Gram-negative bacterium Burkholderia pseudomallei. The name melioidosis (also known as Whitmore disease, Rangoon beggar’s disease, Vietnamese time bomb) is a combination of Greek words “melis” meaning distemper of assess and “eidos” meaning resembles glanders.

The disease was first recognized in Yangoon (formerly Rangoon), Myanmar (formerly Burma), amongst injecting morphia addicts in 1911 (91), and is now known to be endemic to a large part of South and East Asia and Northern Australia (11, 25, 34). Majority of the melioidosis cases are from Thailand, Malaysia, Vietnam, Cambodia, Laos, andMyanmar (59). Sporadic cases have been described elsewhere, mainly in the tropics. The organism is an environmental saprophyte and is found in wet soils in particular (e.g. in rice paddies). In endemic areas it may be a leading cause of community-acquired septicaemia, particularly during the rainy season months; in Ubon Ratchahani in northeast Thailandit is responsible for approximately 20% of such cases per year (11). Increase in melioidosis cases was noted after two natural disasters--a Tsunami in 2004 and typhoon Haitang in Southwest Taiwan in 2005 (19, 79). After the disaster inTaiwan, the melioidosis cases incurred from 0.7 to 70 per 10000 cases (79). In Malaysia, reported seroprevalence in healthy individuals was 17-22% in farmers and 26% in blood donors (82).

Risk factors include diabetes mellitus, heavy alcohol consumption, chronic lung disease, renal disease, renal calculi, retroviral infection, parenteral drug use,  malignancy, corticosteroid use, thalassemia, previous trauma, surgery, juvenile rheumatoid arthritis, Pott’s disease and working in paddy plantation (55, 61, 63). The peak incidence is in the fifth decade of life, although melioidosis can occur at any age.  The rise in melioidosis cases with increasing age is possibly due to the exposure to the environment as well as the predisposing risk factors. In one third of childhood cases melioidosis presents with the unique syndrome of localised parotid abscess (36). Emergence of the paediatric cases has recently been reported from Cambodia. In this case series melioidosis infection was mostly recorded in immunocompetent children. Thirty nine cases were identified over three year period (between October 2005 to December 2008) after utilizing specific diagnostictests for melioidosis (55).

Three major routes of transmission such as inhalation, ingestion and inoculation through skin from the contaminated soil have been recognized for B. pseudomallei. The other possible modes of acquisition are person to person spread especially between patient and his siblings and patient with their playmates. Vertical transmission from mother to newborn has also been reported (1, 40, 41). B. pseudomallei can be transmitted through sexual intercourse (49). Several studies have revealed that heavy rain and winds are also responsible for increased inhalation of B. pseudomallei(52, 57, 60).

The period between acquisition of B. pseudomallei and onset of signs and symptoms of melioidosis remains variable. Theincubation period was between one to 21 days (mean 9 days) in 25 reported cases (28). The incubation period possibly depends on the inoculum size of the bacterium. Disease onset is usually early in case of acquisition of higher number of the organism. One study reported the longest incubation period of 68 years (53). Acquisition is usually through small abrasions or inhalation. Local abscesses may occur but disseminated infection is more usual (25, 35, 60, 80).  Around 13 to 24% patients with melioidosis present with skin and soft tissue infections. Primary skin infection can be less severe or it can lead to internal organ abscess, septicaemia and necrotising fasciitis. Of 486 cultured confirmed melioidosis fromAustralia, 58 (12%) had primary melioidosis while 10 patients suffered with secondary melioidosis such as multiple pustules from haematogenous spread (37).  The infection may involve almost any organ system, with acute septicaemia, disseminated disease, or lung infection the most common presentations, but chronic suppurative infections also occur. Abscess formation is characteristic, particularly in the lungs, liver (9) and spleen.  Pneumonia is the most common presenting feature of melioidosis. In one large prospective study of patients with melioidosis (540 cases), 51% (278 cases) presented with pneumonia; followed by genitourinary infection in 76 patients (14%), skin infection in 68 cases (13%), bacteraemia without obvious focus in 59 cases (11%), bone and joint infection 20 cases (4%) and neurological infections in 14 cases (3%). Of 540 patients, bacteraemia was noted in 298 cases (55%) and 116 cases (21%) patients progressed to septic shock (27). Meumann et al also reported that pneumonia in 51% (319/624) patients was the main presenting feature. Patients presenting with pneumonia usually develop septic shock and the mortality in this group is higher than patients with other primary presentations (51).

Two main presentations, localised (27/39) and disseminated (12/39) melioidosis were recorded in Cambodia (55). Patients with a reduced susceptibility to pyogenic infections, particularly underlying diabetes mellitus (particularly if poorly-controlled) or renal disease (including renal calculi), are at increased risk of infection. Systemic infections withBurkholderiapseudomallei are life threatening and protracted. Even with prompt effective antibiotic treatment the mortality is approximately 40% (89). On the contrary, Currie et al (27) reported mortality rate of 14% (77/540 case) over 20 years period. The plausible explanation for lower mortality could be due to better diagnostic techniques, more awareness and better understanding about melioidosis among clinicians and laboratory staff and prompt initiation of empirical antimicrobial therapy which covered B. pseudomallei.  In tropics, melioidosis should be considered in the differential diagnosis of acute pyrexia of unknown origin, acute respiratory distress syndrome and acute onset of sepsis. The other possible presentations of melioidosis are acute supparrative lesions, chronic granulomatous lesions, septic arthritis, oesteomyelitis, epididymorchitis and mycoticanerurysm. Rarer conditions in melioidosis include pericardial effusion, abscesses in the gallbladder, in pancreas and parotid gland, paranasal sinus, especially acute ethmoiditis, frontal sinus abscess, and orbital infections such as preseptal abscess.  Melioidosis may mimic miliary tuberculosis (18, 60, 45). Melioidosis rarely causes central nervous systems (CNS) infection particularly primary infection. Twenty one percent mortality (14/540 cases) was recorded in melioidosis cases with neurological complications (27). It is thought that inhalation of B. pseudomallei results in infection of nasal mucosa which ultimately leads to melioidosis and neurological sequelea. Owen et al (54) reported two possible routes of entry of melioidosis in CNS. One is olfactory sensory nerve andthe other is trigeminal nerve which is the nerve supply of respiratory tract, olfactory mucosa and brain stem. Their data suggested that primary route of infection is olfactory nerve; however even minor B. pseudomallei infection of trigeminal nerve would directly lead to brain stem infection.

The diagnosis of melioidosis remains challenging for both the bacteriologist and the clinician. Prompt and accurate diagnosis of this disease is essential in order to achieve desirable outcome. Biochemistry results are helpful in the diagnosis of B. pseudomallei (16, 59, 60, 61, 62, 63).

B. pseudomallei is a motile, non-spore forming Gram negative bacilli with bipolar staining (appears as a safety pin). It is oxidase positive and grows aerobically and produces visible colonies within 24-48 hours on ordinary media at 37ºC. On culture B. pseudomallei exhibits differing colonial morphology, with smooth colonies in young culture and wrinkled after prolonged incubation. These colonies show dry daisy head appearance along with a distinct odour (16,60). B. pseudomallei can survive in hostile conditions such as acidic environment, prolonged nutrient deficiency, antiseptic and detergent solutions, distill water for several years, wide temperature range (24-32ºC) and dehydration (16,60). Several tests such as conventional biochemical tests, API20E substrate utilization test panel (bioMerieux) kit are used for the identification of B. pseudomallei. In addition, molecular methods such as polymerase chain reaction, restriction fragment length polymorphism and serological methods are also employed for the identification of this organism (58).Serology may be helpful particularly when no samples are available form septic patient. However the serology results should be interpreted cautiously in endemic area where local population have raised levels of antibodies toB. pseudomallei. Vadivelu and Puthucheary developed an indirect immunofluroscent test using whole cell of B. pseudomallei as the antigen. The authors found this test quite rapid and reliable (83).

B. pseudomallei is resistant in vitro to many antibiotics, including penicillins, aminopenicillins, many cephalosporins (5), macrolides, rifamycins, and most aminoglycosides (25, 50), including gentamicin. Kanamycin is reported to have intermediate activity. Occasional wild isolates, deficient in the efflux mechanism, are susceptible to macrolides and aminoglycosides (71).   B. pseudomallei is susceptible to some 3rd generation cephalosporins, such as ceftazidime (6, 31), to ureidopenicillins, carbapenems (74), chloramphenicol, trimethoprim-sulfamethoxazole (7), and has intermediate susceptibility to fluoroquinolones (93), Cefotaxime and ceftriaxone have less activity compared to ceftazidime. Treatment options can be limited if the organism has shown resistance to quinolones and macrolides. The organism is unusual amongst pseudomonads in that it is also susceptible to tetracyclines (22, 96) and the combination of amoxicillin and clavulanic acid (co-amoxiclav, Augmentin) (30). The b-lactams and fluoroquinolones possess slow bactericidal activity (32), whereas chloramphenicol, tetracyclines, trimethoprim and sulfamethoxazole are bacteriostatic only -- and mutually antagonistic (31). In one study ciprofloxacin combined with azithromycin was bactericidal (84). The carbapenems and fluoroquinolones also exert a post-antibiotic effect against B. pseudomallei  (87). In time-kill experiments the carbapenems are the most active antibiotics currently available (75, 93). They are also active against strains which are resistant to either ceftazidime or amoxicillin-clavulanic acid. Raja et al reported that majority of B. pseudomalleiisolates were sensitive to ceftazidime (94%), Amoxicillin-clavulanic acid (95%), imipenem (99%), tetracycline (89%), chloramphenicol (94%) and cotrimoxazole (70%) (63). Acquired resistance was relatively common when the conventional bacteriostatic four-drug regimen was used (circa 7% of infections) but is now less frequent with the use of more active acute treatments. B. pseudomallei readily forms antibiotic resistant small colony variants (38), and produces an extracellular polysaccharide, which facilitates formation of biofilm encased microcolonies of relatively antibiotic resistant bacteria.

Timely administration of parenteral antimicrobial chemotherapy in confirmed or suspected severe melioidosis remains crucial in order to reduce morbidity and mortility. The treatment can be problematic because B. pseudomallei is resistant to the first line agents used in many hospitals world-wide to treat community-acquired septicaemias, i.e. penicillin-aminoglycoside combinations. In endemic areas therefore, many patients may receive ineffective empiric therapy. Quadruple or "conventional" therapy with intravenous chloramphenicol (100-150mg/kg/day), doxycycline (4-6mg/kg/day) and trimethoprim-sulfamethoxazole (8-12 and 40-60mg/kg/day respectively) was the mainstay of therapy for many years. However this regimen was associated with a mortality of approximately 70-80% in septicemicmelioidosis in addition to its considerable potential for toxicity. There are few comparative treatment trials in melioidosis (Tables 2 & 3). In the first open, prospective, randomized trial, high-dose intravenous ceftazidime was compared with conventional therapy in severe melioidosis, in patients over 10 years old. The trial was conducted in north-east Thailand. Ceftazidime was associated with a 50% reduction in mortality, to less than 40% in patients who survived for a minimum of 48 hours (90). There was no difference in mortality during the first 48 hours of treatment. Ceftazidime was given at a dose of 120mg/kg/day (usual dose 2g 8 hourly) for a minimum of 7 days. Lower doses were given in patients with renal failure. Of 161 patients entered into the study, 65 had culture-proven melioidosis and 54 of these were septicemic. A similar trial, conducted at two sites in north-east Thailand, compared conventional therapy with a combination of intravenous ceftazidime (100mg/kg/day) and trimethoprim-sulfamethoxazole (8:40mg/kg/day) for a minimum of 10 days (76), and gave similar results. Sixty four patients were subsequently shown to have culture-proven severe melioidosis. Three patients suffered severe adverse reactions (two in the conventional treatment group, one to the trimethoprim-sulfamethoxazole component in the other group). As a result of these trials, ceftazidime became the acute treatment of choice for severe melioidosis. There have been no reported trials of intravenous ceftazidime versus this ceftazidime-trimethoprim-sulfamethoxazole combination. There have been three subsequent randomized trials; in the first intravenous ceftazidime (120 mg/kg/day) was compared with high-dose co-amoxiclav (160 mg/kg/day) (80). This open randomized controlled trial involved 212 culture-positive patients. Overall mortality was the same in both groups (47%). However, there was a significantly higher treatment failure rate for co-amoxiclav (23% v. 5%). Both drugs were well-tolerated and appeared safe at the doses used. The authors concluded that co-amoxiclav was an effective acute treatment, but that ceftazidime remained the drug of choice. Co-amoxiclav has the advantage of a broader anti-bacterial spectrum than ceftazidime and hence may be the more appropriate of the two agents as empirical therapy for community-acquired septicemias in endemic areas. The next trial from the same group compared high-dose ceftazidime with imipenem(50mg/kg/day; normal dose 1g 8 hourly) (72). Imipenem has rapid bactericidal activity and was associated with a lower rate of treatment failure (20.3%) compared with ceftazidime (41.3%); but the mortality in the two groups was similar. Despite high doses in patients with renal failure, there were no adverse CNS effects in the imipenem group. Unfortunately this trial was terminated when imipenem supplies were stopped, so whether a mortality difference would have emerged in a larger trial is not known.  Imipenem (50-60mg/kg/day) is safe and effective and the best alternative to ceftazidime for severe septicaemia due to meliodosis (72). Recently cefoperazone, at the remarkably low dose of 25mg/kg/day in combination with sulbactam, proved as effective as ceftazidime plus trimethoprim-sulfamethoxazole (21). The relatively large differences in overall mortality between trials are explained by differences in entry criteria. One group of researchers carried out the antibiotic susceptibility testing of most commonly used antibiotics for melioidosis on 170 isolates of B. pseudomallei. All isolates (170) were sensitive to meropenem and piperacillin/tazobactam. Low level resistance was observed in ceftazidime, imipenem, amoxicillin/clavulanic acid (0.6%, one isolate each) while 98 isolates (57.7%) exhibited resistance to ciprofloxacin (2).

These trials have established ceftazidime as the treatment of choice for severe melioidosis (66), and amoxicillin-clavulanate as a satisfactory empirical treatment for sepsis in endemic areas. The carbapenems are effective alternatives. These drugs are very expensive. The cost of ceftazidime can be reduced, and blood concentration profiles optimized by administering ceftazidime by constant infusion; 19mg/kg loading dose followed by 3.5mg/kg/hr (4). This dose is nearly 30% less than the conventional 8 hourly bolus dosing. Maintenance doses of the b-lactams, and carbapenems should be adjusted in renal failure (which is common in melioidosis).

In a retrospective review of 1353 treated patients, the mortality associated with initial treatment with ceftriaxone orcefotaxime was 71% (98/138), nearly double that with ceftazidime, which strongly suggests that these cephalosporins should not be used to treat melioidosis (14). Whether trimethoprim-sulfamethoxazole should be added to ceftazidime, as has been recommended by some authors (76), is the subject of an ongoing trial (70). As with the treatment of tuberculosis, this has the theoretical advantage of reducing the emergence of resistant strains during therapy. This is known to occur, but it is very unusual (circa 1%) (32). It is not clear whether it is of clinical importance, or whether such combination therapy would prevent it. Unlike tuberculosis, the emergence of resistant strains does not have public health implications, as there is a vast environmental reservoir, human-human transmission is rare, and patients are not regarded as infectious. There are also worries about the potential for in vivo antagonism between these antibiotic combinations, which can be demonstrated in vitro (31), although clinical evidence is lacking. We do not recommend parenteral combination therapy at present. Whichever of these agents are used for first line therapy for melioidosis, the therapeutic response is usually slow, with a median time to defervescence of 9 days 4 (11, 72, 80, 90). A minimum of 10-14 days parenteral therapy should be given and continued until there is clear evidence of a clinical response. Some patients may require several weeks of parenteral treatment. It is important not to switch to an alternative regimen too early simply because a patient’s fever has failed to lyse after several days treatment - this does not necessarily imply treatment failure. Antimicrobial treatment for melioidosis is summarized in Table 4.

Outpatient antibacterial therapy (OPAT) service in conjunction with the community healthcare services to treat different infectious diseases by suitable antimicrobials is becoming popular in the hospitals worldwide. OPAT service saves hospital bed days, expenditures, and healthcare personnel’s time. Patients who are clinically stable and no more interventions required are referred to OPAT service and receive intravenous antibiotics either at the home or in the community settings. These patients are closely monitored up by the infectious disease team or other specialties. In two large Singapore hospitals, OPAT service initiated intravenous antimicrobial therapy in fifty six patients with melioidosis over six years period. . The inclusion criteria for OPAT service included; defervesence, haemodynamical stability, and no further intervention. Ceftizidime (100-200 mg/kg/day) was administered via peripherally inserted central catheter (PICC) and elastomeric infuser to all patients. Of 56, 47 (86%) patients completed the course. Four patients developed adverse reactions, two needed surgical intervention and three deteriorated due to underlying illness.  The majority (7/9) received treatment either via OPAT or as an inpatient later. The ultimate outcome was good (69).

Treatment failure, defined as the development of septic shock more than 72 hours after starting treatment, fever that persists without signs of resolution for 14 days, or blood cultures remaining positive 7 or more days after starting appropriate therapy, is uncommon on ceftazidime treatment. This may require a change of treatment, although repeat cultures usually show continued susceptibility, and there is often an equally indolent course with the second line antibiotic. The development of new abscesses during the first week on treatment should not be considered a treatment failure. Suitable second line agents include co-amoxiclav and imipenem.

Despite appropriate antimicrobial therapy, melioidosis has a high relapse rate. The average time between discharge from hospital and relapse is of 21 weeks. Treated patients need follow up for long time as B. pseudomallei remains latent for up to 26 years in the body (48). Relapses should be treated as for first episodes. Mortality and morbidity in relapsed cases are similar to that in first episodes (12). Frequently the antimicrobial susceptibility pattern of the relapse isolate is unchanged but repeat susceptibility testing is mandatory. The development of resistance whilst on treatment has been described for all the commonly used agents (32). Currie et al., from Australia found that 13% patients had laboratory confirmed relapses and mortality rate was 11% in relapse cases. Relapses were due to poor compliance to oral eradications therapy (50%) and doxycycline as monotherapy (37%) (28). Higher laboratory confirmed relapse rate (23%) with yearly relapse rate 15% was reported from Thailand (12). This group also reported 27% mortality rate in the relapse group. Darwin melioidosis prospective study group reported that with improved antimicrobial therapy, the relapse rate has been declining. Over the period of 23 years only 5.7% (39/679 patients) cases had recurrent melioidosis. Relapse was recorded in 29 patients while 10 patients developed new infection (68).

In endemic areas, patients presenting with a febrile illness consistent with a diagnosis of melioidosis require early treatment that will cover infection with B. pseudomallei. This also applies to patients from, or those with a travel history to, endemic areas. If the diagnosis is not clear, then broad-spectrum agents that have activity, such as co-amoxiclav or a carbapenem are indicated. Ceftazidime should usually be substituted once the diagnosis has been confirmed.

There are very few reported studies of oral treatment in non-severe melioidosis. Much of the current knowledge stems from studies of oral maintenance therapy (See Maintenance Treatment section below). Superficial abscesses can be treated effectively with drainage and shorter courses of antibiotics than following systemic infection. Parotid abscesses require very careful incision and drainage and oral antibiotic treatment (usually amoxicillin-clavulanate for 8-12 weeks).

Intravenous antibiotics are not always indicated to treat localised melioidosis. Oral conventional therapy as mentioned in Table 4 can successfully be used in majority of cases. However in some cases especially in elderly patients with co-morbidities parenteral antimicrobials should be initiated initially before switching over to oral regimen. Oral regimen for 6-8 weeks is usually effective in children with uncomplicated wound infection after trauma (58). New drugs such as doripenem a memeber of carbapenem group, and ceftobiprole a memeber of cephalosporins have shown bactericidal in vitro activity aganist B. pseudomallei. Their efficacy in clinical trials is yet to be tested. The clinicians and scietists are also optimistic about the future treatment and better outcome with new/future drugs  such as ceftalorine and iclaprim (42). Oral maintenance therapy has been summarized in Table 5.

Following successful acute treatment of melioidosis, there remains a substantial risk of relapse, with similar morbidity and mortality to first episodes. Prolonged maintenance therapy is necessary (13). Most experience has been gained with oral "conventional: antibiotics i.e. chloramphenicol, doxycycline and trimethoprim-sulfamethoxazole (Table 4). Treatment courses of 8 weeks have been associated with a relapse rate of 23% (13, 89) but 20 weeks courses have reduced this to under 10%.  Several studies reported that the conventional antibiotic exhibit antagonism in vitro as well as associated with more side effects. There are always risks of emergence of resistance to these antibiotics (31, 32, 67).

"Conventional" oral therapy has been compared with oral co-amoxiclav in one randomized study (64). Relapse rates after 20 weeks therapy were 4% and 16% respectively. Doses were chloramphenicol (40mg/kg/day in 4 divided doses),doxycycline (4mg/kg/day in 2 divided doses) and trimethoprim-sulfamethoxazole (10mg & 50mg/kg/day respectively in 2 divided doses), or co-amoxiclav (amoxicillin 30mg/kg/day, clavulanic acid 15mg/kg/day) plus amoxicillin(30mg/kg/day). Chloramphenicol was given for the first 8 weeks of therapy only. The authors concluded that co-amoxiclav was safer and better tolerated, but possibly less effective. Not surprisingly, there were considerable problems with compliance; the conventional regimen involves taking up to 18 tablets or capsules and co-amoxiclav 12 capsules per day. Cost is also an important consideration; co-amoxiclav costs approximately 15 times as much as the conventional regimen. However, co-amoxiclav should be considered the treatment of choice in children or pregnant women.

Fluoroquinolone therapy (with either ciprofloxacin or ofloxacin) appears unsatisfactory, with a relapse rate approaching 30% despite prolonged treatment (13). A recent trial evaluated azithromycin plus ciprofloxacin but the results were also disappointing (20). The fluoroquinolones should probably not be used, or at the very most considered as third line drugs. Monotherapy with doxycycline alone proved significantly inferior to the four drug conventional regimen in a recent comparative study (14), so current trials are determining whether chloramphenicol adds significantly to doxycycline and trimethoprim-sulfamethoxazole. One study from Thailand compared the efficacy of monotherapy of trimethoprim-sulfamethoxazole with combined therapy of trimethoprim-sulfamethoxazole plus doxycycline as a maintenance dose. This study found trimethoprim-sulfamethoxazole non inferior to the combination of trimethoprim-sulfamethoxazole plus doxycycline and recommended trimethoprim-sulfamethoxazole as monotherapy as it is safe and well tolerated by patients (23). Chusri et al (24) compared patients who received monotherapy of trimethoprim-sulfamethoxazole with patients on trimethoprim-sulfamethoxazole and doxycycline in Thailand.  They confirmed that trimethoprim-sulfamethoxazole alone is as effective as trimethoprim-sulfamethoxazole plus doxycycline for melioidosis eradication therapy. There remains an urgent need for simple, cheap and less-toxic regimens for the maintenance treatment of melioidosis. Failure of compliance with complex regimens remains a major risk factor for relapse (12).

Adjunctive therapy for instance the treatment for co-morbidities, fluid replacement, intensive care unit support if indicated, maintaining blood pressure should be included in the management of melioidosis. Surgical drainage of large abscesses is highly indicated. Frequently drainage is not possible as multiple small abscesses are present, particularly in the liver or spleen. Appropriate supportive measures should be instituted in acutely ill patients. Isolation of patients is not necessary. Neutrophil forms an essential part of innate immunity and play an important role in controlling infections in the body. One study from Northern Australia reported that mortality rate in septic shock due to melioidosis dropped from 95% to 10% after the administration of granulocyte colony stimulating factor (G-CSF) 300mg/day for 10 days in addition to the standard therapy (17).

As in other febrile infections clinical well being and fever are used to monitor the response to treatment. This is an indolent refractory infection, and there is a tendency for physicians who are not familiar with it to consider the infection refractory or resistant and switch antibiotics prematurely. In some cases, particularly those with deep seated multiple abscesses or empyema, fever will persist for more than a month.

B. pseudomallei infections are difficult to treat with antibiotics and despite appropriate treatment relapse rate is reasonably high. Furthermore there are no available vaccines at present. Veterinary vaccines have been developed but it is not clear whether they are effective.

Persons with underlying illness such as diabetes mellitus, and skin lesions should avoid contacting with standing water and soil in endemic areas. Farmers can prevent infection during work in the agriculture fields by wearing protective clothing, rubber boots and gloves (60). Human-to-human transmission of B. pseudomallei appears to be very rare (1). Occasional laboratory-acquired infections have been reported, but very little is known about the appropriateness, dose or duration of prophylaxis. There is no documented experience with primary prophylaxis and it is not advised in contacts of known cases (33). There is a concern that the terrorist may use B. pseudomallei as a biochemical weapon. A case may be made for offering secondary prophylaxis in certain circumstances, for example following a laboratory accident involving cultures of the organism, but such cases can only be assessed on their individual merits. An oral agent such as co-amoxiclav would be most suitable in such a situation.

The discovery of melioidosis in poor countries creates a terrible dilemma as the cost of treatment is often greater than the entire annual per capita income (56)! It is highly likely that the infection is considerably more widespread than currently appreciated, and therefore that morbidity and mortality are underestimated. The high mortality rate is probably associated with delay in diagnosis and the fulminant nature of melioidosis. It is also often "missed" in travellers or servicemen who return to their temperate country of origin. Melioidosis may also lie dormant for many years until reactivated by the development of diabetes mellitus or an immunosuppressing illness or treatment. The organism is sometimes discarded as a contaminant in clinical specimens! The optimum treatment for melioidosis remains to be determined. In vitro the carbapenems are the most active drugs, but there is insufficient clinical evidence to displace ceftazidime as the acute treatment of choice.  Whether the maintenance course can be shortened from a total of 20 weeks is also not known. Certainly 8 weeks treatment is not enough to prevent relapse. The four drug conventional regimen (chloramphenicol, doxycycline and trimethoprim-sulfamethoxazole) gives the best results but whether chloramphenicol is necessary has not yet been determined. For patients with chronic melioidosis, very limited treatment options exist. It remains extremely important to establish effective pre and post exposure treatment options including monotherapy or combination therapy and duration of the treatment. More funding should be allocated for melioidosis research and invention of new antimicrobials.

Burkholderia mallei is genetically very similar to B. pseudomallei. Human infection with B. mallei, which is the cause of glanders, a highly contagious disease and farcy in equine animals, is rare and usually confined to those in contact with infected horses or mules. Human glanders is rare in humans now. The organism is also a considerable hazard to the laboratory workers, veterinarians, and slaughterhouse workers.

The modes of transmission of the disease are usually through contaminated food and water troughs, favoured under crowding conditions. Apart from the natural host animals, B. mallei has no environmental reservoir. It is also transmissible from human-to-human and patients should be isolated. Glanders has been eradicated from many parts of the world though; it is believed that sporadic cases still occur in the Middle East, North Africa, South America and Asia (81).

Human glanders has similarities to melioidosis, ranging from acute septicaemic disease to localized chronic suppurative infection. The usual presentation of infected individuals with disease is swollen lymph nodes, respiratory tracts symptoms, ulcerating nodules in the alimentary and weight loss, as well as numerous subcutaneous abscesses. It has a high mortality without immediate treatment.

Prompt identification of B. mallei remains crucial in the mammalian host in order to management of advancement and prevention of disease. Standard laboratory methods for the identification of this organism are time consuming and take roughly seven days. So rapid molecular identification methods for example polymerase chain reaction are important to treat this highly infectious pathogen (81).

Although there are fewer studies than with B. pseudomallei, B. mallei is susceptible in vitro to tetracyclines (8, 9), sulphonamides, aminoglycosides, trimethoprim-sulfamethoxazole (3), some cephalosporins, imipenem (46) as well as ciprofloxacin. Overall it is much more sensitive to antibiotics in vitro than is B. pseudomallei (Table 1) (39, 46). In experimental infections however the response to treatment is relatively slow, as in melioidosis. Doxycycline is superior to ciprofloxacin in preventing experimental infections (65).

There are few data on the treatment of human infection because of the rarity of the disease. Treatment similar to that for melioidosis is probably most appropriate i.e. high-dose ceftazidime (120 mg/kg/day) or imipenem (50 mg/kg/day).Antimicrobial resistance is on the rise in B. mallei. Use of combination antimicrobial therapy and surgical intervention in case of abscess formation may be beneficial in glanders disease (47). One researcher was successfully treated with imipenem and doxycycline for two months followed by azithromycin and doxycyline for 6 months after developing glanders disease due to accidental laboratory exposure. (77).

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Tables

Table 1: Minimum Inhibitory Concentrations (Ug/Ml) for Selected Antibiotics Against Burkholderia pseudomalleiand Burkholderia mallei

	Burkholderia pseudomallei		Burkholderia mallei
	MIC90	Range	MIC90	Range
Ampicillin	32	16 - >128	64	32 - 64
Amoxycillin- Clavulanic  acid	2	0.5 - 4	4	1 - 4
Piperacillin	2	0.5-2	8	1 - 8
Ticarcillin-Clavulanic acid	4	0.5-16
Azlocillin	4	0.5 - 4
Cefuroxime	16	8-64	64	32 - 64
Cefoperazone-sulbactam	4	1- 16
Cefotaxime	4	1-16	16	4 - 64
Ceftriaxone	4	1-16	32	16 -64
Ceftazidime	4	0.5- 16	4	1-16
Cefixime	2	0.5 -4
Aztreonam	16	4-32	32	32 - >64
Imipenem	1	0.25 -2	0.25	0.12 -1
Azithromycin			1	0.25 -1
Rifampicin	32	8-64	8	2 - 16
Trimethoprim	64*	4 - >256*	16	1 - 32
Sulfamethoxazole	320	40- 2560	16	0.25 - >64
Chloramphenicol	32	4- >256	32	4 - 64
Doxycycline	4	0.5 - 16	0.12	<0.03 - 0.5
Gentamicin	128	8->256	0.5	0.25 - 1
Kanamycin	64	8- 256
Amikacin	128	16-256	2	0.5- 4
Ciprofloxacin	4	1-32	1	<0.03 - 4
Ofloxacin	8	1-8	8	0.5 - 8

Table 2: Randomized Treatment Trials in Severe Melioidosis

Trial	Drugs	No enrolled	Patients with melioidosis confirmed	Dose (mg/kg)/ day	Duration	Treatment Failure (%)	Mortality (%)
White et al 1989	Ceftazidime versus Chloramphenicol + Doxycycline + TMP/SMX	161	34 31	120 100 4 + 10 + 50	>  7 days >  7 days >  7 days		37 74
Sookpranee  et al 1992	Ceftazidime + TMP/SMX versus Chloramphenicol + Doxycycline + TMP/SMX	136	27   34	100+8+40   100 4 + 8 + 40	10-14 days   10-14 day 10-14 day		18.5   47
Supputamongkol et al 1994	Ceftazidime versus Amoxicillin-clavulanate	379	106 106	120 160	>  7 days >  7 days	39 51	47 47
Simpson et al 1999	Ceftazidime versus Imipenem	296	106 108	120 50	>  10 days >  10 days	41 20	38 36

Table 3: Randomized Trials of Oral Treatment in Melioidosis

Trial	Drugs	No enrolled	Dose (mg/kg)/day	Total duration (weeks)	Relapse rate (%)
Rajchanuvong et al 1995	Amoxicillin-clavulanate versus Chloramphenicol + Doxycycline + TMP/SMX	49   52	60/15   40+ 4 + 10 + 50	20   20	10   4
Chaowagul et al 1999	Doxycycline versus Chloramphenicol + Doxycycline + TMP/SMX	58   58	4   40+ 4 + 10 + 50	20   20	26   1
Chetchotisakd et al 2001	Azithromycin + Ciprofloxacin versus Doxycycline + TMP/SMX	36   29	10 + 20   4 + 10 + 50	12   20	22   3
Chusrii et al 2012	Cotrimoxazole Versus Cotrimoxazole + doxycycline	31   109	40+8   40+8+4	32   29	3.2   4.5
Chetchotisakd Et al 2014	Cotrimoxazole Versus Cotrimoxazole + doxycycline	226   218	See reference	Minimum 20   Minimum 20	8   9

Table 4. Antimicrobial Therapy for Treating Severe Melioidosis  (29, 45,  58, 60)

Severe Melioidosis

 With no complication

IV Ceftazidime 50mg/kg/day (maximum 2g) in 3 divided doses or 6 g/day after 2 g bolus

  With neuromelioidosis, persistent bacteraemia, or in intensive care unit

 IV Meropenem 25mg/kg (maximum 1 g) every 8 hours

 Duration of IV antimicrobial therapy in acute phase is usually 10-14 days. Intravenous antibiotics are required for longer period in case of septic shock, deep seated infection such osteomyelitis, discitis, septic arthritis,  endocarditis, or neurological melioidosis.

 Or

Severe Melioidosis

 Ceftazidime 100-120 mg/kg/day in 3 divided doses

Plus

Cotrimoxazole (8-12 and 40-60 mg/kg/day)

 Or

ceftazidime plus ciprofloxacin 500 mg x 12 hourly (only two weeks)

or Meropenem Plus Cotrimoxazole

  Localized Melioidosis

 Amoxicillin clavulanate 160mg/kg/day

 Or

Cotrimoxazole plus doxycycline

Table 5. Oral maintenance therapy for melioidosis (29)

Drug	Patients characteristic	Dose/frequency
Trimethoprim-sulfamethoxazole	Adult >60kg	160 mg/800mg tablets; two tablets every 12 h
	Adult, 40–60 kg	80 mg/400mg tablets; three tablets every 12 h
	Adult, <40 kg	160 mg/800mg tablets; one tablet every 12 h OR  80 mg/400mg tablets; two tablets every 12 h
	Child	8mg/40mg per kg; maximum dose 320 mg/1600mg every 12 h
OR
Amoxicillin/clavulanic acid (co-amoxiclav)	Adult, 40–60 kg	500 mg/125mg tablets; three tablets every 8 h
	Adult, <40 kg	60kg500mg/125mgtablets;twotabletsevery8h c
	Child	20 mg/5mg per kg every 8 h; maximum dose 1000 mg/250mg every 8 h

Recommended duration of the therapy is a minimum of 12 weeks

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