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Melioidosis is an infectious disease caused
by a Gram-negative bacterium, Burkholderia pseudomallei, found
in soil and water. It is
of public health importance in endemic areas, particularly in Vietnam and northern Australia. It
exists in acute and chronic forms.
Signs and symptoms may include pain in chest, bones, or joints; cough; skin
infections, lung nodules, and pneumonia.
B. pseudomallei was previously classed as part of the Pseudomonas genus; until 1992, it was known as Pseudomonas pseudomallei. It is
phylogenetically related closely to Burkholderia mallei which causes glanders, an
infection primarily of horses, donkeys, and mules. The name melioidosis is
derived from the Greek melis (μηλις) meaning "a distemper of
asses" with the suffixes -oid meaning "similar to" and -osis
meaning "a condition", that is, a condition similar to glanders.[1]
Acute melioidosis
In the subgroup of patients
where an inoculating event was noted, the mean incubation
period of
acute melioidosis was 9 days (range 1–21 days).[2] Patients with latent melioidosis may be
symptom-free for decades; the longest period between presumed exposure and
clinical presentation is 62 years.[3] The potential for prolonged incubation was
recognized in US servicemen involved in the Vietnam War, and was referred to as
the "Vietnam time-bomb". A wide spectrum of severity exists; in
chronic presentations, symptoms may last months, but fulminant infection, particularly associated with
near-drowning, may present with severe symptoms over hours.
A patient with active
melioidosis usually presents with fever. Pain or other symptoms may be
suggestive of a clinical focus, which is found in around 75% of patients. Such
symptoms include cough or pleuritic chest pain suggestive of pneumonia, bone or
joint pain suggestive of osteomyelitis or septic arthritis, or cellulitis.
Intra-abdominal infection (including liver and/or splenic abscesses, or
prostatic abscesses) do not usually present with focal pain, and imaging of
these organs using ultrasound or computed tomography should
be performed routinely. In one series of 214 patients, 27.6% had abscesses in
the liver or spleen (95% confidence interval, 22.0% to 33.9%). B. pseudomallei abscesses may have a characteristic
"honeycomb" or "swiss cheese" architecture (hypoechoic,
multiseptate, multiloculate) on CT.[4][5]
Regional variations in disease
presentation are seen: parotid abscesses characteristically occur in Thai
children, but this presentation has only been described once in Australia.[6] Conversely, prostatic abscesses are found
in up to 20% of Australian males, but are rarely described elsewhere. An
encephalomyelitis syndrome is recognised in northern Australia.
Patients with melioidosis
usually have risk factors for disease, such as diabetes, thalassemia, hazardous
alcohol use, or renal disease, and frequently give a history of occupational or
recreational exposure to mud or pooled surface water.[7] However, otherwise healthy patients,
including children, may also get melioidosis.
In up to 25% of patients, no
focus of infection is found and the diagnosis is usually made on blood cultures
or throat swab. Melioidosis is said to be able to affect any organ in the body
except the heart valves (endocarditis). Although meningitis has been described secondary to ruptured
brain abscesses, primary meningitis has not been described. Less common
manifestations include intravascular infection, lymph
node abscesses
(1.2–2.2%),[8] pyopericardium and myocarditis, mediastinal
infection, and thyroid and scrotal abscesses and ocular infection.
Chronic melioidosis
Chronic melioidosis is usually
defined by a duration of symptoms greater than two months and occurs in about
10% of patients.[9] The clinical presentation of chronic
melioidosis is protean and includes such presentations as chronic skin
infections, chronic lung nodule, and pneumonia. In particular, chronic
melioidosis closely mimics tuberculosis, and
has sometimes been called "Vietnamese tuberculosis".[10][11][12]
A definitive diagnosis is made
by culturing the organism from any clinical sample, because the organism is
never part of the normal human flora.
A definite history of contact
with soil may not be elicited, as melioidosis can be dormant for many years
before manifesting.[13] Attention should be paid to a history of
travel to endemic areas in returned travellers. Some authors recommend
considering possibility of melioidosis in every febrile patient with a history
of traveling to and/or staying at endemic areas.
A complete screen (blood
culture, sputum culture, urine culture, throat swab, and
culture of any aspirated pus) should be performed on all patients with suspected
melioidosis (culture on blood
agar as well
as Ashdown's
medium). A definitive diagnosis is made by growing B. pseudomallei from any site. A throat swab is not
sensitive, but is 100% specific if positive, and compares favourably with
sputum culture.[14] The sensitivity of urine culture is
increased if a centrifuged specimen is cultured, and any bacterial growth
should be reported (not just growth above 104 organisms/ml which is the usual
cutoff).[15] Very occasionally, bone marrow culture may
be positive in patients who have negative blood cultures for B. pseudomallei, but these
are not usually recommended.[16] A common error made by clinicians
unfamiliar with melioidosis is to only send a specimen from the affected site
(which is the usual procedure for most other infections) instead of sending a
full screen.
Ashdown's medium, a selective
medium containing gentamicin, may
be required for cultures taken from nonsterile sites. Burkholderia cepacia medium may be a useful alternative
selective medium in nonendemic areas, where Ashdown's is not available.[17] A new medium derived from Ashdown, known as
Francis medium, may help differentiate B.
pseudomallei from B. cepacia and may help in the early diagnosis of
melioidosis,[18] but has not yet been extensively clinically
validated.
Many commercial kits for
identifying bacteria may misidentify B.
pseudomallei (see Burkholderia pseudomallei for a more detailed discussion of this
topic).
A serological
test for
melioidosis (indirect haemagglutination) is available, but not
commercially in most countries. A high background titre may reduce the positive
predictive value of serological tests in endemic countries. A specific direct
immunofluorescent test and latex agglutination, based on monoclonal antibodies,
are used widely in Thailand, but are not available elsewhere. Cross-reactivity
with B. thailandensis is almost complete.[19] A commercial ELISA kit for melioidosis appears to perform
well.[20] but no ELISA test has yet been clinically
validated as a diagnostic tool.[21]
It is not possible to make the
diagnosis on imaging studies alone (X-rays and scans),[22] but imaging is routinely performed to assess
the full extent of disease.[23] Imaging of the abdomen using CT scans or
ultrasound is recommended routinely, as abscesses may not be clinically
apparent and may coexist with disease elsewhere. Australian authorities suggest
imaging of the prostate specifically due to the high incidence of
prostatic abscesses in northern Australian patients. A chest X-ray is also
considered routine, with other investigations as clinically indicated. The
presence of honeycomb abscesses in the liver are considered characteristic, but
are not diagnostic.[22][23]
The differential diagnosis is extensive; melioidosis may mimic many
other infections, including tuberculosis.[10]
Current
treatment[edit]
The treatment of melioidosis is
divided into two stages, an intravenous high-intensity phase and an eradication
phase to prevent recurrence.
Intravenous intensive phase
Intravenous ceftazidime is the current drug of
choice for treatment of acute melioidosis.[24][25] Meropenem,[26] imipenem[2] and the cefoperazone-sulbactam combination (Sulperazone)[27] are also active.[28] Intravenous
amoxicillin-clavulanate (co-amoxiclav) may be used if none of
the above four drugs is available, but it produces inferior outcomes.[29] Intravenous antibiotics are given for a minimum of
10 to 14 days, and are not usually stopped until the patient's temperature has
returned to normal for more than 48 hours. Even with appropriate antibiotic
therapy, fevers often persist for weeks or months, and patients may continue to
develop new lesions even while on appropriate treatment. The median fever
clearance time in melioidosis is 10 days:[29] and failure of the fever
to clear is not a reason to alter treatment. It is not uncommon for patients to
require parenteral treatment continuously for
a month or more.
Intravenous meropenem is routinely used in
Australia;[9] outcomes appear to be good
and meropenem is currently being tested with ceftazidime in a Thai clinical
trial.[30]
Theoretical reasons are given for believing mortality might be
lower in patients treated with imipenem: first, less endotoxin is released by dying
bacteria during imipenem treatment,[31] and the minimum
inhibitory concentration (MIC) for imipenem is
lower than for ceftazidime. However, no clinically relevant difference was
found in mortality between imipenem and ceftazidime treatments.[2] The MIC of meropenem is
higher for B. pseudomallei than for many other organisms, and patients
being haemofiltered will need more frequent or higher doses.[32]
Moxifloxacin, cefepime, tigecycline, and ertapenem do not appear to be
effective in vitro.[33][34] Piperacillin-sulbactam ,[33] doripenem and biapenem[34][35] appear to be effective in vitro, but no clinical experience exists on
which to recommend their use.
Adjunctive treatment with granulocyte colony-stimulating
factor[36] or co-trimoxazole[37][38] were not associated with
decreased fatality rates in trials in Thailand.
Eradication phase
Following the treatment of the acute disease, eradication (or
maintenance) treatment with co-trimoxazole and doxycycline is recommended to be used
for 12 to 20 weeks to reduce the rate of recurrence.[39] Chloramphenicol is no longer routinely recommended
for this purpose. Co-amoxiclav is an alternative for those patients who are
unable to take co-trimoxazole and doxycycline (e.g., pregnant women and
children under the age of 12),[40][41] but is not as effective.
Single agent treatment with a fluoroquinolone (e.g., ciprofloxacin)[42][43] or doxycycline[44] for the oral maintenance
phase is ineffective.[45]
In Australia, co-trimoxazole is used on its own for eradication
therapy,[9] with relapse rates that
are lower than those seen in Thailand; in
vitro evidence also suggests
co-trimoxazole and doxycycline are antagonistic, and co-trimoxazole on its own
may be preferable.[46] Results from a randomised
controlled trial (MERTH) support the use of co-trimoxazole alone.[47] Studies reinforce the need
for adequate follow-up and good adherence to the eradication phase of therapy.
Dosing for co-trimoxazole is based on weight: (<40 kg: 160/800 mg
every 12 hours; 40–60kg: 240/1200 mg every 12 hours,
>60 kg: 320/1600 mg every 12 hours).[48]
Surgical treatment[edit]
Surgical drainage is usually
indicated for prostatic abscesses and septic arthritis, may be indicated for parotid
abscesses, and is not usually indicated for hepatosplenic abscesses. In
bacteraemic melioidosis unresponsive to intravenous antibiotic therapy,
splenectomy has been attempted, but only anecdotal evidence supports this
practice.[49]
Prognosis
Without access to appropriate
antibiotics (principally ceftazidime or meropenem), the
septicemic form of melioidosis exceeds 90% in mortality rate.[51][52] With appropriate antibiotics, the mortality
rate is about 10% for uncomplicated cases but up to 80% for cases with
bacteraemia or severe sepsis. It seems certain that access to intensive care
facilities is also important, and probably at least partially explains why
total mortality is 20% in Northern Australia but 40% in Northeast Thailand.
Response to appropriate antibiotic treatment is slow, with the average duration
of fever following treatment being 5–9 days.[53][54]
Recurrence occurs in 10 to 20%
of patients, but with co-trimoxazole eradication therapy, this can be reduced
to 4%.[55] While molecular studies have established
the majority of recurrences are due to the original infecting strain, a
significant proportion of recurrences (perhaps up to a quarter) in endemic
areas may be due to reinfection, particularly after two years.[56] Risk factors include severity of disease
(patients with positive blood cultures or multifocal disease have a higher risk
of relapse), choice of antibiotic for eradication therapy (doxycycline
monotherapy and fluoroquinolone therapy are not as effective), poor compliance
with eradication therapy and duration of eradication therapy less than 8 weeks.[45][57]
Prevention
Person-to-person transmission
is exceedingly unusual;[58][59][60] and patients with melioidosis should not be
considered contagious. Lab workers should handle B. pseudomallei under BSL-3 isolation conditions,[61] as laboratory-acquired melioidosis has been
described.
In endemic areas, people
(rice-paddy farmers in particular) are warned to avoid contact with soil, mud,
and surface water where possible.[citation needed] Case clusters have been described following
flooding and cyclones and probably relate to exposure. Other case clusters have
related to contamination of drinking water supplies. Populations at risk
include patients with diabetes mellitus, chronic renal failure, chronic lung disease, or an
immune deficiency of any kind. The effectiveness of measures to reduce exposure
to the causative organism have not been established. A vaccine is not yet
available.
Epidemiology
Melioidosis is endemic in parts
of southeast Asia (including Thailand,[67] Laos,[68][69][70] Singapore,[71] Brunei,[72] Malaysia, Burma and Vietnam), China,[73] Taiwan[74][75] and northern Australia.[53][76] Flooding can increase its extent, including
flooding in central Australia.[77] Multiple cases have also been described in
Hong Kong and Brunei[78] India,[79][80][81][82] and sporadic cases in Central and South
America,[83][84][85] the Middle East, the Pacific and several
African countries.[86][87] Although only one case of melioidosis has
ever been reported in Bangladesh,[88] at least five cases have been imported to
the UK from that country. Recent news reports indicate B. pseudomallei has been isolated from soil in
Bangladesh,[89] but this remains to be verified
scientifically. This suggests melioidosis is endemic to Bangladesh and a problem of
underdiagnosis or under-reporting exists there.[90] most likely due to a lack of adequate
laboratory facilities in affected rural areas. A high isolation frequency
(percentage of positive soil samples) was found in east Saravan in rural Lao PDR distant from the Mekong
River, thought by the investigators to be the highest geometric mean
concentration in the world (about 464 (25-10,850 CFU/g soil).[91]
A statistical
model indicated
that the incidence will be 165,000 cases per year in 2016 (95% confidence interval, 68,000 to 412,000), with
138,000 of those occurring in East and South Asia and the Pacific.[92] About half of those cases will die.
Northeast Thailand has the highest incidence of melioidosis recorded in the
world (an average incidence of 12.7 cases per 100,000 people per year).[93] In Northeast Thailand, 80% of children are
positive for antibodies against B.
pseudomallei by the age of 4;[94] the figures are lower in other parts of the
world.[95][96][97][98]
Melioidosis is a recognised
disease in animals, including cats,[99] goats, sheep, and horses. Cattle, water
buffalo, and crocodiles are considered to be relatively resistant to
melioidosis despite their constant exposure to mud.[100] An outbreak at the Paris Zoo in the 1970s
("L’affaire du jardin des plantes") was thought to have
originated from an imported panda.[101]
B. pseudomallei is normally found in soil and surface
water; a history of contact with soil or surface water is, therefore, almost
invariable in patients with melioidosis;[53] that said, the majority of patients who do
have contact with infected soil suffer no ill effects. Even within an area, the
distribution of B. pseudomallei within the soil can be extremely
patchy,[102][103] and competition with other Burkholderia species has been suggested as a
possible reason.[104] Contaminated ground water was implicated in
one outbreak in northern Australia.[105] Also implicated are severe weather events
such as flooding[106] tsunamis[107] and typhoons.[108][109]
Based on whole genome
sequencing, humans may play a role in moving B. pseudomallei from place to place.[110]
The single most important risk
factor for developing melioidosis is diabetes
mellitus, followed by hazardous alcohol use, chronic kidney disease, and
chronic lung disease. Other risk factors include thalassaemia,
occupation (rice paddy farmers),[111] and cystic
fibrosis.[58][84] The mode of infection is believed to be
either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei cells. Person-to-person spread has
been described, but is extremely unusual.[58][59][60] HIV infection
does not predispose to melioidosis.[112][113][114]
The disease is clearly
associated with increased rainfall, with the number (and severity) of cases
increasing following increased precipitation
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