Transcript Document

Melioidosis :
An Emerging
Problem?
S. H. How
Department of
Internal Medicine,
Kulliyyah of Medicine,
International Islamic
University Malaysia
?Problem in Malaysia
We know about Dengue mortality…TB
mortality? Melioidosis mortality?
How many Dengue death/year??(<100)
In Malaysia, estimated around 700 culture
confirmed melioidosis patients died a
year!!!
Possible > 3000/year if including culture
negative patients.
?Action
Last updated
?Melioidosis: Problem in
Malaysia?
Lubuk Yu
Last updated
Lubuk Yu Outbreak 2010
 A boy was suspected to have drowned
 A 150-member team of police and army officers,
divers, firemen and volunteers from a nearby village
searched for his body
 Following this rescue operation, 22 people presented
with an acute febrile illness
 10 were blood culture confirmed melioidosis (4 were
positive for leptospirosis based on PCR)
 Among those cultured confirmed: 7 died(all DM, with
severe pneumonia, 1 patient died at home, no
culture)
Last updated
Med J Malaysia. 2012 Jun;67(3):293-7
Am J Trop Med Hyg. 2012 Oct;87(4):737-40
Soil and water samples were
positive
Last updated
What is B.pseudomallei?
 Melioidosis is caused by gram-negative bacilli, Burkholderia




pseudomallei
Common soil and fresh water saprophyte
In tropical and subtropical areas.
First decribed by Alfred Whitmore as a “glanders-like” disease
in Rangoon, Burma, in 1911
UMMC data: associated with very high in-hospital mortality
especially in the septicaemic form (65%) in the 1980s in
Malaysia.
Last updated
Melioidosis in Pahang
 January 2000 to June 2003
 157 cultured positive in Pahang
 The calculated annual incidence of adult melioidosis
in Pahang state was 6.07 per 100, 000 population per
year.
 78.5% were male.
 Malays:83%, Chinese:9.6%, Indians:3%,
 Orang Asli :3%
Figure I: Histogram showing number of melioidosis cases
by age in Pahang , Malaysia ( Jan 2000-June 2003) .
50
40
30
20
10
0
15 - 25
25 - 35
Age in years
35 - 45
45 - 55
55 - 65
65 - 75
75 - 85
85 - 95
Figure 2: Bar chart showing average number of melioidosis cases
per year by month of presentation in Pahang, Malaysia (Jan 2000June 2003).
7
6
5
4
Average No. Of Patients
3
2
1
0
Jan
Feb
Mac
April
May
Jun
Jul
Month of presentation
Aug
Sep
Oct
Nov
Dec
EPIDEMIOLOGY
 Farming has been shown to be strongly associated with
incidences of melioidosis. In Thailand, 81% of
melioidosis patients were rice-farmers and their family
members
 Mode of transmission
 direct entry of the organism into the blood stream via very minor






wounds
inhalation of contaminated dust
drowning
motor vehicle accident
breast milk
perinatal transmission
human-to-human transmission
Pediatr Infect Dis J 2004; 23:1169-71
N Engl J Med 2001; 344:1171-2
Lancet 1991; 337:1290-1
Table I: Number of melioidosis cases and in-hospital mortality by
foci of infection in Pahang , Malaysia ( Jan 2000-June 2003).
Foci of infection
Pneumonia
Septicemia with unknown source
Multiple organ involvement
Subcutaneous abscess or
musculoskeletal involvement
Involvement of internal organs*
Total
Number
(n=135)
%
Inhospital
mortality
in %
(n=113)
55
26
21
20
40.7
19.3
15.6
14.8
68.8
47.4
73.7
18.8
13
135
9.6
100
18.2
54.0
Logistic Regression
 N = 79
 Independent significant factors
 Duration of fever (OR 0.90 CI95% 0.82-0.99 )
 Pneumonia (OR 8.91 CI95% 1.19-67.22)
 Bilirubin (OR 1.03 CI95% 1.00-1.07)
Figure 3: Pie chart showing time of melioidosis death
after admission in Pahang , Malaysia ( Jan 2000-June 2003).
more than 14 days
8.2%
7 to 14 days
1.6%
48 hours to 7 days
24.6%
24 to 48 hours
23.0%
w ithin 24 hours
42.6%
Kedah data
 Alor Star(2005-2008)
 ?16.5 per 100000 per year
Include positive serology(35%)
? Correct denominator, only Alor Star population
was used
 Culture confirmed cases:
Mortality 45%(83% bacteremic)
72% diabetic
43% pneumonia
Last updated
BMC Infect Dis. 2010 Oct 21;10:302.
Terengganu Data
 2000-2006
 81% male
 59% DM
 85% of cases were bacteremic
 Overall mortality: 52.6%
 Mortality in septicaemic patients: 91.9%
 Other single centre data: HUSM, JB, etc
Last updated
Med J Malaysia. 2005 Dec;60(5):599-605
J Infect Dev Ctries 2010; 4(7):430-435.
Dr. Balkis Ab Karim
EPIDEMIOLOGY
Table 1: Epidemiology and mortality of melioidosis in endemic countries
Australia 1
Thailand4
Pahang,
Singapore5
Malaysia3
No of cases
252
423
135
372
Incidence*
16.5
4.4
6.1
1.7
Median age (year)
49
45
51
55
Male: female ratio
3:1
1.4:1
3.6:1
4.5:1
Paediatric patients (%)
4
-
7.6
2.4
Bacteraemia (%)
46
60
92
39
19
44
54
40
Bacteraemic cases
37
-
54
55
Underlying disease (%
of cases)
At least one
80
53
85
77
37
20
74
57
Mortality rate (%):
Overall
Diabetes mellitus
* Per 100000 populations per year
More worrying data………
Is melioidosis under diagnosed?
Last updated
CAP in HTAA
 Streptococcus pneumoniae (21.7% - all by PCR
alone)
 Klebsiella pneumoniae (17.3%)
 Burkholderia pseudomallei (13%)
Note: 83% diagnosed by PCR alone
 Pseudomonas aeruginosa (6.5%)
 Mycoplasma pneumoniae (6.5% - all by serology)
 Chlamydophila pneumoniae (4.3% -all positive by
both PCR and serology)
 Legionella pneumophila (2.1% - all by PCR alone).
Clinical Presentation
Last updated
CLINICAL MANIFESTATION
 Asymptomatic seroconversion
 Acute form: septicaemia and is associated with very high
mortality
 Chronic form: long-standing suppurative focal abscesses
with or without fever and is associated with a good
prognosis
 Fever
 >95% of patients
 a few days to months
 White blood cell counts:
 Increased:55.6%
 low :3.7%
Pulmonary melioidosis
 Fever
 Cough
 purulent sputum
 Haemoptysis is rare
 Acute fulminant pneumonia with septicaemia which commonly
requires mechanical ventilation and intensive care, mortality
exceeding 80%
 Chest radiograph
 Acute: localised patch or bilateral diffuse patchy alveolar infiltration or
multiple nodular lesions which may coalesce, cavitate and form
abscesses.
 Chronic: mimic pulmonary tuberculosis
 Rarely pleural effusion, empyema, pyopericardium and hilar
lymphadenopathy
Intra-abdominal abscesses

Liver and/or spleen abscesses are present in 4-17% of
adult melioidosis

Liver abscesses are frequently
multiple(82%)
 Associated with splenic abscess
in 56% of cases which are commonly multiple

In Northern Thailand, majority of
liver and splenic abscesses are due
to melioidosis9-10
 Empyema of the gall bladder,
pancreatic abscess and adrenal
abscess1-2
9Clin Infect Dis 1992; 14:412-7, 10J Med Assoc Thai 2003; 86:436-41
Musculoskeletal melioidosis
 Septic arthritis most commonly affects the
knee (50%) followed by the ankle (13%),
wrist (10%) and elbow (10%) 38 joints
 Osteomyelitis is less common1-4
Urogenital tract infection
 Prostatic abscess
 18% of adult males with melioidosis in Australia
 Pahang: Routine CT abd and pelvis in male patients

30% has prostatic abscess
 Commonly multiple
MR Razali et al e-IMJ
 Pyonephrosis, pyelonephritis, perinephric abscess and scrotal
abscess1-5
Skin and subcutaneous
involvement
 Skin and subcutaneous involvement is the
second commonest presentation
 Blisters, superficial erythematous pustules,
clusters of violaceous skin abscesses,
cellulitis and subcutaneous abscesses
 Lymphadenitis or lymph node abscess
Neurological melioidosis
 4% of melioidosis
 Macroscopic or microscopic brain abscesses,
meningo-encephalitis, brain stem encephalitis
and transverse myelitis.

11 Acta Trop 2000; 74:145-51
 Initial brain CT may be normal or show non-
specific changes.
 Magnetic resonance imaging is the
investigation of choice
Other organs
 mycotic aneurysm, pericardial effusion,
psoas abscess, peri-orbital cellulitis and
infected thyroid cyst.
Melioidosis in Children
 Acute septicemia with foci of infection in the
lungs (the most frequently involved organ), liver,
spleen or other organs
 Localised infection is common
 Unilateral suppurative parotitis has been reported to
account for 40% of localised melioidosis in Thailand
 unilateral parotid swelling with abscess formation
 facial nerve paralysis
 periorbital cellulitis
 conjunctivitis
 purulent discharges at the opening of Stensen’s duct and the
ear
 Pharyngocervical melioidosis: fever and sore throat
with or without cervical lymphadenopathy.
LABORATORY DIAGNOSIS

Ashdown /Francis medium that contains
aminoglycoside to which this organism is
resistant: non-sterile specimens

Blood agar and chocolate media: sterile
specimens

Throat swab has been shown to have 100%
specificity with 38% and 47% sensitivity in
adult and paediatric patients, respectively


J Clin Microbiology 2001; 39:3901-2 , J Infect Dis 1993; 167: 230-33
Trans R Soc Trop Med Hyg. 2012 Feb;106(2):131-3
Table II: Sensitivity tests of B. pseudomallei against various antibiotics in Pahang ,
Malaysia ( Jan 2000-June 2003).
Tests performed
Sensitive
(%)
Intermediate
Resistant
(%)
Ceftazidime
129
128(99.2)
0(0)
1(0.8)
AmoxicillinClavulinic acid
72
59(81.9)
0(0)
13(18.1)
CefoperazoneSulbactam
34
34(100)
0(0)
0(0)
TrimethoprimSulfamethoxazole
122
71(58.2)
9(7.4)
42(34.4)
Tetracycline
125
109(87.2)
5(4.0)
11(8.8)
Imipenem
106
105(99.1)
0(0)
1(0.9)
Ciprofloxacin
124
104(83.9)
11(8.9)
9(7.3)
Antibiotic
IFAT in HTAA
 Retrospective study
 January 2007 to December 2010
 664 patients with acute febrile illness
 73(11%) culture confirmed melioidosis
 If using IFAT less than 1:80 :negative
 61.6% had positive serology in culture
positive
 28% IFAT positive in culture negative
(p<0.0001)(titre as high as 1:1280)
Sensitivity and specificity of varies cut off levels
in diagnosing melioidosis using IFAT
Last updated
Background Serology
 Cross sectional study in Pahang
 IFAT Ig G in healthy adults
 >50 years of age: 65% positive
 35-50 years of age :60.4%
 18-34 years of age : 49.1%
Last updated
Positive
Immunoglobulin
G titre (1:80 and
above)
Number of
respondents
Percentage
IgG
positive
(%)
Signific
ance
(pvalue)
Age
18-34
years
35-50 years
>50
years
54
29
38
110
48
58
49.1
60.4
65.5
0.098
Male
Female
103
18
184
32
56
56.3
0.977
Construction site
Paddy plantation
Oil palm plantation
Kg Sentul (near Lubuk Yu)
Educational status
Primary School
Secondary School
Diploma
Degree
Occupation
Labourers
Farmers
Others
Contact with soil
Yes
No
Injury at work (hands and
feet)
Yes
No
Use of Protective gear at
work
none
gloves only
boots only
gloves and boots
26
42
32
21
70
56
49
41
37.1
75
65.3
51.2
.000
33
81
6
1
66
140
8
2
50
57.9
75.0
50.0
65
34
22
134
48
34
48.5
70.8
64.7
0.015
91
30
159
57
57.2
52.6
0.548
53
68
87
129
60.9
52.7
0.233
51
37
3
30
101
61
5
49
50.5
60.7
60.0
61.2
0.502
12
109
13
203
92.3
53.7
0.007
Gender
Residence
0.501
Last updated
Diabetic status
Yes
No
PCR: Blood
 Detection of B.pseudomallei were done by
amplifications of the selected virulence
genes, LPS.
 Among culture-confirmed melioidosis
 31 isolates out of 32 clinical isolates: positive for
LPS virulence genes.
 One specimen was negative initially but became
positive after one week.
 20 other organisms which were used as
negative control were tested negative.
MANAGEMENT
 General management
 Large abscesses should be drained
 Patients with persistent fever lasting more
than a week require further examination and
investigations to look for occult abscesses
 Control of blood sugar is important in diabetic
patients
antibiotic treatment of
melioidosis
 Conventional regimen for the intensive phase
 IV chloramphenicol, tetracycline and co-trimoxazole
bacteriostatic and toxic
 Two randomised controlled trials showed
treatment with ceftazidime resulted in a 50%
reduction in mortality of severe melioidosis


Antimicrobial Agents and Chemotherapy 1992; 36:158-62,
Lancet 1989; 2:697-701
 Imipenam vs ceftazidime
 no difference in mortality but ceftazidime was
associated with a higher failure rate

Clin Infect Dis 1999; 29:381-7
antibiotic treatment of
melioidosis

Co-amoxiclav vs ceftazidime

no difference in mortality but less failure rate in the ceftazidime
group


Cefoperazole-sulbactam with co-trimoxazole vs
ceftazidime with co-trimoxazole

similar efficacy, mortality rate and bacteria clearance rate


lower mortality than ceftazidime in severe sepsis

Antimicrob Agents and Chemother 2004; 48: 1763-5
Ceftazidime vs ceftazidime/ co-trimoxazole

No difference in mortality


J Med Assoc Thai 1998; 81:265-71 , Clin Infect Dis 2001; 33:29-34
Meropenam


Clin Infect Dis 1994; 19:846-53
Clin Infect Dis 2006; 41:1105-13
Granulocyte colony-stimulating factor (G-CSF)

reduction in mortality

Clin Infect Dis 2003; 38:32-7
Last updated
oral earadication therapy
 Conventional regimen
 chloramphenicol, doxycycline and cotrimoxazole.
 Doxycycline and co-trimoxazole is as
effective as conventional therapy

Antimicrob Agents Chemother 2005; 49:4020-5
 Co-amoxiclav or doxycline or
ciprofloxacin and azithromycin
 Higher relapses

Cochrane Database Syst Rev. 2002;(4):CD001263
Recommended antibiotic
treatment for melioidosis
Intensive therapy
Life threatening melioidosis (presence of respiratory failure requiring
mechanical ventilation, impaired consciousness, acute renal failure
requiring dialysis, DIVC or multi-organ failure.)

IV meropenem (25mg/kg/dose; usual dose for adult: 750 mg to 1 gm
TDS).

May substitute meropenam with imipenam (50mg/kg/day).

Consider IV G-CSF 300 g daily for 10 days in patients with
septicaemic shock.
Severe melioidosis (Presence of organ dysfunction, hypotension or
disseminated infection)

IV ceftazidime (100 mg/kg a day; usual dose for adult, 2 gm TDS).

May substitute ceftazidime with cefoperazone-sulbactam 1 gm TDS.

Consider IV G-CSF 300 g daily for 10 days in patients with
septicaemic shock.
Mild to moderate melioidosis

IV amoxycillin-clavulanate (160mg/kg/day in 6 divided doses daily)
for at least 2 weeks.
Eradication therapy
 Oral co-trimoxazole (trimethoprim
8mg/kg/day and sulfamethoxazole
40mg/kg/day) and doxycycline
(4mg/kg/day in 2 divided doses per day) (
 Usual dose 3 tabs BD and doxycycline
100mg BD
 Duration of 20 weeks
 Augmentin if allergic to co-trimoxazole
Last updated
Augmentin dose
 IV augmentin 1.2gm 4 hourly (50kg)
 <60kg
Oral augmentin 2 tabs tds (625mg/tab)with
amoxycillin 500mg tds
 >60kg
Oral augmentin 2 and half tabs tds
(625mg/tab)with amoxycillin 500mg tds
Last updated
Relapse and recurrence
 Chaowagal et al found that 23% of their patients
had culture proven relapse with a first year
relapse rate of 15%.
 Higher relapses
 Septicaemia
 Disseminated infection
 Short course of eradication therapy
 Intensive therapy with antibiotics other than ceftazidime
 J Infect Dis 1993; 168:1181-5
 Australian study, 13% of patients relapse
 Poor adherence to the eradication therapy
 Doxycycline monotherapy
 Trans R Soc Trop Med Hyg 2000; 94: 301-4
Relapse in Pahang
 19.2% had culture proven relapses. 20% of
these patients died during a second relapse
30
20
10
Outcome
No relapse
Relapse
0
Appropriate >2 weeks
Appropriate <2 weeks
Antibiotic given
other antibiotic
Conclusion
 Melioidosis is endemic in Malaysia
 Mortality is extremely high despite
antibiotic treatment
 Early diagnosis and treatment is essential
to reduce mortality