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Original Article

Clinical characteristics and outcomes of bacteraemic in a teaching hospital in a northeastern state of Malaysia: a five-year review

Zakuan Zainy Deris1, Habsah Hasan2 and Mohd Noor Siti Suraiya 1

1Department of and Parasitology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan,Malaysia 2Epidemiology and Control Unit, Hospital Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

Abstract Background: Melioidosis is an important public health problem causing community acquired in the northeastern part of Malaysia. Methodology: From January 2001 to December 2005, we reviewed case reports of all bacteraemic melioidosis admitted to a tertiary teaching hospital, Hospital Universiti Sains Malaysia. Results: Thirty-five patients had positive blood culture for meliodosis and 27 case reports were traceable for further analysis. The mean age was 46.8 + 20.0 years. Twenty patients (74.1%) were male. The main clinical presentation was that occurred in 23 (85.2%) patients. Eighteen patients (66.7%) had lung involvement and three patients had liver . Two patients presented with scrotal swelling, one of whom further developed Fournier's . Nineteen (70.4%) patients had underlying , five of whom were newly diagnosed during the admission. Thirteen (48.1%) patients were treated with high-dose ceftazidime and six (22.2%) patients were treated with imipenem. Eight (29.6%) patients were not given anti-melioidosis therapy because the causative agents were not identified until after the patients died. The patients were admitted 16.8 days + 18.1. Seventeen patients (63.0%) died in this series, 13 patients of whom died within four days of admission. Conclusions: The wide range of clinical presentations and the fatal outcomes of melioidosis require a high level of suspicion among physicians to develop an early appropriate therapy and reduce the .

Key words: melioidosis, clinical features, Malaysia

J Infect Dev Ctries 2010; 4(7):430-435.

(Received 12 September 2009 – Accepted 7 April 2010)

Copyright © 2010 Mohd Noor et al. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction However, not many publications on meliodosis come Melioidosis is a tropical infectious caused from Malaysia. This study aimed to determine the by Gram-negative bacteria Burkholderia demographic profiles, clinical characteristics, and pseudomallei. This soil-borne disease is endemic in outcome of patients with bacteraemic melioidosis southeast Asia and northern Australia. Melioidosis who attended Hospital Universiti Sains Malaysia, has a diverse spectrum of clinical presentation and Kelantan. can affect any organ. It is important to define the demographic profiles, clinical characteristics, and Materials and methods outcomes of melioidosis because of the regional A retrospective study was performed in Hospital differences that have been described in the Universiti Sains Malaysia (HUSM) by reviewing the prevalence of organ involvement [1,2]. blood culture results from the years 2001 to 2005 Kelantan State, which is located in the using the WHO-net program. HUSM is an 800-bed northeastern part of Malaysia, has a heavy monsoon tertiary teaching hospital that is located in Kelantan, a season from November to March every year. This northeastern state of Malaysia. state is located in what is known as the Malaysian All confirmed cases of bacteraemic melioidosis rice bowl and has more than 60,000 hectares of were selected for the study Bacteraemic melioidosis paddy fields [3]. Thousands of people are at risk of is defined as any positive blood culture for B. contracting B. pseudomallei, which is a great public pseudomallei with or without sepsis. The patients’ health concern and an important of community records were reviewed accordingly to determine the acquired sepsis in the northeastern part of Malaysia. demographic profiles, clinical characteristics, and

Mohd Noor et al. – Bacteraemic Melioidosis in Malaysia J Infect Dev Ctries 2010; 4(7):430-435. outcomes. Anti-melioidosis therapy for intensive The main clinical presentation was fever that phases used in HUSM during the study period was occurred in 23 (85.2%) patients. Eighteen patients intravenous every eight hours of either 40 (66.7%) had lung involvement and three patients had mg/kg ceftazidime or 20 mg/kg imipenem. The use of liver abscess. Two patients presented with scrotal other antimicrobial agents or the use of ceftazidime swelling, one of whom further developed Fournier's or imipenem below these suggested doses without Gangrene. The mean total white cell count during renal dose adjustment was not considered anti- admission was 15.8 + 7.5 X103 cell/mL. Seven melioidosis therapy. due to melioidosis was patients had normal total white cell counts during defined as a patient’s death within 72 hours of blood presentation and five of them died. culture positive for B. pseudomallei or a patient’s Nineteen (70.4%) patients had underlying clinical sepsis parameter that did not improve after diabetes, five of whom were newly diagnosed during the last blood culture positive for B. pseudomallei. the admission. Four (14.8%) patients had chronic Organ involvement of melioidosis was defined as renal , and five patients had no identified present with clinical findings and/or investigative underlying disease. One patient had underlying modalities of malfunctioning of that organ. The systemic lupus erythematosus. affected organ was probably the primary site of For anti-melioidosis therapy, thirteen (48.1%) bacteraemia or its malfunction was a of patients were treated with high dose ceftazidime and bacteraemia. In HUSM, at least 5 ml of blood six (22.2%) patients were treated with imipenem. were collected aseptically and inoculated into Eight (29.6%) patients were not given anti- BACTECTM (Becton Dickinson, New Jersey, USA) melioidosis therapy because identification of the blood culture bottles and incubated in the causative agents was not made until after the patient BACTECTM automated blood culture system. B. died. The patients were admitted for 16.8 + 18.1 pseudomallei was identified by the growth of silver- days. whitish colonies on blood agar, was Gram negative, Seventeen patients (63.0%) died in this series of oxidase positive, produced a neutral-alkaline reaction which 16 died directly due to bacteraemic on triple sugar iron, was motile, grew on 42oC and melioidosis and 13 patients died within four days of was colistin-resistant which were also confirmed by admission. One of the patients (patient 11 in Table 1) API NE ® system (bioMérieux, France). was taken home against medical advice in an Results were expressed in terms of the number extremely ill state, failing to respond to imipenem. It and percentage or the mean + standard deviation. For is likely that this patient also died. This case was categorical variables, the differences in patient analyzed as death due to melioidosis. characteristics and associated factors were tested by In the association studies, death due to Chi-square and Fisher’s exact test. For continuous melioidosis among bacteraemic melioidosis was variables, the independent t-test was used. The p associated with shorter hospitalization, no identified value of ≤ 0.05 was considered significant. All underlying disease, and no anti-melioidosis therapy. analyses were done using SPSS software (SPSS, Chicago, Illinois, USA) in the Medical Informatics’ Discussion Laboratory, School of Medical Sciences, Universiti There was no specific age for melioidosis. Sains Malaysia. Neonatal melioidosis is not uncommon in Malaysia. The youngest case in this series was a 15-day-old boy Results who presented with abdominal distention and shock. Out of 69,934 blood-culture request forms, 63 Our centre had reported one case of neonatal (0.09%) were positive for B. pseudomallei coming due to B. pseudomallei in 1998 [4]. from 35 patients. We managed to trace the case Another reported case of neonatal melioidosis in folders of 27 cases for further analysis (Table 1). The Malaysia was from the east coast state of Pahang in mean age was 46.8 + 20.0 years. The youngest was 2005 [5]. A case series of paediatric melioidosis in 15 days old and the eldest was 80 years old. Twenty Kuala Lumpur reported one case of bacteraemic patients (74.1%) were male. Fifteen (55.6%) patients melioidosis in a neonate [6]. The baby was admitted presented during the northeast monsoon rainy season. for neonatal sepsis with fatal outcome. Only one patient’s work was directly related to We agree with the previous report from Kuala gardening soil. Lumpur that the correlation of melioidosis and rainfall is less strong in Malaysia compared to that in

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Mohd Noor et al. – Bacteraemic Melioidosis in Malaysia J Infect Dev Ctries 2010; 4(7):430-435.

Table 1. Summary of bacteraemic melioidosis cases in Hospital Universiti Sains Malaysia from January 2001-December 2005

Antibiotic therapy Age Month of Organ TWC on No Gender Occupation Presentation Associated illness for intensive Outcome (year) admission Involvement admission phase Fever Working DM Died due to 1 45 Male October Abdominal Lung 8.0 Ceftazidime at rice mill Renal failure melioidosis distention Jaundice Fever 2 44 Male NA July Neck after Soft DM 18.2 Ceftazidime Recover dental extraction Retired Recovered 3 63 Female July Fever Lung DM 12.8 Imipenem teacher with relapse DM No anti- Died due to 4 54 Female Housewife January Admitted in shock NA Severe heart 16.2 melioid melioidosis valve problem therapy No anti- Retired Fever Died due to 5 80 Male December Lung No 10.9 melioid teacher Weakness melioidosis therapy Lung No anti- Fever Died due to 6 61 Male Odd job January Urinary DM 13.4 melioid Urinary retention melioidosis tract therapy Retired Fever 7 61 Male November Lung DM 20.8 Imipenam Recovered staff Scrotum swelling Fever Died due to 8 52 Male Policeman December Lung DM 15.0 Ceftazidime Cough melioidosis No anti- Retired Fever Chronic liver Died due to 9 56 Female December Lung 16.8 melioid staff Cough disease meliodosis therapy DM – newly 10 38 Male Policeman June Seizures Lung 28.2 Ceftazidime Recovered diagnosed Died due to 11 25 Female Gardener June Fever NA No 40.7 Imipenem melioidosis* Fever SLE Died due to 12 12 Female Student January Brain 7.7 Imipenem Seizures Lupus nephritis melioidosis No anti- Fever Died due to 13 62 Male NA September Lung DM 5.6 melioid Cough melioidosis therapy Died due to upper gastro- Lethargy DM intestinal bleed 14 75 Female NA March Lung 4.3 Caftazidime Vomiting CRF and nosocomial sepsis Fever Died due to 15 46 Male NA February Lung DM 25.3 Ceftazidime Abdominal pain melioidosis Fever Cough DM - newly Died due to 16 60 Male NA September Lung 18.1 Ceftazidime Diarrhea diagnosed melioidosis Abdominal pain

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Mohd Noor et al. – Bacteraemic Melioidosis in Malaysia J Infect Dev Ctries 2010; 4(7):430-435.

Table 1. Continued therapy Age Month of Organ TWC on No Gender Occupation Presentation Associated illness for intensive Outcome (year) admission Involvement admission phase Retired Fever 17 70 Male August Soft tissue DM 19.5 Ceftazidime Recovered staff Scrotal swelling Abdominal No antimelioid Died due to 18 1# Male - December NA No 15.7 distention Shock therapy melioidosis Fever Retired Lung DM – newly Died due to 19 49 Male June Epigastric pain 12.8 Imipenem army Liver diagnosed melioidosis Jaundice No anti- Fever Died due to 20 62 Female NA October Lung No 12.4 melioid Cough melioidosis therapy Fever Left leg swelling Lung Recovered 21 56 Male NA November DM 16.7 Ceftazidime Multiple skin Skin with relapse abscess Fever No anti- Died due to 22 5 Male - November Diarrhoea NA No 20.2 melioid melioidosis Vomiting therapy Liver DM – newly 23 41 Male NA October Fever Soft tissue 14.6 Ceftazidime Recovered diagnosed Skin Sea diver Liver DM – newly 24 34 Male November Fever 8.6 Ceftazidime Recovered instructor Spleen diagnosed Fever Lung Nausea DM Died due to 25 40 Male Laborer March Right hip 19.9 Ceftazidime Vomiting CRF melioidosis joint Jaundice Fever 26 48 Male NA April Lung DM 10.8 Imipenem Recovered Cough 27 Fever Assistant 24 Male November Nausea Lung CRF 13.6 Ceftazidime Recovered engineer Vomiting # 15 day-old; * This patient was taken home against medical advice in an extremely ill state. It is likely that this patient also died and was analyzed as died due to melioidosis. DM – Diabetes mellitus; CRF – Chronic renal failure; SLE – Systemic lupus erymathosus; NA – not available

Thailand and in northern Australia [7]. We found that but we observed normal total white cell months of presentation were not significant counts in seven patients although they had severe association of mortality due to melioidosis. We also sepsis; nevertheless, these two factors were not found that the occupation of bacteraemic melioidosis significantly associated with mortality in associated patients was not necessarily related to soil. Only one studies. Other presentations included cough, scrotal patient was working as a gardener. One other patient swelling, Fournier's Gangrene, urinary retention, worked in a rice mill. This is in contrast with a neck cellulitis, abdominal distention, jaundice, previous study in Thailand that found that more than vomiting, and seizures. The wide diversity of clinical half of melioidosis patients were paddy farmers [8,9]. syndromes are known phenomena in melioidosis As in other studies on melioidosis [2,6,8-10], men [11]. were predominantly affected, perhaps because they Nineteen patients (70.4%) had underlying were more frequently exposed to soil and water. diabetes in this series, five of whom were newly Fever was the most common clinical diagnosed during the admission. Puthucheary et al. presentation; however, absence of fever during reported only 28% of the patients in their study with presentation was observed in four patients. High total diabetes [12]. Undiagnosed diabetes mellitus is an white cell counts were present in many bacterial occult risk factor of melioidosis and the patient might 433

Mohd Noor et al. – Bacteraemic Melioidosis in Malaysia J Infect Dev Ctries 2010; 4(7):430-435.

Table 2. Selected associated factors of mortality among bacteraemic melioidosis patient

Died due to bacteraemic Recovered or died due to melioidosis other causes Variable p value# N = 16 N = 11

Mean (sd)*/ Freq (%) Mean (sd)*/ Freq (%)

Gender Male 11 (68.8) 9 (81.8) 0.446a Female 5 (31.3) 2 (18.2) Age (years) 44.4 (22.5) 50.1 (16.0) 0.455b Month of presentation

Dry 6 (37.5) 6 (55.5) 0.381a Rainy 10 (62.5) 5 (45.5) Length of hospital stay 3.1 (2.3) 36.7 (10.4) <0.001b (days) Fever during 14 (87.5) 9 (81.8) 0.683a presentation

Total white count 16.2 (8.3) 15.3 (6.5) 0.769b during admission Lung involvement 11 (68.8) 7 (63.6) 0.782a Underlying disease 11 (68.8) 11 (100.0) 0.014c identify Anti-melioidosis 8 (50.0) 11 (100.0) 0.001c therapy given # p value significant at 0.05 b Independent t-test a Pearson chi square c Fisher’s exact test present very severe sepsis. In the present study, two From the results of this study, we suggest that, in an out of five patients with newly diagnosed diabetes endemic area such as our region, melioidosis should mellitus died. Renal disease was another risk factor always be included as a working diagnosis in cases identified in four patients with bacteraemic presenting with community-acquired infection even if melioidosis. Five patients had no identified the patient has no underlying medical illness. Low underlying disease. index of suspicion in cases with unidentified The pulmonary involvement in this study underlying diseases puts the patient at risk of not (66.7%) was higher than that in previous cases from getting proper anti-melioidosis treatment. This study Kuala Lumpur (58%) [12]. Another series from found that anti-melioidosis therapy was given to only Australia reported 60% of pulmonary involvement one of the patients who had no identified underlying among bacteraemic melioidosis patients [13]. The diseases. liver and spleen were also common sites for abscess Lack of clinical suspicion leading to delay in formation. Liver and/or spleen abscess were also treatment is well described in other studies. Only one reported as the most common sites for out of seven (14.3%) paediatric bacteraemic extrapulmonary infection in Thailand [9]. In this melioidosis patients was treated empirically with series, we found three cases of liver abscess and one active drugs for melioidosis in Pahang, Malaysia case of splenic abscess. Involvement of the brain is in [16]. There were better findings in Singapore where the form of brain abscess [14,15]. We found one case 43.3% bacteraemic melioidosis patients had initial of possible cerebral melioidosis, but the patient died empiric antibiotic therapy that was appropriate for before proper diagnostic work was commenced. melioidosis [13]. This is in contrast with the study in The mortality rate was very high. There was not Australia that found no fatal cases among patients much difference in the mortality rate in this series with no identified underlying illness [10] who were when compared to the previous report in 1992 (65%) treated empirically with active drugs for melioidosis. [12]. Thirteen of the occurred within four days As stated above, thirteen patients died within four of admission. The patients died before the laboratory days of admission. We were able to identify five was able to confirm the causative organism. This cases of newly diagnosed diabetes mellitus condition was significantly associated with mortality presenting with melioidosis. It was unfortunate that in this series. these patients died before a proper, full laboratory

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Mohd Noor et al. – Bacteraemic Melioidosis in Malaysia J Infect Dev Ctries 2010; 4(7):430-435. investigation was done, and as a result, these cases Budhsarawong D, Mootsikapun P, Wuthiekanun V, were categorized as having no identified medical Teerawatasook N, Lulitanond A (1999) Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis 29: illness. The bottom line is that a higher index of 408-413. suspicion of melioidosis among physicians is very 9. Reechaipichitkul W (2004) Clinical manifestation of important, even in patients with no identified pulmonary melioidosis in adults. Southeast Asian J Trop underlying diseases. Med Public Health 35: 664-669. In this study, 20.0% of the surviving patients 10. Currie BJ, Jacups SP, Cheng AC, Fisher DA, Anstey NM, Huffam SE, Krause VL (2004) Melioidosis epidemiology suffered a relapse. Currie et al. reported a 13.0% and risk factors from a prospective whole-population study relapse in a greater number of patients with 2.4% of in northern Australia. Trop Med Inter Health 9: 1167-1174. patients relapsing twice [17]. Relapse can be due to 11. Dance DA (1991) Melioidosis: the tip of the iceberg? Clin poor compliance with eradication therapy, failure of Microbiol Rev 4: 52-60. 12. Puthucheary SD, Parasakthi N, Lee MK (1992) Septicaemic eradication therapy, inadequate intensive therapy, re- melioidosis: a review of 50 cases from Malaysia. Trans R inoculation from bone flap re-implant, chronic B. Soc Trop Med Hyg 86: 683-685. pseudomallei carriage, and new infection [17]. 13. Mukhopadhyay A, Lee KH, Tambyah PA (2004) In conclusion, this review shows the importance Bacteraemic melioidosis pneumonia: impact on outcome, of a high index of suspicion among physicians in clinical and radiological features. J Infect 48: 334-338. 14. Padiglione A, FerrisN, Fuller A, Spelman D (1998) Brain order to provide early therapy and reduce the caused by Burkholderia pseudomallei. J of Infect mortality rate among melioidosis patients. 36: 335-337. 15. Chadwick DR, Ang B, Sitoh YY, Lee CC (2002) Cerebral Acknowledgement melioidosis in Singapore: a review of five cases. Trans R Soc Trop Med Hyg 96: 72-76. We would like to thank the Universiti Sains Malaysia for 16. How HS, Ng KH, Yeo HB, Tee HP and Shah A (2005) providing us with the Incentive Grant to complete the study. Pediatric melioidosis in Pahang, Malaysia. J Microbiol Immunol Infect 38: 314-319. References 17. Currie BJ, Fisher DA, Anstey NM, Jacups SP (2000) 1. White NJ (2003) Melioidosis. Lancet 361: 1715-1722. Melioidosis: acute and chronic disease, relapse and re- 2. Malczewski AB, Oman KM, Norton RE, Ketheesan N activation. Trans R Soc Trop Med Hyg 94: 301-304. (2005) Clinical presentation of melioidosis in Queensland, Australia. Trans R Soc Trop Med Hyg 99: 856-860. 3. Department of Agriculture Annual Report, (2001) Kuala Lumpur, Malaysia. Corresponding Author 4. Halder D, Zainal N, Wah CM, Haq JA (1998) Neonatal Mohd Noor Siti Suraya meningitis and septicaemia caused by Burkholderia Department of Medical Microbiology and Parasitology, pseudomallei. Ann Trop Paediatr 18: 161-164. School of Medical Sciences, 5. Ang YM (2005) Neonatal meliodosis: very rare but be Universiti Sains Malaysia Health Campus, aware. Med J Malaysia 60: 99-102. 16150 Kubang Kerian, Kelantan, 6. Sam IC and Puthucheary SD (2006) Melioidosis in children Malaysia from Kuala Lumpur, Malaysia. Ann Trop Paediatr 26: 219- email: [email protected] 224. 7. Sam IC and Puthucheary SD (2007) Melioidosis and rainfall Conflict of interests: No conflict of interests is declared. in Kuala Lumpur, Malaysia. J Infect 54: 519-520. 8. Suputtamongkol Y, Chaowagul W, Chetchotisakd P, Lertpatanasuwun N, Intaranongpai S, Ruchutrakool T,

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