Melioidosis at Maharaj Nakorn Chiang Mai Hospital, Thailand

Original Article Melioidosis at Maharaj Nakorn Chiang Mai Hospital, Thailand Romanee Chaiwarith, M.D.* Phongsatron Patiwetwitoon, M.D.* Khuanchai Supparatpinyo, M.D.* Thira Sirisanthana, M.D.* ABSTRACT A retrospective study was carried out at Maharaj Nakorn Chiang Mai Hospital from January 2001 to December 2003 to assess the clinical features, laboratory data, and clinical outcome of 26 patients with melioidosis. There were 21 men and 5 women; the mean age was 52 years (range 30-81 years). Diabetes was the most common underlying disease (34.6%). Clinical manifestations included disseminated septicemic, non-disseminated septicemic infection, and localized infections in 12, 10, and 4 patients, respectively. The bloodstream was the most common site of infection (22 patients), followed by a pulmonary site (13 patients). The overall mortality rate was 42.3% (11 patients). Disseminated septicemic infection was significantly correlated with a high mortality rate. In conclusion, melioidosis is not uncommon in northern Thailand. The case fatality rate is high, particularly in disseminated septicemic meiloidosis. High suspicion and early detection are important and could lead to the successful treatment. (J Infect Dis Antimicrob Agents 2005;22:45-51.) INTRODUCTION Melioidosis is an infectious disease caused by Burkholderia pseudomallei, a gram-negative bacillius. The bacteria can be found in the environment, such as in soil and water in the tropics. 1 The endemic area of this infection is countries in Southeast Asia and northern Australia. 2,3 However, melioidosis has been reported from countries in various parts of the world and could become a global public health problem. 4 The first case of melioidosis in Thailand was reported in 1955. 5 The endemic area was found to be in the northeastern part of the country, although cases of meliodosis have been reported from every region of the country. A study to look at the frequency at which B. pseudomallei could be cultured from soil samples from various regions of Thailand was commissioned by the Thailand Research Fund (TRF) and conducted * Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50002, Thailand. Received for publication: April 22, 2005. Reprint request: Romanee Chaiwarith, M.D., Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50002, Thailand. Keywords: Melioidosis, diabetes, disseminated septicemic infection 45

46 J INFECT DIS ANTIMICROB AGENTS May-Aug. 2005 between August and December 1997. 6 The bacteria could be cultured from 179 of 357 soil samples from northeastern Thailand (50.1%), 12 of 49 from central Thailand (24.5%), 57 of 310 from southern Thailand (18.4%), and only 25 of 180 from northern Thailand (13.8%). During the same period, the incidence of meliodosis in northeastern Thailand was the highest in the country at 137.9 per 100,000, accounting for 77.6 percent of the total number of cases diagnosed in Thailand. 6 The clinical manifestations of melioidosis vary from asymptomatic infection to disseminated septicemic infection. The latter has a case fatality rate of 70 percent. 7,8 Most of the reports of melioidosis in Thai patients were from the endemic area of northeastern Thailand. In this report, we studied the clinical manifestations as well as risk factors that determined the clinical outcome of patients with melioidosis in northern Thailand, an area with lower incidence of the disease. PATIENTS AND METHODS We conducted a retrospective chart review of patients with diagnosis of melioidosis who were admitted at Maharaj Nakorn Chiang Mai Hospital, a referral center in northern Thailand, between January 2001 and December 2003. The diagnosis was made by isolating of B. pseudomallei from blood or other clinical specimens. The cultures were performed at the central laboratory of Maharaj Nakorn Chiang Mai Hospital. The following information was extracted from the medical records including demographic data (age, sex, occupation, and address), symptoms and signs, underlying medical conditions, results of laboratory tests, treatment regimen and outcome. Demographic data, symptoms and signs and outcome of the patients were reported as percentage, mean, range, and standard deviation (SD), as appropriate. Comparison between patients who survived and those who died was done using the Student s t-test, Mann Whitney U test, Chi square test, or Fisher s exact test, as appropriate. A two-tailed p value of less than 0.05 was considered significant. The analysis was performed using the SPSS program (SPSS for windows, Rel. 10.0.1997. Chicago: SPSS Inc.). RESULTS During the study period, 30 cases of melioidosis were diagnosed. The medical records were available for review in 26 cases. Twenty-one were male and five were female, accounting to a male-to-female ratio of 4.2. The mean age (+SD) was 52.1 + 11.4 years (range 30-81 years). Twenty-one patients (80.8%) had underlying medical conditions. Nine had diabetes mellitus, four had malignant diseases (one each of acute myelogenous leukemia, metastatic carcinoma of the liver, laryngeal carcinoma, and bronchogenic carcinoma), two had chronic renal failure, and two had hypertension. Among the remaining patients, there was one each of valvular heart disease, chronic obstructive pulmonary disease, systemic lupus erythematosus, and thalassemia. Six patients (23.4%) were farmers, four (15.4%) were hired laborers, and one each was a monk, a housewife, and a soldier. In the remaining 13 cases, the occupation had not been recorded. Eight patients were from Chiang Mai and another eight were from Lampang. Of the remaining patients, five, two, and one were from Lamphun, Phayao, and Nan, respectively. The majority of cases were diagnosed near the end of the rainy season (August to October) as shown in Figure 1. The patients were classified by the onset and severity of the disease (Table 1). The onset of the disease was classified as acute if the patient presented within seven days of the first symptom. It was classified

Vol. 22 No. 2 Melioidosis in northern Thailand:- Chaiwarith R, et al. number of patients month Figure 1. The number of cases of melioidosis diagnosed between January 2001 and December 2003 by month of diagnosis. Table 1. Number of cases of melioidosis at Maharaj Nakorn Chiang Mai Hospital classified according to the onset and severity of the disease. Classification Onset Acute Subacute Chronic Disseminated septicemic melioidosis 5 (19.2%) 4 (15.4%) 3 (11.5%) Non-disseminated septicemic melioidosis 1 (3.9%) 7 (26.9%) 2 (7.7%) as subacute if the patient presented within 7-30 days of the first symptom, and as chronic if presented one month or more after the first symptom. The severity of the disease was classified as disseminated septicemic melioidosis, non-disseminated septicemic melioidosis, or localized infection according to the guidelines of the Infectious Disease Association of Thailand. 9 In our study, seven patients (26.8%), 13 (49.9%), and six (23.1%) had acute, subacute, and chronic onset of the disease, respectively. According to the severity of the disease, 12 patients (46%), 10 (38.6%), and four (15.4%) had disseminated septicemic melioidosis, nondisseminated septicemic, and localized melioidosis, respectively (Table 1). In 13 patients, the site of the infection was in the lungs. It was in the joints in four patients. Three patients each had the infection in the liver, spleen, and skin. Two had infection of the pleural cavity, and one patient each had infection of the meninges, brain, and paranasal sinus. Four patients had infection at more than one site. One had the infection of the skin, lungs, and meninges. The other three had infection in the joint and spleen, liver and lungs, and spleen and lungs. The laboratory data of the patients at admission are shown in Table 2. At Maharaj Nakorn Chiang Mai Hospital, an indirect hemagglutination (IHA) antibody titer against B. pseudomallei of >1:256 is considered positive. The serum samples of 11 patients were tested by IHA. The results were positive in eight patients, with the IHA titers ranging from 1:256 to 1:8,192. The tests

48 J INFECT DIS ANTIMICROB AGENTS May-Aug. 2005 Table 2. Laboratory data (+standard deviation) of the patients with melioidosis at admission. Laboratory data All patients Disseminated Non-disseminated Localized (N=26) septicemia (N=12) septicemia (N=10) infection (N=4) Hemoglobin (g/dl) 10.3 + 2.2 * 10.5 + 2.7 10.3 + 1.9 * 9.9 + 1.3 White blood cells (/mm 3 ) 12,738 + 6,569 * 11,614 + 5,180 12,798 + 8,465 * 15,975 + 6,061 Platelets (/mm 3 ) 249,040 + 174,004 * 206,750 + 164,283 190,777 + 114,647 * 507,000 + 46,339 Blood glucose (mg/dl) 186.5 + 93.5 204.7 + 117.0 153.8 + 10.2 164 + 88.4 Blood urea nitrogen (mg/dl) 30.3 + 32.6 39.8 + 45.4 25.8 + 21.3 21.3 + 11.3 Serum creatinine (mg/dl) 1.9 + 1.7 2.3 + 2.3 1.6 + 0.9 1.8 + 1.5 Serum sodium (mmol/l) 133.2 + 10.2 134.9 + 10.1 132.7 + 11.8 129.5 + 3.5 Serum albumin (g/dl) 2.9 + 0.8 2.8 + 0.6 3.3 + 1.1 2.9 + 0.3 Serum AST (U/L) 160.4 + 240.5 237.4 + 330.9 86.4 + 103.8 88.3 + 59.8 Serum ALT (U/L) 76.3 + 80.1 70.9 + 57.9 74.1 + 108.7 76.3 + 75.7 Serum bilirubin (mg/dl) 1.9 + 1.7 1.9 + 1.4 1.9 + 2.3 1.6 + 1.2 * Excluding the value from one patient with acute myelogenous leukemia Aspartate aminotransferase Alanine aminotransferase were negative in the other three patients. Two of these three patients had another test performed one week after the first one. The results were also negative. The antibiotic treatment regimens in our patients are shown in Table 3. Eleven of the 15 patients who survived (73.3%) had received ceftazidime, which is the treatment of choice for melioidosis. There were four patients who survived despite no receiving of ceftazidime as part of the treatment regimen. Two patients had localized infection; one had septic arthritis and received cloxacillin and ceftriaxone, the other had lung abscess and received clindamycin and ceftriaxone. One patient who received ceftriaxone had subacute non-disseminated septicemic melioidosis. In the other case, the patient had subacute disseminated septicemic melioidosis, and was treated with cefotaxime and cotrimoxazole. Eleven of the 26 patients died, accounting for a case fatality rate of 42.3 percent. Nine of the 11 patients who died had the disseminated septicemic form of the disease. None of the four patients with localized melioidosis died. Table 4 shows the clinical and laboratory parameters in patients who survived, compared to those who died. The disseminated septicemic form of the disease was associated with poor prognosis of the patients (95% confidence interval of odd ratio of survival = 0.001-0.886). DISCUSSION In this study, we have reported a series of cases with melioidosis from an area in Thailand with lower incidence of the disease. All patients were from provinces in the upper north of Thailand. The majority of cases were male. The average age was 52.1 years and most cases were diagnosed near the end of the rainy season. This was similar to a report from northeastern Thailand where the incidence was higher in the rainy season. 10 It is the season when farmers work in the

Vol. 22 No. 2 Melioidosis in northern Thailand:- Chaiwarith R, et al. Table 3. Antibiotic treatment in patients with melioidosis according to the treatment outcome. Antibiotic(s) Patients who survived (N=15) Patients who died (N=11) Ceftazidime 11 5 Inappropriate drug(s) 3 6 Ceftriaxone 1 4 Ceftriaxone and clindamycin 1 0 Ceftriaxone and cloxacillin 1 1 Piperacillin and clindamycin 0 1 TMP/SMX * and Cefotaxime 1 0 * Trimethoprim and sulfamethoxazole (co-trimoxazole) Table 4. Comparison of clinical and laboratory parameters of patients with melioidosis at admission who survived and those who died. Characteristics Patients who survived (N=15) Patients who died (N=11) P value Age (years) 51.2 + 11.8 53.3 + 11.2 0.656 Acute onset 2/15 5/11 0.095 Disseminated septicemic melioidosis 3/15 9/11 0.002 Diabetes mellitus as underlying disease 6/15 2/11 0.395 Hemoglobin (g/dl) 10.0 + 2.3 10.3 + 2.8 0.767 White blood cells (/mm 3 ) 12,697.1 + 5,910.5 12,790.9 + 7,627.0 0.827 Platelets (/mm 3 ) 272,733 + 180,541 197,363 + 166,707 0.288 Blood glucose (mg/dl) 165.0 + 84.1 208.2 + 108.2 0.263 Serum creatinine (mg/dl) 1.6 + 1.0 2.6 + 2.5 0.149 Serum AST (U/L) 83.6 + 81.3 294.2 + 371.1 0.102 Serum ALT (U/L) 66.3 + 88.6 86.5 + 59.7 0.180 Serum bilirubin (mg/dl) 1.3 + 1.1 2.9 + 2.3 0.055 Serum albumin (g/dl) 3.2 + 0.7 2.6 + 0.9 0.127 Treatment with ceftazidime (number of cases) (%) 11 (73.3%) 5 (45.5%) 0.228 Length of hospital stay (days) Mean + SD 24.3 + 12.2 14.5 + 13.1 0.083 Median (range) 27 (4-44) 7 (3-34) Aspartate aminotransferase Alanine aminotransferase

50 J INFECT DIS ANTIMICROB AGENTS May-Aug. 2005 field and come into contact with the organism in the soil and water. In another report from Australia, there was also a higher incidence of melioidosis in the rainy season. 3 The majority of our patients had underlying medical conditions, most commonly diabetes mellitus. This was similar to report of 423 patients from northeastern Thailand 11 and another report from Australia 3 where the majority also had diabetes mellitus as the underlying medical condition. Diabetic patients had leukocytes with impaired phagocytosis and intracellular killing. 12 This may increase susceptibility to the disease. Other underlying conditions included chronic renal failure, renal calculi, malignancy, and glucocorticoid treatment. Interestingly, a high proportion of patients in the Australian series were chronic alcoholic. Chronic alcoholism had not been reported as underlying condition in Thai patients with melioidosis. 10,11 B. pseudomallei can infect any organ system of the body and thus has highly variable clinical manifestations. The onset of the disease can vary from acute to subacute or to chronic. The clinical spectrum can vary from disseminated to non-disseminated septicemic melioidosis, or to localized infection. Rare cases of patients who had B. pseudomallei bacteremia but who otherwise had a relatively benign clinical manifestation have been reported. 13 Thus, melioidosis has been called the great imitator by some authors. 14,15 In a summary of cases reported in Thailand up to 1989, Punyagupta reported that 44.6 percent of cases were of the disseminated septicemic form and 42.3 percent were localized infection. 9 In our study, 46.2 percent and 15.4 percent of cases were disseminated septicemic melioidosis and localized melioidosis, respectively. In a referral hospital like Maharaj Nakorn Chiang Mai Hospital, cases of localized infection may not be seen very often because they were usually cared for in the district or provincial hospitals. B. pseudomallei can be cultured from the blood and sputum in 42 percent and 30 percent of our cases, respectively. This is similar to those reported by Punyagupta. 9 The IHA titer for antibody titer against B. pseudomallei was positive in only 8 of 11 patients tested. Thus, in patients suspected of having melioidosis, the treatment decision should not depend on an IHA test. In addition, because melioidosis is a potentially fatal disease, one should not wait for positive culture identification of the organism before starting treatment of septicemic patients. The case fatality rate of disseminated septicemic melioidosis was 81.8 percent which was similar to the 87 percent reported by Punyakupta. 9 In two randomized control trials of the treatment of severe melioidosis, ceftazidime was found to reduce the mortality rate from 74 percent to 37 percent, and ceftazidime given with cotrimoxazole was found to reduce the mortality rate from 47 percent to 18.5 percent. 7,8 In our study, 11 of the 15 patients who survived had been treated with ceftazidime. The case fatality rate in our series was 42.3 percent. There were 4 patients who had not received ceftazidime but survived; one patient had septic arthritis and receive ceftriaxone and cloxacillin with intermittent arthrocenthesis. One patient had lung abscess and received ceftriaxone and clindamycin. The other two patients who had subacute septicemic melioidosis received ceftriaxone and cefotaxime with cotrimoxazole. All isolates from the first three patients were susceptible to ceftriaxone, and one isolate from the last patient was susceptible to cefotaxime and co-trimoxazole. These patients had a clinical response but no long-term outcome were available. For the patients who received ceftriaxone-based regimen, the fatality rate was 62.5 percent (5 of 8 patients) which was comparable to 71.0 percent in the previous report. 16 In our study, a risk factor associated with death was having the disseminated septicemic form of the disease. However, in a study by Chaowagul and col-

Vol. 22 No. 2 Melioidosis in northern Thailand:- Chaiwarith R, et al. leagues, unfavorable outcome was associated with a body temperation < 38 C, a low white blood cell count, high levels of aminotransferase, and a high serum bilirubin level. 17 However, our study has too small sample size to reliably conclude the risk factors of death. Further prospective study with a large sample size is needed. References 1. Currie BJ. Burkhoderia pseudomallei and Burkhoderia mallei: melioidosis and glanders. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett s Principles and Practice of Infectious Diseases. 6 th ed. Philadelphia: Chirchill Livingstone, 2005: 2622-32. 2. Leelarasamee A. Melioidosis in Southeast Asia. Acta Trop 2000;74:129-32. 3. Currie BJ, Fisher DA, Howard DM, et al. The epidemiology of melioidosis in Australia and Papua New Guinea. Acta Trop 2000;74:121-7. 4. Dance DA. Melioidosis as an emerging global problem. Acta Trop 2000;74:115-9. 5. Jittivej J, Busapavanich S, Chawanasai A. Melioidosis: report of 1 Thai case. Vithayasarn Senarak 1955;8:11-8. 6. Vuddhakul V, Tharavichitkul P, Na-ngam N, et al. Epidemiology of Burkholderia pseudomallei in Thailand. Am J Trop Med Hyg 1999;60:458-61. 7. White NJ, Dance DA, Chaowagul W, Wattanagoon Y, Wuthiekanun V, Pitakwatchara N. Halving of mortality of severe melioidosis by ceftazidime. Lancet 1989;2: 697-701. 8. Sookpranee M, Boonma P, Susaengrat W, Bhuripanyo K, Punyagupta S. Multicenter prospective randomized trial comparing ceftazidime plus co-trimoxazole with chloramphenicol plus doxycycline and co-trimoxazole for treatment of severe melioidosis. Antimicrob Agents Chemother 1992;36:158-62. 9. Punyagupta S. Melioidosis: review of 686 cases and presentation of a new clinical classification. In: Punyagupta S, Sirisanthana T, Stapatayavong B, eds. Melioidosis. Proceedings of National Workshop on Melioidosis. Bangkok: Bangkok Medical Publisher, 1989:217-29. 10. Suputtamongkol Y, Hall AJ, Dance DA, et al. The epidemiology of melioidosis in Ubon Ratchatani, northest Thailand. Int J Epidemiol 1994;23:1082-90. 11. Suputtamongkol Y, Chaowagul W, Chetchotisakd P, et al. Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis 1999;29:408-13. 12. Bagdade JD, Root RK, Bulker RJ. Impaired leukocyte function in patients with poorly controlled diabetes. Diabetes 1974;23:9-15. 13. Sirisanthana T, Tharavichitkul P, Preuksakorn S. Benign bacteremic melioidosis. In: Punyagupta S, Sirisanthana T, Stapatayavong B, eds. Melioidosis. Bangkok: Bangkok Medical Publisher, 1989:74-9 14. Yee KC, Lee MK, Chua CT, Phthucheary SDl. Meioidosis: the great mimicker report 10 cases from Malasia. J Trop Med Hyg 1988;91:249-54. 15. Poe RH, Vassallo CL, Domm BM. Melioiodosis: the remarkable imitator. Am Rev Respir Dis 1971; 104:427-31. 16. Chaowagul W, Simpson AJ, Suputtamongkol Y, White NJ. Empirical cephalosporin treatment of melioidosis. Clin Infect Dis 1999;28:1328. 17. Chaowagul W, White NJ, Dance DA, et al. Melioido-