Methods: We carried out a retrospective study of eight culture proven ... Internal Medicine, 5Consultant and G.I. Intensivist, Apollo Gleneagles Hospitals, Kolkata, ...
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Journal of The Association of Physicians of India ■ Vol. 64 ■ May 2016
Original Article
Melioidosis: Series of Eight Cases Ujjwayini Ray1, Soma Dutta2, Suresh Ramasubban3, Dhiman Sen4, Indrajeet Kumar Tiwary 5 Abstract
Editorial Viewpoint
Objectives: Melioidosis caused by the Gram-negative bacterium Burkholderia pseudomallei is a very serious infection and has been sporadically reported from the Indian subcontinent. This disease entity can have acute and chronic presentations involving different organ systems. The purpose of this study is to analyze the risk factors, clinical presentations, therapy and outcome of culture proven cases of melioidosis.
• Melioidosis is probably endemic in India or parts of India.
Methods: We carried out a retrospective study of eight culture proven cases of melioidosis at a tertiary care hospital in West Bengal. Results: In this series we have found that melioidosis presents with a variety of symptoms ranging from acute presentations in the form of fulminant septicaemia, multiple abscesses in internal organs, osteomyelitis to more chronic form of the infection masquerading as tuberculosis. Bone and joint involvement are particularly common. Diabetes mellitus and chronic alcoholism are significant risk factors. Conclusions: India or parts of India are possibly endemic areas for melioidosis. Lack of awareness and the diversity of its presentation are probably responsible for underdiagnosis and under reporting.
Introduction
M
elioidosis caused by the bacterium Burkholderia pseudomallei, is an important cause of sepsis in several tropical areas including South-East Asia and Northern Australia. In India it had been reported sporadically, mostly from large centers in the south. 1,2 But with better diagnostic facilities coming up and improved awar e n e ss t h e r e are m or e and more reports of melioidosis from the rest of India. 3 Melioidosis is not generally considered in the differential diagnosis of community acquired sepsis syndrome because of a low degree of suspicion and the similarity of its presentation w i t h a h o s t o f o t h e r i n f e c t i ve conditions. Here we present eight culture proven cases of melioidosis.
All of the patients were residents of the eastern part of India and had presented with a variety of clinical features of varying degrees of severity.
Cases Series Eight culture proven cases of melioidosis admitted and treated in the Apollo Gleneagles Hospitals, Kolkata were studied from the medical files for clinical features, investigational findings, treatment and outcome.
Case 1 A 71 year old diabetic patient
• Presentations are diverse, bone and joint involvement are particularly common. • D i a b e t e s i n t h e s i n g l e most common risk factor. • Melioidosis associ a t ed with high mortality and relapse. presented with history of high grade intermittent fever (Tmax 102°F) for 3 weeks and a gangrenous ulcer on the right foot for 1 month. He had been treated with various antibiotics (ciprofloxacin, chloramphenicol, and ceftriaxone) by local physicians but there was no remission of fever. He became extremely weak and bedridden. Detailed work up was done. Blood c u l t u r e r e ve a l e d g r o w t h o f B . pseudomallei. X ray of the foot lesion did not reveal any osteomyelitic changes. Administration of meropenem resulted in rapid clinical response and the patient was discharged after 2 weeks of antibiotic therapy with the advice to take cotrimoxazole for a further 6 months.
Case 2 A 32 year old male, a resident of Jharkhand, was admitted to our hospital with history of fever (Tmax 105°F) for last 4 weeks associated
Consultant Microbiologist, 2Registrar Microbiologist, 3Consultant Critical Care Medicine, 4Senior Consultant Internal Medicine, 5Consultant and G.I. Intensivist, Apollo Gleneagles Hospitals, Kolkata, West Bengal Received: 02.12.2014; Accepted: 09.01.2015 1
Journal of The Association of Physicians of India ■ Vol. 64 ■ May 2016
with left knee joint pain and swelling of the same duration. Imaging studies revealed osteomyelitic changes of the left knee joint with surrounding muscle abscess. The patient was initially treated with Piperacillin / Tazobactam, Amikacin and Linezolid. But his condition deteriorated and he became hypotensive and had to be transferred to the ICU. Blood culture collected at the time of a d m i s s i o n , s h o we d g r o w t h o f B. pseudomallei. Fasciotomy, pus drainage and bone decompression of the affected knee joint was done and thick pus was evacuated. The initial antibiotics were changed to imipenem. The pus from the knee lesion also showed growth of B. pseudomallei. The patient was managed in the intensive care unit with all supportive therapy but he succumbed to the infection after about 5 days of imipenem therapy
Case 3 A 29 years old diabetic male was admitted with complaints of high grade fever (Tmax 104°F) and altered sensorium for 5 days and pain and swelling of the right knee joint. Further examination and relevant investigations r e ve a l e d o s t e o m ye l i t i c l e s i o n s of the right knee and proximal tibia with overlying skin and soft tissue infection. The patient was advised antibiotic meropenem and teicoplanin. Arthotomy of right knee with decompression of proximal tibia was done and thick pus was evacuated. The pus sample and the blood culture collected at the time of admission showed growth of B. pseudomallei. Following isolation of B. pseudomallei the teicoplanin was replaced with cotrimoxazole. The patient continued to have low grade fever (Tmax 100°F) till day 6 of antibiotic therapy, following which he became afebrile. The meropenem was continued for 2 weeks and thereafter he was discharged with the advice to take cotrimoxazole and doxycycline. At follow up after 3 months, he was
doing well and his inflammatory parameters had subsided.
Case 4 A 51 years old male patient from Assam, diabetic for the past 8 years, presented to us with high grade fever with rigor, vomiting, oliguria, jaundice and pain and swelling over both ankles and feet. Further history revealed that he was suffering from high grade fever (Tmax 105°F) for one and a half months with progressive weight loss, for which he was treated in a local nursing home. But his condition deteriorated and he was brought to our hospital, for further management. The patient was admitted in the ICU and was immediately intubated, ventilated and put on pressor agents to maintain his vitals. Initially he was treated with antibiotics cefepime and clarithromycin. Blood culture collected at the time of admission showed growth of B. pseudomallei. Other relevant findings included bilateral fluffy alveolar opacities on chest X-ray. After isolation of B. pseudomallei, Cefepime was replaced with meropenem, but the patient’s condition worsened and he succumbed to the disease after 7 days in the hospital.
Case 5 A 57 years old male with poorly controlled diabetes (HBA1C 11%) presented to us with high grade f e ve r ( T m a x 1 0 2 ° F ) a n d c h i l l s for the past 10 days along with painful swelling of the shoulder and foot. He was unable to stand and move the right upper limb. Further history revealed that the patient was suffering from fever on and off for the last three months. Significant findings of the imaging studies revealed cavitary lesion in the left lung and multiple abscesses in the liver and spleen along with periportal and peripancreatic lymphadenopathy. Other significant findings included thromocytopenia. The
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patient was admitted in the ward and was administered meropenem and teicoplanin. His condition deteriorated and he required ionotropes and ventilatory support and was transferred to the ICU the next day. Blood culture collected at that time showed growth of B. pseudomallei. The patient continued to be febrile although his vitals improved and he was off ventilator and ionotropes after 4 days. Meropenem was continued for two weeks and he was discharged with the advice to take doxycycline for 6 months.
Case 6 A 33 years old patient of Type 2 diabetes mellitus from Jharkhand, presented to us with fever (Tmax 104°F) associated with pain and swelling of left knee joint for one week. Clinical examination revealed septic arthritis of the left knee and purulent fluid was aspirated from the affected knee.Arthrotomy wa s p e r f o r m e d t h e f o l l o w i n g day and drainage and thorough debridement of the joint cavity was done. Synovial fluid was sent for relevant investigations on both the occasions. Routine examination of the fluid was suggestive of pyogenic infection (Neutrophil 95%, Lymphocyte 5%). B. pseudomallei was isolated from both synovial fluid samples. Initially the patient wa s t r e a t e d w i t h i n t r a ve n o u s clindamycin and amoxycillin / clavulanate. Following isolation of B. pseudomallei, the antibiotics were replaced with ceftazidime. The patient’s symptoms started improving and he was apyrexial after 4 days of ceftazidime therapy. He was discharged with the advice to continue ceftazidime for a total of 2 weeks followed by oral cotrimoxazole for 6 months. The patient remained well following completion of treatment but after one year there was recurrence of joint pain and swelling and he was found to have a relapse following isolation of B. pseudomallei from the curetted material of the medullary
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Journal of The Association of Physicians of India ■ Vol. 64 ■ May 2016
Table 1: Demographic details, risk factors, blood picture and outcome of the eight culture proven cases of melioidosis Case Age Sex Residence Occupation Risk factors No. 1
71
2 3
32 29
4 5
51 57
6
33
7
55
8
57
M West Bengal M Jharkhand M West Bengal M Assam M West Bengal M Jharkhand M West Bengal M Tripura
Hb TC ESR (gm%) (/cumm) (mm) Presentation 7 17100 102
Retired DM serviceman Business Doctor DM
Outcome
Discharged
7 10.8
1500 12500
130 126
Death Discharged
Policeman DM, Alcoholism Business DM
9.5 9.2
34000 5740
124 103
Death Discharged
Site engineer Service
7.3
29870
135
DM, Alcoholism, 11.3 COPD DM, Chronic 7.8 renal disease
9800
102
Relapsed after 1 year Discharged
12000
140
Discharged
Business
DM, Alcoholism
cavity of the left distal femur.
Case 7 A 56 year old post operative case of left parietal osteomyelitis, presented to us with swelling and discharge from the surgical site. The patient had undergone left parietal craniotomy one year ago, with evacuation of pus and scraping of infective granulation tissue. Histopathological examination of the excised tissue had revealed granulomatous infection suggestive of tuberculosis for which he was advised antitubercular drugs ( AT D ) . T h e w o u n d d i s c h a r g e persisted despite regular dressing and even after completion of the ATD regimen. He was admitted again and wound debridement was done and the debrided material was sent for culture and sensitivity. This time the culture showed growth of B. pseudomallei. Following isolation of the organism, the patient was treated with Ceftazidime for two weeks and was advised to take co-trimoxazole subsequently for 6 months. During his follow up visit after 3 months, his wound had healed and there was no discharge.
Case 8 A 57 year old patient of diabetes mellitus and chronic kidney disease was admitted with history of high grade fever (Tmax 105 °F) and
chills for 15 days, associated with jaundice, nausea, vomiting and loss of appetite. USG of abdomen revealed focal splenic lesion and peri-splenic collection along with distal ileal stricture with left para-aortic and retroperitoneal lymphadenopathy. The perisplenic fluid was aspirated and sent for pyogenic and mycobacterial culture. A provisional diagnosis of abdominal tuberculosis was made and the patient was advised AT D i n i t i a l l y . T h e a s p i r a t e d perisplenic fluid showed growth of B. pseudomallei. The ATD was then discontinued and meropenem was administered for 2 weeks. He became afebrile and his symptoms improved and he was discharged with the advice to take doxycyline. Summary of the eight culture proven cases are shown in Table 1. All the patients were male patients. The age ranged from 29-71 years, the median age being 53 years. Six patients (75%) presented acutely with disseminated disease while 2 patients had localized disease in the form of septic arthritis and chronic osteomyelitis. Four patients (50%) had bone and joint involvement. Diabetes mellitus was the single most common risk factor in that 7 out of the 8 patients (87.5%) had diabetes mellitus. Three patients (37.5%) had history of chronic alcoholism. All the patients had high ESR (>100 mm at 1 st hour ) at
Fig. 1: Colonies of Burkholderia pseudomallei in Mac Conkey agar showing a wrinkled metallic appearance
presentation. Two of the patients (25%) died due to fulminant sepsis. One patient had a relapse after one year. The rest 5 patients did well at follow up.
Discussion Melioidosis, also known as Whitmore’s Disease, is an infectious disease caused by gram negative, oxidase positive bacilli Burkholderia pseudomallei. Burkholderia pseudomallei is a non-fastidious bacteria which can grow on a variety of ordinary culture media (such as blood agar, McConkey agar ) producing wrinkled colonies with metallic appearance (Figure 1). In the laboratory it can be confused with Pseudomonas species. The pattern of antibiotic susceptibility provides clue to its identification. The majority of B. pseudomallei isolates are intrinsically resistant to all Aminoglycosides (via an efflux pump mechanism), 4 but sensitive to Co-amoxiclav. 5 This pattern of resistance almost never occurs in P. aeruginosa and is helpful in identification (Figure 2). It is intrinsically resistant to Polymyxin B (PB). Carbapenems like Imipenem (IPM) and Ceftazidime (CAZ) have good sensitivity. All the B. pseudomallei strains isolated by us exhibited this typical antibiogram. Unfortunately, it has been shown in Sarawak, Borneo, that the majority of strains there are susceptible to Aminoglycosides and Macrolides, which means that conventional recommendations for isolation and identification do not apply in certain cases. 6 B. pseudomallei is also intrinsically resistant to Polymyxin g roup of drug s . Thus unusual
Journal of The Association of Physicians of India ■ Vol. 64 ■ May 2016
Fig. 2: The majority of B. pseudomallei isolates are intrinsically resistant to all aminoglycosides (AK – Amikacin, GEN Gentamycin), but sensitive to co-amoxiclav (AMC)
resistance patterns in Pseudomonas sp. should serve as an alert for performing further biochemical tests. Identification by automated systems such as VITEK 1 and Mini API give reliable results. 7,8 Infection by B. pseudomallei can present acutely as septicaemia or may present as chronic indolent abscesses. Melioidosis is an important cause of sepsis in several tropical areas including Southeast Asia and Northern Australia. In India, multiple cases have been reported mostly from the southern part. Sporadic cases have been reported from the eastern p a r t . 9,10 A r e c e n t s t u d y f r o m Chennai has reported 32 cases of which 20 patients are residents of eastern India.3 In this series we have reported cases who are residents of different parts of eastern India such as Assam, West Bengal, Tripura and Jharkhand. This shows that melioidosis is prevalent in this part of the country as well. Melioidosis presents with wide range of signs and symptoms that can be mistaken for other diseases such as tuberculosis and pneumonia. That is why it is referred to as the great mimicker as it can cause almost any symptoms. It has been widely reported in the literature that pneumonia is the most common manifestation of melioidosis. The clinical features of melioidosis are wide
ranging varying from septicaemia, pneumonia, abscesses in internal organs, parotitis, septic arthritis a n d o s t e o m y e l i t i s . 11 H o w e v e r differences in clinical features have been observed in different geographical areas. There is high incidence of genitourinary infection in Australian patients and suppurative parotitis, which is not reported from Australia is prevalent in Thai children. In our series 50% (4/8) of patients had bone and joint involvement that required surgical debridement. Bone and joint involvement are well recognized, but relatively less common presentation of melioidosis. A high index of suspicion and microbiological confirmation is required since this necessitates prolonged courses of specific antibiotic therapy. Two studies have shown that clinical presentation and outcome may depend on the strain type. In one of the studies certain ribotypes appeared to be associated with a higher mortality or risk of relapse.12 A second small study (n = 18) using multilocus enzyme electrophoresis and RAPD analysis suggested that soft tissue infections were restricted to one cluster and respiratory and neurological infections were seen in another. 13 We feel that strains from this part of the country may have a predilection for soft tissue, bones and joints, although studies involving more number of cases are required to establish this fact. Sub-acute and chronic forms of melioidosis often mimic tuberculosis. 14 In our series, two of the eight cases (7 and 8) were initially diagnosed and treated as tuberculosis on the basis of radiological and histopathological reports. But after isolation of Burkholderia pseudomallei from culture specimens and after institution of appropriate antibiotics in place of anti tubercular drugs, there was rapid subsidence of signs and symptoms. Since chronic melioidosis closely mimics tuberculosis, it has also
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been referred to as “Vietnamese tuberculosis”. 15 India being an endemic area for tuberculosis, many of the chronic cases may be misdiagnosed as tuberculosis and erroneously treated with anti tubercular drugs. Diabetes has been recognized as an important risk factor for acquiring this infection. Diabetes mellitus results in impaired chemotaxis, phagocytosis, oxidative burst, and killing activity of granulocytes as a result of which, B. pseudomallei is able to survive and multiply within phagocytes 16,17 Other comorbidities recognized as risk factors include alcoholism, chronic kidney disease and chronic granulomatous disease. 17 In our study all patients except one was diabetic at the time of presentation. Three of the patients had history of chronic alcohol abuse and one patient had chronic renal disease. It has been suggested that B. pseudomallei enters the human body either through inhalation, ingestion or inoculation. But in our case series we have found bone and joint involvement more common than other presentations and so we feel that inoculation may be the most common mode of acquiring this infection. T h e a va i l a b l e a n t i m i c r o b i a l agents for treating B. pseudomallei are limited. B. pseudomallei exhibits resistance to different groups of antibiotics, including several third-generation cephalosporins, penicillins, rifamycins, and aminoglycosides. In addition, its relative resistance to quinolones and macrolides limits therapeutic options. Ceftazidime, carbapenem antibiotics (imipenem and meropenem), and to a lesser degree amoxicillin-clavulanate remain the backbone of current initial treatment. Resistance to these antimicrobial agents was not observed in 170 isolates from the Darwin prospective study, and ceftazidime resistance emerged on
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therapy in only one patient. 18 In our series 5 patients were treated with carbapenem antibiotics in the intensive phase and the rest three with ceftazidime. It has been suggested that carbapenem antibiotics may have an advantage over ceftazidime since there is less endotoxin released by dying bacteria during Imipenem t r e a t m e n t , 19 a n d t h e m i n i m u m inhibitory concentration for Imipenem is lower than that of ceftazidime. Also important is the fact that carbapenems are effective against ESBL producing strains. But properly planned clinical trials are required to support or refute this contention. Without access to appropriate antibiotics (principally ceftazidime or carbapenems), the septicemic form of melioidosis has a mortality rate that exceeds 90%. 20 With appropriate antibiotics, the mortality rate is about 10% for uncomplicated cases but up to 80% for cases with bacteraemia or severe sepsis. 21 Mortality is also high for patients who receive inappropriate antibiotics or delayed appropriate antibiotics. 22 In our series, two of the patients with septicaemic melioidosis succumbed despite adequate aetiological diagnosis, appropriate antibiotics and good intensive care. In both these patients with acute melioidosis, the diagnosis was delayed by more than a month.
Conclusion Melioidosis is a serious and sometimes life threatening infection which seems to be prevalent in our country and is often not diagnosed due to lack of awareness on the part of clinicians and microbiologists. The presentation of this infection i s d i ve r s e a s we h a ve s e e n i n this case series. Diabetes mellitus is an important risk factor.
Involvement of bones and joints are not uncommon occurrences. The chronic form of this infection may be misdiagnosed as tuberculosis and treated erroneously. All oxidase positive non-fermenting bacilli with unusual susceptibility patterns should be further speciated. Melioidosis requires prolonged antibiotic therapy to affect a cure and prevent relapse, so awareness amongst clinicians and microbiologists is important in order to be able to diagnose and treat this infection effectively.
References 1.
Jesudason MV, Anbarasu A, John TJ. Septicemic melioidosis in a tertiary care hospital in south India. Indian J Med Res 2003; 117:119-21.
Microbiol 2003; 21:129–32. 10. Ray U, Sen D, Kar S. Septicaemic Melioidosis - A Case Report. J Assoc Physicians India 2009; 57:598-99. 11. Allen C. Cheng, Bart J. Currie. Melioidosis: Epidemiology Pathophysiology and Management. Clin Microbiol Rev 2005; 18:383-416. 12. Pi t t T L , Tr a k u l s o m b o o n S , D a n c e DA. Molecular phylogeny of Burkholderiapseudomallei. Acta Trop 2000; 74:181–85. 13. Norton R, Roberts B, Freeman M, et al. Characterisation and molecular typing of Burkholderiapseudomallei: are disease presentations of melioidosis clonally related? FEMS Immunol Med Microbiol 1998; 20:37–44. 14. Vidyalakshmi K, Chakrapani M, Shrikala B, et al. Tuberculosis mimicked by melioidosis. Int J Tuberc Lung Dis 2008; 12:1209-15.
2.
Saravu K, Vishwanath S, Kumar RS, et al. Melioidosis—a case series from south India. Trans R Soc Trop Med Hyg 2008; 102: 18-20.
15. Suntornsut P, Kasemsupat K, Silairatana S, et al. Prevalence of Melioidosis in Patients with Suspected Pulmonary Tuberculosis and Sputum Smear Negative for Acid-Fast Bacilli in Northeast Thailand. Am J Trop Med Hyg 2013; 89: 983–85.
3.
Gopalakrishnan R, Sureshkumar D, Thirunarayan MA, Ramasubramanian V. Melioidosis : An Emerging Infection in India. J Assoc Physicians India 2013; 61:612-14
16. Currie BJ, Fisher DA, Howard DM, et al. Endemic melioidosis in tropical northern Australia: a 10-year prospective study and review of the literature. Clin Infect Dis 2000; 31:981–86.
4.
Moore RA, DeShazer D, Reckseidler S, Weissman A, Woods DE. Efflux-mediated aminoglycoside and macrolide resistance in Burkholderiapseudomallei. Antimicrob Agents and Chemother 1999; 43:465–70.
17. Suputtamongkol Y, Chaowagul W, Chetchotisakd P, et al. Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis 1999; 29:408–13.
5.
Wuthiekanun V, Peacock SJ. Management of melioidosis. Expert Rev Anti Infect Ther 2006; 4:445–55.
6.
Podin Y, Sarovich DS, Price EP, et al. Burkholderia pseudomallei from Sarawak, Malaysian Borneo are predominantly susceptible to aminoglycosides and macrolides. Antimicrob Agents Chemother 2013; 55:1029–31.
18. J e n n e y AW, L u m G , F i s h e r D A , Currie BJ. Antibiotic susceptibility of Burkholderiapseudomallei from tropical northern Australia and implications for therapy of melioidosis. Int J Antimicrob Agents 2001; 17:109-13. 19. Simpson AJH, Opal SM, Angus BJ, et al. Differential antibiotic-induced endotoxin release in severe melioidosis. J Infect Dis 2000; 181:1014–19.
7.
Lowe P, Engler C, Norton R.Comparison of automated and nonautomated systems for identification of Burkholderia pseudomallei. J Clin Microbiol 2002; 40:4625–27.
20. Warner JM, Pelowa DB, Currie BJ, Hirst RG. Melioidosis in a rural community of Western Province, Papua New Guinea. Trans R Soc Trop Med Hyg 2007; 101:809-13.
8.
Amornchai P, Chierakul W, Wuthiekanun V, et al. Accuracy of Burkholderiapseudomallei identification using the API 20NE system and a latex agglutination test. J Clin Microbiol 2007; 45:3774–76.
21. White NJ. Melioidosis. Lancet 2003; 361:1715–22.
9.
Anuradha K, Meena AK, Lakshmi V. Isolation of Burkholderia pseudomallei from a case of septicaemia: Acase report. Indian J Med
22. C h a o w a g u l W , S i m p s o n A J , Suputtamongkol Y, White NJ. Empirical cephalosporin treatment of melioidosis. Clin Infect Dis 1999; 28:1328.
