Melioidosis, also known as Whitmore disease, is caused by the bacterium Burkholderia pseudomallei, a motile, aerobic, non-spore-forming bacillus. The bacterium is known to thrive in tropical climates. However, the worldwide incidence of the disease appears to be increasing as a result of increased travel and epidemiological sophistication.  We report two patients who were diagnosed to have melioidosis, and the challenges faced in treating them.
Keywords: Drug resistance, melioidosis, meropenem
Melioidosis is a deadly disease with more than 50% mortality in the acute setting. In the two cases we have encountered, both patients were in vitro sensitive to meropenem and ceftazidime, but showed in vivo resistance. According to the Expert Rev Anti Infect Ther. 2010 March; 8(3) 325-338, 10-15% of patients relapse when antibiotic therapy is withdrawn. In our cases, there was clinical deterioration even on appropriate culture sensitive antibiotics. This article highlights the alarming situation of emerging drug resistance in melioidosis, which stresses the need for early diagnostic techniques and newer antibiotic regimens.
A 34-year-old male presented to the emergency room with high-grade continuous fever, associated with chills and rigors of 2 days’ duration. Three weeks prior, the patient had sustained a fracture of the right fifth toe in a road traffic accident and had undergone a K-Nail insertion. He was also diagnosed to have glioblastoma multiforme 2 years back and had undergone chemoradiation. At the time of admission, he was receiving steroids for the perilesional edema subsequent to chemoradiation and had drug induced hyperglycemia.
On physical examination, the patient was found to have tachycardia and tachypnea. Systemic examination was unremarkable. Investigations showed neutrophilic leukocytosis (total leukocyte counts 16,200/cu mm, 88% neutrophils) and elevated C-reactive protein (CRP) levels (44.89). Serum creatinine (1.5 mg/dL) and serum glutamic-pyruvic transaminase (SGPT) (115.9 mg/dL) levels were also elevated. The haemoglobin count, platelet count, and urine examination were normal. The serological markers for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C were negative, as was the malarial antigen. X-ray chest and electrocardiography (ECG) were also normal.
However, the blood culture was positive for Burkholderia pseudomallei and sensitive to meropenem, doxycycline, imipenem, levofloxacin, and ceftazidime. He was treated with ceftazidime for 14 days as a part of the intensive phase and with doxycycline as a part of the continuation phase. He improved clinically and was subsequently discharged. However, he was readmitted 5 days later with complaints of high-grade fever and breathlessness. X-ray chest was suggestive of bronchopneumonia. Repeat blood cultures were again positive for the growth of B. pseudomallei.
He was treated with meropenem for 2 weeks along with co-trimoxazole. Despite adequate antibiotic therapy with two first-line agents (meropenem and ceftazidime), the patient did not show good improvement. Repeat blood cultures after 2 weeks of treatment with meropenem still grew B. pseudomallei. The patient gradually deteriorated and eventually succumbed to his illness.
A 58-year-old male, a known case of type 2 diabetes mellitus, chronic kidney disease, and systemic hypertension for the past 20 years, presented at our hospital with a history of continuous fever for the past 3 weeks and pain over the left knee joint since 2 days. He had received multiple antibiotics from various hospitals. The left knee joint was tender and inflammatory signs were present. Systemic examination was unremarkable.
Investigations showed normocytic normochromic anemia (7.17 g% Hb), normal leukocyte counts (4,570/cu mm), and thrombocytopenia (1,20,000/cu mm). Erythrocyte sedimentation rate (ESR) (60 mm first hour) and CRP (80.6 ng/dL) levels were raised. Serum creatinine was 6.16 mg/dL, albumin 1.8 mg/dL, alkaline phosphatase 468 IU/L, and serum sodium 128 mEq/L. Serum potassium, corrected calcium, phosphorus, and uric acid were normal. ECG and x-ray chest were also normal. Urine and blood cultures were negative. A synovial fluid aspiration was done from the left knee joint, which revealed inflammatory cells. However, the synovial fluid cultures were negative. At the time of admission, the patient had already received 5 days of treatment with meropenem and had also received antituberculous therapy in view of suspicious granulomatous hepatitis.
We continued treatment with meropenem. Computed tomography (CT) chest and abdomen were done to rule out any occult abscesses in view of the high spiking fever. High-resolution CT (HRCT) chest was suggestive of a cavitatory lung disease [Figure 1]. The patient was also treated with antifungals and there was minimal improvement. Meropenem was stopped after 2 weeks. However, a few days later, the patient developed features of severe septicemia and had to be initiated on hemodialysis due to further worsening of renal failure. Repeat blood cultures were positive for B. pseudomallei, which was sensitive to carbapenems, ceftazidime, and co-trimoxazole. The patient was treated with ertapenem and co-trimoxazole, as he had already received meropenem for 2 weeks. However, the patient continued to deteriorate and eventually succumbed to his illness.
So, we had two patients with culture-proven melioidosis. The bacterium was in vitro sensitive to meropenem and ceftazidime, the currently recommended first-line agents for melioidosis. Both patients were treated with these drugs for the recommended duration. However, repeat blood cultures were still positive for B. pseudomallei and the patients did not show good clinical improvement. This forces us to consider that there could now be emerging in vivo resistant strains of this organism, and the treatment of the same would be extremely difficult, especially in the context of underlying immunosuppression.
Melioidosis is endemic in Southeast Asia and Northern Australia. It is an emerging infectious disease in India, as is evident from case reports from different parts of the country. B. pseudomallei is an environmental pathogen, affecting persons who are in regular contact with soil and water.
Infection can result from the following:
As more than 80% of patients with melioidosis have one or more risk factors for the disease, it has been suggested that melioidosis should be considered an opportunistic infection that is unlikely to have a fatal outcome in a previously healthy person, provided that the infection is diagnosed early and that appropriate antibiotic agents and intensive care resources are available. The risk factors for melioidosis include diabetes (present in 23-60% of patients), heavy alcohol use (in 12-39%), chronic pulmonary disease (in 12-27%), chronic renal disease (in 10-27%), thalassemia (in 7%), glucocorticoid therapy (in <5%), and cancer (in <5%). ,
The incubation period for melioidosis has been evaluated in a single published study, in which 25% of patients who recalled a specific event such as an injury had clinical manifestations 1-21 days (mean, 9 days) later.  Patients can present with a myriad of manifestations, which can vary from chronic debilitating illness to overwhelming septicemia. In a descriptive study involving 540 patients in tropical Australia over a 20-year period, the primary presenting feature was pneumonia (in 51% of patients), followed by genitourinary infection (in 14%), skin infection (in 13%), bacteremia without evident focus (in 11%), septic arthritis or osteomyelitis (in 4%), and neurologic involvement (in 3%). The remaining 4% of patients had no evident focus of infection.  Internal organ abscesses and secondary foci in the lungs, joints, or both are common. Therefore, a careful search for internal organ abscesses is recommended, such as with the use of CT or ultrasonography of the abdomen and pelvis. Both of our patients presented with similar clinical features.
A delay in diagnosis can be fatal, as empirical antibiotic regimens used for suspected bacterial sepsis often do not provide adequate coverage for B. pseudomallei.
A culture of B. pseudomallei from any clinical sample is the sine qua non for the diagnosis of melioidosis. Laboratory procedures for maximizing the culture and identification of B. pseudomallei have been developed, but a delay in the identification of B. pseudomallei or a misidentification as another species is not uncommon in laboratories that are unfamiliar with this organism.  Melioidosis has a notoriously protracted course; a cure is difficult without a prolonged course of appropriate antibiotics.
B. pseudomallei is inherently resistant to penicillin, ampicillin, first-generation and second-generation cephalosporins, gentamicin, tobramycin, streptomycin, and polymyxin. Of the newer antibiotics, ertapenem, tigecycline, and moxifloxacin have limited in vitro activity against clinical isolates of B. pseudomallei, and the minimum inhibitory concentration for doripenem is similar to that for meropenem. 
The treatment for melioidosis consists of an intensive phase of at least 10-14 days of ceftazidime, meropenem, or imipenem administered intravenously, followed by oral eradication therapy, usually with trimethoprim-sulfamethoxazole (TMP-SMX) or co-trimoxazole for 3-6 months. The current recommendation for the oral phase of therapy is TMP-SMX. 
We acknowledge the Departments of Microbiology and Radiology for providing excellent support in diagnostic evaluation.
Source of Support: None, Conflict of Interest: None