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 ~ Introduction
 ~ Case Report
 ~ Discussion
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  Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 36  |  Issue : 4  |  Page : 597-599
 

A case of septicaemic melioidosis: Utility of therapeutic drug monitoring and high-dose meropenem in successful management


1 Department of General Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Clinical Pharmacology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication18-Mar-2019

Correspondence Address:
Dr. Ramya Iyyadurai
Department of General Medicine Unit V, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_18_433

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 ~ Abstract 

Melioidosis is an emerging infectious disease of major public health importance. We describe a patient who presented with septicaemic melioidosis with multi-organ dysfunction. He had only marginal response on standard doses of meropenem. Therapeutic drug monitoring (TDM) revealed suboptimal concentration of meropenem following which drug dose was increased, with which he showed rapid clinical improvement and microbiological clearance. Melioidosis presents with multisystem involvement with disseminated abscess, standard dosing of meropenem may not be sufficient in achieving therapeutic levels and TDM with increased dosing in these critically ill patients will improve outcome.


Keywords: Burkholderia pseudomallei, melioidosis, meropenem, therapeutic drug monitoring


How to cite this article:
Gunasekaran K, Amladi A, Mathew SK, Miraclin T A, Iyyadurai R. A case of septicaemic melioidosis: Utility of therapeutic drug monitoring and high-dose meropenem in successful management. Indian J Med Microbiol 2018;36:597-9

How to cite this URL:
Gunasekaran K, Amladi A, Mathew SK, Miraclin T A, Iyyadurai R. A case of septicaemic melioidosis: Utility of therapeutic drug monitoring and high-dose meropenem in successful management. Indian J Med Microbiol [serial online] 2018 [cited 2019 May 21];36:597-9. Available from: http://www.ijmm.org/text.asp?2018/36/4/597/254399



 ~ Introduction Top


Melioidosis, caused by Gram-negative bacteria Burkholderia pseudomallei, is an important cause of sepsis in Southeast Asia and other tropical countries.[1] The typical hosts are either directly exposed to soil or those with underlying risk factors such as alcohol dependence, cirrhosis, diabetes, thalassaemia, renal disease or any form of systemic immunosuppression.[2] Clinical infection presents as a spectrum ranging from febrile illness to septicaemic disease as well as localised infection, with characteristic abscess formation.[1] Bacteraemia at admission occurs in 40%–60% of the cases, septic shock in around 20% and pneumonia is the presenting illness in over 50% of all cases.[3] Mortality rates are reported to be as high as 40%. Culture isolation of B. pseudomallei is the current diagnostic gold standard.[1] Therapeutic drug monitoring (TDM) and achievement of meropenem trough concentrations, five times above minimum inhibitory concentration (MIC), have shown to improve clinical outcome.[4]


 ~ Case Report Top


A 40-year-old gentleman presented with a history of prolonged febrile illness for 3 weeks, associated with cough and expectoration and worsening breathing difficulty with altered sensorium for 1 week. Clinical examination revealed features of systemic inflammatory response syndrome with low sensorium (GCS– E4M5V3-12/15). Systemic examination revealed coarse crackles in left mammary, infra-axillary and infra-scapular regions and mild hepatosplenomegaly. Investigations revealed haemoglobin of 14.4 gm%, total white blood cell count of 5800/mm 3 with left shift and platelet count of 35,000/mm 3. His random blood sugar was recorded as high (>500 mg/dl) with urine ketones being positive. His glycosylated haemoglobin was 13.5 gm%. His serum creatinine was 0.88 mg% and urea was 35 mg% with evidence of transaminitis (SGOT – 61 U/l, SGPT– 32 U/l and alkaline phosphatase – 152 U/l). Blood cultures isolated B. pseudomallei which was susceptible to ceftazidime (MIC – 1 mcg/ml), co-trimoxazole (MIC – 1.5 mcg/ml), imipenem (MIC – 0.25 mcg/ml), doxycycline (MIC – 0.75 mcg/ml) and meropenem (MIC – 0.75 mcg/ml). Chest radiography revealed left upper lobe and lingular consolidation [Figure 1]. Computed tomography of brain was normal and examination of cerebrospinal fluid was normal. Imaging of abdomen showed multiloculated visceral abscesses in the liver, spleen and kidneys. Bone scan revealed osseoarticular involvement, with focus in lumbar vertebra and the sacroiliac joint. He progressed to develop haemodynamic decompensation and acute respiratory distress syndrome. He was transferred to the intensive care unit and was initiated on mechanical ventilation and inotropic supports. He was initiated on intravenous meropenem 1 g Q8 h as a 3 h infusion and co-trimoxazole Q12 h. However, he continued to be bacteraemic 1 week after the initiation of intravenous antibiotic at the recommended doses. The meropenem trough level was assessed and was found to be 1.1 mcg/ml (therapeutic range – four times MIC for the organism). Hence, the doses of meropenem were escalated with a bolus of 2 g intravenously followed by 2 g every 8th hourly as 3 h infusion, subsequent to which he improved clinically and achieved culture conversion in 48 h. His glycaemic status was optimised and was initiated on maintenance therapy with ceftazidime and trimethoprim-sulphamethoxazole. He improved clinically and was discharged.
Figure 1: Chest radiography showing left upper lobe consolidation

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 ~ Discussion Top


Management of melioidosis is challenging in view of the organism being intrinsically resistant to multiple antibacterial agents and the predilection to form deep-seated abscesses and osseous involvement. International Consensus Recommendations published in 2010 indicate ceftazidime as the drug of choice in acute phase among patients with no complications.[5] Among patients with neuromelioidosis and bacteraemic illness, meropenem is the standard of care. This is followed by oral eradication phase consisting of trimethoprim-sulphamethoxazole or amoxicillin-clavulanate.

Antimicrobial therapy using meropenem may not yield the desired response despite adhering to standardised dosing regimens in critically ill patients because of fluctuations in meropenem pharmacokinetics (PKs) during the course of management of the patient. This makes achievement of target concentrations of meropenem difficult due to variations in underlying pathophysiological conditions.[6] TDM is currently being used for antibiotic dose optimisation to improve attainment of PK/pharmacodynamic targets and outcomes of severe infections in the critically ill.[7] The changes in the volume of distribution (Vd) and drug clearance are the most common reasons for subtherapeutic dosing as well as dose-related toxicity.[8] In a study on the PKs of meropenem in critically ill patients, extended regimens of meropenem in combination with higher dosage were preferable for treating infections caused by bacteria with higher MICs.[9] Meropenem has time-dependent bactericidal property with the percentage of time; the drug concentrations are above MIC (%T>MIC) deciding the therapeutic response.[10],[11] In critically ill patients, keeping a target concentration of five times above MIC of the organism may improve the clinical outcome.[10] The MIC50 and MIC90 for B. pseudomallei isolate over 10-year period (n-203) reveal high susceptibility to carbapenems [Table 1]. However, the conventional dosing regimen failed to attain the therapeutic range (five times above MIC), this could predispose to the development of antimicrobial resistance.
Table 1: Average minimal inhibitory concentration 50 and minimal inhibitory concentration 90 profile for patients (n=203) with Burkholderia pseudomallei

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In our patient, TDM on standard drug dosing regimen had led to change in the dosing regimen and further to a favourable clinical as well as bacteriological response. The limitation in this particular case was the lack of continuous drug monitoring following dose escalation, rather clinical and microbiological response was used to guide therapy. Among patients with septicaemic melioidosis, use of high-dose meropenem (2 g 8th hourly as 3 h infusion) in combination with TDM might yield better results.


 ~ Conclusion Top


This case reiterates the importance of TDM of meropenem and the need for higher drug dosing in critically ill patients with septicaemic melioidosis, especially in those patients with deep-seated visceral abscesses, endovascular and osteoarticular involvement.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initial will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 ~ References Top

1.
White NJ. Melioidosis. Lancet 2003;361:1715-22.  Back to cited text no. 1
    
2.
Currie BJ. Melioidosis: Evolving concepts in epidemiology, pathogenesis, and treatment. Semin Respir Crit Care Med 2015;36:111-25.  Back to cited text no. 2
    
3.
Vidyalakshmi K, Lipika S, Vishal S, Damodar S, Chakrapani M. Emerging clinico-epidemiological trends in melioidosis: Analysis of 95 cases from Western Coastal India. Int J Infect Dis 2012;16:e491-7.  Back to cited text no. 3
    
4.
Pea F, Della Siega P, Cojutti P, Sartor A, Crapis M, Scarparo C, et al. Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing Klebsiella pneumoniae? Int J Antimicrob Agents 2017;49:255-8.  Back to cited text no. 4
    
5.
Wuthiekanun V, Peacock SJ. Management of melioidosis. Expert Rev Anti Infect Ther 2006;4:445-55.  Back to cited text no. 5
    
6.
Udy AA, Roberts JA, Lipman J. Clinical implications of antibiotic pharmacokinetic principles in the critically ill. Intensive Care Med 2013;39:2070-82.  Back to cited text no. 6
    
7.
Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: A review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005;44:1009-34.  Back to cited text no. 7
    
8.
Wong G, Sime FB, Lipman J, Roberts JA. How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? BMC Infect Dis 2014;14:288.  Back to cited text no. 8
    
9.
Mathew SK, Mathew BS, Neely MN, Naik GS, Prabha R, Jacob GG, et al. A nonparametric pharmacokinetic approach to determine the optimal dosing regimen for 30-minute and 3-hour meropenem infusions in critically ill patients. Ther Drug Monit 2016;38:593-9.  Back to cited text no. 9
    
10.
Li C, Du X, Kuti JL, Nicolau DP. Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob Agents Chemother 2007;51:1725-30.  Back to cited text no. 10
    
11.
Nicolau DP. Pharmacokinetic and pharmacodynamic properties of meropenem. Clin Infect Dis 2008;47 Suppl 1:S32-40.  Back to cited text no. 11
    


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