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A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe Melioidosis (ATOM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00579956
Recruitment Status : Unknown
Verified August 2007 by University of Oxford.
Recruitment status was:  Recruiting
First Posted : December 24, 2007
Last Update Posted : June 4, 2008
Mahidol University
Wellcome Trust
Information provided by:
University of Oxford

Tracking Information
First Submitted Date  ICMJE December 18, 2007
First Posted Date  ICMJE December 24, 2007
Last Update Posted Date June 4, 2008
Study Start Date  ICMJE December 2007
Estimated Primary Completion Date September 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 18, 2007)
All cause mortality [ Time Frame: In hospital ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2007)
  • All cause mortality in patients culture positive for melioidosis [ Time Frame: In hospital ]
  • Switch of antimicrobial therapy [ Time Frame: In hospital ]
  • Adverse drug reactions [ Time Frame: 1 month ]
  • Fever clearance time (time to body temperature of less than 37.5°C for at least 48 hours) [ Time Frame: In hospital ]
  • Length of hospital stay [ Time Frame: months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe Melioidosis
Official Title  ICMJE A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe Melioidosis
Brief Summary Melioidosis, an infection caused by the bacterium Burkholderia pseudomallei, is a major cause of community-acquired septicaemia in northeast Thailand. Common manifestations include cavitating pneumonia, hepatic and splenic abscesses, and soft tissue and joint infections. Despite improvements in diagnostic procedures and treatment, the mortality of severe melioidosis remains unacceptably high - approximately 35% with currently used antibiotics (ceftazidime or co-amoxiclav). There is clear evidence that antibiotics can affect mortality; the use of ceftazidime rather than previous regimens (doxycycline + chloramphenicol + co-trimoxazole) led to a 50% reduction in mortality from 80% to 35%. However, the mortality in the first 48 hours has not been altered by any treatment regimen. A key question is whether alternative antibiotics could improve early outcome. The hypothesis tested is that meropenem is superior to ceftazidime in terms of mortality for the treatment of melioidosis.
Detailed Description Mortality rate of patients with severe melioidosis is still unacceptably high. Response to high dose parenteral ceftazidime treatment in survivors is also slow, as median time to abatement of fever is approximately 9 days. B. pseudomallei is susceptible to ceftazidime, imipenem, co-amoxiclav (Augmentin®), piperacillin and doxycycline, but unlike most other pseudomonads it is resistant to aminoglycosides, apart from kanamycin which has borderline activity. The fluoroquinolone compounds also have borderline activity. Two large published in-vitro studies have shown that the carbapenem group are the most active antibiotics against B. pseudomallei, with an MIC90 of 0.5 or 1.0 mg/L, and an MBC90 of 1 mg/L. We have tested the susceptibility to meropenem of 100 recently isolated strains of B. pseudomallei, all of which were assessed as susceptible (MIC90 = 0.5 mg/L; range 0.125-1 mg/L). Furthermore, 13 isolates in our collection assessed as resistant to ceftazidime were susceptible to meropenem. Using time-kill kinetic studies, ceftazidime did not show "significant" bactericidal activity whereas meropenem was bactericidal (99.9% kill) within 6 hours. Previous treatment trials have demonstrated the importance of the choice of antibiotic at the time of presentation. A study that compared a four-drug combination of chloramphenicol, doxycycline, and trimethoprimsulfamethoxazole (TMP-SMX) with ceftazidime alone demonstrated a 50% reduction in the mortality rate from 80% to 35%. Several previous randomized controlled trials have been conducted to determine whether the administration of alternative antimicrobial drugs are associated with further improvements in outcome. A comparison of TMP-SMX plus ceftazidime versus ceftazidime alone demonstrated that the addition of TMPSMX did not reduce the acute mortality rate. A previous study comparing ceftazidime and imipenem/cilastatin in the treatment of severe melioidosis was performed in Ubon Ratchathani between 1994 and 1997. This showed that "treatment failure" rate (a potentially subjective endpoint in this open-labelled trial) in the imipenem/cilastatin group was lower than in the ceftazidime group. Endotoxin release, believed to be important to the pathogenesis of severe sepsis, was also lower in the imipenem group than the ceftazidime group. No difference in mortality was observed, but this study was underpowered following early termination due to a lack of imipenem supply from the manufacturer. As a result, ceftazidime has remained the treatment of choice for melioidosis, but the question remains as to whether a carbapenem drug would be more effective. A second, sufficiently powered clinical trial would address this important question.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Melioidosis
Intervention  ICMJE
  • Drug: Meropenem
    Meropenem 1gm, diluted with 50ml normal saline solution IV every 8 hours for at least 10 days. The dose will be adjusted according to the creatinine clearance.
  • Drug: Ceftazidime
    Ceftazidime 120mg/kg/day divided into 3 equal doses (maximum dose 2 gram/dose), diluted with 50ml normal saline solution IV every 8 hours for at least 10 days The dose will be adjusted according to the plasma creatinine level
Study Arms  ICMJE
  • Experimental: Meropenem
    Intervention: Drug: Meropenem
  • Active Comparator: Ceftazidime
    Intervention: Drug: Ceftazidime
Publications * Foong YC, Tan M, Bradbury RS. Melioidosis: a review. Rural Remote Health. 2014;14(4):2763. Epub 2014 Oct 30. Review.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: December 18, 2007)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2010
Estimated Primary Completion Date September 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria (all criteria must be satisfied)

A. Community acquired sepsis, and melioidosis is suspected:

Suspected melioidosis (12): all of the following are defined as 'clinically probable' melioidosis

  • A history of frequent contact with soil or surface water in the endemic area
  • At least one of the following risk factors: diabetes mellitus, chronic renal failure or renal calculi, thalassaemia, aplastic anaemia or steroid abuse
  • An illness compatible with melioidosis, including the presence of sepsis, acute pneumonia, acute pyelonephritis, septic arthritis, parotid disease or skin or soft tissue infection, or
  • An evidence of intra-abdominal suppuration (hepatic or splenic abscesses) regardless of risk factors or exposure history

Sepsis: defined as patients who have Systemic Inflammatory Response Syndrome (SIRS) - two or more of the following, clinically ascribed to infection:

  • Fever: temperature >38°C or <36°C
  • Tachycardia: heart rate >90 beats/min
  • Tachypnoea:

    1. Respiratory rate >20 breaths/minute; or
    2. PaCO2 <32 mmHg; or
    3. Mechanical ventilation
  • White cell count >12,000 cells/mL or <4,000 cells/mL or >10% band forms B. Age > 14 years. C. Need hospitalisation and intravenous antibiotic administration. D. Willingness to participate in the study and written, informed consent obtained from the patient.

Exclusion Criteria (any one of the following):

A. Pregnant or lactating women. B. Known hypersensitivity to meropenem or ceftazidime. C. Previous isolate with known resistance to ceftazidime or meropenem. D. Patients not expected to remain in hospital for treatment. E. Patients with community-acquired sepsis with cultures positive for other organisms.

F. Patients treated with antibiotics active against B. pseudomallei (including ceftazidime, amoxicillin-clavulanate, meropenem) for this episode for greater than 24 hours.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Thailand
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00579956
Other Study ID Numbers  ICMJE OXTREC 018-06
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nick Day, Oxford University
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE
  • Mahidol University
  • Wellcome Trust
Investigators  ICMJE
Principal Investigator: Wirongrong Chierakul, MD Mahidol University
PRS Account University of Oxford
Verification Date August 2007

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP