Clinical Trials Logo

Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT00579956
Other study ID # OXTREC 018-06
Secondary ID
Status Recruiting
Phase N/A
First received December 18, 2007
Last updated June 3, 2008
Start date December 2007
Est. completion date September 2010

Study information

Verified date August 2007
Source University of Oxford
Contact Wirongrong Chierakul, MD
Phone 6689 1058571
Email kae@tropmedres.ac
Is FDA regulated No
Health authority United Kingdom: Research Ethics CommitteeThailand: Ministry of Public Health
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 750
Est. completion date September 2010
Est. primary completion date September 2010
Accepts healthy volunteers No
Gender Both
Age group 15 Years and older
Eligibility 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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment


Related Conditions & MeSH terms


Intervention

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.
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

Locations

Country Name City State
Thailand Sappasithiprasong Hospital Ubonratchathani Ubon
Thailand Udon Thani General Hospital Udon Thani

Sponsors (3)

Lead Sponsor Collaborator
University of Oxford Mahidol University, Wellcome Trust

Country where clinical trial is conducted

Thailand, 

Outcome

Type Measure Description Time frame Safety issue
Primary All cause mortality In hospital No
Secondary All cause mortality in patients culture positive for melioidosis In hospital No
Secondary Switch of antimicrobial therapy In hospital Yes
Secondary Adverse drug reactions 1 month Yes
Secondary Fever clearance time (time to body temperature of less than 37.5°C for at least 48 hours) In hospital No
Secondary Length of hospital stay months No
See also
  Status Clinical Trial Phase
Completed NCT04299412 - Diagnostic Accuracy of the DPP II Assay
Recruiting NCT06089668 - An Observational Study to Evaluate Clinical Characteristics of Adult Patients With Suspected or Confirmed Melioidosis
Completed NCT03528265 - Adapting LFI for Melioidosis
Completed NCT05105035 - Oral ARV-1801 Given in Combination With Intravenous Ceftazidime or Meropenem for Treatment of Melioidosis in Hospitalized Patients Phase 2
Completed NCT01766830 - Rapid Diagnostic Tests and Clinical/Laboratory Predictors of Tropical Diseases In Patients With Persistent Fever in Cambodia, Nepal, Democratic Republic of the Congo and Sudan (NIDIAG-Fever) N/A
Recruiting NCT03048513 - Clinical Presentation of Melioidosis in Head and Neck Region N/A
Completed NCT02668406 - Study to Obtain Blood and Voided Urine Samples to Improve the Diagnosis of Melioidosis
Completed NCT01420341 - Co-trimoxazole as Maintenance Therapy for Melioidosis Phase 4
Completed NCT02089152 - A Single-blind Stepped Wedge Cluster Randomized Controlled Behaviour Change Trial to Determine Effectiveness of Prevention Programme of Melioidosis in Diabetics in Ubon Ratchathani, Northeast Thailand N/A