A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe Melioidosis
Information source: University of Oxford
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Melioidosis
Intervention: Meropenem (Drug); Ceftazidime (Drug)
Phase: N/A
Status: Recruiting
Sponsored by: University of Oxford Official(s) and/or principal investigator(s): Wirongrong Chierakul, MD, Principal Investigator, Affiliation: Mahidol University
Overall contact: Wirongrong Chierakul, MD, Phone: 6689 1058571, Email: kae@tropmedres.ac
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.
Clinical Details
Official title: A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe Melioidosis
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: All cause mortality
Secondary outcome: All cause mortality in patients culture positive for melioidosisSwitch of antimicrobial therapy Adverse drug reactions Fever clearance time (time to body temperature of less than 37.5°C for at least 48 hours) Length of hospital stay
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.
Eligibility
Minimum age: 15 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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.
Locations and Contacts
Wirongrong Chierakul, MD, Phone: 6689 1058571, Email: kae@tropmedres.ac
Udon Thani General Hospital, Udon Thani, Thailand; Recruiting Prapit Teparakkul, MD, Phone: 6681 8779864
Sappasithiprasong Hospital, Ubonratchathani, Ubon, Thailand; Recruiting Direk Limmathurotsakul, MD, Phone: 6681 6149551, Email: direk@tropmedres.ac
Additional Information
Starting date: December 2007
Last updated: June 3, 2008
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