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PubMed2000

Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis.

AIMS: Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta-lactam antibiotics for serious Gram-negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality of 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis. METHODS: Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg-1 8 hourly by bolus injection or 4 mg kg-1 h-1 by constant infusion following a 12 mg kg-1 priming dose to perform estimation of pharmacokinetic and pharmacodynamic parameters. RESULTS: Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l-1, giving a target concentration CT, of 8 mg l-1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half-lives of ceftazidime were 0.468 (0.241-0.573) l kg-1, 0.058 (0.005-0.159) l kg-1 h-1 and 7.74 (1.95-44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0. 71; P < 0.001) and there was no evidence of significant nonrenal clearance. CONCLUSIONS: Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure which is common in these patients is Clearance = k * creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg-1 (1. 9-4.6) and infusion rate I = 0.46 mg kg h-1 (0.04-1.3) (which equals 14.8 mg kg-1 day-1). A nomogram for adjustment in renal failure is given.

Adult↗

PubMed1998

Stability of strain genotypes of Burkholderia pseudomallei from patients with single and recurrent episodes of melioidosis.

The constancy of strain genotypes of multiple isolates of Burkholderia pseudomallei from 13 patients with melioidosis was examined by BamHI ribotyping and pulsed-field gel electrophoresis (PFGE) of XbaI digests of DNA. Seven of 8 patients with single episodes of melioidosis each yielded genetically identical isolates and only one of five patients with recurrent episodes was infected with a new strain clearly distinct from the original primary strain. Variation was observed in PFGE patterns of primary and relapse isolates of another patient but this was insufficient to define genetically distinct strains. We conclude that most patients with single or multiple episodes of melioidosis retain a single strain.

Burkholderia pseudomallei↗

PubMed2003

Relapsing melioidosis as cause of iliac mycotic aneurysm: an indigenous case in Taiwan.

Melioidosis, an infectious disease caused by Burkholderia pseudomallei, an aerobic gram-negative bacillus, is normally transmitted through skin wounds and contact with infected human beings and animals. Its primary source is rice paddy soil and stagnant water. Melioidosis manifesting as an arterial mycotic aneurysm is rare, and, to our knowledge, infected true and false aneurysms of the iliac artery have never been reported. We report the case of a patient without contact with the normal sources of infection in whom an iliac mycotic aneurysm was caused by relapsing melioidosis and treated with an extra-anatomic bypass graft.

Aged↗

PubMed2006

Cutaneous melioidosis in a Swedish tourist after the tsunami in 2004.

A tourist from Sweden developed cutaneous melioidosis after the tsunami in Thailand on 26 December 2004. Melioidosis is a severe, chronic infection which is endemic in Thailand and is caused by Burkholderia pseudomallei. Persons with traumatic injuries inflicted by the tsunami have increased risks of being infected by B. pseudomallei and melioidosis should be suspected if abscesses of the skin or inner organs develop in the months or years after the trauma.

Anti-Bacterial Agents↗

PubMed2003

Melioidosis presenting as spinal epidural abscess.

Central nervous system melioidosis is an unusual infection in humans. This article reports a case of melioidosis presenting as an acute spinal epidural abscess. A discussion of this case and its management together with a brief review of melioidosis of the central nervous system is presented.

Acute Disease↗

PubMed1958

Melioidosis: pathogenesis and immunity in mice and hamsters. I. Studies with virulent strains of Malleomyces pseudomallei.

The pathogenesis of acute respiratory melioidosis mice and hamsters is described. Inhaled organisms giving rise to lesions seemed to be first engulfed by the mononuclear alveolar phagocytes, but in less than 1 day polymorphonuclear cells made their appearance. In spite of this defense reaction, the bacteria continued to multiply and their products caused focal necrosis. These foci enlarged and gave rise to septicemia, toxemia, and eventually death, which usually occurred in 3 to 10 days depending on the dose. Melioidosis, is, therefore, an acute septicotoxemic disease resembling plague and anthrax in this respect. In hamsters the disease process developed more rapidly than in mice and death occurred sooner. The course of the disease in hamsters was sometimes complicated by intraglomerular deposits resembling "fibrinoid," which were similar to those of the generalized Shwartzman phenomenon. This phenomenon may have been an indirect cause of both the perifocal hemorrhage and the extremely large number of bacteria in some of the hamster lesions. When low infecting doses of organisms were employed, mice, but not hamsters, developed a chronic type of disease, lasting 2 to 8 weeks. This was characterized by large abscesses in the spleen or lung, marked proliferation of mononuclear phagocytes and plasma cells, and increased immunity against reinfection (about 40-fold against respiratory challenge). When mice and hamsters inhaled high infecting doses of organisms, a peracute disease resulted with death in 1 to 3 days. Increased numbers of bacteria were observed in the lesions, and the histological changes in the spleen resembled those following the intravenous injection of Malleomyces pseudomallei toxin or the intramuscular injection of large doses of cortisone. These changes were characterized by a swelling of the phagocytes of the white pulp with nuclear debris. The peracute, the acute, and the chronic forms of melioidosis in mice are similar to analogous clinical forms found in man.

Acute Disease↗

PubMed2000

Differential antibiotic-induced endotoxin release in severe melioidosis.

Severe melioidosis is a life-threatening, systemic bacterial infection caused by Burkholderia pseudomallei. A prospective, randomized treatment trial was conducted in northeast Thailand to compare ceftazidime (a penicillin-binding protein [PBP]-3-specific agent that causes release of large amounts of endotoxin in vitro) and imipenem (a PBP-2-specific agent that kills B. pseudomallei more rapidly but releases low amounts of endotoxin) in severe melioidosis over a 6-h time course after the first dose of antibiotic. Despite similar clinical, microbiological, endotoxin, and cytokine measures at study entry, ceftazidime-treated patients (n=34) had significantly greater systemic endotoxin (P<.001) than patients treated with imipenem (n=34) after the first dose of antibiotic. No overall difference in mortality was observed (35% in both groups [95% confidence interval, 20%-50%]). Differential antibiotic-induced endotoxin release is demonstrable in severe melioidosis. These differences in endotoxin release did not appear to have a significant impact on survival in this group of patients.

Adult↗

PubMed2001

Randomized, double-blind, controlled study of cefoperazone-sulbactam plus cotrimoxazole versus ceftazidime plus cotrimoxazole for the treatment of severe melioidosis.

We conducted a prospective randomized, double-blind, controlled study of cefoperazone-sulbactam (ratio, 1:1; cefoperazone 25 mg/kg/day) plus cotrimoxazole (trimethoprim-sulfamethoxazole [TMP-SMZ] at a ratio of 80:400; TMP, 8 mg/kg/day) versus ceftazidime (100 mg/kg/day) plus cotrimoxazole (TMP, 8 mg/kg/day) for the treatment of severe melioidosis. Of 219 patients enrolled in the study, 102 (47%) had culture-proven melioidosis. These patients were assigned randomly to 2 treatment groups, each with 50 patients (2 patients were excluded). Mortality rates were not significantly different between the 2 groups: 18% in the cefoperazone-sulbactam group versus 14% in the ceftazidime group. The crude difference in the mortality rate was 4%, but when adjusted for type of infection the difference was 0.9% (95% confidence interval, -3.6% to 5.4%; P = .696). The duration of defervescence and the bacteriological response of successfully treated patients were similar in both groups, and both treatment regimens were well tolerated. Cefoperazone-sulbactam plus cotrimoxazole might be used as an alternative to ceftazidime plus cotrimoxazole as treatment for severe melioidosis.

Adult↗

PubMed1989

Melioidosis: a major cause of community-acquired septicemia in northeastern Thailand.

In a prospective study of all patients with Pseudomonas pseudomallei infections admitted to a large provincial hospital in northeastern Thailand, 63 cases of septicemic melioidosis and 206 patients with other community-acquired septicemias were documented during a 1-y period. Apart from P. pseudomallei, the spectrum of bacteria isolated from blood cultures and the overall mortality (32%) were similar to those previously reported elsewhere. Death from septicemia was associated with failure to develop a leukocytosis or pyrexia over 38 degrees C, azotemia, hypoglycemia, and jaundice. Septicemic melioidosis presented mainly in the rainy season, occurred predominantly in rice farmers or their families, and was significantly associated with preexisting diabetes mellitus or renal failure (P = .03). Blood-borne pneumonia and visceral abscesses were common and the mortality was high (68%; P less than .001). The response to appropriate treatment was slow (median fever clearance time 5.5 d) and the median duration of hospital stay was 4 w. Septicemic melioidosis is a major cause of morbidity and mortality in northeast Thailand.

Diabetes Complications↗

PubMed2006

Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis.

OBJECTIVES: We conducted a prospective pharmacokinetic study of oral co-amoxiclav in patients with melioidosis to determine the optimal dosage and dosing interval in this potentially fatal infection. PATIENTS AND METHODS: Serial plasma concentrations were measured after administration of two 1 g tablets of Augmentin (1750 mg of amoxicillin and 250 mg of clavulanate) to 14 adult patients with melioidosis. Monte Carlo simulation was used to predict the concentration of each drug following multiple doses of co-amoxiclav at different dosages and dose intervals. The proportion of the dose-interval above MIC (T > MIC) was calculated from 10,000 simulated subject plasma concentration profiles together with chequerboard MIC data from 46 clinical isolates and four reference strains of Burkholderia pseudomallei. RESULTS: The median (range) observed maximum plasma concentrations of amoxicillin and clavulanate were 11.5 (3.3-40.2) mg/L and 5.1 (0.8-12.1) mg/L, respectively. The median (range) elimination half-lives were 94 (73-215) and 89 (57-140) min, respectively. Simulation indicated that co-amoxiclav 1750/250 mg given at 4, 6, 8 or 12 hourly dosing intervals would be associated with a T > MIC of < or = 50% in 0.7%, 2.8%, 8.6% and 33.2% of patients, respectively. Corresponding proportions for T > MIC of > or = 90% were 95.8%, 78.6%, 50.2% and 10.8%, respectively. CONCLUSIONS: The dosing interval for co-amoxiclav (750/250 mg) in melioidosis should not be greater than 6 h.

Adolescent↗

PubMed2004

Recent development in melioidosis.

PURPOSE OF REVIEW: Burkholderia pseudomallei, the causative agent of melioidosis and a potential biological weapon, is still unfamiliar in some areas where sporadic cases are being reported among travelers. This review highlights findings in 2002-2003 and is an extension of a recent review by Dance. RECENT FINDINGS: The allele profiles of B. pseudomallei are distinguishable from avirulent Burkholderia thailandensis, but Burkholderia mallei is a clone of B. pseudomallei. Capsule and a type III protein secretion apparatus enable B. pseudomallei to survive intracellular killing and facilitate intercellular spread. A strong antibody response to infection is useful for monitoring disease activity. A mutant that is auxotrophic in the branched chain amino acid biosynthetic pathway has been found to be attenuated and protective. A new selective media is useful for isolation from contaminated specimens and the environment. Molecular techniques have been developed to distinguish B. pseudomallei from B. thailandensis and B. mallei as well as for serological diagnosis. Classification of the clinical manifestation is proposed to facilitate global communication, and will be useful to compare the efficacies of new regimens and adjunctive immunomodulatory therapies, such as granulocyte colony-stimulating factor and activated protein C for septicemic melioidosis. SUMMARY: Study of pathogenesis and intracellular survival of B. pseudomallei is advancing and may lead to better methods of therapy and vaccine production. New antimicrobial agents and immunomodulators are being studied to shorten the duration of treatment in the acute and maintenance phases, reduce the high mortality rate in septicemic melioidosis, and prevent relapses.

Bacterial Vaccines↗

PubMed2001

Demonstration of different patterns of musculoskeletal, soft tissue and visceral involvement in melioidosis using 99m Tc stannous colloid white cell scanning.

Melioidosis is an infectious disease that can present with multiple foci of disease involvement. Assessment of disease extent can be difficult, especially in musculoskeletal, visceral and soft tissue infection. This study examined the usefulness of white cell scans in this condition. 99mTc stannous colloid white cell scanning was performed in 21 patients with culture-proven melioidosis. Scan results were compared with clinical assessment and correlated with other forms of imaging. White cell scans demonstrated all but one of the clinically apparent sites of musculoskeletal, visceral and other soft tissue infection. Unsuspected disseminated soft tissue lesions were seen in two patients, including femoral node uptake in both, and these patients subsequently presented with relapsing musculoskeletal disease. Unsuspected musculoskeletal disease was found in one patient. Clinically suspected musculoskeletal disease was accurately excluded by white cell scan in another patient. The results of white cell scanning were also examined in disease of other viscera. Renal and prostatic disease were visualized. Unsuspected parotid involvement was found in two patients. Only one of two spinal lesions was visualized. Pulmonary disease was not necessarily associated with abnormal uptake. White cell scanning is a quick and effective way of assessing the extent of musculoskeletal, visceral and soft tissue disease in melioidosis.

Adult↗

PubMed2006

Melioidosis.

PURPOSE OF REVIEW: Melioidosis is increasingly recognized around the world. Despite several decades of clinical research, the mortality rate for melioidosis remains high. This review focuses on studies that relate to patient management, including risk factors, diagnosis, treatment and prediction of the outcome. A brief summary of studies relating to genomics and genotyping, immunology and pathogenesis is provided. RECENT FINDINGS: Involvement in the tsunami of December 2004 is a risk factor for melioidosis, and risk may extend to individuals who were uninjured bystanders. Several standard microbiological techniques used to culture and identify Burkholderia pseudomallei have been evaluated. Polymerase chain reaction has been developed for bacterial identification, although limited evaluation has been performed in the clinical setting. Two trials of antimicrobial therapy provide evidence with which to refine existing treatment protocols. Inexpensive clinical and laboratory predictors for poor outcome have been described. Several putative vaccine candidates have been proposed and studied in animals, but no vaccine is on the immediate horizon. SUMMARY: None of the studies reviewed here report strategies that reduce mortality. A key area for future research is the identification of affordable interventions that lower the death rate, and are applicable to low-resource settings.

Bacterial Vaccines↗

PubMed2001

Distribution of immunoglobulin classes and IgG subclasses against a culture filtrate antigen of Burkholderia pseudomallei in melioidosis patients.

The class and subclass distribution of antibody response to the culture filtrate antigen (CFA) of Burkholderia pseudomallei was examined in the sera of 45 septicaemic and 17 localised melioidosis cases and 40 cases clinically suspected of melioidosis and the results were compared with those from high-risk and healthy control groups. The geometric mean titre index (GMTI) values for all classes and subclasses of immunoglobulins examined were higher for sera from the proven and clinically suspected melioidosis cases than for the control groups. However, the highest response in the three patient groups was that of IgG with GMTIs ranging from 219.4 to 291.6 and the lowest was for IgM with GMTIs of 22.5, 24.3 and 28.7. The IgA response was intermediate with GMTIs ranging from 119.2 to 170. The GMTIs were highest for IgG in septicaemic and localised infections and for IgA and IgM in localised infections. As regards IgG subclass distribution, IgG1 and IgG2 were the predominant subclasses produced against the CFA in contrast to IgG3 and IgG4, which were produced in low amounts. None of the sera from the control groups had any significant titres of antibodies.

Antibodies, Bacterial↗

PubMed2004

Evaluation of lipopolysaccharide and capsular polysaccharide as subunit vaccines against experimental melioidosis.

Burkholderia pseudomallei is the causative agent of melioidosis, which is a major cause of morbidity and mortality in endemic regions. Currently there is no human vaccine against melioidosis. In this study, LPS or capsular polysaccharide was used to immunize BALB/c mice. The different polysaccharide antigens induced antibody responses. Mice vaccinated with LPS developed predominantly IgM and IgG3 responses. Contrastingly, mice vaccinated with capsular polysaccharide developed a predominantly IgG2b response. After immunization, mice were challenged by the intra-peritoneal route and an increased mean time to death was observed compared with unvaccinated controls. Immunization with LPS provided an optimal protective response. Mice challenged by the aerosol route showed a small increase in the mean time to death compared with the unvaccinated controls. The passive transfer of antigen from immunized into naive mice provided protection against a subsequent challenge. This study is the first time antigens protective by active immunization have been identified and suggests that polysaccharides have potential as vaccine candidates against melioidosis.

Aerosols↗

PubMed1998

Prevalence of human melioidosis on Hainan Island in China.

Eight human cases of melioidosis were diagnosed at Hainan People's Hospital over a period of one year. Four of the cases were of septicemia form, while the rest were of chronic form with abscesses in different organs. All the isolates were intrinsically resistant to cefazolin, cefuroxime, and gentamicin, while being rather sensitive to ampicillin/sulbactam, ticarcillin/clavulanic acid, and imipenem. A serological survey of exotoxin antibodies at different farms showed that Xinglong was a farm seriously devastated by Burkholderia pseudomallei, while the mountainous farm of Licai had the lowest prevalence (P< 0.01). From the results of serological survey and melioidosis case distribution, it could be clearly seen that melioidosis predominantly exists in coastal plain regions around this island, where the altitude above sea-level is below 100 m, the annual rainfall is up to 2,300 mm and a rather warm climate in coldest months of December and January.

Adult↗

PubMed2000

Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis.

AIMS: Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta-lactam antibiotics for serious Gram-negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality over 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis. METHODS: Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg(-1) 8 hourly by bolus injection or 4 mg kg(-1) h(-1) by constant infusion following a 12 mg kg(-1) priming dose and pharmacokinetic and pharmacodynamic parameters were compared. RESULTS: Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l(-1), giving a minimum target concentration (4*MIC) of 8 mg l(-1). The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half-lives of ceftazidime were 0.468 (0.241-0. 573) l kg(-1), 0.058 (0.005-0.159) l kg(-1) h(-1) and 7.74 (1.95-44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0.71; P < 0.001) and there was no evidence of significant nonrenal clearance. CONCLUSIONS: Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure, which is common in patients with meliodosis is Clearance = k(*) creatinine clearance where k = 0.72. Calculation of a loading dose gives median (range) values of loading dose, DL of 18.7 mg kg(-1) (9.5-23) and infusion rate I = 3.5 mg k(-1) h(-1) (0.4-13) (which equals 84 mg kg(-1) day(-1)). A nomogram for adjustment in renal failure is given.

Adult↗

PubMed2004

Out of hospital treatment of patients with melioidosis using ceftazidime in 24 h elastomeric infusors, via peripherally inserted central catheters.

BACKGROUND: In the tropical north of the Northern Territory, Australia, 25-50 patients are admitted to Royal Darwin Hospital (RDH) each year with Burkholderia pseudomallei infection, or melioidosis. Treatment consists of initial intensive therapy with 2-4 weeks of intravenous antibiotics. Clinical improvement may occur early and patients often prefer to be managed out of hospital in the Hospital in the Home (HITH). OBJECTIVES: To evaluate safety and efficacy of HITH management of patients with melioidosis. METHODS: A prospective observational study of our standard management which consists of 24 h infusions of ceftazidime infused through a peripherally inserted central catheter (PICC) line, plus oral sulphamethoxazole trimethoprim. Treatment is administered in the home, which may be in Darwin, regional areas or remote communities, or in a self-care unit located in the hospital grounds. RESULTS: From February 1998 to December 2001 150 patients were admitted to RDH with culture confirmed B. pseudomallei infection. Of these, 73 patients were treated with 24 h infusions of ceftazidime, of which 70 patients were managed by HITH. Complications of treatment include a PICC line complication rate of 10.6/1000 days in situ. Nine patients had relapse or recrudescence of disease, nearly all as a result of poor adherence to subsequent oral eradication therapy, these patients were all re-treated successfully. One patient remains infected with B. pseudomallei. CONCLUSION: This clinical outcome study suggests that out of hospital management of melioidosis with 24 h infusions of ceftazidime via a PICC line is safe and effective.

Adolescent↗