Differential Antibiotic‐Induced Endotoxin Release in Severe Melioidosis

Simpson, Andrew J. H.; Opal, Steven M.; Angus, Brian; Prins, Jan M.; Palardy, John E.; Parejo, Nicolas A.; Chaowagul, Wipada; White, Nicholas J.

doi:10.1086/315306

Cited by 64 publications

(52 citation statements)

References 29 publications

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“…However, it is unclear what the in vivo significance is concerning the increased levels of release of endotoxin due to antibiotic-induced filamentation. A study examining the treatment of melioidosis with ceftazidime, which causes higher levels of release of endotoxin compared to that caused by imipenem, which causes lower levels of release, did not show any correlation between endotoxin release and disease prognosis (31). Yet, our finding that at 16 h filaments could induce an increase in TNF-␣ and IL-1␤ production independent of cell lysis and internalization suggests that filaments could potentially contribute to increased levels of inflammation in patients.…”

Section: Discussioncontrasting

confidence: 64%

“…Such enlargements were not seen in ofloxacin-or trimethoprim-induced filaments or untreated bacteria. Because increased levels of endotoxin production have been observed to be induced by both B. pseudomallei (31) and many other filamentous gram-negative bacteria (5,6,11,17) during antibiotic treatment for sepsis caused by gramnegative bacteria and because most of these antibiotics affect the bacterial cell wall through PBP 3, we think that the enlargement of the periplasmic space observed in ceftazidimeinduced filaments could be structural features resulting from increased levels of endotoxin production.…”

Section: Discussionmentioning

confidence: 94%

“…Present antibiotic therapy regimens for the treatment of melioidosis typically involve the ␤-lactam ceftazidime in various combinations with chloramphenicol, co-trimoxazole, doxycycline, and amoxicillin-potassium clavulanate (31). Some antibiotics on this list have been known to induce morphological changes in the bacteria, such as filamentation.…”

mentioning

confidence: 99%

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Modified Virulence of Antibiotic-Induced Burkholderia pseudomallei Filaments

Chen

Sun

Chua

et al. 2005

Antimicrob Agents Chemother

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Melioidosis is a life-threatening bacterial infection caused by Burkholderia pseudomallei. Some antibiotics used to treat melioidosis can induce filamentation in B. pseudomallei. Despite studies on the mechanism of virulence of the bacteria, the properties of B. pseudomallei filaments and their impact on virulence have not been investigated before. To understand the characteristics of antibiotic-induced filaments, we performed in vitro assays to compare several aspects of virulence between normal, nonfilamentous and filamentous B. pseudomallei. Normal, nonfilamentous B. pseudomallei could cause the lysis of monocytic cells, while filaments induced by sublethal concentrations of ceftazidime, ofloxacin, or trimethoprim show decreased lysis of monocytic cells, especially after prolonged antibiotic exposure. The motility of the filamentous bacteria was reduced compared to that of nonfilamentous bacteria. However, the filamentation was reversible when the antibiotics were removed, and the revertant bacteria recovered their motility and ability to lyse monocytic cells. Meanwhile, antibiotic resistance developed in revertant bacteria exposed to ceftazidime at the MIC. Our study highlights the danger of letting antibiotic concentration drop to the MIC or sub-MICs during antibiotic treatment of melioidosis. This could potentially give rise to a temporary reduction of bacterial virulence, only to result in bacteria that are equally virulent but more resistant to antibiotics, should the antibiotics be reduced or removed.

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Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 94%

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Modified Virulence of Antibiotic-Induced Burkholderia pseudomallei Filaments

Chen

Sun

Chua

et al. 2005

Antimicrob Agents Chemother

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“…No clinical tests of this hypothesis have been reported from studies of patients with brucellosis or typhoid fever, but inflammatory reactions due to antibioticinduced endotoxin release have been observed when treating local tissue infections due to bacteria that produce hexaacyl LPS (4, 103). In contrast, antibiotic treatment of patients with Burkholderia pseudomallei bacteremia increased endotoxin levels in plasma with no change in signs or symptoms (121).…”

Section: Limitations Possible Implicationsmentioning

confidence: 89%

Sensing Gram-Negative Bacterial Lipopolysaccharides: a Human Disease Determinant?

2008

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“…6). However, the difference in endotoxin release did not have a significant impact on survival in these patients (154).…”

Section: Relationship Between Proinflammatory Compound Concentration mentioning

confidence: 71%

Modulation of Release of Proinflammatory Bacterial Compounds by Antibacterials: Potential Impact on Course of Inflammation and Outcome in Sepsis and Meningitis

2002

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SUMMARY Several bacterial components (endotoxin, teichoic and lipoteichoic acids, peptidoglycan, DNA, and others) can induce or enhance inflammation and may be directly toxic for eukaryotic cells. Bactericidal antibiotics which inhibit bacterial protein synthesis release smaller quantities of proinflammatory/toxic bacterial compounds than Β-lactams and other cell wall-active drugs. Among the Β-lactams, compounds binding to penicillin-binding protein 2 (PBP-2) release smaller amounts of bacterial substances than antibacterials inhibiting PBP-3. Generally, high antibiotic concentrations (more than 10 times the MIC) induce the release of fewer bacterial proinflammatory/toxic compounds than concentrations close to the MIC. In several in vitro and in vivo systems, bacteria treated with protein synthesis inhibitors or Β-lactams inhibiting PBP-2 induce less inflammation than bacteria treated with PBP-3-active Β-lactams. In mouse models of Escherichia coli peritonitis sepsis and of Streptococcus pneumoniae meningitis, lower release of proinflammatory bacterial compounds was associated with reduced mortality. In conclusion, sufficient evidence for the validity of the concept of modulating the release of proinflammatory bacterial compounds by antibacterials has been accumulated in vitro and in animal experiments to justify clinical trials in sepsis and meningitis. A properly conducted study addressing the potential benefit of bacterial protein synthesis inhibitors versus Β-lactam antibiotics will require both strict selection and inclusion of a large number of patients. The benefit of this approach should be greatest in patients with a high bacterial load.

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Differential Antibiotic‐Induced Endotoxin Release in Severe Melioidosis

Cited by 64 publications

References 29 publications

Modified Virulence of Antibiotic-Induced Burkholderia pseudomallei Filaments

Modified Virulence of Antibiotic-Induced Burkholderia pseudomallei Filaments

Sensing Gram-Negative Bacterial Lipopolysaccharides: a Human Disease Determinant?

Modulation of Release of Proinflammatory Bacterial Compounds by Antibacterials: Potential Impact on Course of Inflammation and Outcome in Sepsis and Meningitis

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