Why is the response rate slow in ceftazidime therapy for melioidosis?

Puthucheary, S. D.; Sam, I‐Ching

doi:10.1586/eri.11.158

Cited by 4 publications

(3 citation statements)

References 12 publications

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“…Despite intensive antibiotic treatment, the mortality rates for melioidosis can be 40 to 50% in areas where the disease is endemic, and recurring disease occurs in 5 to 25% of cases ( 15 , 59 – 61 ). Granuloma-like abscesses formed during chronic melioidosis might provide a hypoxic environment ( 15 , 16 , 62 , 63 ), and bacteria that reside in hypoxic abscesses would not be targeted by ceftazidime treatment. Our results might suggest that ciprofloxacin or a combination therapy of ceftazidime and ciprofloxacin would be highly effective for the treatment of melioidosis, but previous studies have shown a variable efficacy for ciprofloxacin ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Bacterial Drug Tolerance under Clinical Conditions Is Governed by Anaerobic Adaptation but not Anaerobic Respiration

Hemsley

Luo

Andreae

et al. 2014

Antimicrob Agents Chemother

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Noninherited antibiotic resistance is a phenomenon whereby a subpopulation of genetically identical bacteria displays phenotypic tolerance to antibiotics. We show here that compared to Escherichia coli, the clinically relevant genus Burkholderia displays much higher levels of cells that tolerate ceftazidime. By measuring the dynamics of the formation of drug-tolerant cells under conditions that mimic in vivo infections, we show that in Burkholderia bacteria, oxygen levels affect the formation of these cells. The drug-tolerant cells are characterized by an anaerobic metabolic signature and can be eliminated by oxygenating the system or adding nitrate. The transcriptome profile suggests that these cells are not dormant persister cells and are likely to be drug tolerant as a consequence of the upregulation of anaerobic nitrate respiration, efflux pumps, β-lactamases, and stress response proteins. These findings have important implications for the treatment of chronic bacterial infections and the methodologies and conditions that are used to study drug-tolerant and persister cells in vitro.

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Section: Discussionmentioning

confidence: 99%

Bacterial Drug Tolerance under Clinical Conditions Is Governed by Anaerobic Adaptation but not Anaerobic Respiration

Hemsley

Luo

Andreae

et al. 2014

Antimicrob Agents Chemother

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“…Formation of biofilm has been proposed as a contributory factor in the occurrence of persistent infection in the host. Clinical response to antimicrobials is slow and recurrent disease is common [ 5 ]. Sawasdidoln et al [ 6 ] demonstrated that B. pseudomallei isolates which were sensitive to doxycycline, ceftazidime, imipenem and trimethoprim/sulfamethoxazole became resistant under conditions that promoted the formation of biofilm.…”

Section: Introductionmentioning

confidence: 99%

Global transcriptional analysis of Burkholderia pseudomallei high and low biofilm producers reveals insights into biofilm production and virulence

Chin

Hara

Ghazali³

et al. 2015

BMC Genomics

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BackgroundChronic bacterial infections occur as a result of the infecting pathogen’s ability to live within a biofilm, hence escaping the detrimental effects of antibiotics and the immune defense system. Burkholderia pseudomallei, a gram-negative facultative pathogen, is distinctive in its ability to survive within phagocytic and non-phagocytic cells, to persist in vivo for many years and subsequently leading to relapse as well as the development of chronic disease. The capacity to persist has been attributed to the pathogen’s ability to form biofilm. However, the underlying biology of B. pseudomallei biofilm development remains unresolved.ResultsWe utilised RNA-Sequencing to identify genes that contribute to B. pseudomallei biofilm phenotype. Transcriptome analysis of a high and low biofilm producer identified 563 differentially regulated genes, implying that expression of ~9.5 % of the total B. pseudomallei gene content was altered during biofilm formation. Genes involved in surface-associated motility, surface composition and cell wall biogenesis were over-expressed and probably play a role in the initial attachment of biofilms. Up-regulation of genes related to two component signal transduction systems and a denitrification enzyme pathway suggest that the B. pseudomallei high biofilm producer is able to sense the surrounding environmental conditions and regulate the production of extracellular polymeric substance matrix, a hallmark of microbial biofilm formation.ConclusionsThe transcriptome profile described here provides the first comprehensive view of genes that contribute to the biofilm phenotype in B. pseudomallei.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1692-0) contains supplementary material, which is available to authorized users.

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“…Thus, treatment of melioidosis is still solely dependent on a lengthy course of antibiotics. Nevertheless, B. pseudomallei is becoming increasingly resistant to a diverse group of antimicrobials including third generation cephalosporins whilst quinolones and aminoglycosides have no reliable effect (Puthucheary and Sam, 2012 ). For example, two important antibiotic candidates in melioidosis treatment are ceftazidime and amoxicillin-clavulanic acid and cases of resistance have been reported in recent years (Wuthiekanun et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Curcumin rescues Caenorhabditis elegans from a Burkholderia pseudomallei infection

Eng

Nathan

2015

Front. Microbiol.

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The tropical pathogen Burkholderia pseudomallei requires long-term parenteral antimicrobial treatment to eradicate the pathogen from an infected patient. However, the development of antibiotic resistance is emerging as a threat to this form of treatment. To meet the need for alternative therapeutics, we proposed a screen of natural products for compounds that do not kill the pathogen, but in turn, abrogate bacterial virulence. We suggest that the use of molecules or compounds that are non-bactericidal (bacteriostatic) will reduce or abolish the development of resistance by the pathogen. In this study, we adopted the established Caenorhabditis elegans-B. pseudomallei infection model to screen a collection of natural products for any that are able to extend the survival of B. pseudomallei infected worms. Of the 42 natural products screened, only curcumin significantly improved worm survival following infection whilst not affecting bacterial growth. This suggested that curcumin promoted B. pseudomallei-infected worm survival independent of pathogen killing. To validate that the protective effect of curcumin was directed toward the pathogen, bacteria were treated with curcumin prior to infection. Worms fed with curcumin-treated bacteria survived with a significantly extended mean-time-to-death (p < 0.0001) compared to the untreated control. In in vitro assays, curcumin reduced the activity of known virulence factors (lipase and protease) and biofilm formation. To determine if other bacterial genes were also regulated in the presence of curcumin, a genome-wide transcriptome analysis was performed on curcumin-treated pathogen. A number of genes involved in iron acquisition and transport as well as genes encoding hypothetical proteins were induced in the presence of curcumin. Thus, we propose that curcumin may attenuate B. pseudomallei by modulating the expression of a number of bacterial proteins including lipase and protease as well as biofilm formation whilst concomitantly regulating iron transport and other proteins of unknown function.

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Why is the response rate slow in ceftazidime therapy for melioidosis?

Cited by 4 publications

References 12 publications

Bacterial Drug Tolerance under Clinical Conditions Is Governed by Anaerobic Adaptation but not Anaerobic Respiration

Bacterial Drug Tolerance under Clinical Conditions Is Governed by Anaerobic Adaptation but not Anaerobic Respiration

Global transcriptional analysis of Burkholderia pseudomallei high and low biofilm producers reveals insights into biofilm production and virulence

Curcumin rescues Caenorhabditis elegans from a Burkholderia pseudomallei infection

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