Efficacy of Daptomycin against
            <i>Bacillus anthracis</i>
            in a Murine Model of Anthrax Spore Inhalation

Heine, Henry S.; Bassett, Jennifer; Miller, Loren M.; Purcell, Bret K.; Byrne, William R.

doi:10.1128/aac.00210-10

Cited by 18 publications

(14 citation statements)

References 18 publications

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“…Daptomycin efficacy has been demonstrated in models of hematogenous pneumonia induced by S. aureus (50,52) and pulmonary anthrax infections (53). The pathophysiology of these infections, both of which induce significant destruction of tissue integrity and consequent bacteremia, differs significantly from that of bronchio-alveolar pneumonia, which is largely confined to the intra-alveolar space (50).…”

Section: Daptomycin In Pneumonia Modelsmentioning

confidence: 99%

A Current Perspective on Daptomycin for the Clinical Microbiologist

2013

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SUMMARY Daptomycin is a lipopeptide antimicrobial with in vitro bactericidal activity against Gram-positive bacteria that was first approved for clinical use in 2004 in the United States. Since this time, significant data have emerged regarding the use of daptomycin for the treatment of serious infections, such as bacteremia and endocarditis, caused by Gram-positive pathogens. However, there are also increasing reports of daptomycin nonsusceptibility, in Staphylococcus aureus and, in particular, Enterococcus faecium and Enterococcus faecalis . Such nonsusceptibility is largely in the context of prolonged treatment courses and infections with high bacterial burdens, but it may occur in the absence of prior daptomycin exposure. Nonsusceptibility in both S. aureus and Enterococcus is mediated by adaptations to cell wall homeostasis and membrane phospholipid metabolism. This review summarizes the data on daptomycin, including daptomycin's unique mode of action and spectrum of activity and mechanisms for nonsusceptibility in key pathogens, including S. aureus , E. faecium , and E. faecalis . The challenges faced by the clinical laboratory in obtaining accurate susceptibility results and reporting daptomycin MICs are also discussed.

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Section: Daptomycin In Pneumonia Modelsmentioning

confidence: 99%

A Current Perspective on Daptomycin for the Clinical Microbiologist

2013

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“…In addition, it has been approved to treat S. aureus-induced bacteremia and infective endocarditis (21), and animal model studies suggest that it may be a useful alternative for treatment of inhalational anthrax (26). The mechanism of action involves the calcium-dependent insertion of DAP into the bacterial membrane, followed by depolarization of the membrane and extrusion of potassium ions, leading to arrest of macromolecular synthesis and to cell death (49,51).…”

Section: Daptomycin (Dap) Is a Cyclic Lipopeptide That Disrupts The Fmentioning

confidence: 99%

“…These results suggest that different bacteria, particularly those with significantly different membrane lipid profiles, likely evolve resistance by distinct pathways: PhG synthesis is perhaps not a relevant target in S. aureus because membranes in this organism are typically 80% PhG and significant reductions are not compatible with viability. Conversely, reductions in PhG synthesis could be a relevant pathway were DAP to be used clinically against Bacillus anthracis (26) or other bacteria with a similar membrane composition. A common feature of each of these resistance mechanisms is a reduction of the net negative charge of the cell membrane achieved by reductions in PhG levels in B. subtilis and increased LPG synthesis in S. aureus.…”

mentioning

confidence: 99%

Reduction in Membrane Phosphatidylglycerol Content Leads to Daptomycin Resistance in Bacillus subtilis

Hachmann

Sevim

Gaballa

et al. 2011

Antimicrob Agents Chemother

127

134

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Daptomycin (DAP) is a cyclic lipopeptide that disrupts the functional integrity of the cell membranes of Gram-positive bacteria in a Ca2؉ -dependent manner. Here we present genetic, genomic, and phenotypic analyses of an evolved DAP-resistant isolate, Dap R 1, from the model bacterium Bacillus subtilis 168. Dap R 1 was obtained by serial passages with increasing DAP concentrations, is 30-fold more resistant than the parent strain, and displays cross-resistance to vancomycin, moenomycin, and bacitracin. Dap R 1 is characterized by aberrant septum placement, notably thickened peptidoglycan at the cell poles, and pleiotropic alterations at both the transcriptome and proteome levels. Genome sequencing of Dap R 1 revealed 44 point mutations, 31 of which change protein sequences. An intermediate isolate that was 20-fold more resistant to DAP than the wild type had only three of these point mutations: mutations affecting the cell shape modulator gene mreB, the stringent response gene relA, and the phosphatidylglycerol synthase gene pgsA. Genetic reconstruction studies indicated that the pgsA(A64V) allele is primarily responsible for DAP resistance. Allelic replacement with wild-type pgsA restored DAP sensitivity to wild-type levels. The additional point mutations in the evolved strain may contribute further to DAP resistance, serve to compensate for the deleterious effects of altered membrane composition, or represent neutral changes. These results suggest a resistance mechanism by which reduced levels of phosphatidylglycerol decrease the net negative charge of the membrane, thereby weakening interaction with the positively charged Ca 2؉ -DAP complex.Daptomycin (DAP) is a cyclic lipopeptide antibiotic used to treat complicated skin and skin structure infections caused by Staphylococcus aureus or enterococci. In addition, it has been approved to treat S. aureus-induced bacteremia and infective endocarditis (21), and animal model studies suggest that it may be a useful alternative for treatment of inhalational anthrax (26). The mechanism of action involves the calcium-dependent insertion of DAP into the bacterial membrane, followed by depolarization of the membrane and extrusion of potassium ions, leading to arrest of macromolecular synthesis and to cell death (49, 51).The introduction of new antibacterial compounds seems to be followed inevitably by the emergence of resistant isolates. It is estimated that over 1 million patients have been treated with DAP (J. Silverman, personal communication). According to the SENTRY Antimicrobial Surveillance Program in the United States for the years 2002 to 2010, 99.9% of methicillin-resistant S. aureus (MRSA) isolates treated with DAP had an MIC of 1.0 g/ml or lower, with only a slight increase of MIC over time (47; http://www.gp-pathogens.com/data/default.cfm).Previous studies to define mechanisms of resistance to DAP were performed on clinical isolates and by in vitro selection (22,31). After serial passages with increasing DAP concentrations, Friedman et al. characterized three...

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“…Its unique mode of action [13] , ie, inserting into bacterial membrane and perturbing membrane function, makes it a useful alternate therapeutic for B anthracis infection if resistant isolates emerged. However, limited data are available on the www.nature.com/aps Xing YH et al Acta Pharmacologica Sinica npg effect of this drug on B anthracis species, and only one study has been reported by Heine et al [14] . This group demonstrated that daptomycin was active against B anthracis using a murine model of spore inhalation.…”

Section: Introductionmentioning

confidence: 99%

Daptomycin exerts rapid bactericidal activity against Bacillus anthracis without disrupting membrane integrity

Xing

Wang

Dai³

et al. 2013

Acta Pharmacol Sin

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Aim: To examine whether the novel cyclic lipopeptide antibiotic daptomycin could be used to treat anthrax and to study the mechanisms underlying its bactericidal action against Bacillus anthracis. Methods: Spore-forming B anthracis AP422 was tested. MIC values of antibiotics were determined. Cell membrane potential was measured using flow cytometric assays with membrane potential-sensitive fluorescent dyes. Cell membrane integrity was detected using To-Pro-3 iodide staining and transmission electron microscopy. K + efflux and Na + influx were measured using the fluorescent probes PBFI and SBFI-AM, respectively. Results: Daptomycin exhibited rapid bactericidal activity against vegetative B anthracis with a MIC value of 0.78 μg/mL, which was comparable to those of ciprofloxacin and penicillin G. Furthermore, daptomycin prevented the germinated spores from growing into vegetative bacteria. Daptomycin concentration-dependently dissipated the membrane potential of B anthracis and caused K + efflux and Na + influx without disrupting membrane integrity. In contrast, both ciprofloxacin and penicillin G did not change the membrane potential of vegetative bacteria or spores. Penicillin G disrupted membrane integrity of B anthracis, whereas ciprofloxacin had no such effect. Conclusion: Daptomycin exerts rapid bactericidal action against B anthracis via reducing membrane potential without disrupting membrane integrity. This antibiotic can be used as an alternate therapy for B anthracis infections.

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Efficacy of Daptomycin against Bacillus anthracis in a Murine Model of Anthrax Spore Inhalation

Cited by 18 publications

References 18 publications

A Current Perspective on Daptomycin for the Clinical Microbiologist

A Current Perspective on Daptomycin for the Clinical Microbiologist

Reduction in Membrane Phosphatidylglycerol Content Leads to Daptomycin Resistance in Bacillus subtilis

Daptomycin exerts rapid bactericidal activity against Bacillus anthracis without disrupting membrane integrity

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