Mechanisms of daptomycin resistance in Staphylococcus aureus

Kaatz, Glenn W.; Lundstrom, Tammy; Seo, Susan M.

doi:10.1016/j.ijantimicag.2006.05.030

Cited by 75 publications

(82 citation statements)

References 39 publications

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“…Several recent reports have focused on the elucidation of the mechanism of resistance to daptomycin within S. aureus. The loss of an 81 kDa membrane protein correlated with decreased susceptibility to daptomycin (Kaatz et al, 2006). In addition, loss of this membrane protein was correlated with decreased binding of daptomycin to isolated cell membranes and resistance to daptomycinmediated membrane potential dissipation.…”

Section: Discussionmentioning

confidence: 91%

Daptomycin non-susceptible meticillin-resistant Staphylococcus aureus USA 300 isolate

Murthy

Olson

Wickert

et al. 2008

Journal of Medical Microbiology

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Daptomycin is a novel bactericidal agent active against Gram-positive pathogens including meticillin-resistant Staphylococcus aureus (MRSA). Our case is unique in the description of an MRSA USA 300 isolate that developed decreased susceptibility to daptomycin during daptomycin and vancomycin therapy. Directed sequencing detected a previously reported mutation in mprF, resulting in a T345A substitution, associated with non-susceptibility to daptomycin. Case reportA 40-year-old white male with a previous history of intravenous drug abuse and hepatitis C was admitted to a local hospital for fever and shortness of breath. He was empirically treated with intravenous vancomycin (1 g i.v. q.12 h) starting 11/11/2006 (dates in American format throughout). The first set of blood cultures drawn on the day of admission turned positive after 12 h incubation. A subsequent transoesophageal echocardiogram showed native aortic valve endocarditis.The first set of blood cultures grew meticillin-resistant Staphylococcus aureus (MRSA) with a vancomycin MIC of ¡2 mg ml 21 (Microscan; Dode-Behring). The patient had repeat blood cultures on 11/17/2006, which were persistently positive for MRSA (with blood cultures turning positive after 20 h incubation), after 5 days of vancomycin therapy. No serum vancomycin levels were available from the local hospital.Vancomycin was discontinued and intravenous daptomycin 6 mg kg 21 per day was started on 11/17/2006 at the local hospital. No baseline serum creatine phosphokinase level results were available. A computed tomography scan of the head to evaluate agitation revealed right temporal lesions, which were thought to be embolic in nature. The third set of repeat blood cultures dated 11/21/2006 also turned positive for MRSA after 12 h incubation.The patient was transferred to our facility on 11/24/2006 with persistent MRSA bacteraemia, aortic valve endocarditis and intracranial haemorrhagic septic emboli. On examination, he was found to be tachypnoeic and in moderate respiratory distress with a respiratory rate of 44 min 21 , pulse 131 beats min 21 , blood pressure 135/ 83 mmHg, temperature 37 u C and weight of 176 lbs. Laboratory results showed a white blood cell count of 2200 cells ml 21 , with 86 % polymorphonuclear leukocytes; a platelet count of 73 000 cells ml 21 ; blood urea nitrogen level of 52 mg dl 21 ; creatinine level of 2.2 mg dl 21 (baseline creatinine 1.4); and bicarbonate level of 14 mg dl 21 . His estimated creatinine clearance was 47.5 ml min 21 at the time of transfer.Chest X-ray showed a mild cardiomegaly with bilateral oedema and basilar opacities. The patient was later intubated for respiratory distress and airway protection. Review of the blood culture and susceptibility testing results (11/11, 11/17, 11/21) from the local hospital revealed that the MRSA isolates were susceptible to vancomycin with an MIC of ¡2 mg ml 21 . Daptomycin therapy was discontinued on the day of transfer, and vancomycin (15 mg kg 21 i.v. q.12 h) and gentamicin (1 mg kg 21 i.v. q.24 h) were initia...

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Section: Discussionmentioning

confidence: 91%

Daptomycin non-susceptible meticillin-resistant Staphylococcus aureus USA 300 isolate

Murthy

Olson

Wickert

et al. 2008

Journal of Medical Microbiology

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“…The heterogeneous resistance profile was observed with daptomycin-nonsusceptible derivative strains, and they were found to have higher membrane potentials than their parental strains (27,47). Recently, Jones et al (23) also observed a heterogeneous pattern of resistance, but they did not observe any difference in membrane potential between nonsusceptible and susceptible strains during exponential and postexponential growth.…”

mentioning

confidence: 98%

“…Kaatz et al (27) observed that smaller numbers of daptomycin molecules bind to the resistant strain than to its parental strain (27). They also demonstrated a loss of a membrane protein of 81 kDa in one of the nonsusceptible strains.…”

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confidence: 99%

Serial Daptomycin Selection Generates Daptomycin-Nonsusceptible Staphylococcus aureus Strains with a Heterogeneous Vancomycin-Intermediate Phenotype

Camargo

Neoh

Cui

et al. 2008

Antimicrob Agents Chemother

109

107

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In order to better understand the mechanism of daptomycin resistance, we generated a daptomycinnonsusceptible derivative strain, strain 10‫3ء‬d1 (MIC ‫؍‬ 3.0 g/ml), by in vitro exposure of methicillinresistant Staphylococcus aureus strain N315⌬IP (MIC ‫؍‬ 0.5 g/ml) to daptomycin. We also obtained a daptomycin-susceptible phenotypic revertant strain, strain 10‫3ء‬d1-10 (MIC ‫؍‬ 1.0 g/ml), by passaging 10‫3ء‬d1 in drug-free medium for 10 days. The resultant triple-isogenic strains were analyzed for their phenotypes and gene expression by microarray analysis. No significant differences in the membrane fluidities of 10‫3ء‬d1 and 10‫3ء‬d1-10 compared to the membrane fluidity of N315⌬IP were observed. Resistant strain 10‫3ء‬d1 had the highest membrane potential, followed by strains 10‫3ء‬d1-10 and N315⌬IP. The vancomycin and teicoplanin MICs also increased. Teichoic acid genes (tagA, tagG), mprF encoding lysyl-phosphatidylglycerol, and cls encoding cardiolipin synthase were downregulated in 10‫3ء‬d1 and 10‫3ء‬d1-10. The vraF and vraG genes, which encode ATP binding cassette transporter proteins, were upregulated in 10‫3ء‬d1. The vraSR two-component regulatory system was upregulated, and electron microscopy revealed that the cell wall of 10‫3ء‬d1 was significantly thicker than that of the parental strain. Taken together, daptomycin exposure selected a daptomycin-nonsusceptible strain with a phenotype similar to that of heterogeneous vancomycin-intermediate S. aureus and a transcription profile that partially overlapped that of heterogeneous vancomycin-intermediate S. aureus.

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“…BoyleVavra et al described uniform decreases in the MICs of vancomycin and teicoplanin after 15 days of serial passage on nonselective medium; the presence of vancomycin in the medium prevented such reversion (7). Kaatz et al reported that continuous exposure to daptomycin appears to be necessary to select stable mutants (13). Instability of vancomycin resistance has also been demonstrated in VRSA strains carrying the van(A) gene (22).…”

mentioning

confidence: 99%

Antistaphylococcal Activity of CG400549, a New Experimental FabI Inhibitor, Compared with That of Other Agents

Bogdanovich

Clark

Kosowska-Shick

et al. 2007

Antimicrob Agents Chemother

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Among 203 strains of Staphylococcus aureus, the MICs of CG400549 were 0.06 to 1.0 g/ml, with MIC 50 and MIC 90 values of 0.25 g/ml each. All strains were susceptible to linezolid and quinupristin-dalfopristin (MICs, 0.25 to 2.0 g/ml). The daptomycin MICs were 0.25 to 2.0 g/ml for methicillin-susceptible and 0.25 to 4.0 g/ml against methicillin-resistant strains (including vancomycin-intermediate strains). Single-passage selection testing showed low resistance frequencies with CG400549, but multistep analysis showed that CG400549 yielded resistant mutants after 14 to 17 days in all strains tested.

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Mechanisms of daptomycin resistance in Staphylococcus aureus

Cited by 75 publications

References 39 publications

Daptomycin non-susceptible meticillin-resistant Staphylococcus aureus USA 300 isolate

Daptomycin non-susceptible meticillin-resistant Staphylococcus aureus USA 300 isolate

Serial Daptomycin Selection Generates Daptomycin-Nonsusceptible Staphylococcus aureus Strains with a Heterogeneous Vancomycin-Intermediate Phenotype

Antistaphylococcal Activity of CG400549, a New Experimental FabI Inhibitor, Compared with That of Other Agents

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