Dataset Information

Device-Associated Meningitis by Linezolid-Resistant Staphylococcus haemolyticus in a Vancomycin- Hypersensitive Patient.

ABSTRACT: Postsurgical device-related meningitis caused by multidrug-resistant coagulase-negative staphylococci often complicates the treatment options. We report a rare and, to our knowledge, the first clinical case report of drain-associated meningitis caused by methicillin- and linezolid-resistant Staphylococcus haemolyticus following linezolid therapy in a vancomycin-hypersensitive patient subsequently treated with cotrimoxazole, resulting in clinical improvement. The molecular mechanisms responsible for linezolid resistance were found to be the presence of G2576T mutation in domain V of 23srRNA region, which often arises during linezolid usage and also carriage of cfr gene, which promotes resistance independent of antibiotic pressure. We emphasize on monitoring the rational use of linezolid to avoid the spread of resistance and also comprehensive perioperative care to prevent health care-associated infection.

SUBMITTER: Vijayan P

PROVIDER: S-EPMC6906101 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Device-Associated Meningitis by Linezolid-Resistant <i>Staphylococcus haemolyticus</i> in a Vancomycin- Hypersensitive Patient.

Vijayan Priya P Srinivas Dwarakanath D Siddaiah Nagarathna N Bahubali Veena Kumari Haradara VKH

Journal of neurosciences in rural practice 20191001 4

Postsurgical device-related meningitis caused by multidrug-resistant coagulase-negative staphylococci often complicates the treatment options. We report a rare and, to our knowledge, the first clinical case report of drain-associated meningitis caused by methicillin- and linezolid-resistant <i>Staphylococcus haemolyticus</i> following linezolid therapy in a vancomycin-hypersensitive patient subsequently treated with cotrimoxazole, resulting in clinical improvement. The molecular mechanisms respo ...[more]

PMID: 31831996

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Project description:The precise mechanism and effects of antibiotics in host gene expression and immunomodulation in MRSA infection is unknown. Using a well characterized Methicillin Resistant Staphylococcus aureus (MRSA) isolate USA300 in a murine model of infection, we determined that linezolid and vancomycin induced differential production of bacterial toxins and host cytokines, differences in host gene expression, and differences in immunomodulators during MRSA bloodstream infection. A total of 35 A/J mice, categorized into seven groups (no infection; no infection with linezolid; no infection with vancomycin; 2 hour post-infection (hpi) S. aureus; 24 hpi S. aureus; 24 hpi S. aureus with linezolid; and 24 hpi S. aureus with vancomycin), were used in this study. Mice were injected with USA300 (6 x 106 CFU/g via i.p. route), then intravenously treated with linezolid (25 mg/kg) or vancomycin (25 mg/kg) at 2 hpi. Control and S. aureus infected mice were euthanized at each time point (2 h or 24h) following injection. Whole blood RNA was used for microarray; three cytokines and two S. aureus toxins [PantonValentine Leukocidin (PVL) and alpha hemolysin] were quantified in mouse serum by ELISA. S. aureus CFUs were significantly reduced in blood and kidney after linezolid or vancomycin treatment in S. aureus-infected mice. In vivo IL-1β in mouse serum was significantly reduced in both linezolid (p=0.001) and vancomycin (p=0.006) treated mice compared to untreated ones. IL-6 was significantly reduced only in linezolid treated (p<0.001) but not in vancomycin treated mice. However, another proinflammatory cytokine, TNF-α, did not exhibit altered levels in either linezolid or vancomycin treated mice (p=0.3 and p=0.51 respectively). In vivo level of bacterial toxin, Panton-Valentine leukocidin, in mouse serum was significantly reduced only in linezolid treated mice (p=0.02) but not in vancomycin treated mice. There was no significant effect of either treatment in in vivo level of alpha hemolysin production. Unsupervised hierarchical clustering using the gene expression data from 35 microarrays revealed distinct clustering based on infection status and treatment group. Study of the antibiotic-specific difference in gene expression identified the number of genes uniquely expressed in response to S. aureus infection, infection with linezolid treatment, and infection with vancomycin treatment. Pathway associations study for the differentially expressed genes in each comparison group (Control vs. 24 h S. aureus infection, 24 h S. aureus infection vs. 24 h S. aureus linezolid, and 24 h S. aureus infection vs. 24 h S. aureus vancomycin) in mice using Kyoto Encyclopedia of Genes and Genomes (KEGG) identified toll-like receptor signaling pathway to be common to every comparison groups studied. Glycerolipid metabolism pathway was uniquely associated only with linezolid treatment comparison group. The findings of this study provide the evidence that protein synthesis inhibitor like linezolid does a better job in treating MRSA sepsis compared to cell wall acting antibiotics like vancomycin.

Project description:The genomic evolution in vivo in persistent infection was critical information for understanding how methicillin-resistant Staphylococcus aureus (MRSA) was adapted to host environments with high antibiotic selective pressure. Thirty-two successive MRSA blood isolates with incremental non-susceptibility to vancomycin (VISA), daptomycin (DRSA), and/or linezolid (LRSA) were isolated from a patient failing multiple courses of antimicrobial therapy during 1,356 days of bacteremia. Whole genome sequencing (WGS) for all consecutive isolates were conducted to characterize the evolutionary pathways, resistance-associated mutations and their temporal relationship with antimicrobial treatment. The WGS-based phylogeny categorized the isogenic strains into three major clades, I (22 isolates), II (7 isolates), and III (3 isolates), respectively, harboring a median (range) of 7 (1-30), 62 (53-65), and 118 (100-130) non-synonymous mutations when compared to the very first isolate. Clade I strains were further grouped into early and late subclades, which, respectively, shared the most recent common ancestor with Clade III strains at day 393.7 and Clade II strain at day 662.5. Clade I and Clade III strains were characterized, respectively, with high rates of VISA (9/22, 40.9%) and VISA-and-DRSA phenotype (2/3, 66.7%). Linezolid-resistance including VISA-DRSA-and-LRSA phenotype was exclusively identified in Clade II strains after eight courses of linezolid treatment. The LRSA displayed a small colony variant phenotype and were associated with G2576T mutations in domain V region of 23S rRNA. Substantial loss of mobile elements or alleles mediating resistance or virulence were identified during the evolution of multi-resistance. However, the gene loss might not be correlated to the development of VISA, DRSA, or LRSA phenotype. In conclusion, MRSA in persistent bacteremia was adapted to harsh host environment through multiple pathways involving both resistance-associated mutations and extensive gene loss.

Project description:The precise mechanism and effects of antibiotics in host gene expression and immunomodulation in MRSA infection is unknown. Using a well characterized Methicillin Resistant Staphylococcus aureus (MRSA) isolate USA300 in a murine model of infection, we determined that linezolid and vancomycin induced differential production of bacterial toxins and host cytokines, differences in host gene expression, and differences in immunomodulators during MRSA bloodstream infection. A total of 35 A/J mice, categorized into seven groups (no infection; no infection with linezolid; no infection with vancomycin; 2 hour post-infection (hpi) S. aureus; 24 hpi S. aureus; 24 hpi S. aureus with linezolid; and 24 hpi S. aureus with vancomycin), were used in this study. Mice were injected with USA300 (6 x 106 CFU/g via i.p. route), then intravenously treated with linezolid (25 mg/kg) or vancomycin (25 mg/kg) at 2 hpi. Control and S. aureus infected mice were euthanized at each time point (2 h or 24h) following injection. Whole blood RNA was used for microarray; three cytokines and two S. aureus toxins [PantonValentine Leukocidin (PVL) and alpha hemolysin] were quantified in mouse serum by ELISA. S. aureus CFUs were significantly reduced in blood and kidney after linezolid or vancomycin treatment in S. aureus-infected mice. In vivo IL-1M-NM-2 in mouse serum was significantly reduced in both linezolid (p=0.001) and vancomycin (p=0.006) treated mice compared to untreated ones. IL-6 was significantly reduced only in linezolid treated (p<0.001) but not in vancomycin treated mice. However, another proinflammatory cytokine, TNF-M-NM-1, did not exhibit altered levels in either linezolid or vancomycin treated mice (p=0.3 and p=0.51 respectively). In vivo level of bacterial toxin, Panton-Valentine leukocidin, in mouse serum was significantly reduced only in linezolid treated mice (p=0.02) but not in vancomycin treated mice. There was no significant effect of either treatment in in vivo level of alpha hemolysin production. Unsupervised hierarchical clustering using the gene expression data from 35 microarrays revealed distinct clustering based on infection status and treatment group. Study of the antibiotic-specific difference in gene expression identified the number of genes uniquely expressed in response to S. aureus infection, infection with linezolid treatment, and infection with vancomycin treatment. Pathway associations study for the differentially expressed genes in each comparison group (Control vs. 24 h S. aureus infection, 24 h S. aureus infection vs. 24 h S. aureus linezolid, and 24 h S. aureus infection vs. 24 h S. aureus vancomycin) in mice using Kyoto Encyclopedia of Genes and Genomes (KEGG) identified toll-like receptor signaling pathway to be common to every comparison groups studied. Glycerolipid metabolism pathway was uniquely associated only with linezolid treatment comparison group. The findings of this study provide the evidence that protein synthesis inhibitor like linezolid does a better job in treating MRSA sepsis compared to cell wall acting antibiotics like vancomycin. To identify differences in host gene expression in a murine sepsis model treated with a) linezolid and b) vancomycin, we used whole blood gene expression (RNA) signatures from A/J inbred mice infected with USA 300 MRSA to evaluate differences in host gene expression among mice treated with linezolid and vancomycin. We used 5 RNA samples from MRSA-infected, linezolid- or vancomycin-treated mice. A total of 7 experimental groups have been employed: 1) Uninfected control group: (negative controls). 2) Uninfected, linezolid-treated group: Uninfected, linezolid-treated mice. 3) Uninfected vancomycin-treated group: Uninfected, vancomycin-treated mice. 4) Infected control group (positive control 2 h) MRSA-infected, untreated mice. 5) Infected control group (positive control 24 h): MRSA-infected, untreated mice. 6) Infected linezolid group: MRSA-infected, linezolid-treated mice. 7) Infected vancomycin group: MRSA-infected, vancomycin-treated mice.

Dataset Information

Device-Associated Meningitis by Linezolid-Resistant Staphylococcus haemolyticus in a Vancomycin- Hypersensitive Patient.

Publications

Device-Associated Meningitis by Linezolid-Resistant <i>Staphylococcus haemolyticus</i> in a Vancomycin- Hypersensitive Patient.

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