Heterogeneity of Genetic Pathways toward Daptomycin Nonsusceptibility in Staphylococcus aureus Determined by Adjunctive Antibiotics

ABSTRACTDaptomycin is increasingly used in combination with other antibiotics to enhance antimicrobial efficacy and/or to mitigate the emergence of daptomycin nonsusceptibility (DNS). This study used a clinical methicillin-resistantStaphylococcus aureus(MRSA) strain in which DNS emerged upon therapy to examine the influence of antibiotic combinations on the development of mutations in specific genes (mprF,rpoBC,dltA,cls2, andyycFG) previously associated with DNS. Whole genomes of bacteria obtained following 28 days ofin vitroexposure to daptomycin with or without adjunctive clarithromycin, linezolid, oxacillin, or trimethoprim-sulfamethoxazole were sequenced, and the sequences were compared to that of the progenitor isolate. The addition of oxacillin to medium containing daptomycin prevented the emergence ofmprFmutation but did not preventrpoBCmutation (P< 0.01). These isolates maintained susceptibility to daptomycin during the combined exposure (median MIC, 1 mg/liter). Daptomycin plus clarithromycin or linezolid resulted in low-level (1.5 to 8 mg/liter) and high-level (12 to 96 mg/liter) DNS, respectively, and did not preventmprFmutation. However, these same combinations preventedrpoBCmutation. Daptomycin alone or combined with linezolid or trimethoprim-sulfamethoxazole resulted in high-level DNS and mutations inmprFplusrpoBC,cls2, andyycFG. Combining daptomycin with different antimicrobials alters the mutational space available for DNS development, thereby favoring the development of predictable collateral susceptibilities.

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Ceftobiprole- and Ceftaroline-Resistant Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05004-14 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2960-2963 ◽

Cited By ~ 45

Author(s):

Liana C. Chan ◽

Li Basuino ◽

Binh Diep ◽

Stephanie Hamilton ◽

Som S. Chatterjee ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Methicillin Resistant ◽

Content Type ◽

Low Level ◽

Mrsa Strains ◽

High Level ◽

Level Resistance

ABSTRACTThe role ofmecAmutations in conferring resistance to ceftobiprole and ceftaroline, cephalosporins with anti-methicillin-resistantStaphylococcus aureus(MRSA) activity, was determined with MRSA strains COL and SF8300. The SF8300 ceftaroline-passaged mutant carried a singlemecAmutation, E447K (E-to-K change at position 447), and expressed low-level resistance. This mutation in COL conferred high-level resistance to ceftobiprole but only low-level resistance to ceftaroline. The COL ceftaroline-passaged mutant, which expressed high-level resistance to ceftobiprole and ceftaroline, had mutations inpbp2,pbp4, andgdpPbut notmecA.

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Examination of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Mutants with Low-Level Fluoroquinolone Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.12.3317 ◽

1998 ◽

Vol 42 (12) ◽

pp. 3317-3319 ◽

Cited By ~ 9

Author(s):

Mark C. Sulavik ◽

Neil L. Barg

Keyword(s):

Staphylococcus Aureus ◽

Ethidium Bromide ◽

Quinolone Resistance ◽

Fluoroquinolone Resistance ◽

Methicillin Resistant ◽

Low Level ◽

High Level

ABSTRACT For Staphylococcus aureus, stepwise mutations result in high-level quinolone resistance. Methicillin-resistant and -susceptible quinolone-resistant, first-step mutants generated in vitro were obtained and found to be no different than those recovered from murine abscesses. Approximately 10% of all first-step mutants were resistant to ethidium bromide, and selected strains had mutations that mapped toflqB. NorA-mediated resistance among first-step mutants may be more prevalent than previously reported.

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In VitroActivities of Daptomycin-, Vancomycin-, and Teicoplanin-Loaded Polymethylmethacrylate against Methicillin-Susceptible, Methicillin-Resistant, and Vancomycin-Intermediate Strains of Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05312-11 ◽

2011 ◽

Vol 55 (12) ◽

pp. 5480-5484 ◽

Cited By ~ 45

Author(s):

Yuhan Chang ◽

Wen-Chien Chen ◽

Pang-Hsin Hsieh ◽

Dave W. Chen ◽

Mel S. Lee ◽

...

Keyword(s):

Staphylococcus Aureus ◽

High Performance ◽

Low Dose ◽

Antibacterial Activities ◽

High Dose ◽

Bone Cements ◽

Antibacterial Effects ◽

Methicillin Resistant ◽

Content Type

ABSTRACTThe objective of this study was to evaluate the antibacterial effects of polymethylmethacrylate (PMMA) bone cements loaded with daptomycin, vancomycin, and teicoplanin against methicillin-susceptibleStaphylococcus aureus(MSSA), methicillin-resistantStaphylococcus aureus(MRSA), and vancomycin-intermediateStaphylococcus aureus(VISA) strains. Standardized cement specimens made from 40 g PMMA loaded with 1 g (low-dose), 4 g (middle-dose) or 8 g (high-dose) antibiotics were tested for elution characteristics and antibacterial activities. The patterns of release of antibiotics from the cement specimens were evaluated usingin vitrobroth elution assay with high-performance liquid chromatography. The activities of broth elution fluid against differentStaphylococcus aureusstrains (MSSA, MRSA, and VISA) were then determined. The antibacterial activities of all the tested antibiotics were maintained after being mixed with PMMA. The cements loaded with higher dosages of antibiotics showed longer elution periods. Regardless of the antibiotic loading dose, the teicoplanin-loaded cements showed better elution efficacy and provided longer inhibitory periods against MSSA, MRSA, and VISA than cements loaded with the same dose of vancomycin or daptomycin. Regarding the choice of antibiotics for cement loading in the treatment ofStaphylococcus aureusinfection, teicoplanin was superior in terms of antibacterial effects.

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Comparison of Borate Bioactive Glass and Calcium Sulfate as Implants for the Local Delivery of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus-Induced Osteomyelitis in a Rabbit Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00196-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7571-7580 ◽

Cited By ~ 16

Author(s):

Wei-Tao Jia ◽

Qiang Fu ◽

Wen-Hai Huang ◽

Chang-Qing Zhang ◽

Mohamed N. Rahaman

Keyword(s):

Staphylococcus Aureus ◽

Bioactive Glass ◽

Calcium Sulfate ◽

Rabbit Model ◽

Local Delivery ◽

Methicillin Resistant ◽

Content Type ◽

Borate Bioactive Glass ◽

Phosphate Buffered Saline

ABSTRACTThere is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TECin vitroand to cure methicillin-resistantStaphylococcus aureus(MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC.

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Evaluation of Ceftaroline Alone and in Combination against Biofilm-Producing Methicillin-Resistant Staphylococcus aureus with Reduced Susceptibility to Daptomycin and Vancomycin in anIn VitroPharmacokinetic/Pharmacodynamic Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00386-15 ◽

2015 ◽

Vol 59 (8) ◽

pp. 4497-4503 ◽

Cited By ~ 23

Author(s):

Katie E. Barber ◽

Jordan R. Smith ◽

Cortney E. Ireland ◽

Blaise R. Boles ◽

Warren E. Rose ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Medical Device ◽

Bloodstream Infections ◽

Methicillin Resistant ◽

Content Type ◽

Elimination Half ◽

Antimicrobial Protection ◽

Mrsa Strains ◽

Post Hoc

ABSTRACTAnnually, medical device infections are associated with >250,000 catheter-associated bloodstream infections (CLABSI), with up to 25% mortality.Staphylococcus aureus, a primary pathogen in these infections, is capable of biofilm production, allowing organism persistence in harsh environments, offering antimicrobial protection. With increases inS. aureusisolates with reduced susceptibility to current agents, ceftaroline (CPT) offers a therapeutic alternative. Therefore, we evaluated whether CPT would have a role against biofilm-producing methicillin-resistantS. aureus(MRSA), including those with decreased susceptibilities to alternative agents. In this study, we investigated CPT activity alone or combined with daptomycin (DAP) or rifampin (RIF) against 3 clinical biofilm-producing MRSA strains in anin vitrobiofilm pharmacokinetic/pharmacodynamic (PK/PD) model. Simulated antimicrobial regimens were as follows: 600 mg of CPT every 8 h (q8h) (free maximum concentration of drug [fCmax], 17.04 mg/liter; elimination half-life [t1/2], 2.66 h), 12 mg/kg of body weight/day of DAP (fCmax, 14.7 mg/liter;t1/2, 8 h), and 450 mg of RIF q12h (fCmax, 3.5 mg/liter;t1/2, 3.4 h), CPT plus DAP, and CPT plus RIF. Samples were obtained and plated to determine colony counts. Differences in log10CFU/cm2were evaluated by analysis of variance with Tukey'spost hoctest. The strains were CPT and vancomycin susceptible and DAP nonsusceptible (DNS). CPT displayed activity throughout the experiment. DAP demonstrated initial activity with regrowth at 24 h in all strains. RIF was comparable to the drug-free control, and little benefit was observed when combined with CPT. CPT plus DAP displayed potent activity, with an average log10CFU/cm2reduction of 3.33 ± 1.01 from baseline. CPT demonstrated activity against biofilm-producing DNS MRSA. CPT plus DAP displayed therapeutic enhancement over monotherapy, providing a potential option for difficult-to-treat medical device infections.

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Bacteriocins of Non-aureus Staphylococci Isolated from Bovine Milk

Applied and Environmental Microbiology ◽

10.1128/aem.01015-17 ◽

2017 ◽

Vol 83 (17) ◽

Cited By ~ 24

Author(s):

Domonique A. Carson ◽

Herman W. Barkema ◽

Sohail Naushad ◽

Jeroen De Buck

Keyword(s):

Staphylococcus Aureus ◽

Bacterial Infections ◽

Genome Mining ◽

Bovine Milk ◽

Gene Clusters ◽

Antibiotic Use ◽

Content Type ◽

Treatment And Prevention ◽

Whole Genomes

ABSTRACT Non-aureus staphylococci (NAS), the bacteria most commonly isolated from the bovine udder, potentially protect the udder against infection by major mastitis pathogens due to bacteriocin production. In this study, we determined the inhibitory capability of 441 bovine NAS isolates (comprising 26 species) against bovine Staphylococcus aureus. Furthermore, inhibiting isolates were tested against a human methicillin-resistant S. aureus (MRSA) isolate using a cross-streaking method. We determined the presence of bacteriocin clusters in NAS whole genomes using genome mining tools, BLAST, and comparison of genomes of closely related inhibiting and noninhibiting isolates and determined the genetic organization of any identified bacteriocin biosynthetic gene clusters. Forty isolates from 9 species (S. capitis, S. chromogenes, S. epidermidis, S. pasteuri, S. saprophyticus, S. sciuri, S. simulans, S. warneri, and S. xylosus) inhibited growth of S. aureus in vitro, 23 isolates of which, from S. capitis, S. chromogenes, S. epidermidis, S. pasteuri, S. simulans, and S. xylosus, also inhibited MRSA. One hundred five putative bacteriocin gene clusters encompassing 6 different classes (lanthipeptides, sactipeptides, lasso peptides, class IIa, class IIc, and class IId) in 95 whole genomes from 16 species were identified. A total of 25 novel bacteriocin precursors were described. In conclusion, NAS from bovine mammary glands are a source of potential bacteriocins, with >21% being possible producers, representing potential for future characterization and prospective clinical applications. IMPORTANCE Mastitis (particularly infections caused by Staphylococcus aureus) costs Canadian dairy producers $400 million/year and is the leading cause of antibiotic use on dairy farms. With increasing antibiotic resistance and regulations regarding use, there is impetus to explore bacteriocins (bacterially produced antimicrobial peptides) for treatment and prevention of bacterial infections. We examined the ability of 441 NAS bacteria from Canadian bovine milk samples to inhibit growth of S. aureus in the laboratory. Overall, 9% inhibited growth of S. aureus and 58% of those also inhibited MRSA. In NAS whole-genome sequences, we identified >21% of NAS as having bacteriocin genes. Our study represents a foundation to further explore NAS bacteriocins for clinical use.

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In VitroEfficacies and Resistance Profiles of Rifampin-Based Combination Regimens for Biofilm-Embedded Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01236-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5717-5720 ◽

Cited By ~ 31

Author(s):

Hung-Jen Tang ◽

Chi-Chung Chen ◽

Kuo-Chen Cheng ◽

Kuan-Ying Wu ◽

Yi-Chung Lin ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Fusidic Acid ◽

Antibacterial Activities ◽

Methicillin Resistant ◽

Content Type ◽

Biofilm Model ◽

Rifampin Resistance ◽

Combination Regimens ◽

Resistant Mutation

ABSTRACTTo compare thein vitroantibacterial efficacies and resistance profiles of rifampin-based combinations against methicillin-resistantStaphylococcus aureus(MRSA) in a biofilm model, the antibacterial activities of vancomycin, teicoplanin, daptomycin, minocycline, linezolid, fusidic acid, fosfomycin, and tigecycline alone or in combination with rifampin against biofilm-embedded MRSA were measured. The rifampin-resistant mutation frequencies were evaluated. Of the rifampin-based combinations, rifampin enhances the antibacterial activities of and even synergizes with fusidic acid, tigecycline, and, to a lesser extent, linezolid, fosfomycin, and minocycline against biofilm-embedded MRSA. Such combinations with weaker rifampin resistance induction activities may provide a therapeutic advantage in MRSA biofilm-related infections.

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Prevalence of Chlorhexidine-Resistant Methicillin-Resistant Staphylococcus aureus following Prolonged Exposure

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02419-14 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4404-4410 ◽

Cited By ~ 32

Author(s):

Carey D. Schlett ◽

Eugene V. Millar ◽

Katrina B. Crawford ◽

Tianyuan Cui ◽

Jeffrey B. Lanier ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Molecular Analysis ◽

Prolonged Exposure ◽

Controlled Trial ◽

Epidemiological Data ◽

Methicillin Resistant ◽

Content Type ◽

Mupirocin Resistance ◽

High Level ◽

Study Participants

ABSTRACTChlorhexidine has been increasingly utilized in outpatient settings to control methicillin-resistantStaphylococcus aureus(MRSA) outbreaks and as a component of programs for MRSA decolonization and prevention of skin and soft-tissue infections (SSTIs). The objective of this study was to determine the prevalence of chlorhexidine resistance in clinical and colonizing MRSA isolates obtained in the context of a community-based cluster-randomized controlled trial for SSTI prevention, during which 10,030 soldiers were issued chlorhexidine for body washing. We obtained epidemiological data on study participants and performed molecular analysis of MRSA isolates, including PCR assays for determinants of chlorhexidine resistance and high-level mupirocin resistance and pulsed-field gel electrophoresis (PFGE). During the study period, May 2010 to January 2012, we identified 720 MRSA isolates, of which 615 (85.4%) were available for molecular analysis, i.e., 341 clinical and 274 colonizing isolates. Overall, only 10 (1.6%) of 615 isolates were chlorhexidine resistant, including three from the chlorhexidine group and seven from nonchlorhexidine groups (P> 0.99). Five (1.5%) of the 341 clinical isolates and five (1.8%) of the 274 colonizing isolates harbored chlorhexidine resistance genes, and four (40%) of the 10 possessed genetic determinants for mupirocin resistance. All chlorhexidine-resistant isolates were USA300. The overall prevalence of chlorhexidine resistance in MRSA isolates obtained from our study participants was low. We found no association between extended chlorhexidine use and the prevalence of chlorhexidine-resistant MRSA isolates; however, continued surveillance is warranted, as this agent continues to be utilized for infection control and prevention efforts.

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In VitroPharmacodynamics of Human Simulated Exposures of Ceftaroline and Daptomycin against MRSA, hVISA, and VISA with and without Prior Vancomycin Exposure

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01516-13 ◽

2013 ◽

Vol 58 (2) ◽

pp. 672-677 ◽

Cited By ~ 17

Author(s):

Amira A. Bhalodi ◽

Mao Hagihara ◽

David P. Nicolau ◽

Joseph L. Kuti

Keyword(s):

Staphylococcus Aureus ◽

Body Weight ◽

Sequential Therapy ◽

Free Drug ◽

Pharmacodynamic Model ◽

Prior Exposure ◽

Methicillin Resistant ◽

Content Type ◽

Mrsa Infection

ABSTRACTThe effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistantStaphylococcus aureus(MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-hin vitropharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediateS. aureus(hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10CFU was largest for sequential therapy with vancomycin followed by ceftaroline (−5.22 ± 1.2,P= 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (−3.60 ± 0.6,P= 0.037 versus daptomycin), compared with daptomycin (−2.24 ± 1.0), vancomycin (−1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (−1.32 ± 1.0,P> 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

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Susceptibility of Methicillin-Resistant Staphylococcus aureus to Five Quinazolinone Antibacterials

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01344-19 ◽

2019 ◽

Vol 64 (1) ◽

Author(s):

Sara Ceballos ◽

Choon Kim ◽

Yuanyuan Qian ◽

Shahriar Mobashery ◽

Mayland Chang ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Amino Acid ◽

Binding Proteins ◽

Methicillin Resistant Staphylococcus Aureus ◽

Methicillin Resistant ◽

Content Type ◽

Penicillin Binding Proteins

ABSTRACT The in vitro activities of five quinazolinone antibacterials, compounds Q1 to Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (in μg/ml) were as follows: Q1, 0.5/2; Q2, 1/4; Q3, 2/4; Q4, 0.06/0.25; and Q5, 0.125/0.5. Several strains with high MIC values (from 8 to >32 μg/ml) for some of these compounds exhibited amino acid changes in the penicillin-binding proteins, which are targeted by these antibacterials.

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