scholarly journals The Emerging Role of β-Lactams in the Treatment of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Kyle C. Molina ◽  
Taylor Morrisette ◽  
Matthew A. Miller ◽  
Vanthida Huang ◽  
Douglas N. Fish
Keyword(s):  
Staphylococcus Aureus ◽  
Bloodstream Infections ◽  
The United States ◽  
Synergistic Activity ◽  
First Line ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Preclinical And Clinical Studies

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN and DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the “seesaw effect,” where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.

scholarly journals 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

2015 ◽  
Vol 59 (8) ◽  
pp. 4497-4503 ◽  
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.

scholarly journals Updating Molecular Diagnostics for Detecting Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Isolates in Blood Culture Bottles

2019 ◽  
Vol 57 (11) ◽  
Author(s):  
Fred C. Tenover ◽  
Isabella A. Tickler ◽  
Victoria M. Le ◽  
Scott Dewell ◽  
Rodrigo E. Mendes ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Blood Culture ◽  
False Negative ◽  
The United States ◽  
Molecular Diagnostic ◽  
Methicillin Resistant ◽  
Content Type ◽  
Target Nucleic Acid ◽  
Antimicrobial Resistance Genes

ABSTRACT Molecular diagnostic tests can be used to provide rapid identification of staphylococcal species in blood culture bottles to help improve antimicrobial stewardship. However, alterations in the target nucleic acid sequences of the microorganisms or their antimicrobial resistance genes can lead to false-negative results. We determined the whole-genome sequences of 4 blood culture isolates of Staphylococcus aureus and 2 control organisms to understand the genetic basis of genotype-phenotype discrepancies when using the Xpert MRSA/SA BC test (in vitro diagnostic medical device [IVD]). Three methicillin-resistant S. aureus (MRSA) isolates each had a different insertion of a genetic element in the staphylococcal cassette chromosome (SCCmec)-orfX junction region that led to a misclassification as methicillin-susceptible S. aureus (MSSA). One strain contained a deletion in spa, which produced a false S. aureus-negative result. A control strain of S. aureus that harbored an SCCmec element but no mecA (an empty cassette) was correctly called MSSA by the Xpert test. The second control contained an SCCM1 insertion. The updated Xpert MRSA/SA BC test successfully detected both spa and SCCmec variants of MRSA and correctly identified empty-cassette strains of S. aureus as MSSA. Among a sample of 252 MSSA isolates from the United States and Europe, 3.9% contained empty SCCmec cassettes, 1.6% carried SCCM1, <1% had spa deletions, and <1% contained SCCmec variants other than those with SCCM1. These data suggest that genetic variations that may interfere with Xpert MRSA/SA BC test results remain rare. Results for all the isolates were correct when tested with the updated assay.

scholarly journals Ceftobiprole EfficacyIn Vitroagainst Panton-Valentine Leukocidin Production andIn Vivoagainst Community-Associated Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rabbits

2012 ◽  
Vol 56 (12) ◽  
pp. 6291-6297 ◽  
Author(s):  
Azzam Saleh-Mghir ◽  
Oana Dumitrescu ◽  
Aurélien Dinh ◽  
Yassine Boutrad ◽  
Laurent Massias ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Content Type ◽  
The Mean ◽  
Mrsa Strains ◽  
Time Kill ◽  
Panton Valentine Leukocidin ◽  
Valentine Leukocidin

ABSTRACTCommunity-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected.In vitrosub-MIC antibiotic effects on growth and PVL production by 11 PVL+MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL+methicillin-susceptibleS. aureus(MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 107CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days.In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log10-CFU-count decrease.In vivo, the mean log10CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P= 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P= 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P= 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.

scholarly journals Comparative Genomics of Vancomycin-Resistant Staphylococcus aureus Strains and Their Positions within the Clade Most Commonly Associated with Methicillin-Resistant S. aureus Hospital-Acquired Infection in the United States

mBio ◽  
2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Veronica N. Kos ◽  
Christopher A. Desjardins ◽  
Allison Griggs ◽  
Gustavo Cerqueira ◽  
Andries Van Tonder ◽  
...  
Keyword(s):  
United States ◽  
Staphylococcus Aureus ◽  
The United States ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Infection ◽  
Vancomycin Resistant ◽  
Foreign Dna ◽  
Mrsa Strains ◽  
Hospital Acquired

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) strains are leading causes of hospital-acquired infections in the United States, and clonal cluster 5 (CC5) is the predominant lineage responsible for these infections. Since 2002, there have been 12 cases of vancomycin-resistantS. aureus(VRSA) infection in the United States—all CC5 strains. To understand this genetic background and what distinguishes it from other lineages, we generated and analyzed high-quality draft genome sequences for all available VRSA strains. Sequence comparisons show unambiguously that each strain independently acquired Tn1546and that all VRSA strains last shared a common ancestor over 50 years ago, well before the occurrence of vancomycin resistance in this species. In contrast to existing hypotheses on what predisposes this lineage to acquire Tn1546, the barrier posed by restriction systems appears to be intact in most VRSA strains. However, VRSA (and other CC5) strains were found to possess a constellation of traits that appears to be optimized for proliferation in precisely the types of polymicrobic infection where transfer could occur. They lack a bacteriocin operon that would be predicted to limit the occurrence of non-CC5 strains in mixed infection and harbor a cluster of unique superantigens and lipoproteins to confound host immunity. A frameshift indprA, which in other microbes influences uptake of foreign DNA, may also make this lineage conducive to foreign DNA acquisition.IMPORTANCEInvasive methicillin-resistantStaphylococcus aureus(MRSA) infection now ranks among the leading causes of death in the United States. Vancomycin is a key last-line bactericidal drug for treating these infections. However, since 2002, vancomycin resistance has entered this species. Of the now 12 cases of vancomycin-resistantS. aureus(VRSA), each was believed to represent a new acquisition of the vancomycin-resistant transposon Tn1546from enterococcal donors. All acquisitions of Tn1546so far have occurred in MRSA strains of the clonal cluster 5 genetic background, the most common hospital lineage causing hospital-acquired MRSA infection. To understand the nature of these strains, we determined and examined the nucleotide sequences of the genomes of all available VRSA. Genome comparison identified candidate features that position strains of this lineage well for acquiring resistance to antibiotics in mixed infection.

scholarly journals Missense Mutations in PBP2A Affecting Ceftaroline Susceptibility Detected in Epidemic Hospital-Acquired Methicillin-Resistant Staphylococcus aureus Clonotypes ST228 and ST247 in Western Switzerland Archived since 1998

2015 ◽  
Vol 59 (4) ◽  
pp. 1922-1930 ◽  
Author(s):  
William L. Kelley ◽  
Ambre Jousselin ◽  
Christine Barras ◽  
Emmanuelle Lelong ◽  
Adriana Renzoni
Keyword(s):  
Staphylococcus Aureus ◽  
University Hospital ◽  
Surveillance Program ◽  
Missense Mutations ◽  
Unknown Parameters ◽  
Methicillin Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
Mrsa Strains

ABSTRACTThe development and maintenance of an arsenal of antibiotics is a major health care challenge. Ceftaroline is a new cephalosporin with activity against methicillin-resistantStaphylococcus aureus(MRSA); however, no reports concerning MRSA ceftaroline susceptibility have been reported in Switzerland. We tested thein vitroactivity of ceftaroline against an archived set of 60 MRSA strains from the University Hospital of Geneva collected from 1994 to 2003. Our results surprisingly revealed ceftaroline-resistant strains (MIC, >1 μg/ml in 40/60 strains; EUCAST breakpoints, susceptible [S], ≤1 μg/ml; resistant [R], >1 μg/ml) were present from 1998 to 2003. The detected resistant strains predominantly belonged to sequence type 228 (ST228) (South German clonotype) but also to ST247 (Iberian clonotype). A sequence analysis of these strains revealed missense mutations in the penicillin-binding protein 2A (PBP2A) allosteric domain (N146K or E239K and N146K-E150K-G246E). The majority of our ST228 PBP2A mutations (N146K or E150K) were distinct from ST228 PBP2A allosteric domain mutations (primarily E239K) recently described for MRSA strains collected in Thailand and Spain during the 2010 Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance program. We also found that similar allosteric domain PBP2A mutations (N146K) correlated with ceftaroline resistance in an independent external ST228 MRSA set obtained from the nearby University Hospital of Lausanne, Lausanne, Switzerland, collected from 2003 to 2008. Thus, ceftaroline resistance was observed in our archived strains (including two examples of an MIC of 4 µg/ml for the Iberian ST247 clonotype with the triple mutation N146K/E150K/G246E), at least as far back as 1998, considerably predating the commercial introduction of ceftaroline. Our results reinforce the notion that unknown parameters can potentially exert selective pressure on PBP2A that can subsequently modulate ceftaroline resistance.

scholarly journals Antimicrobial Constituents from Machaerium Pers.: Inhibitory Activities and Synergism of Machaeriols and Machaeridiols against Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus faecium, and Permeabilized Gram-Negative Pathogens

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6000
Author(s):  
Ilias Muhammad ◽  
Melissa R. Jacob ◽  
Mohamed A. Ibrahim ◽  
Vijayasankar Raman ◽  
Mallika Kumarihamy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Enterococcus Faecium ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Polymyxin B ◽  
Synergistic Activity ◽  
Vancomycin Resistant Enterococcus ◽  
Methicillin Resistant ◽  
Vancomycin Resistant ◽  
Mrsa Strains

Two new epimeric bibenzylated monoterpenes machaerifurogerol (1a) and 5-epi-machaerifurogerol (1b), and four known isoflavonoids (+)-vestitol (2), 7-O-methylvestitol (3), (+)-medicarpin (4), and 3,8-dihydroxy-9-methoxypterocarpan (5) were isolated from Machaerium Pers. This plant was previously assigned as Machaerium multiflorum Spruce, from which machaeriols A-D (6–9) and machaeridiols A-C (10–12) were reported, and all were then re-isolated, except the minor compound 9, for a comprehensive antimicrobial activity evaluation. Structures of the isolated compounds were determined by full NMR and mass spectroscopic data. Among the isolated compounds, the mixture 10 + 11 was the most active with an MIC value of 1.25 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA) strains BAA 1696, −1708, −1717, −33591, and vancomycin-resistant Enterococcus faecium (VRE 700221) and E. faecalis (VRE 51299) and vancomycin-sensitive E. faecalis (VSE 29212). Compounds 6–8 and 10–12 were found to be more potent against MRSA 1708, and 6, 11, and 12 against VRE 700221, than the drug control ciprofloxacin and vancomycin. A combination study using an in vitro Checkerboard method was carried out for machaeriols (7 or 8) and machaeridiols (11 or 12), which exhibited a strong synergistic activity of 12 + 8 (MIC 0.156 and 0.625 µg/mL), with >32- and >8-fold reduction of MIC’s, compared to 12, against MRSA 1708 and −1717, respectively. In the presence of sub-inhibitory concentrations on polymyxin B nonapeptide (PMBN), compounds 10 + 11, 11, 12, and 8 showed activity in the range of 0.5–8 µg/mL for two strains of Acinetobacter baumannii, 2–16 µg/mL against Pseudomonas aeruginosa PAO1, and 2 µg/mL against Escherichia coli NCTC 12923, but were inactive (MIC > 64 µg/mL) against the two isolates of Klebsiella pneumoniae.

scholarly journals β-Lactams Increase the Antibacterial Activity of Daptomycin against Clinical Methicillin-Resistant Staphylococcus aureus Strains and Prevent Selection of Daptomycin-Resistant Derivatives

2012 ◽  
Vol 56 (12) ◽  
pp. 6192-6200 ◽  
Author(s):  
Shrenik Mehta ◽  
Christopher Singh ◽  
Konrad B. Plata ◽  
Palas K. Chanda ◽  
Arundhati Paul ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mutant Selection ◽  
Methicillin Resistant ◽  
Content Type ◽  
Oxacillin Resistance ◽  
Worm Model ◽  
Mrsa Strains ◽  
Selection Of

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) has emerged to be one of the most important pathogens both in health care and in community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin infections, bacteremia, and right-sided endocarditis caused by MRSA. Resistance to DAP (DAPr) has been reported in MRSA and is mostly accompanied by a parallel decrease in oxacillin resistance, a process known as the “seesaw effect.” Our study provides evidence that the seesaw effect applies to other β-lactams and carbapenems of clinical use, including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC), and imipenem (IMP), in heterogeneous DAPrMRSA strains but not in MRSA strains expressing homogeneous β-lactam resistance. The antibacterial efficacy of DAP in combination with β-lactams was evaluated in isogenic DAP-susceptible (DAPs)/DaprMRSA strains originally obtained from patients that failed DAP monotherapy. Bothin vitro(MIC, synergy-kill curve) andin vivo(wax worm model) approaches were used. In these models, DAP and a β-lactam proved to be highly synergistic against both heterogeneous and homogeneous clinical DAPrMRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge, reverting the increased repulsion provoked by DAP alone, an effect that may favor the binding of DAP to the cell surface. The ease ofin vitromutant selection was observed when DAPsMRSA strains were exposed to DAP. Importantly, the combination of DAP and a β-lactam prevented the selection of DAPrvariants. In summary, our data show that the DAP–β-lactam combination may significantly enhance both thein vitroandin vivoefficacy of anti-MRSA therapeutic options against DAPrMRSA infections and represent an option in preventing DAPrselection in persistent or refractory MRSA infections.

scholarly journals The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-ResistantStaphylococcus aureusin a Rabbit Model of Experimental Endocarditis

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Cristina García-de-la-Mària ◽  
Oriol Gasch ◽  
Javier García-Gonzalez ◽  
Dolors Soy ◽  
Evelyn Shaw ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Combined Therapy ◽  
Rabbit Model ◽  
Bactericidal Effect ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTWe investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistantStaphylococcus aureus(MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to performin vitrotime-kill studies using standard (106) and high (108) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 μg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%,P= 0.046) and the decrease in the density of bacteria within the vegetations (P= 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%,P= 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%,P= 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.

scholarly journals β-Lactams Enhance Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus Bacteremia Compared to Vancomycin Alone

2013 ◽  
Vol 58 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Thomas J. Dilworth ◽  
Omar Ibrahim ◽  
Pamela Hall ◽  
Jora Sliwinski ◽  
Carla Walraven ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Synergistic Activity ◽  
Methicillin Resistant ◽  
Content Type ◽  
Staphylococcus Aureus Bacteremia ◽  
High Incidence ◽  
The Difference ◽  
Initiation Of Therapy ◽  
The Impact

ABSTRACTVancomycin (VAN) is often used to treat methicillin-resistantStaphylococcus aureus(MRSA) bacteremia despite a high incidence of microbiological failure. Recentin vitroanalyses of β-lactams in combination with VAN demonstrated synergistic activity against MRSA. The goal of this study was to examine the impact of combination therapy with VAN and a β-lactam (Combo) on the microbiological eradication of MRSA bacteremia compared to VAN alone. This was a retrospective cohort study of patients with MRSA bacteremia who received Combo therapy or VAN alone. Microbiological eradication of MRSA, defined as a negative blood culture obtained after initiation of therapy, was used to evaluate the efficacy of each regimen. A total of 80 patients were included: 50 patients in the Combo group and 30 patients in the VAN-alone group. Microbiological eradication was achieved in 48 patients (96%) in the Combo group compared to 24 patients (80%) in the VAN-alone group (P= 0.021). In a multivariable model, the Combo treatment had a higher likelihood of achieving microbiological eradication (adjusted odds ratio, 11.24; 95% confidence interval, 1.7 to 144.3;P= 0.01). In patients with infective endocarditis (n= 22), 11/11 (100%) who received Combo therapy achieved microbiological eradication compared to 9/11 (81.8%) treated with VAN alone, but the difference was not statistically significant (P= 0.20). Patients with MRSA bacteremia who received Combo therapy were more likely to experience microbiological eradication of MRSA than patients who received VAN alone.

scholarly journals Pharmacodynamics of a Simulated Single 1,200-Milligram Dose of Oritavancin in anIn VitroPharmacokinetic/Pharmacodynamic Model of Methicillin-Resistant Staphylococcus aureus Infection

2012 ◽  
Vol 57 (1) ◽  
pp. 205-211 ◽  
Author(s):  
Adam Belley ◽  
Francis F. Arhin ◽  
Ingrid Sarmiento ◽  
Hong Deng ◽  
Warren Rose ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Effect ◽  
Pharmacodynamic Model ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Mrsa Strains ◽  
Kill Curve

ABSTRACTThe safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, anin vitropharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistantStaphylococcus aureus(MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC0-24), 48 h (AUBKC0-48), and 72 h (AUBKC0-72). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC0-24s for the three MRSA strains than with vancomycin (P< 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC0-48and AUBKC0-72against one MRSA strain and a lower AUBKC0-48for another strain than did vancomycin exposure (P< 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC0-48and AUBKC0-72for one of the MRSA isolates than did vancomycin exposure (P< 0.05). Lower AUBKC0-24s for two of the MRSA strains (P< 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in anin vitropharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.

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