Treatment Of Multidrug-resistant Gram-positive Infections Research Articles

Tedizolid Phosphate: a Next-Generation Oxazolidinone.

Treatment of multidrug-resistant Gram-positive infections continues to challenge clinicians as the emergence of new resistance mechanisms outpaces introduction of novel antimicrobial agents. Tedizolid phosphate is a next-generation oxazolidinone with activity against both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. Tedizolid has consistently shown potency advantages over linezolid against Gram-positive microorganisms including those with reduced susceptibility to linezolid. Of particular significance, minimum inhibitory concentrations of tedizolid appear to be largely unaffected by the chloramphenicol–florfenicol resistance (cfr) gene, which has been implicated in a number of published linezolid-resistant organism outbreaks. Tedizolid phosphate also has been found to have a favorable pharmacokinetic profile allowing for once-daily dosing in both oral and intravenous forms. Potency and pharmacokinetic advantages have allowed for lower total daily doses of tedizolid, compared to linezolid, being needed for clinical efficacy in the treatment of acute bacterial skin and skin structure infections (ABSSSI). The decreased total drug exposure produced may in part be responsible for a decrease in the observed adverse effects including thrombocytopenia. Tedizolid phosphate is currently indicated for the treatment of ABSSSI and under investigation for the treatment of nosocomial pneumonia. Although much of the role of tedizolid remains to be defined by expanding clinical experience, tedizolid is likely a welcomed addition to the mere handful of agents available for the treatment of multidrug-resistant Gram-positive infections.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-015-0060-3) contains supplementary material, which is available to authorized users.

Resistance to "last resort" antibiotics in Gram-positive cocci: The post-vancomycin era

New therapeutic alternatives have been developed in the last years for the treatment of multidrug-resistant Gram-positive infections. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are considered a therapeutic challenge due to failures and lack of reliable antimicrobial options. Despite concerns related to the use of vancomycin in the treatment of severe MRSA infections in specific clinical scenarios, there is a paucity of solid clinical evidence that support the use of alternative agents (when compared to vancomycin). Linezolid, daptomycin and tigecycline are antibiotics approved in the last decade and newer cephalosporins (such as ceftaroline and ceftobiprole) and novel glycopeptides (dalvavancin, telavancin and oritavancin) have reached clinical approval or are in the late stages of clinical development. This review focuses on discussing these newer antibiotics used in the "post-vancomycin" era with emphasis on relevant chemical characteristics, spectrum of antimicrobial activity, mechanisms of action and resistance, as well as their clinical utility.

Loading Dose Required to Achieve Rapid Therapeutic Teicoplanin Trough Plasma Concentration in Patients with Multidrug‐Resistant Gram‐Positive Infections

Teicoplanin is an antibiotic drug prescribed for the treatment of multidrug-resistant Gram-positive infections. However, there is currently no consensus as to the optimal teicoplanin loading dose. The objective of this study was to compare plasma concentrations of teicoplanin in patients with multidrug-resistant Gram-positive infections after the administration of two different loading doses. Two groups of patients were infused intravenously with four loading doses of 6mg/kg body-weight (group A, n=12) or 12mg/kg body-weight (group B, n=11). The first three loading doses were administered at 12-hr intervals, and the fourth was given 24hr after the third dose. Maintenance doses of 6mg/kg were administered every day, every other day or every third day depending on the individual's creatinine clearance, and teicoplanin trough plasma concentrations were monitored. Only samples obtained on the same day for both groups were compared statistically. A higher percentage of group B patients achieved the desired therapeutic concentration of teicoplanin (C(min.) ≥10mg/L) on days2 and 3 (90.0% and 100%, respectively) compared with patients in group A (18.2% and 16.7%, respectively) (p<0.001). In addition, more patients in group B achieved therapeutic concentrations from days2 through 12. In conclusion, despite limitations in drawing definitive conclusions because of a relatively small sample size and variability in renal impairment among patients, our findings suggest that a teicoplanin loading dose of 12mg/kg body-weight results in a safe and rapid attainment of therapeutic trough plasma concentrations. This regimen may enhance treatment efficacy.

Comparison of Continuous and Intermittent IV Infusion of Vancomycin: Systematic Review

There is some evidence that administration of vancomycin by continuous infusion has pharmacokinetic and pharmacodynamic advantages over traditional intermittent dosing. Whether these advantages translate into clinical efficacy remains controversial. To review the literature comparing continuous infusion of vancomycin and conventional intermittent IV dosing in terms of efficacy and safety. A literature search was conducted in the PubMed/MEDLINE and Embase databases and the Cochrane Central Register of Controlled Trials, and by means of the Google search engine, and the reference lists of pertinent articles were searched manually. All human studies published in English or French that evaluated vancomycin given by continuous and intermittent IV infusion were reviewed. Articles that did not include a comparator arm and those that assessed continuous and intermittent intraperitoneal infusions were excluded. The level of evidence of each study was categorized according to the US Preventive Services Task Force rating scale. In total, 9 studies were identified: 1 in a pediatric population and 8 in adult populations. Of the 3 studies with the highest quality of evidence (level I), one demonstrated pharmacodynamic advantages with continuous infusion of vancomycin. Of the 6 studies representing a moderate level of evidence (level II), 3 also favoured continuous infusion in terms of pharmacokinetic and pharmacodynamic outcomes, but the findings in terms of clinical outcomes were mixed. Current evidence evaluating the pharmacokinetic and pharmacodynamic advantages and clinical efficacy of continuous versus intermittent vancomycin infusions is inconsistent and does not support the routine use of continuous infusion for the treatment of multidrug-resistant gram-positive infections.

Telavancin: A novel lipoglycopeptide antimicrobial agent

The pharmacology, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and place in therapy of telavancin are reviewed. Telavancin is a lipoglycopeptide antimicrobial agent under development for use in the treatment of multidrug-resistant gram-positive infections. Telavancin, like vancomycin, inhibits cell-wall biosynthesis by binding to late-stage cell-wall precursors. However, unlike vancomycin, telavancin also depolarizes the bacterial cell membrane and disrupts its functional integrity. Telavancin has concentration-dependent bactericidal activity and is active against gram-positive aerobic and anaerobic organisms. It is highly protein bound (93%) and has a volume of distribution of 115 mL/kg and a half-life of approximately eight hours. Telavancin is eliminated renally, and a dosage reduction is required in renally impaired patients. Animal models suggest that telavancin may be effective in the treatment of soft-tissue infections, bacteremia, endocarditis, meningitis, and pneumonia caused by gram-positive pathogens. Telavancin was not inferior to standard treatment for complicated skin and soft-tissue infections in two Phase II clinical trials and two Phase III clinical trials. A new drug application has been submitted for this indication, and Phase III trials to evaluate use in hospital-acquired-pneumonia, including infections caused by methicillin-resistant Staphylococcus aureus (MRSA), are planned. Adverse effects include metallic taste, nausea, vomiting, headache, foamy urine, Q-Tc-interval prolongation, hypokalemia, and serum creatinine increases. In trials evaluating telavancin for skin and soft-tissue infections, the dosage was 10 mg/kg i.v. once daily. Telavancin is a promising new agent for gram-positive infections and may offer an alternative to vancomycin for MRSA-associated infections.