Whole genome analysis of linezolid resistance in Streptococcus pneumoniae reveals resistance and compensatory mutations

<p>Abstract</p> <p>Background</p> <p>Several mutations were present in the genome of <it>Streptococcus pneumoniae </it>linezolid-resistant strains but the role of several of these mutations had not been experimentally tested. To analyze the role of these mutations, we reconstituted resistance by serial whole genome transformation of a novel resistant isolate into two strains with sensitive background. We sequenced the parent mutant and two independent transformants exhibiting similar minimum inhibitory concentration to linezolid.</p> <p>Results</p> <p>Comparative genomic analyses revealed that transformants acquired G2576T transversions in every gene copy of 23S rRNA and that the number of altered copies correlated with the level of linezolid resistance and cross-resistance to florfenicol and chloramphenicol. One of the transformants also acquired a mutation present in the parent mutant leading to the overexpression of an ABC transporter (spr1021). The acquisition of these mutations conferred a fitness cost however, which was further enhanced by the acquisition of a mutation in a RNA methyltransferase implicated in resistance. Interestingly, the fitness of the transformants could be restored in part by the acquisition of altered copies of the L3 and L16 ribosomal proteins and by mutations leading to the overexpression of the spr1887 ABC transporter that were present in the original linezolid-resistant mutant.</p> <p>Conclusions</p> <p>Our results demonstrate the usefulness of whole genome approaches at detecting major determinants of resistance as well as compensatory mutations that alleviate the fitness cost associated with resistance.</p

Spectrum and potency evaluation of a new oxazolidinone, linezolid: report from the SENTRY Antimicrobial Surveillance Program, 1998-2000

Copyright © 2002 Elsevier Science Inc. All rights reserved.Resistance (R) among Gram-positive cocci has escalated in the last two decades to levels necessitating the development and use in the newer drug classes, oxazolidinones (linezolid) and streptogramins (quinupristin/dalfopristin [Q/D]). The SENTRY Antimicrobial Surveillance Program has monitored these classes before, during and after their release by various regulatory agencies. Over 30,000 Gram-positive strains were tested against >30 drugs by reference broth microdilution methods between 1998-2000 in four geographic regions (Asia-Western Pacific [APAC], Europe [EU], Latin America [LA], North America [NA]). The tested strains were 23,188 staphylococci; 5,103 enterococci and 2,045 streptococci. Among staphylococci, linezolid was active against all isolates (MICs, EU (3.2%) > LA (1.6%) > APAC (1.3%). Among streptococci, linezolid was consistently active (MIC(90,) 1 microg/ml) as were the glycopeptides and Q/D. Variable penicillin-R (MIC, > or = 2 microg/ml) was observed among regions: EU (32.5%) > APAC (15.1%) > LA (13.8%) > NA (9.6%), and macrolide-R was higher in EU (40.3%). Ciprofloxacin-R at > or =4 microg/ml in streptococcal strains was noted world wide highest in viridans group streptococci (18.4-25.6%). Linezolid remained active (MIC, < or =4 microg/ml) against all Gram-positive species strains tested in the SENTRY Program (1998-2000). Q/D, glycopeptides and newer FQ compounds were generally less effective in vitro. It remains a prudent practice to continue surveillance programs to detect emerging resistance patterns and recognize significant regional variations in the oxazolidinone susceptibilities.Alan H. Mutnick, Douglas J. Biedenbach, John D. Turnidge and Ronald N. Joneshttp://www.elsevier.com/wps/find/journaldescription.cws_home/505759/description#descriptio

Recombinant Human Erythropoietin vs Transfusions in the Treatment of Anemia of Prematurity: A Cost-benefit Analyis

Objective: To evaluate the costs relative to the benefits of using recombinant human erythropoietin (rHuEPO) therapy as an alternative to red blood cell (RBC) transfusions in infants with anemia of prematurity. Design: A cost-benefit analysis of rHuEPO therapy was performed based on its use in very-low-birth-weight premature infants. Setting and Patients: Data were drawn from published studies or were provided by the University of Iowa Hospitals and Clinics, Iowa City. Main Outcome Measures: Costs and benefits were analyzed as a comparison of incurred costs to averted costs. Incurred and averted costs of rHuEPO therapy and RBC transfusions included direct product costs and estimates of costs of adverse events. The analysis was viewed in terms of net savings. Sensitivity analysis was performed. Results: The base case analysis yielded a net loss of $299.48 per infant. A 54% reduction in the direct product costs of rHuEPO therapy yielded a break-even point. No other variations in the sensitivity analysis resulted in a net savings. Conclusion: Using assumptions based on the current state of clinical research, it appears that routine use of rHuEPO with supplemental RBC transfusions would not generate any cost savings as an alternative to RBC transfusions alone. As further evidence is compiled on the efficacy of rHuEPO therapy in very-low-birth-weight premature infants, the true costs may be better established.(Arch Pediatr Adolesc Med. 1994;148:582-588

A cost analysis comparing erythropoietin and red cell transfusions in the treatment of anemia of prematurity

BACKGROUND: Anemia of prematurity is invariably observed in very low birth weight infants and may become symptomatic enough to be treated with packed red cell transfusions. Recently, treatment of this condition with recombinant human erythropoietin has been advocated. STUDY DESIGN AND METHODS: To compare the costs of training symptomatic anemia in hospitalized premature infants with transfusions alone or with erythropoietin plus red cell transfusions as needed, cost estimates were derived from local hospital and published cost data. Decision analysis and sensitivity analysis were applied to a “base case.” The base case was derived from results of a multicenter erythropoietin trial in the United States in which premature infants received 500 U of erythropoietin per kg of body weight each week. Because erythropoietin treatment began on average at 3 weeks of life, when infants were clinically stable, they had already received 3.5 red cell transfusions. During the 6-week treatment period, erythropoietin- treated infants received significantly fewer additional transfusions: a mean of 1.6 versus 1.1. RESULTS: The base-case cost in 1993 dollars for treating anemia in hospitalized premature infants with erythropoietin and transfusions was $1,326. This was nearly twice the cost of conventional treatment with transfusions alone ($721). If the 6-week treatment period alone is considered, erythropoietin is 3.6 times more costly: $840 versus$235. CONCLUSION: The largest available US study using erythropoietin to treat anemia in premature infants has demonstrated a small, but significant, reduction in transfusion needs. However, this study\u27s cost data alone do not justify the widespread use of erythropoietin in premature infants. When this issue is probed in great depth, sensitivity analyses demonstrate that major reductions in erythropoietin\u27s cost and/or improvements in its effectiveness quite possibly will make its use economically more attractive