Reply to Tarchini

TO THE EDITOR—We appreciate the opportunity to respond to Dr. Tarchini regarding the important questions he poses in his letter. The following addresses each of his points in turn. First, as has been repeatedly demonstrated, achievement of vancomycin trough concentrations in the range of 15–20 mcg/mL does not necessarily result in improved outcomes (compared with lower trough concentrations). There have been several papers published showing just the opposite, similar, or worse clinical outcomes [1–3] with higher rates of nephrotoxicity associated with vancomycin trough concentrations >15 mcg/mL [1–6]. Importantly, this has been demonstrated using multivariate techniques to adjust for severity of illness and other risk factors [4, 5]. We performed a similar analysis using the data from the telavancin studies, wherein we examined outcome measures by vancomycin trough category (<10 mcg/mL, 10–14 mcg/mL, and ≥15 mcg/mL) and found lower clinical response rate, higher mortality, and higher rates of nephrotoxicity in the highest trough group [7]. Importantly, Acute Physiology and Chronic Health Evaluation (APACHE) scores at baseline were also similar across the three patient groups, and the findings held up after adjusting for important covariates that would predict poor outcomes. These observations, along with the mortality reported in the vancomycin arm of the Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia trials, suggest that inadequate dosing of vancomycin in these studies is unlikely. In addition, it is important to note that the support for the vancomycin trough concentration recommendations are graded as IIIB (moderate evidence for support and from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees), which is rather soft [8]. Unfortunately, there are no adequately controlled prospective studies to support the recommended trough concentrations. Finally, the studies were conducted as registrational studies. In the recent FDA guidance on conduct of registrational trials, the following recommendation was made: “The active comparator should be an antibacterial drug at the recommended dosage that is FDA-approved for the treatment of ‘nosocomial pneumonia’” [9]. In response to Dr. Tarchini's second question, there were only 20 patients (2.7% of 754 treated) who were switched from vancomycin to an antistaphylococcal penicillin (footnote Table 3, original report) [10]. Given that the efficacy and safety outcomes of this small cohort were similar to that of the entire vancomycin-treated group, their data were included with that of the larger population. With regard to the third question, all but 19 of 92 patients with baseline blood cultures containing a respiratory pathogen had the same pathogen in respiratory cultures. Only 5 of these 19 patients were included in the microbiologically evaluable population. Identity between the two sources was based on genus, species, and antimicrobial susceptibility pattern. More sophisticated techniques to determine identity were not carried out, so it is possible that some of these patients had other sources for their bacteremia. We sincerely hope that our responses reassure the readership of the validity and robustness of the telavancin clinical trial data. The ATTAIN authors are Ethan Rubinstein, Tahaniyat Lalani, G. Ralph Corey, Zeina A. Kanafani, Esteban C. Nannini, Marcelo G. Rocha, Galia Rahav, Michael S. Niederman, Marin H. Kollef, Andrew F. Shorr, Patrick C. Lee, Arnold L. Lentnek, Carlos M. Luna, Jean-Yves Fagon, Antoni Torres, Michael M. Kitt, Fredric C. Genter, Steven L. Barriere, H. David Friedland, and Martin E. Stryjewski.Financial support. This work was supported jointly by Theravance, Inc., and Astellas Pharma Global Development, Inc. Manuscript preparation. Theravance, Inc. (South San Francisco) provided assistance with statistical analyses. Editorial support was provided by Ed Parr and Emily Hutchinson, medical writers with Envision Scientific Solutions, funded by Astellas Pharma Global Development, Inc. Potential conflicts of interest. E. R. received grants or other financial support from Theravance, Inc., Astellas, Daiichi, Wyeth, Pfizer, Bayer-Schering, Merck, and Cubist Pharmaceuticals; has served as a consultant for Theravance, Inc., Astellas, Pfizer, Bayer, Wyeth, Merck, Atox, Ortho-McNeill, MeMed, BiondVax, and Sanofi-Aventis; has provided expert testimony for Johnson & Johnson; and has served on speaker's bureaus for Cubist Pharmaceuticals. G. R. C. has served as a consultant for Theravance, Inc.; has received grants or other financial support from Cubist Pharmaceuticals and Theravance, Inc.; has participated in advisory boards for Pfizer; and serves as a consultant for Cerexa, Merck, Pfizer, Cempra, and Astellas. E.C.N. has received honoraria from Theravance, Inc., and research support from Astellas and Johnson & Johnson. M. G. R. has received grants or other financial support from Theravance, Inc., Astellas, Hospira, Novartis, and Chiron, and is a consultant for Hospira. G. R. has received grants or other financial support from Pfizer; Theravance, Inc.; and Astellas. M. S. N. is a board member for Theravance, Inc., and Pfizer; has served as a consultant and received honoraria from Pfizer, Merck, Astellas, Astra-Zeneca, Johnson & Johnson, Theravance, Inc., Schering-Plough, and Nektar; and has received research or other financial support from Nektar, Astellas, and Pfizer. M. H. K. is a consultant for Pfizer, Merck, Bard, Kimberly Clark, and Ortho-McNeil; has served on the speaker's bureau for Pfizer, Merck, Bard, Kimberly Clark, Astra-Zeneca, Bayer, and Ortho-McNeil; and has received research support from Merck, Pfizer, and Astellas. A. F. S. has either served as a consultant or investigator or has delivered promotional lectures, or served on speaker's bureaus for Astellas, Theravance, Inc., Pfizer, Merck, Johnson & Johnson, Boehringer Ingelheim, GSK, Sanofi-Aventis, Canyon, Bard, Covidien, Forrest, and Medicine Comp; and has received honoraria or other financial support from Astellas, Boehringer Ingelheim, Bard, Covidien, Johnson & Johnson, Sanofi-Aventis, GSK, Theravance, Inc., Pfizer, Forrest, Canyon, Eli Lilly, and Cadence. P. L. has served as a consultant for Smiths Medical; has received research or other financial support from Theravance, Inc., and Astellas; serves on the speaker's bureau for Astellas; and has received honoraria from Wyeth, Astellas, King Pharmaceutical, and Adolor Corporation. A. L. L. has received research support from Wellstar Health System, Ortho-McNeill, Cerexa, Targanta, Optimer, and Theravance, Inc., and has received honoraria from Cubist Pharmaceuticals. C. M. L. has served as a consultant for and received honoraria from Pfizer, Merck, Astra-Zeneca, and Bayer and has received research support from Pfizer and Theravance, Inc. J.-Y. F. has received research support from Astellas and is a board member for Sanofi-Aventis. A. T. is a board member for Astellas; is a consultant for Bayer; has served as a speaker for Astellas, Novartis, and Bayer; and has research support and gifts to his institution from Pfizer. M. M. K. is a former employee of and holds stock/stock options for Theravance, Inc. F. C. G. is an employee of and holds stock/stock options for Theravance, Inc. S. L. B. is an employee of Theravance, Inc. H. D. F. is a former employee of and holds stock/stock options for Theravance, Inc. M. E. S. has served as a consultant for Theravance, Inc., The Medicines Company, and Trius Therapeutics; has received honoraria from Astellas and Theravance, Inc.; and received research or other financial support from Theravance, Inc.

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