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Evaluation of Pharmacodynamic Interactions Between Telavancin Infect Dis Ther DOI 10.1007/s40121-016-0121-2 ORIGINAL RESEARCH Evaluation of Pharmacodynamic Interactions Between Telavancin and Aztreonam or Piperacillin/ Tazobactam Against Pseudomonas aeruginosa, Escherichia coli and Methicillin-Resistant Staphylococcus aureus Juwon Yim . Jordan R. Smith . Katie E. Barber . Jessica A. Hallesy . Michael J. Rybak Received: May 2, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com ABSTRACT Methods: In vitro one-compartment PK/PD models were run over 96 h simulating TLV Introduction: In clinical trials comparing 10 mg/kg every 48 h, ATM 500 mg every 8 h telavancin (TLV) with vancomycin for and PTZ continuous infusion 13.5 g over 24 h treatment of hospital-acquired pneumonia, alone and in combination against P. aeruginosa, TLV demonstrated lower clinical cure rates E. coli and methicillin-resistant S. aureus than vancomycin in patients who had mixed (MRSA). The efficacy of antimicrobials was gram-positive and -negative infections and were evaluated by plotting time-kill curves and concomitantly treated with either aztreonam calculating the reduction in log10 cfu/ml over (ATM) or piperacillin/tazobactam (PTZ). Here, 96 h. we investigated therapeutic interactions Results: Against both MRSA strains, TLV was between TLV and ATM or PTZ in an in vitro rapidly bactericidal at 4 h and maintained its pharmacokinetic/pharmacodynamic (PK/PD) activity over 96 h with no observed antagonism model under simulated reduced renal function by either ATM or PTZ. PTZ maintained conditions. bacteriostatic and bactericidal activities against Enhanced content To view enhanced content for this E. coli ATCC 25922 and clinical strain R1022 at article go to http://www.medengine.com/Redeem/ 96 h, whereas both strains regrew as soon as 22E4F0603737CC9F. 24 h in ATM models. Against P. aeruginosa J. Yim Á J. R. Smith Á J. A. Hallesy Á M. J. Rybak (&) ATCC 27853, regrowth was noted at 24 h in Anti-Infective Research Laboratory, Department of models simulating ATM and PTZ. The addition Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State of TLV to ATM or PTZ had no appreciable University, 259 Mack Ave., Detroit, MI 48201, USA impact on activity against the two E. coli strains e-mail: [email protected] and P. aeruginosa strain. K. E. Barber Conclusions: The combinations of TLV and School of Pharmacy, The University of Mississippi, 2500 North State Street, Jackson, MS 39216, USA either ATM or PTZ did not demonstrate any antagonistic activity. Clinical variables and M. J. Rybak School of Medicine, Wayne State University, patient characteristics should be further 540 E. Canfield St., Detroit, MI 48201, USA Infect Dis Ther explored to determine possible reasons for 7–21 days. In cases of polymicrobial infections, discrepancies in outcomes. the addition of aztreonam or Funding: Theravance Biopharma Antibiotics, piperacillin/tazobactam was permitted. Inc. Telavancin achieved better or comparable cure rates for monomicrobial infections caused by S. Keywords: Aztreonam; Drug interactions; aureus including MRSA. However, patients with Escherichia coli; Methicillin resistant; polymicrobial pneumonia had a better cure rate Staphylococcus aureus; Piperacillin/tazobactam; when they were treated with vancomycin Pseudomonas aeruginosa; Telavancin (79.4%) compared to telavancin (66.2%), even though the difference did not reach statistical significance [4]. While it is possible that the INTRODUCTION reduced efficacy may be due to inadequacy of treatment based on susceptibility patterns of Telavancin is a semisynthetic lipoglycopeptide the isolated gram-negative pathogens, the with broad-spectrum activity against reason for these discrepancies in cure rates is gram-positive bacteria with different resistance unknown. phenotypes including methicillin-resistant S. There was a concern about reduced efficacy aureus (MRSA), vancomycin-intermediate S. in patients with pre-existing renal impairment aureus (VISA), heterogeneous VISA (hVISA) and in comparison to vancomycin. In the study of VanB vancomycin-resistant enterococci (VRE) Assessment of Telavancin in Complicated Skin [1, 2]. Telavancin is approved for treatment of and Skin Structure Infections (ATLAS), 1867 complicated skin and skin structure infections patients were randomly assigned to (cSSSIs) caused by susceptible gram-positive vancomycin 1 g every 12 h or telavancin organisms and hospital-acquired and 10 mg/kg every 24 h for treatment of ventilator-associated bacterial pneumonia confirmed or suspected cSSSIs caused by (HABP/VABP) caused by susceptible S. aureus gram-positive organisms. Clinical cure rates in in the USA [3]. patients with MRSA infections were comparable Even though telavancin demonstrated a between the vancomycin and telavancin similar efficacy to vancomycin in clinical trials groups, achieving 86% and 91%, respectively. for treatment of both cSSSIs and nosocomial However, patients with creatinine clearance pneumonia, there are two subgroups of patients (CrCl) B50 ml/min had decreased clinical cure where cure rates were lower when treated with rates when treated with telavancin at 67.4% telavancin compared to vancomycin. In the versus 82.7% when treated with vancomycin Assessment of Telavancin for Treatment of [5, 6]. Hospital-Acquired Pneumonia (ATTAIN) trials, We hypothesize that there might be telavancin efficacy appeared to be lower in a antagonistic interactions between telavancin subset of the population with mixed and either piperacillin/tazobactam or gram-positive and -negative nosocomial aztreonam, especially in patients with pneumonia. In these studies, patients were impaired renal functions. Therefore, the aim of randomized to either vancomycin 1 g every this study was to perform in vitro 12 h or telavancin 10 mg/kg every 24 h for pharmacokinetic/pharmacodynamic (PK/PD) treatment of hospital-acquired pneumonia for model evaluations against MRSA and selected Infect Dis Ther gram-negative pathogens, including the most drug loss due to binding to plastic materials frequently isolated pathogens in the ATTAIN [7, 8]. Colony counts were determined using trials, to determine whether any antagonistic Tryptic Soy Agar (TSA, Difco, Detroit, MI) plates. relationships exist between telavancin and either aztreonam or piperacillin/tazobactam Susceptibility Testing under simulated reduced renal function conditions. Minimum inhibitory concentration (MIC) values were determined by broth METHODS microdilution in duplicate at an inoculum of *1 9 106 cfu/ml according to the CLSI Bacterial Strains guidelines [8]. Any isolate for which the MIC results were more than one dilution different P. aeruginosa ATCC 27853, two Escherichia coli was repeated. For telavancin MICs, 0.002% strains (ATCC 25922 and clinical isolate R1022) Polysorbate 80 (Sigma Chemical Co., St. Louis, and two MRSA strains (ATCC 43300 and clinical MO) was incorporated into broth. For isolate R5255) were evaluated in this study. piperacillin/tazobactam MICs, tazobactam These isolates were randomly selected from concentrations were fixed at 4 mg/l. All the isolate collection of the Anti-infective samples were incubated at 37 °C for 24 h. Research Laboratory at Wayne State University and consisted mostly of well-referenced ATCC In Vitro PK/PD Model strains. All gram-positive bacteria were susceptible to both vancomycin and An in vitro one-compartment PK/PD model with telavancin, while gram-negative bacteria were a 250-ml capacity and input and outflow ports susceptible to aztreonam and was used. Prior to each experiment, bacterial piperacillin/tazobactam. lawns from an overnight growth on TSA were harvested, re-suspended in MHB and injected Antimicrobial Agents into each model prefilled with media to obtain a starting inoculum of *107 cfu/ml. For models Telavancin powder was provided by its with telavancin, aztreonam and antimicrobial manufacturer (Theravance Biopharma combinations, antimicrobials were administered Antibiotics, Inc., South San Francisco, CA). as boluses over a 96-h time period to simulate Piperacillin, tazobactam and aztreonam were human pharmacokinetics. Fresh media were purchased commercially (Sigma Chemical Co., continuously supplied and removed from the St. Louis, MO). compartment along with the drug via a peristaltic pump (Masterflex, Cole-Parmer Media Instrument Co., Chicago, IL) at an appropriate rate to simulate the average human half-lives (t1/ Cation-adjusted Mueller-Hinton broth (MHB, 2) of the antimicrobials. Antimicrobial exposures Difco, Detroit MI) was used for PK/PD models were based on free drug pharmacokinetics and susceptibility testing. Polysorbate-80 was pertinent to each antimicrobial agent. For incorporated into the broth at 0.002% for any models with piperacillin/tazobactam, a bolus experiment involving telavancin to minimize dose was administered to achieve a steady-state Infect Dis Ther concentration at T0, and fresh media containing concentrations. All samples were then stored at a constant concentration of -80 °C until ready for analysis. Telavancin and piperacillin/tazobactam were pumped in at the piperacillin/tazobactam concentrations were appropriate rate to simulate continuous infusion measured by bioassay using Kocuria rhizophila of piperacillin/tazobactam as used clinically in (formerly Micrococcus luteus) ATCC 9341 [16, 17]. renal failure (CrCl 20–40 ml/min) [9]. For bioassay in combination models, Antimicrobial simulations, including free peak pharmacokinetic models using a single agent concentrations,
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