Evaluation of Pharmacodynamic Interactions Between Telavancin and Aztreonam or Piperacillin/Tazobactam Against Pseudomonas aeruginosa, Escherichia coli and Methicillin-Resistant Staphylococcus aureus

INTRODUCTION: In clinical trials comparing telavancin (TLV) with vancomycin for treatment of hospital-acquired pneumonia, TLV demonstrated lower clinical cure rates than vancomycin in patients who had mixed gram-positive and -negative infections and were concomitantly treated with either aztreonam (ATM) or piperacillin/tazobactam (PTZ). Here, we investigated therapeutic interactions between TLV and ATM or PTZ in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model under simulated reduced renal function conditions. METHODS: In vitro one-compartment PK/PD models were run over 96 h simulating TLV 10 mg/kg every 48 h, ATM 500 mg every 8 h and PTZ continuous infusion 13.5 g over 24 h alone and in combination against P. aeruginosa, E. coli and methicillin-resistant S. aureus (MRSA). The efficacy of antimicrobials was evaluated by plotting time-kill curves and calculating the reduction in log(10) cfu/ml over 96 h. RESULTS: Against both MRSA strains, TLV was rapidly bactericidal at 4 h and maintained its activity over 96 h with no observed antagonism by either ATM or PTZ. PTZ maintained bacteriostatic and bactericidal activities against E. coli ATCC 25922 and clinical strain R1022 at 96 h, whereas both strains regrew as soon as 24 h in ATM models. Against P. aeruginosa ATCC 27853, regrowth was noted at 24 h in models simulating ATM and PTZ. The addition of TLV to ATM or PTZ had no appreciable impact on activity against the two E. coli strains and P. aeruginosa strain. CONCLUSIONS: The combinations of TLV and either ATM or PTZ did not demonstrate any antagonistic activity. Clinical variables and patient characteristics should be further explored to determine possible reasons for discrepancies in outcomes. FUNDING: Theravance Biopharma Antibiotics, Inc.