Evaluating Aztreonam and Ceftazidime Pharmacodynamics with Escherichia coli in Combination with Daptomycin, Linezolid, or Vancomycin in an In Vitro Pharmacodynamic Model

Abstract

In an in vitro pharmacodynamic model, linezolid attenuated the activity of aztreonam and ceftazidime against Escherichia coli. Conversely, synergy was detected at 24 and 48 h when daptomycin or vancomycin was added to aztreonam and ceftazidime. We conclude that significant yet underappreciated interactions may occur between gram-positive-spectrum and gram-negative-spectrum antibacterials. Chicago, IL, 2007). Linezolid demonstrates minimal activity against gram-negative bacteria, so an explanation for worse outcomes in patients receiving linezolid is not obvious (22). However, there are cases of documented antagonism between beta-lactam agents and chloramphenicol, a drug similar to linezolid, by mechanisms of action (binding to domain V of the 50S subunit of rRNA) and resistance mechanisms (1,12,17,19,27,28). Therefore, it is practical to hypothesize that beta-lactam agents may be antagonized in the presence of linezolid or other protein synthesis inhibitors. The aim of this study was to evaluate the in vitro activities of aztreonam and ceftazidime in the presence or absence of linezolid, daptomycin, and vancomycin against two Escherichia coli strains.( Drug concentrations for time kill analyses were equal to one (0.19 mg/ml for aztreonam and 0.19 mg/ml for ceftazidime) and two (0.38 mg/ml for aztreonam and 0.38 mg/ml for ceftazidime) times the MIC of each drug. Linezolid (16 g/ml) was used to simulate clinically achievable peak serum concentrations in patients administered 600 mg every 12 h (q12h) (10). Additionally, a previously described one-compartment in vitro pharmacodynamic model (IVPM) provided continuous exposure of bacteria to changing concentrations of antibiotics (3, 29). All model simulations were conducted over 48 h and were performed at minimum in triplicate. Calculated free-drug concentrations were simulated from the following total pharmacokinetic concentrations: for aztreonam, 1 g q8h (half-life [t 1/2 ], 2 h; maximum concentration of drug in serum [C max ], 75 g/ml; protein binding, 55%; free maximum concentration (fC max ), 34 g/ml) (25); for ceftazidime, 1 g q8h (t 1/2 , 2.3 h; C max , 60 g/ml; protein binding, 10%; fC max , 54 g/ml) (4); for daptomycin, 6 mg/kg of body weight q24h (t 1/2 , 8 h; C max , 98.6 g/ml; protein binding, 92%; fC max , 7.9 g/ml) (8); for linezolid, 600 mg q12h; (t 1/2 , 6 h; C max , 18 g/ml; protein binding, 31%; fC max , 12.4 g/ml) (23); and for vancomycin, 1.25 g q12h (t 1/2 , 6 h; C max , 45 g/ml; minimum concentration of drug in serum, 15 to 20 g/ml; protein binding, 55%; fC max , 20.3 g/ml) (18). A peristaltic pump (Masterflex; Cole-Parmer Instrument Company, Chicago, IL) was used to continually replace antibiotic-containing medium with fresh Mueller-Hinton broth supplemented with 25 g/ml calcium and 12.5 g/ml

Effect of Linezolid on the 50% Lethal Dose and 50% Protective Dose in Treatment of Infections by Gram-Negative Pathogens in Naive and Immunosuppressed Mice and on the Efficacy of Ciprofloxacin in an Acute Murine Model of Septicemia

“…Consistent with previous in vitro checkerboard studies (6,11,20), there was no evidence of in vivo antagonism or synergy of the combination of linezolid and ciprofloxacin. These findings are of particular interest given the recent phase 3 comparison of linezolid and vancomycin in patients with complicated skin and skin structure infections and catheter-related bloodstream infections due to Gram-positive pathogens, in which a mortality imbalance was reported for the linezolid arm (22).…”

“…Although the FIC index derived using the checkerboard technique is both popular and simple to obtain (15), it has several well-documented limitations (9). A more recent in vitro study of linezolid, daptomycin, and vancomycin suggested there was some attenuation of activity against Escherichia coli ATCC 25922 when linezolid was used in combination with ceftazidime or aztreonam at 48 h in an in vitro pharmacodynamic model (IVPM) system (11). However, in a separate study, no antagonism was observed in an IVPM system using linezolid in combination with aztreonam or ceftazidime at clinically relevant concentrations against the same E. coli strain (6).…”

Evaluating Polymyxin B-Based Combinations against Carbapenem-Resistant Escherichia coli in Time-Kill Studies and in a Hollow-Fiber Infection Model

“…Time-kill studies (TKS) were performed on all five CREC strains with amikacin, aztreonam, cefepime, doripenem, imipenem, levofloxacin, meropenem, piperacillin-tazobactam, rifampin, and tigecycline singly and in two-antibiotic combinations with polymyxin B. The antibiotic concentrations used were based on maximal clinically relevant unbound concentrations when maximum antibiotic doses were administered and are shown in Table 5 (13,(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The procedures for the TKS have been described in detail in our previous study (10).…”

Observed Antagonistic Effect of Linezolid on Daptomycin or Vancomycin Activity against Biofilm-Forming Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Model

“…To date, there have been limited investigations of daptomycin and linezolid in combination (5, 6). The combined use of these agents prompted an investigation into pharmacokinetic and pharmacodynamic activity and possible interactions when using combinations of bactericidal and bacteriostatic antimicrobials as previously described (7,8).(A portion of these results were presented as a poster at the 53rd annual Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], Denver, CO, 10 September 2013.) Two randomly selected clinical MRSA blood isolates (L31 and L328) from the LaPlante Laboratory at the Providence Veterans Affairs Medical Center were selected for analysis.…”