Pharmacodynamics of once-daily amikacin in various combinations with cefepime, aztreonam, and ceftazidime against Pseudomonas aeruginosa in an in vitro infection model

Abstract

The pharmacodynamics of once-daily amikacin administered as monotherapy and in combination with aztreonam, ceftazidime, and cefepime against Pseudomonas aeruginosa ATCC 27853 and clinical isolate 16690 (moderately susceptible to ceftazidime) were investigated with an in vitro model of infection over a 24-h period. Monotherapy with aztreonam, ceftazidime, and cefepime and combinations of aztreonam with cefepime or ceftazidime were also studied. MICs and MBCs were determined for viable organisms at 24 h to test for the development of resistance. Once-daily amikacin demonstrated killing activity over the initial 8 h superior to those of all other drugs administered as monotherapy against both strains tested (P < 0.01). Regrowth by 24 h was greatest for the amikacin regimen (P < 0.01) but was apparent for all monotherapy regimens against both strains. No changes in susceptibilities were observed. All combination therapies containing once-daily amikacin achieved 99.9% reductions in log10 CFU/ml by 2.0 h against both strains, with no regrowth of organisms at 24 h. Aztreonam-cefepime and -ceftazidime combinations required approximately 5 to 6 h to achieve a 99.9% reduction in log10 CFU/ml. Although there was no difference in time to the 99.9% kill between the aztreonam-cefepime and -ceftazidime regimens against either strain, the killing activity of these combinations was significantly less than those of regimens containing once-daily amikacin (P < 0.01). Minor differences in the initial susceptibilities of beta-lactams and the monobactam aztreonam against P. aeruginosa may not be important for therapeutic outcomes when used in combination with single-daily aminoglycoside therapy.

Dual beta-lactam therapy for serious Gram-negative infections: is it time to revisit?

“…Consistent with in vitro synergy studies, aztreonam was found to enhance the activity of other beta-lactams (Lister et al, 1998;McGrath et al, 1992;Van Laethem et al, 1984). In a P. aeruginosa in vitro PD model, aztreonam combined with ceftazidime or cefepime led to a shorter time required to achieve 99.9% reduction in log 10 CFU/mL than monotherapy (McGrath et al, 1992).…”

“…Particularly impressive results were found in 2 separate E. coli rabbit meningitis models, where mecillinam plus ampicillin led to a significant decrease in bacterial titers compared to each agent alone (P b 0.01) (Schaad et al, 1982;Scheld et al, 1979). Third-generation cephalosporins also led to improved activity when used with other beta-lactams Tsuchiya, 1981a, 1981b;Lister et al, 1998;McGrath et al, 1992;Shyu et al, 1987;Zinner et al, 1981). In a P. aeruginosa rat peritonitis model, significantly higher survival rates were seen when ticarcillin was combined with ceftazidime than when each agent was used alone (P b 0.05) (Shyu et al, 1987).…”

“…In a P. aeruginosa in vitro PD model, aztreonam combined with ceftazidime or cefepime led to a shorter time required to achieve 99.9% reduction in log 10 CFU/mL than monotherapy (McGrath et al, 1992). In addition, Lister et al (1998) found that aztreonam combined with cefepime or ceftazidime resulted in a N2-fold decrease in mean log 10 CFU/mL at 24 hours against many of the P. aeruginosa isolates studied relative to ceftazidime or cefepime used alone.…”

“…While Chen et al (2004) did not find similarly promising outcomes with aztreonam combinations, synergy was detected iñ 8% of dual beta-lactam regimens, and there was no antagonism seen with any combination. The most recent evaluation explored the combination of ceftaroline with amikacin, levofloxacin, and various 10 10 5 × 10 3 10 9 10 3 TIC 100 mg/kg q3h 10 6 10 5 10 6 10 3 CAZ 70 mg/kg q8h 10 4 b 10 2 5 × 10 6 10 3 TIC 100 mg/kg q3h + AMK 11 mg/kg q2h 10 5 b 10 2 NR 10 5 CAZ + AMK (same dosages) 10 10 b 10 2 10 8 5 × 10 2 TIC + CAZ (same dosages) 10 5 b 10 2 NR 10 3 McGrath et al (1992) Time ( beta-lactams (Vidaillac et al, 2009). While ceftaroline plus amikacin was the only combination with synergistic activity against P. aeruginosa (3 of 4 isolates), no antagonism was observed with any dual beta-lactam regimen (Vidaillac et al, 2009).…”

“…Synergy was primarily defined in terms of MIC values where a 4-fold or greater reduction in the MIC of both antibiotics was classified as a synergistic combination (Baltimore et al, 1976;Bosso et al, 1990Bosso et al, , 1991Buesing and Jorgensen, 1984;Daschner and Hoffmann, 1982;Fass, 1980;Fass, 1982aFass, , 1982bFu and Neu, 1978;Kuck et al, 1981;Kurtz et al, 1981;Markowitz and Sibilla, 1983;Neu and Fu, 1978;Peterson et al, 1984;Sader et al, 2003;Scheld et al, 1979;Scribner et al, 1982;Stutman et al, 1984). Other definitions were based on the sum of the fractional inhibitory concentration (ΣFIC) or fractional bactericidal concentration (ΣFBC) (Anderson et al, 1981;Bosso et al, 1990;Chattopadhyay and Hall, 1979;Chen et al, 2004;Drusano et al, 1985;Foweraker et al, 2009;Tsuchiya, 1981a, 1981b;Lister et al, 1998;McGrath et al, 1992;Miles et al, 1981;Neu, 1982;Sader et al, 2003;Schaad et al, 1982;Song et al, 2003;van der Time-kill study ≥2 log 10 CFU/mL decrease compared with most active antibiotic, reduction of original inoculum of ≥2 log 10 CFU/mL, and one of the antibiotics alone did not affect growth curve (6) AMP + MCL (2:1 ratio) 4/6 0 0 2/6 K. pneumoniae (1) 0 Kondo and Tsuchiya (1981a) Combination effect Mouse peritonitis 1 dose at 0 h after infection S. marcescens (1) CFS + CFZ (1:2 and 1:4 ratio) Synergy CFS + CFT (1:1 and 1:2 ratio) Synergy with 1:1 regimen, addi...…”