In vitro activity of cefepime, imipenem, tigecycline, and gentamicin, alone and in combination, against extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Escherichia coli

Study Objective. To evaluate the activity of cefepime, imipenem, tigecycline, and gentamicin, alone and in combination, against extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae and Escherichia coli. Design. In vitro susceptibility and time-kill analysis. Setting. University-affiliated research laboratory. Isolates. Ten K. pneumoniae and 10 E. coli clinical strains known to produce ESBL. Measurements and Main Results. Minimum inhibitory concentration (MIC) testing was performed at 5.5 and 7.0 log₁₀ colony-forming units (cfu)/ml. Time-kill studies were performed over 24 hours with a high inoculum of 7.0 log₁₀ cfu/ml for cefepime, imipenem, tigecycline, and gentamicin at 1 times MIC. Combination studies were tested for cefepime plus tigecycline, cefepime plus imipenem, imipenem plus tigecycline, and for adjunctive gentamicin with cefepime, imipenem, or tigecycline. At the high inoculum, the MIC ranges for cefepime, imipenem, tigecycline, and gentamicin were 0.25-256 (MIC for 90% of tested strains [MIC₉₀] = 32), 0.125-2 (MIC₉₀ = 1), 0.25-16 (MIC ₉₀ = 4), and 0.25-4 mg/L (MIC₉₀ = 1), respectively, for all isolates. At the higher inoculum, MICs shifted for cefepime, imipenem, and tigecycline. Change in log₁₀ cfu/ml from baseline to 24 hours for cefepime, imipenem, and tigecycline alone ranged from 4.85-0.71, 5-4.22, and 3.5-1.01, respectively, for all isolates. Bactericidal activity was observed for cefepime alone (10 [50%] of 20 isolates), imipenem alone (20 [100%] of 20), and tigecycline alone (3 [15%] of 20). Combination studies with cefepime plus tigecycline resulted in synergy against 4 (20%) of 20 isolates. Combination studies with gentamicin resulted in synergy against 6 isolates (30%) with cefepime and 4 isolates (20%) with tigecycline. No synergy was observed with imipenem combinations. No antagonism was observed. With the exception of cefepime, correlations were observed between MIC and terminal densities for studied agents. Conclusions. Cefepime exhibited bactericidal activity but was unrelated to susceptibility. Tigecycline exhibited predictable bacteriostatic activity and synergy in combination against a subset of study isolates. Imipenem exhibited predictable bactericidal activity against all isolates. The utility of combination regimens with novel agents requires further exploration.