Exposure-response analysis of tigecycline in pharmacodynamic simulations using different size inocula of target bacteria.

This study explored tigecycline exposure-bacterial responses in pharmacodynamic simulations (in vitro kinetic model) using different inocula. One meticillin-resistant vancomycin-heteroresistant Staphylococcus aureus, one Enterococcus faecium and one extended-spectrum beta-lactamase-producing Escherichia coli with equal tigecycline minimum inhibitory concentrations/minimum bactericidal concentrations (MICs/MBCs) (0.12/0.25 microg/mL) were used. A computerised pharmacodynamic bicompartmental model simulated three tigecycline twice-daily dosing regimens over 48h: 50mg (100mg loading dose); 100mg; and 150 mg. Areas under bacterial growth curves were calculated, and differences between the growth curve used as control and the killing curve of bacteria exposed to tigecycline (ABBC) were determined. With standard inocula [ca. 1 x 10(6)colony-forming units (CFU)/mL], linear increases in area under the concentration-time curve (AUC)/MIC (25.6 for 50mg, 53.76 for 100mg and 79.52 for 150 mg) produced linear increases in activity against Gram-positive organisms (mean ABBCs of 120.60, 143.20 and 195.80 log CFU x h/mL for S. aureus and of 95.75, 172.55 and 216.90 log CFUxh/mL for E. faecium, respectively), with the activity of the 150 mg regimen being significantly higher (P<0.01) than that of the other two regimens. ABBCs obtained with the 100mg regimen using standard inocula were similar to those obtained with the 150 mg regimen when using high inocula (ca. 1 x 10(7)CFU/mL). Against E. coli, the highest dosing regimen was required to obtain significant antibacterial activity compared with control (mean ABBCs of 145.75 log CFU x h/mL with standard inocula and 63.33 log CFU x h/mL with high inocula). An increase in tigecycline dosing appears to be an interesting therapeutic option to maximise antibacterial activity owing to its linear pharmacokinetics and pharmacodynamics, especially when severe infections with high bacterial load are suspected.

Influence of media and testing methodology on susceptibility to tigecycline of Enterobacteriaceae with reported high tigecycline MIC.

The tigecycline susceptibility of six different Enterobacteriaceae strains with reported high tigecycline MICs was determined in quintuplicate by four methodologies using Mueller-Hinton agar and broth from six manufacturers. The MICs determined by Etest were a >or=1-fold dilution lower than those determined by broth microdilution and agar dilution, with the highest modal values given by agar dilution. The highest modal MICs were obtained using Oxoid medium, and the lowest inhibition zone values (disc diffusion) were obtained using Oxoid and bioMérieux media. The lowest MICs were obtained by Etest using Difco or Merck media.

Influence of testing methodology on the tigecycline activity profile against presumably tigecycline-non-susceptible Acinetobacter spp.

OBJECTIVES: To compare the tigecycline activity profile against Acinetobacter spp. by Etest versus broth microdilution in isolates with high Etest MIC. METHODS: Acinetobacter spp. isolates with tigecycline MICs of >or=0.5 mg/L determined by commercially developed Etests strips (January 2006 to July 2007) in five Spanish hospitals were considered. Values were rounded to the nearest upper double-dilution. Susceptibility by broth microdilution following CLSI (formerly NCCLS) recommendations, as the reference method, was determined in a central laboratory. BSAC breakpoints were used: susceptible 2 mg/L. RESULTS: One hundred and forty-eight isolates were collected: 12 isolates with a tigecycline Etest MIC of 0.5 mg/L, 14 with 1 mg/L, 86 with 2 mg/L, 31 with 4 mg/L and 5 with 8 mg/L. Isolates with Etest MICs of 0.5-1 mg/L showed the same values by broth microdilution. Among isolates with Etest MICs of 2 mg/L, only 5.8% of strains showed the same value by both methods (88.4% showed values that were one or two dilutions lower by microdilution). None of the 36 isolates with Etest MICs of 4-8 mg/L showed the same value by both methods, with values at least two dilutions lower by microdilution. Weak correlation (R = 0.238; P or=2 mg/L for Acinetobacter spp. since strains with Etest MICs of 2-4 mg/L are susceptible when tested by microdilution. False non-susceptibility by Etest may exclude tigecycline as a therapeutic option in a field where multiresistance is the rule.

Evolution of the antimicrobial resistance of Pseudomonas aeruginosa in Spain: second national study (2003).

The second national prevalence study of Pseudomonas aeruginosa has been carried out in Spain. A total of 1250 clinical isolates of P. aeruginosa were collected from 127 hospitals in 1 week in 2003 and the resistance data gathered from the isolates was compared with those of the first study in 1998 (1014 isolates from 136 hospitals). Antimicrobial susceptibility testing was performed in both studies in the same laboratory. The most active antimicrobials were piperacillin, piperacillin-tazobactam, and amikacin (< or =10% resistant) and resistance to these antimicrobials did not change over the time. The least active were ofloxacin and gentamicin (> or =30% resistant). From 1998 to 2003, resistance increased significantly to ciprofloxacin (23% vs. 28%, respectively, p=0.015); ofloxacin (30% vs. 37%, p=0.002); imipenem (14% vs. 18%, p=0.017) and meropenem (8% vs. 13%, p <0.001). Resistance to aztreonam (23%), ceftazidime (16%), cefepime (20%), ticarcillin (13%) and tobramycin (11%) remained stable. Isolates from inpatients were significantly more resistant than those from outpatients to all antimicrobials, with the exception of fluoroquinolones and aminoglycosides (p <0.01). Isolates from outpatients were significantly more resistant to these two groups (p <0.05) than to other antimicrobials. In Spain, from 1998 to 2003, the susceptibility pattern of P. aeruginosa to antimicrobial agents has changed. Isolates have become significantly more resistant to fluoroquinolones and carbapenems. However, resistance to beta-lactams and aminoglycosides remains stable.