1. P1257 Pharmacodynamics of Amikacin Inhale studied in an in vitro pharmacokinetic model of infection KE Bowker, AR Noel, SG Tomaselli, MLG Attwood, AP MacGowan BCARE, Department of Infection sciences, North Bristol NHS Trust, Bristol, UK
26th ECCMID
Amsterdam April 2016
Objectives
Inhalation antibiotic therapy for bacterial infection has attractive pharmacodynamic and clinical features.
Amikacin Inhale is a combination of amikacin with a proprietary liquid pulmonary technology delivery system.
High local concentrations in respiratory secretions may be associated with rapid decrease in bacterial load, and reduced risk of emergence of resistance.
Low systemic concentrations may help avoid adverse events.
Existing clinical breakpoints based on systemic therapy may not be appropriate for inhalational use of drugs.
In this study we sought to establish a potential Extracellular Lining Fluid (ELF) breakpoint for amikacin to treat Gram-negative pulmonary infection.
Materials and methods
An in vitro dilutional pharmacokinetic model was used to simulate ELF amikacin (AMI) concentrations associated with doses of 400mg 12hrly over 5 days (Luyt 2009). A Cmax of 4,000mg/L was targeted declining to 909mg/L 3hr post dose; 136.4mg/L 6hr post dose and 3.6mg/L after 12h.
Nine strains of bacteria E.coli (n=3) AMI MICs 4-8mg/L; P.aeruginosa (n=3) AMI MICs 2-64mg/L and A.baumannii MICs 2-192mg/L were used.
Antibacterial effect was assessed by changes in viable count and recovery of isolates able to grow on MICx4 recovery media
Results
There was no emergence of resistance with E.coli or P.aeruginosa strains. However, with A.baumannii strains
with MICs of 96 and 192mg/L isolates grew on MICx4 recovery plates from 72h onwards and MICx8 from
72-96hrs onwards.
Log MIC was related to reduction in viable counts at 12, 24, 72 and 120hr using a Sigmoid Emax model.
A 2 log reduction was achieved within 24 hours against strains with MIC values of <120 mg/L.
Table 1: Antibacterial effect of amikacin at ELF simulated concentrations
Pathogen
Amikacin
MIC (mg/L)
Log CFU/ml at time
12h
24h
72h
120h
E.coli 896 4
6.1 ± 0.1
<2
E.coli 898
6.0 ± 0.1
E.coli 3093 8
A.baumannii 50742 2
A.baumannii 28899 96
3.2 ± 0.8
3.4 ± 1.3
7.6 ± 0.6
7.9 ± 0.1
A.baumannii 43491
192
4.3 ± 0.1
6.6 ± 1.2
P.aeruginosa 41961
P.aeruginosa 41959 6
2.3
P.aeruginosa 41957 32
2.2
2.9 ± 0.8
3.1 ± 0.7
Results
The targeted ELF amikacin concentrations are shown on Figure 1. The 24h AUC is 16,112mg/L.h.
 The antibacterial effect of simulated ELF concentrations is shown on Table 1.
For strains with MICs of ≤8mg/L there was rapid and sustained reductions in bacterial load with complete clearance occurring after 24h until 120h. For other strains (MICs >8mg/L) regrowth occurred after 12hrs and after 24hrs >106CFU/ml bacteria were isolated on MICx4 plates increasing to >107CFU/ml by 120h.
The relationship between pathogen MIC and clearance from the model is shown on Figure 2. Strains with MIC ≤120mg/L amikacin would achieve a -2 log drop in initial inoculum at 24hrs.
Conclusions
Simulated mean ELF concentrations of amikacin associated with inhaled therapy were associated with rapid
reduction in bacterial load and no resistance for strains with AMI MIC ≤8mg/L.
A pharmacodynamic target of -2 log reduction in load by 24hr could be achieved for strains with
MICs ≤120mg/L but emergence of resistance was a feature of exposure of strains with higher MICs.
Combination of inhaled amikacin with systemic therapy should overcome this.
Reference:
Luyt CE et al. Pharmacokinetics and lung delivery of PDDS-aerolosized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.
Crit Care 2009; 13(6): R200