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Efficacy of ACHN-490 in a Murine Urinary Tract Infection Model with
UNT Health Science Center
3500 Camp Bowie Blvd.
Fort Worth, TX 76107
48th ISDA Annual Meeting
M. PULSE1, W. J. WEISS1, N. REYES2, C.F. KOSTRUB2, P. NGUYEN1, P. RENICK1, J. SIMECKA1
October 21 - 24, 2010
1UNT Health Science Center, Ft. Worth, TX, 2Achaogen Inc., South San Francisco, CA Abstract
Panel 1: Chemical structure of ACHN-490
Panel 2: MIC Values against UPEC strain, ATCC 700336
Summary and Conclusions
Background: ACHN-490 is a next-generation aminoglycoside (AG), in clinical development
with activity against multidrug resistant Gram-negative and select Gram-positive pathogens. ACHN-490 shows broad-spectrum bactericidal activity in vitro, and its potency is unaffected • MIC values for ACHN-490, gentamicin, and levofloxacin by all clinically relevant AG-modifying enzymes that confer resistance to legacy AGs. In the indicate that the uropathogenic E. coli (UPEC) strain used, present study, ACHN-490 was compared to gentamicin (GEN) and levofloxacin (LVX) in a murine urinary tract infection (UTI) model.
ATCC 700336, was susceptible to all 3 antibiotics. Methods: Female C3H/HeJ mice were placed on 5% glucose water 6 days prior to infection.
Anesthetized animals were transurethrally infected with a strain of E. coli that is • The results from the 4-day infection controls indicated that uropathogenic, but antibiotic susceptible (ACHN-490, GEN and LVX MICs of 0.5, 0.5, and stable and consistent CFU counts were achieved in the colony-forming units (CFU) per animal. Beginning 4 kidneys (6.7 log ), bladders (5.8 log ), and urine (7.5 log ) of days after infection, ACHN-490, GEN, and LVX were dosed subcutaneously twice daily for 3 consecutive days. Kidneys, bladders, and urine were collected for CFU counts 18 hours after the final dose. Efficacy was determined by comparing the mean CFU of treated groups to • MIC values determined by the microdilution method according to CLSI guidelines.
• ACHN-490 administration resulted in 2.4 – 4.5 mean log Results: The mean log
CFU counts in the kidneys, bladders, and urine of 7-day untreated • E. coli reference strain ATCC25922 was included as a quality control for each MIC test (data reduction in the kidneys as compared to 7-day controls. controls were 7.4, 7.3, and 7.4, respectively. ACHN-490 doses ranging from 0.125 to 8 mg/kg Gentamicin counts were reduced by 3.7 – 4.4 log CFU kidney counts by 2.4 to 4.5 compared to the levels in the 7-day controls. The same dose range of ACHN-490 also decreased bladder counts by 0.4 to 4.1 similar dose range, while levofloxacin at 0.125 mg/kg or 0.5 CFU. Against this susceptible strain, GEN reductions of 2.1 and 3.7, respectively. effected a similar dose response; GEN doses ranging from 0.125 to 2 mg/kg decreased mean Panel 3: Mean LOG CFU Reduction in
Panel 4: Mean LOG CFU Reduction
Panel 5: Mean LOG
CFU kidney counts by 3.1 to 3.8, and bladder counts by 2.1 to 2.5 log • As compared to 7-day controls, study associated dose ranges counts from GEN-treated animals were lowered by 0.8 to 3.6 log Kidneys - Antibiotic Treated vs. 7-Day
in Bladders - Antibiotic Treated vs. 7-
in Urine – Antibiotic Treated vs. 7-day
similar response against this susceptible strain; LVX doses of 0.125 and 0.5 mg/kg maximally for ACHN-490, gentamicin and levofloxacin resulted in log10 CFU counts in kidneys, bladders, and urine by 3.7, 2.9, and 0.54, CFU reductions of 0.4 – 4.1, 2.1 – 2.5 and 1.5 – 2.9 in the Controls
bladder and 0.2 – 4.5, 0.8 – 3.6 and 0.5 in the urine, Conclusion: Administration of ACHN-490 effectively reduced CFU counts in the kidneys,
bladders, and urine of animals with an ascending UTI infection, suggesting that ACHN-490 has potential as an option for the clinical treatment of UTIs.
• The results from the current study demonstrate the efficacy of Introduction
ACHN-490 in a murine model of a urinary tract infection with a uropathogenic E. coli and indicate that further testing of ACHN- 490 against drug-resistant UPEC could be warranted in order Urinary tract infections (UTIs) rank among the most prevalent of human-associated infectious to provide additional non-clinical data that supports the diseases and significantly impact the health of many individuals throughout the world. potential use of ACHN-490 in treating UTIs caused by resistant Uropathogenic Escherichia coli (UPEC) has been identified as the most common etiological agent associated with UTIs. With an increasing incidence and prevalence of antibiotic resistance among UPEC isolates, there is a continual need for new antibiotics that are capable of treating UTIs. One such clinical candidate, ACHN-490 Injection, is currently undergoing Phase II trials for complicated UTIs and acute pyelonephritis. ACHN-490 is a next generation aminoglycoside (AG) that is designed to overcome all clinically relevant AG-modifying enzymes that confer resistance to legacy AGs. Additionally, ACHN-490 has displayed broad-spectrum References
activity against MDR Enterobacteriaceae, Pseudomonas aeruginosa, and MRSA. This creates a potential for ACHN-490 to be a useful frontline therapy for the treatment of infections caused by MDR bacterial pathogens. These results, combined with the fact that ACHN-490 Injection produced high C and AUC values in human Phase I trials, suggest that ACHN-490 Injection 1 . Blango MG, Mulvey MA. Persistence of uropathogenic has the potential to be clinically utilized as a treatment option for UTIs caused by UPEC and other agents. Escherichia coli in the face of multiple antibiotics. Antimic CFU reductions were determined as the difference between the mean CFU counts of untreated 7-day controls vs. antibiotic treated groups. The current study was undertaken to evaluate the efficacy of ACHN-490 and two comparators • Urine samples were collected from animals just prior to euthanasia, while kidneys and bladders were taken from euthanized animals, placed into sterile 1 x PBS, and homogenized. The homogenates (kidneys against a susceptible UPEC isolate in an ascending, mouse urinary tract infection model.
and bladder) and urine collected from each animal were serial diluted, plated onto TSA + charcoal, and incubated 37oC for 18 hours. 2. Chakupurakal R, Ahmed M, Sobithadevi DN, Chinnappan • Indicated doses (x-axis) represent the amount subcutaneously administered twice daily for 3 consecutive days, starting 4 days after infection. S, Reynolds T. Urinary tract pathogens and resistance Methods and Materials
pattern. J Clin Pathol 2010; 63(7):652-4. • Urine samples could not be obtained for the animals dosed with Levofloxacin at 0.5 mg/kg Minimum inhibitory concentrations (MICs): MICs were determined for ACHN-490,
• Error bars represent the SD of the reduced mean CFUs for each group. Due to unscheduled deaths and sampling issues, total kidney (pairs) and bladder samples for each group ranged from 5 to 8, while total 3. Endimiani A, Huger KM, Hujer AM, Armstrong ES, gentamicin, and levofloxacin against the UPEC strain, ATCC 700336, by using the microdilution urine samples ranged from 0 to 7 for each group.
Choudhary Y, Aggen JB, Bonomo RA. ACHN-490, a method as described by the Clinical and Laboratory Standards Institute (CLSI). neoglycoside with potent in vitro activity against multidrug- Mouse UTI model
resistant Klebsiella pneumoniae isolates. Antimicrob Bacterial inoculum: The infecting inoculum for ATCC 700336 was generated from overnight
Panel 6: Group Mean Log
CFU Counts (
SD) in Mouse UTI Study with ACHN-490, Gentamicin and Levofloxacin
(18 - 20 hours) cultures incubated at 37°C on tryptic soy agar (TSA). Bacterial agar growth was suspended to 1.0 x 1010 colony-forming units (CFU)/mL in tryptic soy broth (TSB), and the 4 . Judice JK. ACHN-490 Overview: Web Conference. August inoculum was held at room temperature until it was used for infection.
Infection: The UTI model was done in accordance with the protocol approved by the UNTHSC-
Institutional Animal Care and Use Committee. Female, C3H/HeJ mice (The Jackson Laboratory) weighing 18 to 20 grams were used, and diuresis was induced by placing the mice Controls
on 5% (w/v) glucose-water 6 days prior to infection and then maintaining them on the glucose- water throughout the length of the study. On the day of infection, anesthetized mice (ketamine at 40 mg/kg, xylazine at 6 mg/kg) were infected by placing 2 to 3 cm of polyethylene tubing Acknowledgments
(0.61 mm, o.d.) transurethrally into each mouse and injecting 0.05 mL of the inoculum (8.8 log CFU) into the urinary tract’s lumen.
Antibiotic treatment & CFU determination: ACHN-490, gentamicin, and levofloxacin were
subcutaneously dosed, 2 times per day for 3 days beginning 4 days after infection. Urine, The authors would like to thank Jessica Pierce for her technical bladders, and kidneys were collected from each mouse 18 hours after the final antibiotic dose. support during the course of this study.
Bladders and kidney pairs were placed into 2 mL of sterile 1 x PBS, homogenized, and plated
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