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In-vitro activity of PD 131628, a new quinolone antimicrobial agent
M A Cooper1, J M Andrews, R Wise
1Department of Microbiology, Dudley Road Hospital, Birmingham, UK.
Abstract:
The in-vitro activity of PD 131628, the active metabolite of the prodrug PD 131112, was compared with that of ciprofloxacin and members of other groups of antimicrobial agents against 701 recent clinical isolates and strains with known mechanisms of resistance. The MIC90s of PD 131628 against the Enterobacteriaceae were between 0.008 and 0.5 mg/L; PD 131628 was one- to four-fold more active than ciprofloxacin against these strains and was four-fold more active than ciprofloxacin against Pseudomonas aeruginosa. Against the Gram-positive species tested, PD 131628 was two- to four-fold more active than ciprofloxacin, inhibiting all strains of Staphylococcus aureus and Streptococcus pneumoniae with 0.5 mg/L or less. PD 131628 was very active against Neisseria spp., Haemophilus influenzae and Moraxella catarrhalis, with MIC90s ranging from 0.004 to 0.008 mg/L. Organisms with decreased susceptibility to other quinolones had decreased susceptibility to PD 131628, but there was no cross-resistance between this class of antimicrobial and other classes. The protein binding of PD 131628 was at most 25% across a broad range of concentrations. The addition of 70% human serum had little effect on the MICs, but caused a two- to eight-fold increase in MBCs.
Insights
PD 131628, an active metabolite, demonstrates potent in-vitro antimicrobial activity, outperforming ciprofloxacin against key Gram-negative and Gram-positive pathogens. This novel compound shows promise as a new antibiotic agent.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Antimicrobial resistance necessitates the development of new therapeutic agents.
- Fluoroquinolones are a critical class of antibiotics, but resistance is increasing.
- PD 131112 is a prodrug whose active metabolite, PD 131628, warrants investigation.
Purpose of the Study:
- To evaluate the in-vitro antimicrobial activity of PD 131628.
- To compare PD 131628's efficacy against ciprofloxacin and other antimicrobial agents.
- To assess PD 131628's activity against resistant bacterial strains.
Main Methods:
- In-vitro susceptibility testing using MIC90 and MBC assays.
- Testing against 701 recent clinical isolates and resistant strains.
- Comparison with ciprofloxacin and other antimicrobial classes.
- Evaluation of protein binding and serum effects on activity.
Main Results:
- PD 131628 exhibited potent activity against Enterobacteriaceae (MIC90s 0.008-0.5 mg/L), exceeding ciprofloxacin.
- It was four-fold more active than ciprofloxacin against Pseudomonas aeruginosa.
- Against Gram-positive bacteria, PD 131628 was two- to four-fold more active than ciprofloxacin.
- High activity was observed against Neisseria spp., Haemophilus influenzae, and Moraxella catarrhalis (MIC90s 0.004-0.008 mg/L).
- Decreased susceptibility to other quinolones correlated with reduced susceptibility to PD 131628, but no cross-resistance with other classes was noted.
- Protein binding was low (≤25%), and serum had minimal impact on MICs but increased MBCs.
Conclusions:
- PD 131628 displays broad-spectrum in-vitro activity, superior to ciprofloxacin against many clinically relevant pathogens.
- It maintains activity against strains with known resistance mechanisms to other quinolones.
- Low protein binding and minimal serum effect suggest favorable pharmacokinetic potential.
- PD 131628 represents a promising candidate for further development as a novel antimicrobial agent.