Multidrug-resistant (MDR) Gram-negative infections represent a growing and worrisome challenge in modern healthcare. The most commonly encountered MDR Gram-negative bacteria include Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. MDR Gram-negative bacteria have evolved multiple mechanisms to resist antibiotics. These include the production of enzymes that degrade antibiotics, changes in permeability to prevent antibiotic entry, alterations in drug targets, and the ability to efflux (pump out) antibiotics. These mechanisms can sometimes confer resistance to multiple classes of antibiotics, severely limiting treatment options. Many MDR Gram-negative infections are hospital-acquired, occurring in patients with weakened immune systems or those undergoing invasive procedures, making treatment more complex. Moreover, the number of antibiotics effective against MDR Gram-negative bacteria is limited. While new drugs are being developed, the pace is slow compared to the rate at which bacteria develop resistance. Existing polymyxin drugs, such as colistin, are often considered last-resort options due to their potential side effects.
As these pathogens continue to outsmart existing antimicrobial therapies, the quest for new, effective treatments becomes increasingly urgent. A new study published in the Journal Antimicrobial Agents and Chemotherapy conducted by Professor Keith Rodvold, Dr. Justin Bader, Dr. Jon Bruss, and Dr. Kamal Hamed from University of Illinois Chicago and Spero Therapeutics, Inc., centers on SPR206, a next-generation polymyxin designed to reduce cytotoxicity and kidney drug exposure being developed as a potential combatant against MDR Gram-negative pathogens. This Phase 1 bronchoalveolar lavage (BAL) study aimed to evaluate the safety and intrapulmonary pharmacokinetics of SPR206 in healthy volunteers. The research methodology involved administering a 100 mg intravenous dose of SPR206 every 8 hours for three consecutive doses. Post-administration, subjects underwent bronchoscopy with BAL and blood sample collections at various time intervals to measure SPR206 concentrations in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AM).
The authors recruited 34 subjects who completed the study, with 30 undergoing bronchoscopies. The researchers employed a validated LC-MS/MS assay to measure SPR206 concentrations. They meticulously documented the peak concentrations (Cmax) and the area under the concentration-time curve (AUC0-8) in plasma, ELF, and AM. The study’s precision in capturing these pharmacokinetic parameters is commendable. Furthermore, the researchers calculated the mean ELF to unbound plasma concentration ratio and the mean AM to unbound plasma concentration ratio. Such detailed pharmacokinetic profiling is crucial for understanding the drug’s distribution and potential efficacy against targeted pathogens. The significance of the study lies in its demonstration of SPR206’s pulmonary penetration and its potential as an effective treatment for serious and potentially life-threatening hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by MDR Gram-negative pathogens. The findings that SPR206 concentrations in ELF achieved lung exposures above the MIC for target Gram-negative pathogens for the entire 8-hour dosing interval are particularly noteworthy. This indicates that SPR206 can maintain effective drug concentrations in lung tissues, a crucial factor in treating respiratory tract infections.
Moreover, the authors reported the safety profile of SPR206 which is equally noteworthy. The majority of treatment-emergent adverse events reported were mild, with oral paresthesia and nausea being the most frequent. This favorable safety profile, coupled with the drug’s potent activity against Gram-negative pathogens, highlights SPR206’s potential as a game-changer in treating MDR infections. This tolerability is a promising factor, considering the often severe side effects associated with currently available treatments for MDR Gram-negative infections, such as nephrotoxicity and neurotoxicity with polymyxins. SPR206 emerges as a promising alternative, potentially offering a broader spectrum of activity against MDR pathogens with a more favorable safety profile.
The successful pharmacokinetic study of SPR206 is an important milestone that encourages further clinical development of the drug. The journey ahead for SPR206 involves rigorous clinical trials to validate its efficacy and safety in patients with HABP/VABP caused by MDR Gram-negative bacteria. These studies will be important in understanding the drug’s performance in real-world clinical scenarios.
Rodvold KA, Bader J, Bruss JB, Hamed K. Pharmacokinetics of SPR206 in Plasma, Pulmonary Epithelial Lining Fluid, and Alveolar Macrophages following Intravenous Administration to Healthy Adult Subjects. Antimicrob Agents Chemother. 2023;67(7):e0042623. doi: 10.1128/aac.00426-23.