nvestigating in vitro and in vivo efficacy of antibiotic combinations with the small quinolone-like compound HT61 against pulmonary infections ...

The incidence of antimicrobial resistance (AMR) is increasing worldwide and poses significant life-threatening risks to several different patient populations associated with nosocomial infections, especially those of immunocompromised individuals and those in intensive care units (ICU). For common bacterial infections associated with pulmonary infections, sepsis and urinary tract infections (UTI) high rates of AMR against the most frequently used antibiotics has been observed worldwide.

For example, the gram-negative pathogen K. pneumoniae, a major cause of hospital-acquired infections such as pneumonia has developed resistance to B-lactam antibiotics such as carbapenem in all regions of the planet with some countries reporting that carbapenem antibiotics failed to provide effective therapy in more than half of K. pneumonaie infected patients as a direct consequence of AMR1-3. Additionally, P. aeruginosa is heavily implicated in both hospital and community acquired infections and its treatment is particularly problematic in Cystic Fibrosis (CF), due to the emergence of tobramycin resistant P. aeruginosa with approximately 25-45% of CF patients now colonised with MDR P. aeruginosa4-5.

Furthermore, MDR A. baumannii is endemic in hospital acquired infections and has been observed worldwide for the past thirty years6. Finally, MDR gram-positive S. aureus is another leading cause of nosocomial infections which contributes to prolonged hospital stays and is now routinely detected in hospital patients contributing to >15,000 patients in the European Union alone7.

This increase in the prevalence of MDR pathogens combined with the shortage of new antibiotics and the associated high cost of drug development and short window of their use for financial return has significantly reduced the availability of viable antibiotics. Indeed, some antibiotics now require high doses to elicit antimicrobial activity that are associated with substantial adverse events such as the aminoglycoside antibiotic tobramycin.

Furthermore, in some cases the prevalence of MDR pathogens has rendered clinical conditions virtually untreatable and therefore a concomitant decrease in quality of life and increase in mortality. There is therefore an urgent unmet clinical need for innovative approaches to antibiotic therapies which remain resilient to the ongoing threat of AMR. It is important to note that whilst the threat of infections associated with gram-positive infections such as MRSA continue to generate substantial health burdens, there is a critical need for a focus on gram-negative species, notably P. aeruginosa, K. pneumoniae and A. baumanaii as identified by the WHO's global action plan on AMR8.

Antibiotic combinations with 'antibiotic enhancers' are promising candidates for novel treatment regimens for MDR bacterial infections. Previous studies demonstrated that combination therapies of clinically approved antibiotics with antibiotic enhancers exhibited significant synergism in their antimicrobial activity in vitro, however the clinical implication of this synergism requires further investigation9-10.

Our research team has previously shown that HT61, a small quinolone-derived compound is active against gram-positive MSSA and MRSA but not gram-negative P. aeruginosa. However, when given in combination, HT61 augments the in vitro activities of other antimicrobial agents such as gentamicin, neomycin and mupirocin against both MSSA and MRSA11. Significantly, subsequent studies by our research group have demonstrated preliminary evidence for significant synergism between HT61 and tobramycin against the MDR/tobramycin resistant P. aeruginosa strains RP73 and NN212.

However, further research is required to evaluate the clinical benefit of the HT61 combination therapies with classical antibiotics associated with CF therapies through the investigation of this phenomenon of synergism against a larger panel of disease relevant clinical isolates of P.aeruginosa.