Abstract
Hyperammonemia (HA) syndrome caused by respiratory infection with ammonia (NH3)-producing Ureaplasma species occurs in 4% of lung transplant recipients (LTRs) and is associated with high mortality. Although Ureaplasma-targeted antibiotic intervention is effective, the threat of antibiotic resistance development and pre-existing resistance make an alternative to antibiotics desirable. Considering that the underlying pathology of Ureaplasma-induced hyperammonemia (UIHA) is dependent upon ureaplasmal urease converting urea to NH3, urease inhibition could represent a targeted treatment approach. Here, the ability of the urease inhibitor, flurofamide, to prevent and treat UIHA was investigated. To confirm that flurofamide is broadly active against Ureaplasma respiratory isolates, the minimum urease inhibitory concentration against 4 isolates of Ureaplasma parvum and 5 isolates of Ureaplasma urealyticum was first determined in vitro. NH3 production by all isolates was inhibited by ≤2 μM flurofamide. To test the ability of flurofamide to prevent and treat UIHA, a mouse model of Ureaplasma respiratory infection was utilized. When animals were administered 6 mg/kg flurofamide via intraperitoneal injection 1 h prior to infection with U. parvum, flurofamide-administered animals exhibited significantly lower blood NH3 levels than did non-prophylaxed animals (10.9 ± 4.0 μmol/L compared to 26.5 ± 17.7 μmol/L; P = 0.0146) 24 h post-treatment. When U. parvum-infected hyperammonemic mice were treated with 6 mg/kg flurofamide, treated animals had significantly greater decreases in blood-NH3 levels 6 h post-treatment than did untreated mice (56.4 ± 17.1% compared to 9.1 ± 33.5% reduction; P = 0.0152). Together, these results indicate that flurofamide is a promising non-antibiotic treatment for UIHA in LTRs. IMPORTANCE Ureaplasma-associated hyperammonemia syndrome occurs in 4% of lung transplant recipients and has historically been almost universally fatal. While Ureaplasma-targeted antibiotics have been shown to be protective, the possibility of underlying resistance and resistance selection render non-antibiotic interventions an interesting approach.