Oral sulopenem shows promise for uncomplicated UTI

The SURE*-1 trial demonstrated the potential of a novel, broad-spectrum penem antibiotic – sulopenem etzadroxil/probenecid – for women with uncomplicated urinary tract infection (uUTI).

“[Compared with ciprofloxacin,] sulopenem was superior [in women] with quinolone-resistant uropathogen [but] not noninferior [in] patients with quinolone-susceptible uropathogen,” said Dr Michael Dunne from Iterum Therapeutics, Old Saybrook, Connecticut, US. “In a combined analysis without regard to quinolone susceptibility, sulopenem was noninferior to ciprofloxacin.”

A total of 1,671 women** (median age 54 years) were randomized 1:1 to receive sulopenem 500 mg/probenecid 500 mg BID for 5 days and placebo ciprofloxacin for 3 days, or ciprofloxacin 250 mg BID for 3 days and placebo sulopenem for 5 days. Of these, 1,071 had a uropathogen identified on culture. From this cohort, two independent subgroups were evaluated based on organisms that were either resistant or susceptible to quinolones. Overall response rates (ORRs; ie, both clinical and microbiologic success) were evaluated at days 5 (end-of-treatment [EoT]) and 12 (test-of-cure [ToC]). [ID Week 2020, abstract LB-1]

 

Quinolone-resistant pathogens: sulopenem beats ciprofloxacin

Sulopenem was superior to ciprofloxacin in terms of ORRs, both at EoT (65 percent vs 30 percent) and ToC (63 percent vs 36 percent; p<0.001 for both). Independent evaluation of clinical and microbiologic success rate at ToC also reflected the superiority of sulopenem to ciprofloxacin (83 percent vs 63 percent [clinical] and 74 percent vs 50 percent [microbiologic]; p<0.001 for both).

According to Dunne, these results may have been driven by the lower rates of microbiologic failure (18 percent vs 27 percent) and rescue antibiotic use (0 percent vs 8 percent) in the sulopenem vs the ciprofloxacin arm.

“[It is important to] point out that … 5 percent of women in this [cohort had] a uropathogen that was resistant to all four major classes of oral antibiotics,” stressed Dunne. Yet, ORRs consistently favoured sulopenem over ciprofloxacin across all pathogen subsets (67 percent vs 36 percent; p<0.001 [β-lactam-resistant], 58 percent vs 32 percent; p=0.012 [ESBL***-positive], 65 percent vs 36 percent; p<0.001 [TMP-SMX^#-resistant], and 77 percent vs 42 percent; p=0.002 [nitrofurantoin-resistant]).

The findings from this cohort provide substantial evidence reflecting the treatment effect of sulopenem in patients with uUTI, noted Dunne and colleagues.

 

Quinolone-susceptible pathogens: sulopenem worse?

In this cohort, sulopenem was not noninferior to ciprofloxacin in terms of ORR at ToC (67 percent vs 79 percent). However, ORRs were similar at EoT (65 percent for both).

“[The difference suggests that] something is occurring between EoT and ToC,” Dunne pointed out. Indeed, there was a higher rate of asymptomatic bacteriuria (ASB) with sulopenem vs ciprofloxacin (13 percent vs 4 percent), which could have contributed to the lower microbiologic success rate with the former vs the latter (78 percent vs 89 percent).

“ASB occurred more commonly with sulopenem than ciprofloxacin … and that really accounted for the biggest difference in the outcome in this group of patients,” said Dunne, who called for further probing into the impact of ASB on treatment outcomes in this setting.

 

Quinolone-resistant + susceptible pathogens = sulopenem noninferiority

In the combined analysis which, as pert Dunne, is most reflective of what a practicing clinician faces when seeing patients with uUTI, ORRs for sulopenem and ciprofloxacin were similar at ToC (66 percent vs 68 percent), suggesting the noninferiority of the former to the latter. At EoT, ORR was a little better for sulopenem (65 percent vs 56 percent; p=0.006), noted Dunne, which could have been driven by the ORRs observed in the quinolone-resistant subset.

Apart from the higher rate of microbiologic failure with sulopenem vs ciprofloxacin at ToC (14 percent vs 10 percent), results in both arms were generally similar (11 percent vs 10 percent [clinical failure] and 4 percent vs 5 percent [both clinical and microbiologic failure]).

The slightly higher ASB rate with sulopenem vs ciprofloxacin (14 percent vs 10 percent) might have been carried over from that observed in the quinolone-susceptible population, noted Dunne.

Overall, treatment-emergent adverse events (TEAEs) were higher with sulopenem vs ciprofloxacin (25 percent vs 14 percent), the most common being diarrhoea (12 percent vs 3 percent). However, most were mild and self-limiting. Serious TEAE rates were similar (0.7 percent vs 0.2 percent).

Sulopenem is being developed for targeting multidrug-resistant infections. If approved, sulopenem will be the first oral penem antibiotic for uUTI, noted the researchers.