Which Antibiotics for UTI?

Research Highlights

INFECTION PROSTATE CANCER Which antibiotics Surfaceome profiling for NEPC for UTI? target antigens Prostate adenocarcinoma and was enriched in NEPC. Comparison A multinational, open-label, analyst-blinded, randomized neuroendocrine prostate cancer of the genes to identify molecular clinical trial has shown that 5-day nitrofurantoin is more (NEPC) have distinct surfaceomes, functions showed that those enriched likely to result in clinical and microbiological resolution of which can be used to discriminate in NEPC were related to neural acute, uncomplicated lower urinary tract infection (UTI) than between the subtypes and might provide function, including synaptic signalling, single-dose fosfomycin. These results could influence future target antigens for immunotherapy. nervous system development, treatment decisions for managing UTI. The advent of CAR T cell therapy and neurotransmitter transport, This study included 513 women aged >18 years who were shows the potential of targeting whereas those of adenocarcinoma not pregnant and had at least one symptom of acute lower UTI treatment to cell-surface markers. were involved in secretion, immune (including dysuria, urgency, frequency, and/or suprapubic However, identifying target antigens response, and inflammatory response, tenderness), a positive urine dipstick test, and no known in prostate tumours — NEPC in enabling differentiation of the subtypes. colonization or previous infection with antibiotic-resistant particular — is problematic, as markers RNA sequencing (RNA-seq) uropathogens. Participants were randomly assigned 1:1 to upregulated in adenocarcinoma gene expression analysis of receive 100 mg nitrofurantoin orally three times a day for 5 days are often downregulated in human prostate cancer cell lines or 3 g fosfomycin orally as a single dose. Clinical evaluation neuroendocrine disease. showed heterogeneous expression and urine culture collection was undertaken at 14 and 28 days Lee and colleagues derived of androgen-regulated genes, after therapy completion. a panel of putative human cell neuroendocrine markers, and The primary outcome was clinical response, which could surface proteins, which was able to epithelial markers across the two be clinical resolution of infection at day 28 (defined as differentiate adenocarcinoma and tumour types, and corresponded complete resolution of signs and symptoms of UTI without NEPC. Differential expression analysis with expression of previously failure), failure (defined as a requirement for a change of showed that the expression of 330 cell established markers. These antibiotics or discontinuation owing to lack of efficacy), surface genes was enriched fourfold differences were used to nominate or indeterminate (no objective evidence of infection but or more in adenocarcinoma, whereas potential tumour antigens for persistent symptoms). Secondary outcomes included expression of 438 cell surface genes prostate adenocarcinoma and bacteriological response and adverse events. Overall, 93% of women completed the trial and 73% had PROSTATE CANCER a confirmed positive baseline culture. Clinical resolution at day 28 was achieved in 70% of patients receiving nitrofurantoin and 58% receiving fosfomycin (P = 0.004) Aptamer effective in vivo and the effect was greater in the subgroup of patients with confirmed Escherichia coli infections (78% versus 50% of A new study demonstrates that aptamers conjugated to highly toxic an aptamer conjugated to the chemotherapeutics.” patients, P < 0.001). At the earlier time point of day 14, a chemotherapeutic monomethyl The team selected the aptamer significant difference was also observed (75% versus 66% auristan F (MMAF) specifically using a cell–internalization SELEX achieving complete response, P = 0.03). Microbiological targets prostate cancer cells, inhibits approach. Two independent selections resolution was attained in 74% of participants in the tumour growth, and improves survival that included several prostate cancer nitrofurantoin group and 63% in the fosfomycin group in mice. cell lines identified the RNA aptamer (P = 0.04); again the difference was more pronounced Aptamers are oligonucleotides or E3, which specifically internalizes into in the subset of patients with confirmed E. coli infections peptides that bind to a specific target malignant but not benign prostate (72% versus 58%, P = 0.03). The median duration of molecule and can be used to deliver cells. In vitro characterization showed symptoms was one day longer in women receiving cytotoxic agents, similar to antibody– that E3 targets cells derived from nitrofurantoin than those who had fosfomycin, but this drug conjugates; however, aptamers different prostate cancer subtypes difference was not statistically significant. Adverse events can have higher specificity and are and with varying androgen sensitivity. were relatively infrequent and occurred at similar rates easier to produce and modify than The researchers then tested the in both treatment groups. antibodies. “Previous work mostly toxicity of E3 conjugated to the tubulin These data show that 5-day treatment with nitrofurantoin focused on conjugating aptamers polymerization inhibitor MMAF or the results in better clinical and microbiological outcomes 28 days to traditional chemotherapeutics, related MMAE, of which only MMAE is after completion of therapy than single-dose fosfomycin in such as doxorubicin, but trials with membrane permeable. MMAE–E3 was women with acute, uncomplicated lower UTI. Treatment of antibody–drug conjugates have shown considerably more toxic to prostate women presenting with acute UTI could be influenced by that tumour targeting drugs are only cancer cells than MMAF–E3, but a these findings. effective when coupled to agents that nontargeted MMAE control conjugate are too toxic to administer alone,” was also toxic, in contrast to the MMAF Louise Stone explains Bethany Powell Gray, first version; hence, MMAF–E3 was used in author of the paper. “Thus, we sought further studies. As MMAF is highly toxic, Original article Huttner, A. et al. Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in to develop and test a new class of the team also developed a DNA-based women a randomized clinical trial. JAMA 319, 1781–1789 (2018) targeted anticancer therapeutics: antidote to E3, which inhibited 90% of E3