Host responses to infectious and inflammatory stimuli are altered with aging. Because cytokines and their antagonists are significant factors in these host responses, the present research on aged subjects was designed to investigate plasma concentrations of the cytokines interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) and those of their antagonists IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor (sTNFr). For this research, 122 apparently healthy aged subjects (79.6 +/- 5.8 yr), 39 aged individuals with documented urinary tract infections (UTIs) (81.6 +/- 6.3 yr), and 100 young controls (39.32 +/- 11.2 yr) were included. Plasma IL-1 beta, TNF alpha, IL-1ra, sTNFr (55 kDa), and neopterin were measured using enzyme-linked immunosorbent assay techniques. In subsets of normal aged subjects and UTI patients, we investigated relations between plasma concentrations of cytokine antagonists and IL-2 production by phytohemagglutinin-stimulated peripheral blood mononuclear cells. The results show that plasma concentrations of both IL-1ra and sTNFr were greater in healthy aged subjects than in young controls. Plasma neopterin, a product of activated monocytes/macrophages, was likewise elevated in the aged. IL-1 and TNF were not detectable in the majority of plasma samples. There was a positive correlation between neopterin concentration and both IL-1ra and sTNFr. There was a significant negative correlation between plasma IL-1ra and IL-2 production by phytohemagglutinin-stimulated peripheral blood mononuclear cell in healthy aged subjects. IL-1ra and sTNFr concentrations were significantly greater in patients with UTI than in the healthy aged subjects. In UTI patients IL-2 production in vitro was lower than in healthy subjects, but there was no significant correlation with IL-1ra in plasma. Therefore, plasma concentrations of cytokine antagonists are increased in plasma of apparently healthy aged subjects. Elevated concentrations of neopterin suggest that this increase can be traced to monocyte activation. The negative correlation between plasma IL-1ra and IL-2 production in vitro suggests that enhancement of this cytokine antagonist can contribute to immunodepression of aging. We propose that unapparent infections in aged subjects cause monocyte activation and release of cytokine antagonists. These cytokine antagonists reduce IL-2 production and the capability of T cells to proliferate, thereby inhibiting responses in the elderly.

ImportanceCefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections.ObjectiveTo evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis.Design, Setting, and ParticipantsA phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens.InterventionsEligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline).Main Outcomes and MeasuresThe primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was −10%. If noninferiority was established, a superiority comparison was also prespecified.ResultsAmong 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events.Conclusions and RelevanceAmong patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis.Trial RegistrationClinicalTrials.gov Identifier: NCT03687255

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The rise of antimicrobial resistance poses a substantial threat to our health system, and, hence, development of drugs against novel targets is urgently needed. The natural peptide thanatin kills Gram-negative bacteria by targeting proteins of the lipopolysaccharide transport (Lpt) machinery. Using the thanatin scaffold together with phenotypic medicinal chemistry, structural data, and a target-focused approach, we developed antimicrobial peptides with drug-like properties. They exhibit potent activity against Enterobacteriaceae both in vitro and in vivo while eliciting low frequencies of resistance. We show that the peptides bind LptA of both wild-type and thanatin-resistant Escherichia coli and Klebsiella pneumoniae strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge.