Urinary tract infection is a common healthy problem in elderly patients ( 1 , 2 ). In addition, urinary tract infection can be associated with increased morbidity and mortality and cause a significant healthcare burden( 1 , 3 ). Furthermore, the increase of antimicrobial resistance in this clinical condition has negatively impact the outcome of the elderly patients with urinary tract infection ( 3 ). More and more mechanisms of antimicrobial resistances, such as including extended-spectrum-lactamases, AmpC-β-lacta mase, and carbapenemases have developed ( 4 ) and largely limited the options of appropriate antibiotics. All these facts trigger the urgent needs of new agent to enhance our antibiotic armamentarium in this critical situation.

Recently, several novel β-lactam/β-lactamase inhibitor combinations, including ceftazidime/avibactam, ceftolozane/tazobactam, merope nem/vaborbactam,aztreonam/avibactam,imipe nem/cilastatin/relebactam,ceftarolin/avibactam cefepime/zidebactam and meropenem/nacu bactam have been investigated to overcome the threaten of multidrug resistant organisms ( 5 ). Three of them - ceftazidime/avibactam, ceftolo zane/tazobactam, and meropenem/vaborbactam have been evaluated in the treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (APN) in phase 3 studies ( 6 – 8 ). However, the clinical efficacy of these novel β-lactam/β-lactamase inhibitor combinations for treating cUTI among elderly patients remains unclear. Therefore, the data of elderly patients from these three studies extracted ( 6 – 8 ) and did an integrated analysis to assess their usefulness in the treatment of elderly patients with cUTIs.

A RECAPTURE trial by Wagenlehner et al compared ceftazidime/avibactam with doripe nem for treating cUTI/APN ( 6 ). ASPECT-cUTI trial by Wagenlehner et al compared ceftolo zane/tazobactam with levofloxacin in the treatment of cUTI/APN ( 7 ). TANGO-I trial by Kaye et al compared the clinical efficacy and tolerability of meropenem/vaborbactam and piperacillin/tazobactam in the treatment of cUTI/APN ( 8 ). All three trials were randomized, double-blind, multicenter, and multinational studies ( 6 – 8 )(Table-1).

Overall success-composite outcome of clinical cure and microbial eradication for the micro biologic modified intention-to-treat (mMITT) population was extracted as the primary outcome. Modified intent-to-treat (MITT) population was defined as all intent-to-treat patients who received at least one dose of study drug and microbiological MITT (mMITT) population was defined as MITT patients who met the disease definition of cUTI/APN and had a baseline pathogen.

Overall, 598 elderly patients with cUTI/APN were included in this analysis. 286 and 312 patients received novel β-lactam/β-lactamase inhibitor combinations and comparators, respectively. The overall success rates of novel β-lactam/β-lactamase inhibitor combinations and comparators were 71% (203/286) and 64.7% (202/312), respectively. No significant difference in terms of overall success between novel β-lactam/β-lactamase inhibitor combinations was observed (odds ratio [OR], 1.68; 95% confidence interval [CI], 0.76 to 3.58; I ( 2 )=67). In the pooled analysis of two studies reported the clinical efficacy in the subgroups - 65-74 years and 75 years and older, we found the similar trends. For patients aged 65-74 years, the overall success rates of novel β-lactam /β-lactamase inhibitor combinations and comparators were 72.9% and 69.4% (OR, 1.1; 95% CI, 0.58 to 2.11; I ( 2 )=0), respectively. For patients aged 75 years and older, the overall success rates of novel β-lactam/β-lactamase inhibitor combinations and comparators were 70% and 70.7%, respectively (OR, 1.85; 95% CI, 0.22 to 15.45; I ( 2 )=56).

In this study, we demonstrated the clinical efficacy of novel β-lactam/β-lactamase inhibitor combinations was noninferior to comparators in the treatment of cUTI/APN among elderly patients. The non-inferiority of novel β- lactam/β-lactamase inhibitor combinations to comparators was found in both overall elderly population and subgroup analysis. These findings could be supported by previous in vitro studies( 9 , 10 ), in which novel β-lactam/β- lactamase inhibitor combinations show potent activity against most of Gram-negative bacteria from patients with UTI including high potencies against multidrug-resistant organisms. There fore, it should suggest that novel β-lactam/β- lactamase inhibitor combinations could play a significant role for treating elderly patients with cUTI/APN.

However, this study had several limitations. First, the numbers of enrolled patients and study were limited. Second, we did not perform a more detail analysis, such as the usefulness of novel β-lactam/β-lactamase inhibitor combinations for antibiotic-resistant organism, and for different types of infections – cUTI or APN. Third, safety profile remains another important concern, however, we did not assess the tolerability of these agents in the elderly patients. Further large-scale study is warranted to clarify these issues.

In conclusion, novel β-lactam/β-lactamase inhibitor combinations exhibit comparable efficacy with comparator in elderly patients with cUTI/APN. Novel β-lactam/β-lactamase inhibitor combinations may be considered as one potential therapeutic option in this clinical entity.