Bacterial Resistance Drives Need for New Therapies in Treating cUTIs in Adult Patients

Urinary tract infections represent one of the most common bacterial entities encountered throughout the world, comprising a spectrum of diseases including cystitis and pyelonephritis.¹ Complicated urinary tract infections (cUTIs) typically occur in patients with functional or structural abnormalities of the urinary tract.^1,2,3 These infections can also be characterized by the presence of unique host factors (ie, immunosuppression) or systemic involvement.^1,2,3 In view of this, patients presenting with cUTIs are more prone to deleterious complications including sepsis and septic shock.⁴ β-Lactam antibiotics are considered mainstays of therapy. However, in an era of bacterial resistance, the utility of these agents has largely been hindered by the presence of extended-spectrum β-lactamase (ESBL)-producing bacteria.^1,2

Carbapenems were considered last-line agents because of their broad spectrum of activity against gram-negative bacteria, including ESBL-producing organisms. However, use of these agents carries the risk of carbapenem resistance, leading to suboptimal clinical outcomes and thus warranting the need for alternative therapies.^2,3 Although newer, carbapenem-sparing agents have emerged within the past decade, the question of which agent to select for empiric cUTI management is unclear.^2,3 One systematic review comparing efficacy of carbapenems with noncarbapenem agents, including some novel antimicrobials, for cUTI produced inconclusive results limited by factors including heterogeneity of antibiotics used in the randomized controlled trials (RCTs) selected.² In this study, authors sought to tighten the lens of comparison and examine the efficacy and safety of carbapenems vs select novel antibiotics for treatment of cUTI.

METHODS

This meta-analysis included RCTs comparing the use of carbapenems vs novel antibiotics for the treatment of cUTI in adult patients. Novel antibiotics included agents approved by the FDA or the European Medicines Agency for cUTI indication between 2009 and 2019. Trials were notably excluded if the novel agent under investigation was a carbapenem, or if they included patients receiving other antibiotics for concomitant infections. Efficacy between the 2 treatment arms was assessed through individual and composite rates of clinical and microbiological response at the test-of-cure visit. Comparative safety was evaluated through the rates of adverse events during the treatment period.

RESULTS

Six RCTs, encompassing 3343 subjects, were included for analysis. All RCTs were multicentered, multinational, noninferiority trials of adults with cUTIs. One RCT also included patients with intra-abdominal infections, although this study had separate outcomes available for cUTI. Duration of intravenous therapy ranged from 5 to 10 days. Baseline uropathogens were comparable between trials and inclusive of species of the Enterobacterales order and the Pseudomonas genus (see Table). A higher rate of microbiological response was observed in the novel antibiotics group compared with the carbapenem group (relative risk [RR], 0.85; 95% CI, 0.79-0.91; P < .01). Meanwhile, no significant difference was observed in either individual or composite rates of clinical response (RR, 1.00; 95% CI, 0.98- 1.04; P = .83 and RR, 0.91; 95% CI, 0.79- 1.04; P = .15, respectively). Similarly, no difference in rates of adverse or serious adverse events (SAEs) was identified between groups (RRAEs, 1.09; 95% CI, 0.93- 1.29; P = .297 and RRSAEs, 0.96; 95% CI, 0.53- 1.76; P = .896).

Table 1. Characteristics of included RCTs

DISCUSSION

Based on these results, the authors concluded that novel antibiotics appear to have clinical efficacy and safety comparable to carbapenems for treatment of cUTIs. The authors further suggest that novel antibiotics may demonstrate greater microbiological response compared with carbapenems. Although this outcome was statistically significant, the clinical significance of this finding is unclear. Moreover, although statistical significance was not demonstrated for the composite outcome, the favorable trend observed toward the novel antibiotic group may have been influenced largely by microbiological response.

Taken together, the applicability of these findings is limited by a few considerations. First, included studies did not publish rates of organisms resistant to multiple drugs, rendering it difficult to extrapolate these findings to that clinical context. Second, in 2 studies, patients received oral antibiotic therapy initially followed by intravenous antibiotic therapy, opening the possibility for confounding. Additionally, some of the therapies assessed (plazomicin, doripenem, and eravacycline) are not therapeutic options typically utilized for these infections. Last, there was a substantial degree of heterogeneity observed between studies, rendering it difficult to generalize findings. Despite these shortcomings, this article sheds light on an important issue: the evolving need for new therapies to overcome the burden of multidrug-resistant organisms. Ultimately, these findings suggest the need for more robust RCTs evaluating clinical outcomes between the carbapenems and novel agents within the context of bacterial resistance.

References:

1. Tan X, Pan Q, Mo C, Li X, et al. Carbapenems vs alternative antibiotics for the treatment of complicated urinary tract infection: A systematic review and network meta-analysis. Medicine. 2020 Jan;99(2):e18769.
2. Ten Doesschate T, van der Vaart T, Damen J, Bonten M, et al. Carbapenem-alternative strategies for complicated urinary tract infections: A systematic review of randomized controlled trials. J Infect. 2020 Oct;81(4):499-509.
3. Ezure Y, Rico V, Paterson D, Hall L et al. Efficacy and safety of carbapenems versus new antibiotics for treatment of adult patients with complicated urinary tract infections: A systematic review and meta-analysis. Open For Infect Dis. 2020: ofaa480.
4. Nicolle LE; AMMI Canada Guidelines Committee*. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol. 2005 Nov;16(6):349-60.