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Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections

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Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections Infect Dis Ther https://doi.org/10.1007/s40121-021-00509-4 COMMENTARY Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections Balaji Veeraraghavan . Yamuna Devi Bakthavatchalam . Rani Diana Sahni Received: May 16, 2021 / Accepted: July 21, 2021 Ó The Author(s) 2021 ABSTRACT UTI. The b-lactamase inhibitors ETX0282, VNRX7145, ARX1796, and QPX7728 are com- The treatment of urinary tract infections (UTIs) bined with cefpodoxime proxetil or ceftibuten has been complicated by the emergence of that achieve favorable exposures in urine com- multidrug-resistant, b-lactamase-expressing pared to other uropathogen-active oral cepha- pathogens. As a result of the limited treatment losporins. The combination ceftibuten- options, patients often require hospitalization QPX7728 has potential broad-spectrum cover- and intravenous therapy. In essence, a strong age against carbapenemase producers including unmet need for oral antibiotics, active against metallo b-lactamase producers. Other novel extended-spectrum b-lactamase (ESBL) uro- combinations, namely cefpodoxime/ETX0282, pathogens has emerged. Oral carbapenems (te- ceftibuten/VNRX-7145, and ceftibuten/ bipenem and sulopenem) and oral ARX1796, have also demonstrated excellent cephalosporin/b-lactamase inhibitor combina- activity against Klebsiella pneumoniae carba- tions are in various stages of clinical develop- panemase (KPC) and OXA-48-like producers. All ment for the treatment of uncomplicated and these agents, upon their arrival for commercial complicated UTI. Tebipenem, if approved, will use, would strengthen the outpatient therapy. be the first oral treatment for complicated UTI while sulopenem will be for uncomplicated Keywords: Ceftibuten; Cefpodoxime; Tebipenem; Sulopenem; ETX0282; VNRX7145; ARX1796; QPX7728 B. Veeraraghavan (&) Á Y. D. Bakthavatchalam Á R. D. Sahni Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu 632004, India e-mail: [email protected] Infect Dis Ther lactamases in Enterobacterales were a problem Key Summary Points even before, but the former are addressed by piperacillin/tazobactam to some extent and The treatment of urinary tract infections carbapenems while the latter are addressed by (UTIs) has been complicated by the carbapenems alone [2]. emergence of multidrug-resistant and In the last decade, we experienced global extended-spectrum b-lactamase (ESBL)- spread of KPCs and also other carbapenemases, expressing Gram-negative pathogens. viz., New Delhi metallo b-lactamases and OXA- b-lactamases [3]. What we have failed to notice Oral carbapenems (tebipenem and is the quiet increase in ESBL pathogens in sulopenem) and oral cephalosporin/b- community-onset urinary tract infection (UTI), lactamase inhibitor combinations are in a condition usually managed by oral antibiotics various stages of clinical development for such as nitrofurantoin, trimethoprim/sul- treating UTIs. famethaxozole, quinolones, and oral cephalos- Recently tebipenem and sulopenem have porins. The fact that these uropathogens completed phase III trials. Tebipenem, if carrying ESBLs (thus resistant to oral cephalos- approved, will be the first oral treatment porins) have acquired resistance to the afore- for complicated UTI while sulopenem will mentioned non-b-lactam antibiotics (Table 1)is be for uncomplicated UTI. challenging for treatment [31]. As a result, in today’s scenario, in the USA alone, huge num- The combinations cefpodoxime/ETX0282, bers of patients with UTIs are hospitalized ceftibuten/VNRX-7145, and ceftibuten/ because of the failure of oral antibiotics and left QPX7728 are in phase I development. All with intravenous antibiotic options [32, 33]. In these agents, upon their arrival for these cases, even piperacillin/tazobactam is commercial use, would strengthen the often not active because of widely prevalent outpatient therapy. class C and OXA-1 b-lactamases, thus forcing carbapenem use [2]. In essence, a strong unmet need for oral antibiotics that are active against ESBL uropathogens has emerged. Moreover, with an additional activity against carbapenem- INTRODUCTION resistant uropathogens, these oral drugs can be used as step-down for hospital-treated patients Pharmaceutical organizations that are in with UTIs, enabling early hospital discharge. In antibiotic discovery research prioritize their this review, we describe the profile and status of projects on the basis of evolving antibiotic novel oral antibiotics in clinical develop- resistance epidemiology. For instance, the ment. This article is based on previously con- emergence and spread of methicillin-resistant ducted studies and does not contain any studies Staphylococcus aureus, vancomycin-resistant En- with human participants or animals performed terococcus faecium, and macrolide-resistant by any of the authors. Streptococcus pneumoniae during 1980s and 1990s compelled these organizations to focus CARBAPENEMS on discovery of novel agents to tackle these Gram-positive pathogens. Emphasis on Gram- Historically, discovering an orally bioavailable negative pathogens that we witness today star- carbapenem remained a challenge to medicinal ted when carbapenem-resistant Klebsiella pneu- chemists. Initially, the aim was to develop a moniae through expression of a serine carbapenem for outpatient treatment of com- carbapenemase (KPC) was reported in New York munity-origin lower respiratory infections. during the 2000s [1]. Needless to say, extended- With this thinking, faropenem was developed b b spectrum -lactamases (ESBLs) and class C - and approved in Japan. In the USA, a prodrug of Table 1 Epidemiology of community-acquired urinary tract infections caused by ESBL-producing bacteria reported across the globe Infect Dis Ther Location Duration of the Study (age groups) Organisms (n) ESBL producers (%) Resistance (%) reported to References study Nitrofurantoin Fosfomycin Co- Ciprofloxacin trimoxazole USA 2000–2010 Surveillance study E. coli (12,253,679) 2.1 0.8 NA 6.3 14.1 [4] (NA) USA 2011–2019 Retrospective study E. coli (1,513,882) 6.4 3.8 NA 25.4 21.1 [5] (C 12 years) Egypt 2016–2018 Observational study E. coli (134) 59.7 NA NA 76 13.7 [6] (C 18 years) Mexico NA Observational study E. coli (240) E. coli (26) ESBL E. coli ESBL E. coli ESBL E. coli ESBL E. coli [7] (NA) K. pneumoniae (14) K. pneumoniae (NA) (1.3) (6.6) (53) (89) P. aeruginosa (6) P. mirabilis (4) C. freundii (3) S. marcescens (1) India 2012–2018 Retrospective study ESBL-producing E. coli (93) E. coli (1.5) E. coli (1.7) E. coli (68.8) E. coli (47.3) [8] B ( 18 years) bacteria (240) K. pneumoniae (5.2) K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. oxytoca (0.8) (0.8) (1.7) (3.1) (2.3) P. mirabilis (0.8) Germany 2010 Surveillance study E. coli (499) 8 NA 1.2 30.9 19.8 [9] (NA) France 2015–2017 Surveillance study E. coli (658) Overall ESBL producers NA NA NA NA [10] (4.9) Klebsiella spp. (42) P. mirabilis (25) C. koseri (12) Enterobacter spp. (12) Romania 2018 Surveillance study E. coli (787) 9 3 NA 24.3 14.9 [11] (NA) Netherlands 2004–2009 and Surveillance study E. coli (446) 2.2 1 0 19 6 [12] 2014–2015 (NA) Table 1 continued Location Duration of the Study (age groups) Organisms (n) ESBL producers (%) Resistance (%) reported to References study Nitrofurantoin Fosfomycin Co- Ciprofloxacin trimoxazole England 2017–2018 Surveillance study Cefotaxime-resistant 100 7 NA NA 56.9 [13] E. coli (576) France 2015–2017 Surveillance study E. coli (358,291) 3.3 NA NA NA NA [14] Australia 2009–2013 Surveillance study E. coli (4492) 3.7 NA NA NA 6.4 [15] India 2009 and 2014 Retrospective study E. coli (420) Overall ESBL producers E. coli (43) NA E. coli (88) NA [16] \ ( 17 years) K. pneumoniae (66) (33.1) K. oxytoca (24) P. mirabilis (30) P. vulgaris (26) C. freundii (18) C. koseri (6) Morganella spp. (4) Pseudomonas spp. (67) Acinetobacter spp. (8) Serratia spp. (2) India 2010–2011 Retrospective study E. coli (161) E. coli (84.5) NA NA NA E. coli (80.7) [17] (14–72 years) K. pneumoniae (40) K. pneumoniae (35) K. pneumoniae P. aeruginosa (13) P. aeruginosa (31.5) (50) P. aeruginosa P. mirabilis (12) P. mirabilis (100) (23.1) P. mirabilis (58.3) Infect Dis Ther Infect Dis Ther Table 1 continued Location Duration of the Study (age groups) Organisms (n) ESBL producers (%) Resistance (%) reported to References study Nitrofurantoin Fosfomycin Co- Ciprofloxacin trimoxazole India 2017 Surveillance study E. coli (131) E. coli (46.6) ESBL E. coli NA ESBL E. coli ESBL E. coli [18] (NA) K. pneumoniae (47) K. pneumoniae (NA0) (29.5) (86.9) (88.5) Pseudomonas spp. (6) Pseudomonas spp. (NA) Proteus spp. (12) Proteus spp. (NA) Enterobacter spp. (2) Enterobacter spp. (NA) Africa 2015–2019 Descriptive cross- E. coli (1994) E. coli (7) E. coli (5) NA E. coli (62) E. coli (12) [19] sectional study K. pneumoniae (193) K. pneumoniae (9) K. pneumoniae K. pneumoniae K. pneumoniae (15–49 years) P. mirabilis (179) P. mirabilis (1) (60) (35) (4) P. mirabilis P. mirabilis P. mirabilis (1) (NA) (51) Paris 2014–2015 Prospective study E. coli (791) ESBL-producing E. coli (1.1) E. coli (1.6) NA E. coli (15.5) [20] (18–102 years) Klebsiella spp. (95) Enterobacterales (4.2) Proteus spp. (70) Citrobacter spp. (46) Iran 2012–2013 Observational study E. coli (154) 40 3.9 NA 57.8 47.4 [21] (C 18 years) Greece 2008–2014 Surveillance study E. coli (170) E. coli (3) E. coli (3.1) NA E. coli (24.7) NA [22] (NA) Klebsiella spp. (15) Klebsiella spp. (7) Klebsiella spp. Klebsiella spp. Proteus spp. (17) Proteus spp. (100) (38.5) (6.1) P. aeruginosa (9) P. aeruginosa (9) Proteus spp. Proteus spp. (NA) (38.5) Enterobacter spp. (2) Enterobacter spp. (2) P. aeruginosa P. aeruginosa M. morgannii (2) M. morgannii (2) (NA) (NA) S. fonticola (2) S. fonticola (2) Peru 2015 Retrospective study E. coli (172) 40.8 NA NA NA NA [23] (C 18 years) Table 1 continued Location Duration of the Study (age groups) Organisms (n) ESBL producers (%) Resistance (%) reported to References study Nitrofurantoin Fosfomycin Co- Ciprofloxacin trimoxazole Spain 2015 and 2016 Retrospective study E.
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