The antimicrobial activity of tebipenem and other carbapenem agents were tested in vitro against a set of recent clinical isolates responsible for urinary tract infection (UTI), as well as against a challenge set. Isolates were tested by reference broth microdilution and included Escherichia coli (101 isolates), Klebsiella pneumoniae (208 isolates), and Proteus mirabilis (103 isolates) species.
KEYWORDS: ESBL, SPR994, UTI, pyelonephritis, tebipenem-pivoxil hydrobromide
ABSTRACT
The antimicrobial activity of tebipenem and other carbapenem agents were tested in vitro against a set of recent clinical isolates responsible for urinary tract infection (UTI), as well as against a challenge set. Isolates were tested by reference broth microdilution and included Escherichia coli (101 isolates), Klebsiella pneumoniae (208 isolates), and Proteus mirabilis (103 isolates) species. Within each species tested, tebipenem showed equivalent MIC50/90 values to those of meropenem (E. coli MIC50/90, ≤0.015/0.03 mg/liter; K. pneumoniae MIC50/90, 0.03/0.06 mg/liter; and P. mirabilis MIC50/90, 0.06/0.12 mg/liter) and consistently displayed MIC90 values 8-fold lower than imipenem. Tebipenem and meropenem (MIC50, 0.03 mg/liter) showed equivalent MIC50 results against wild-type, AmpC-, and/or extended-spectrum β-lactamase (ESBL)-producing isolates. Tebipenem also displayed MIC50/90 values 4- to 8-fold lower than imipenem against the challenge set. All carbapenem agents were less active (MIC50, ≥8 mg/liter) against isolates carrying carbapenemase genes. These data confirm the in vitro activity of the orally available agent tebipenem against prevalent UTI Enterobacteriaceae species, including those producing ESBLs and/or plasmid AmpC enzymes.
INTRODUCTION
Urinary tract infections (UTIs) are among the most frequent infectious diseases affecting humans, representing an important public health problem with a substantial economic burden (1). UTIs are primarily caused by Gram-negative bacteria, and Escherichia coli remains the main pathogen responsible for uncomplicated cystitis and pyelonephritis, followed by other species, such as Klebsiella pneumoniae and Proteus mirabilis (2). In fact, these 3 species were responsible for approximately 70% of nosocomial UTIs from United States and European hospitals in 2016 (52.8% E. coli, 12.4% K. pneumoniae, and 5.3% P. mirabilis; 2016 SENTRY Antimicrobial Surveillance Program; unpublished data).
Isolates commonly responsible for nosocomial UTIs have become resistant to several antimicrobial agents in hospitals around the world since the late 1980s (3). β-lactamase enzymes constitute the main mechanism of resistance in Enterobacteriaceae against β-lactam agents. The increasing prevalence of potent β-lactamases, including extended-spectrum β-lactamases (ESBLs), challenges current antimicrobial therapy. ESBLs are often encoded by acquired genes, and these enzymes are capable of hydrolyzing penicillins, cephalosporins, and monobactams. Organisms that produce ESBLs are, thus, resistant to most broad-spectrum β-lactam agents, except for carbapenems (4). A group of β-lactamases distinct from the historically common TEM and SHV enzymes, specifically CTX-M-15, emerged during the mid-2000s (5). The nosocomial emergence and dissemination of such resistant isolates were followed by their emergence in the community and have significantly contributed to the rapid global increase in the cephalosporin resistance rates among Enterobacteriaceae (6).
The spread of a specific E. coli clone that is defined by phylogenetic group B2, serotype O25:H4, and multilocus sequence typing (MLST) 131 has also been identified as an important contributor to the epidemic of antimicrobial resistance in hospital and community settings, especially for first-line agents, such as fluoroquinolones and broad-spectrum cephalosporins (7–9). This epidemiologic shift has great implications for the empirical management of community-associated UTIs; therefore, oral agents to treat outpatients at high risk for infections caused by ESBL-producing pathogens or inpatients who could benefit from step-down therapy would become valuable assets in the antimicrobial armamentarium.
Tebipenem (SPR859) is a broad-spectrum agent first introduced in Japan in 2009 as tebipenem-pivoxil, the oral prodrug, for the treatment of pediatric pneumonia, otitis media, and sinusitis (10). SPR994, a novel formulation of tebipenem-pivoxil hydrobromide, possesses an oral bioavailability that originates from a nitrogen heterocyclic group at the C3 side chain interacting with C2 carboxylic acids (11). SPR994 is being developed as the first oral carbapenem as an alternative drug to treat UTIs, including pyelonephritis caused by ESBL-producing Gram-negative pathogens. This study evaluated the antimicrobial activity of tebipenem and comparator compounds tested against a contemporary collection of Enterobacteriaceae members responsible for UTIs, including a challenge set of molecularly characterized isolates carrying ESBL, plasmid AmpC (pAmpC), and/or carbapenemase enzymes.
RESULTS AND DISCUSSION
Activity of tebipenem and comparator agents against UTI pathogens.
Against E. coli isolates, tebipenem (MIC50/90, ≤0.015/0.03 mg/liter) showed equivalent MIC50/90 values to those of meropenem or ertapenem (MIC50/90, ≤0.015/0.03 mg/liter; 100% susceptible) and displayed an MIC90 value 8-fold lower than imipenem (MIC50/90, 0.12/0.25 mg/liter; Table 1). A total of 20.8% to 38.6% of E. coli isolates were resistant to parenteral cephalosporins (cefazolin and ceftriaxone), levofloxacin, and trimethoprim-sulfamethoxazole (Table 2). The oral agents amoxicillin-clavulanate and fosfomycin showed susceptibility rates of 87.1% and 99.0%, respectively, (CLSI criteria) against E. coli (Table 2).
TABLE 1.
Antimicrobial activity of tested carbapenem agents against E. coli, K. pneumoniae, and P. mirabilis uropathogensa
| Antimicrobial agent by organism (no. of isolates) | No. (cumulative %) of isolates inhibited at MIC (mg/liter) of: |
MIC50 (mg/liter) | MIC90 (mg/liter) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | >8 | |||
| E. coli (101) | |||||||||||||
| Tebipenem | 74 (73.3) | 19 (92.1) | 5 (97.0) | 3 (100.0) | ≤0.015 | 0.03 | |||||||
| Meropenem | 86 (85.1) | 10 (95.0) | 4 (99.0) | 1 (100.0) | ≤0.015 | 0.03 | |||||||
| Doripenemb | 98 (97.0) | 2 (99.0) | 1 (100.0) | ≤0.06 | ≤0.06 | ||||||||
| Imipenemb | 20 (19.8) | 69 (88.1) | 7 (95.0) | 5 (100.0) | 0.12 | 0.25 | |||||||
| Ertapenem | 86 (85.1) | 5 (90.1) | 1 (91.1) | 5 (96.0) | 1 (97.0) | 3 (100.0) | ≤0.015 | 0.03 | |||||
| K. pneumoniae (208) | |||||||||||||
| Tebipenem | 17 (8.2) | 151 (80.8) | 20 (90.4) | 4 (92.3) | 5 (94.7) | 0 (94.7) | 1 (95.2) | 1 (95.7) | 1 (96.2) | 1 (96.6) | 7 (100.0) | 0.03 | 0.06 |
| Meropenem | 49 (23.6) | 136 (88.9) | 9 (93.3) | 1 (93.8) | 2 (94.7) | 0 (94.7) | 0 (94.7) | 3 (96.2) | 2 (97.1) | 0 (97.1) | 6 (100.0) | 0.03 | 0.06 |
| Doripenemb | 182 (87.5) | 11 (92.8) | 4 (94.7) | 0 (94.7) | 0 (94.7) | 2 (95.7) | 1 (96.2) | 3 (97.6) | 5 (100.0) | ≤0.06 | 0.12 | ||
| Imipenemb | 1 (0.5) | 13 (6.7) | 133 (70.7) | 37 (88.5) | 8 (92.3) | 6 (95.2) | 1 (95.7) | 1 (96.2) | 3 (97.6) | 5 (100.0) | 0.12 | 0.5 | |
| Ertapenem | 153 (73.6) | 13 (79.8) | 13 (86.1) | 7 (89.4) | 5 (91.8) | 0 (91.8) | 3 (93.3) | 2 (94.2) | 1 (94.7) | 1 (95.2) | 10 (100.0) | ≤0.015 | 0.25 |
| P. mirabilis (103) | |||||||||||||
| Tebipenem | 15 (14.6) | 48 (61.2) | 35 (95.1) | 4 (99.0) | 1 (100.0) | 0.06 | 0.12 | ||||||
| Meropenem | 1 (1.0) | 17 (17.5) | 63 (78.6) | 17 (95.1) | 5 (100.0) | 0.06 | 0.12 | ||||||
| Doripenemb | 3 (2.9) | 15 (17.5) | 43 (59.2) | 31 (89.3) | 8 (97.1) | 3 (100.0) | 0.25 | 1 | |||||
| Imipenemb | 1 (1.0) | 6 (6.8) | 14 (20.4) | 17 (36.9) | 52 (87.4) | 11 (98.1) | 2 (100.0) | 1 | 2 | ||||
| Ertapenem | 100 (97.1) | 1 (98.1) | 2 (100.0) | ≤0.015 | ≤0.015 | ||||||||
Shading represents susceptible MIC values per CLSI 2018.
The lowest concentration tested for doripenem and imipenem was 0.06 mg/liter.
TABLE 2.
Activity of tebipenem and comparator agents when tested against Enterobacteriaceae uropathogens
| Antimicrobial agent by organism (no. of isolates) | MIC (mg/liter) |
Susceptibility rates (%) according toa
: |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| CLSI |
EUCAST |
||||||||
| 50% | 90% | Range | S | I | R | S | I | R | |
| E. coli (101) | |||||||||
| Tebipenem | ≤0.015 | 0.03 | ≤0.015 to 0.12 | ||||||
| Meropenem | ≤0.015 | 0.03 | ≤0.015 to 0.12 | 100.0 | 0.0 | 0.0 | 100.0 | 0.0 | 0.0 |
| Doripenem | ≤0.06 | ≤0.06 | ≤0.06 to 0.25 | 100.0 | 0.0 | 0.0 | 100.0 | 0.0 | 0.0 |
| Imipenem | 0.12 | 0.25 | 0.06 to 0.5 | 100.0 | 0.0 | 0.0 | 100.0 | 0.0 | 0.0 |
| Ertapenem | ≤0.015 | 0.03 | ≤0.015 to 0.5 | 100.0 | 0.0 | 0.0 | 100.0 | 0.0 | 0.0 |
| Amoxicillin-clavulanate | 4 | 16 | ≤1 to 64 | 87.1 | 5.9 | 6.9 | 87.1 | 12.9b | |
| 97.0 | 3.0c | ||||||||
| Piperacillin-tazobactam | 2 | 8 | ≤0.5 to 64 | 97.0 | 3.0 | 0.0 | 95.0 | 2.0 | 3.0 |
| Cefazolin | 4 | >16 | 2 to >16 | 23.8 | 39.6 | 36.6d | |||
| 76.2 | 23.8e | ||||||||
| Ceftriaxone | ≤0.25 | >64 | ≤0.25 to >64 | 79.2 | 0.0 | 20.8 | 79.2 | 0.0 | 20.8 |
| Levofloxacin | ≤0.03 | >4 | ≤0.03 to >4 | 68.3 | 2.0 | 29.7 | 68.3 | 0.0 | 31.7 |
| TMP-SMXf | ≤0.25 | >8 | ≤0.25 to >8 | 61.4 | 38.6 | 61.4 | 1.0 | 37.6 | |
| Fosfomycin | 0.5 | 0.5 | ≤0.25 to >128 | 99.0 | 0.0 | 1.0 | 98.0 | 2.0 | |
| K. pneumoniae (208) | |||||||||
| Tebipenem | 0.03 | 0.06 | ≤0.015 to >32 | ||||||
| Meropenem | 0.03 | 0.06 | ≤0.015 to >32 | 94.7 | 1.4 | 3.8 | 96.2 | 1.0 | 2.9 |
| Doripenem | ≤0.06 | 0.12 | ≤0.06 to >8 | 94.7 | 1.0 | 4.3 | 94.7 | 1.0 | 4.3 |
| Imipenem | 0.12 | 0.5 | 0.03 to >32 | 95.2 | 0.5 | 4.3 | 95.7 | 1.9 | 2.4 |
| Ertapenem | ≤0.015 | 0.25 | ≤0.015 to >32 | 91.8 | 1.4 | 6.7 | 91.8 | 1.4 | 6.7 |
| Amoxicillin-clavulanate | 2 | 16 | ≤1 to >256 | 78.4 | 12.5 | 9.1 | 78.4 | 21.6b | |
| 95.2 | 4.8c | ||||||||
| Piperacillin-tazobactam | 4 | 32 | ≤0.5 to >64 | 88.9 | 2.9 | 8.2 | 80.3 | 8.7 | 11.1 |
| Cefazolin | 4 | >16 | 1 to >16 | 47.6 | 19.2 | 33.2d | |||
| 75.0 | 25.0e | ||||||||
| Ceftriaxone | ≤0.25 | >64 | ≤0.25 to >64 | 76.0 | 0.0 | 24.0 | 76.0 | 0.0 | 24.0 |
| Levofloxacin | 0.06 | >4 | ≤0.03 to >4 | 84.1 | 1.9 | 13.9 | 77.9 | 5.3 | 16.8 |
| TMP-SMX | ≤0.25 | >8 | ≤0.25 to >8 | 72.1 | 27.9 | 72.1 | 1.0 | 26.9 | |
| P. mirabilis (103) | |||||||||
| Tebipenem | 0.06 | 0.12 | 0.03 to 0.5 | ||||||
| Meropenem | 0.06 | 0.12 | ≤0.015 to 0.25 | 100.0 | 0.0 | 0.0 | 100.0 | 0.0 | 0.0 |
| Doripenem | 0.25 | 1 | ≤0.06 to 2 | 97.1 | 2.9 | 0.0 | 97.1 | 2.9 | 0.0 |
| Imipenem | 1 | 2 | 0.06 to 4 | 87.4 | 10.7 | 1.9 | 98.1 | 1.9 | 0.0 |
| Ertapenem | ≤0.015 | ≤0.015 | ≤0.015 to 0.06 | 100.0 | 0.0 | 0.0 | 100.0 | 0.0 | 0.0 |
| Amoxicillin-clavulanate | ≤1 | 8 | ≤1 to 64 | 93.2 | 1.0 | 5.8 | 93.2 | 6.8b | |
| 98.1 | 1.9c | ||||||||
| Piperacillin-tazobactam | ≤0.5 | 1 | ≤0.5 to 8 | 100.0 | 0.0 | 0.0 | 100.0 | 0.0 | 0.0 |
| Cefazolin | 8 | >16 | 4 to >16 | 0.0 | 13.6 | 86.4d | |||
| 82.5 | 17.5e | ||||||||
| Ceftriaxone | ≤0.25 | 1 | ≤0.25 to >64 | 90.3 | 1.0 | 8.7 | 90.3 | 1.0 | 8.7 |
| Levofloxacin | 0.06 | >4 | ≤0.03 to >4 | 83.5 | 2.9 | 13.6 | 70.9 | 9.7 | 19.4 |
| TMP-SMX | ≤0.25 | >8 | ≤0.25 to >8 | 69.9 | 30.1 | 69.9 | 0.0 | 30.1 | |
Criteria as published by CLSI 2018 and EUCAST 2018. S, susceptible; I, intermediate; R, resistant.
Using other than uncomplicated UTI breakpoints.
Using uncomplicated UTI breakpoints.
Using parenteral, complicated UTI breakpoints.
Using parenteral, uncomplicated UTI only breakpoints.
TMP-SMX, trimethoprim-sulfamethoxazole.
Tebipenem (MIC50/90, 0.03/0.06 mg/liter) had equivalent MIC50/90 results to those of meropenem (MIC50/90, 0.03/0.06 mg/liter; 94.7% to 96.2% susceptible) and 4- to 8-fold lower results than imipenem (MIC50/90, 0.12/0.5 mg/liter; 95.2 to 95.7% susceptible) against K. pneumoniae isolates (Tables 1 and 2). While carbapenem agents (91.8% to 95.2% susceptible) demonstrated in vitro activity against K. pneumoniae, other agents tested had marginal coverage (47.6% to 88.9% susceptible) when applying the CLSI criteria (Table 2). A total of 13.9% to 33.2% of K. pneumoniae isolates were resistant to parenteral cephalosporins (cefazolin and ceftriaxone), levofloxacin, and trimethoprim-sulfamethoxazole (Table 2). Amoxicillin-clavulanate showed a susceptibility rate of 78.4% or 95.2% when applying the EUCAST breakpoint for uncomplicated UTI (Table 2).
Tebipenem demonstrated MIC50 results against P. mirabilis isolates (MIC50, 0.06 mg/liter) 2- to 4-fold higher than those obtained against E. coli (MIC50, ≤0.015 mg/liter) or K. pneumoniae (MIC50, 0.03 mg/liter; Table 1). The same pattern was observed for meropenem, while ertapenem demonstrated consistent MIC50 results (≤0.015 mg/liter) regardless of the species tested (Table 1). Ertapenem (MIC50/90, ≤0.015/≤0.015 mg/liter; 100.0% susceptible) was the most potent agent against P. mirabilis, followed by tebipenem (MIC50/90, 0.06/0.12 mg/liter) and meropenem (MIC50/90, 0.06/0.12 mg/liter; 100% susceptible; Table 1). Piperacillin-tazobactam (100.0% susceptible), amoxicillin-clavulanate (93.2% to 98.1% susceptible), and ceftriaxone (90.3% susceptible) showed antimicrobial coverage against P. mirabilis, while levofloxacin (83.5% susceptible) and trimethoprim-sulfamethoxazole (69.9% susceptible) had lower activity against this species (Table 2).
Activity of tebipenem against a challenge set of organisms.
Tebipenem (MIC50, 0.03 mg/liter) showed similar MIC50 results when tested against wild-type, AmpC-, and/or ESBL-producing isolates, as did meropenem (MIC50, 0.03 mg/liter), while ertapenem had MIC results against non-wild-type isolates at least 4-fold higher than wild-type strains (Table 3). When tested against isolates with confirmed pAmpC and/or ESBL enzyme production, tebipenem (MIC50/90, 0.03/0.25 mg/liter) displayed MIC50/90 values 4- to 8-fold lower than imipenem (MIC50/90, 0.12/2 mg/liter). When the AmpC- and/or ESBL-producing isolates were further stratified by species, tebipenem and meropenem displayed equivalent MIC results, with MIC90 values that were 8- to 16-fold lower than that of ertapenem against E. coli and K. pneumoniae (see Tables S1 and S2 in the supplemental material) but 4-fold higher than P. mirabilis (see Table S3 in the supplemental material). As expected, all carbapenem agents were less active (MIC50, ≥8 mg/liter) when tested against isolates with confirmed carbapenemase genes, including KPC, NDM, VIM, and OXA-48-like (Table 3).
TABLE 3.
Antimicrobial activity of tested agents against E. coli, K. pneumoniae, and P. mirabilis, including challenge organisms, stratified by genotypea
| Antimicrobial agent by genotype (no. of isolates) | No. (cumulative %) of isolates inhibited at MIC (mg/liter) of: |
MIC50 (mg/liter) | MIC90 (mg/liter) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | >8 | |||
| Wild type (361) | |||||||||||||
| Tebipenem | 87 (24.1) | 165 (69.8) | 66 (88.1) | 36 (98.1) | 6 (99.7) | 1 (100.0) | 0.03 | 0.12 | |||||
| Meropenem | 130 (36.0) | 143 (75.6) | 66 (93.9) | 17 (98.6) | 5 (100.0) | 0.03 | 0.06 | ||||||
| Doripenemb | 252 (69.8) | 24 (76.5) | 44 (88.6) | 30 (90.7) | 8 (99.2) | 3 (100.0) | ≤0.06 | 0.5 | |||||
| Imipenemb | 32 (8.9) | 184 (59.8) | 53 (74.5) | 26 (81.7) | 52 (96.1) | 12 (99.4) | 2 (100.0) | 0.12 | 1 | ||||
| Ertapenem | 333 (92.2) | 12 (95.6) | 9 (98.1) | 5 (99.4) | 1 (99.7) | 0 (99.7) | 0 (99.7) | 1 (100.0) | ≤0.015 | ≤0.015 | |||
| pAmpC and/or ESBL (118) | |||||||||||||
| Tebipenem | 7 (5.9) | 54 (51.7) | 23 (71.2) | 15 (83.9) | 9 (91.5) | 6 (96.6) | 0 (96.6) | 1 (97.5) | 2 (99.2) | 1 (100.0) | 0.03 | 0.25 | |
| Meropenem | 9 (7.6) | 54 (53.4) | 26 (75.4) | 11 (84.7) | 8 (91.5) | 6 (96.6) | 0 (96.6) | 1 (97.5) | 3 (100.0) | 0.03 | 0.25 | ||
| Doripenemb | 56 (47.5) | 34 (76.3) | 12 (86.4) | 7 (92.4) | 5 (96.6) | 2 (98.3) | 1 (99.2) | 1 (100.0) | 0.12 | 0.5 | |||
| Imipenemb | 3 (2.5) | 61 (54.2) | 10 (62.7) | 11 (72.0) | 13 (83.1) | 14 (94.9) | 5 (99.2) | 1 (100.0) | 0.12 | 2 | |||
| Ertapenem | 25 (21.2) | 33 (49.2) | 20 (66.1) | 16 (79.7) | 8 (86.4) | 6 (91.5) | 4 (94.9) | 1 (95.8) | 2 (97.5) | 0 (97.5) | 3 (100.0) | 0.06 | 0.5 |
| Carbapenemase (50) | |||||||||||||
| Tebipenem | 2 (4.0) | 2 (8.0) | 8 (24.0) | 7 (38.0) | 31 (100.0) | >8 | >8 | ||||||
| Meropenem | 1 (2.0) | 4 (10.0) | 8 (26.0) | 7 (40.0) | 30 (100.0) | >8 | >8 | ||||||
| Doripenemb | 4 (8.0) | 6 (20.0) | 10 (40.0) | 10 (60.0) | 20 (100.0) | 8 | >8 | ||||||
| Imipenemb | 1 (2.0) | 3 (8.0) | 15 (38.0) | 13 (64.0) | 18 (100.0) | 8 | >8 | ||||||
| Ertapenem | 3 (6.0) | 3 (12.0) | 9 (30.0) | 35 (100.0) | >8 | >8 | |||||||
Shading represents susceptible MIC values per CLSI 2018.
The lowest concentration tested for doripenem and imipenem was 0.06 mg/liter.
UTIs are one of the most frequent infectious diseases among humans. Gram-negative bacteria are highly prevalent among UTIs, which are often caused by E. coli, K. pneumoniae, and P. mirabilis (1). Increasing rates of cephalosporin resistance have been reported among these pathogens and a main reason is because of the dissemination of ESBLs, particularly CTX-M-15 and CTX-M-14, depending on the geographic region (5, 12). Another important contributor to the rising rates of antimicrobial resistance is the dissemination of E. coli ST131, particularly the H30Rx subset, which often displays resistance to broad-spectrum cephalosporins and fluoroquinolones (7, 8). A previous study reported an occurrence of 45% of ST131 among E. coli isolates in 2009 in the United States (7). More recently, a rate of 57% of ST131 was described among ESBL-producing E. coli causing UTI or bloodstream infections in the United States in 2016 (13). A similar rate (56.8%) was observed in a recent clinical trial comparing piperacillin-tazobactam and meropenem for treating bloodstream infections (BSIs) caused by E. coli or Klebsiella spp. that were nonsusceptible to ceftriaxone and susceptible to piperacillin-tazobactam (14).
This study describes the antimicrobial activity of tebipenem and other carbapenem compounds tested against contemporary Enterobacteriaceae isolates collected from US and European hospitals in 2016 determined to be responsible for UTIs, along with a collection of challenge isolates selected to provide greater representation of pAmpC-, ESBL-, and carbapenemase-carrying isolates. Overall, tebipenem was highly potent against this collection of organisms, with observed MIC90 values of ≤0.12 mg/liter for all species tested. Based on the MIC90 results, tebipenem potency was at least 8-fold greater than imipenem against E. coli, K. pneumoniae, and P. mirabilis and equipotent to meropenem against these 3 species. Importantly, the production of ESBL and/or pAmpC enzymes did not adversely affect the in vitro activity of tebipenem against E. coli, K. pneumoniae, or P. mirabilis. Not surprisingly, all carbapenem agents tested were less active against Enterobacteriaceae isolates producing carbapenemase enzymes.
Currently, an oral carbapenem option does not exist for the treatment of any infections in adults. Such an agent could prove useful for the empirical treatment of outpatients in areas with a higher risk of infections caused by organisms producing ESBL or as a potential convenient step-down therapy to send inpatients home earlier. These in vitro results obtained for tebipenem confirm its in vitro activity against Enterobacteriaceae with a wild-type phenotype and isolates producing AmpC and/or ESBL enzymes. The data presented here warrant further clinical development for tebipenem as an oral option for treating complicated/uncomplicated UTIs caused by common Enterobacteriaceae species, including those producing ESBL and/or AmpC enzymes.
MATERIALS AND METHODS
Bacterial isolates.
A total of 412 bacterial clinical UTI isolates collected from US (51.7%) and European (Belgium, France, Germany, Greece, Ireland, Italy, Poland, Portugal, Spain, Sweden, and the United Kingdom), Israel, and Turkey hospitals through the SENTRY Antimicrobial Surveillance Program during 2016 were tested. These isolates represented the 3 most prevalent Gram-negative UTI pathogens and were randomly selected to display the current antimicrobial susceptibility trends occurring in US and European hospitals. The following species were included: E. coli (101 isolates), K. pneumoniae (208 isolates), and P. mirabilis (103 isolates) (see Table S4 in the supplemental material). Isolates were determined to be clinically significant based on local guidelines and submitted to a central monitoring laboratory (JMI Laboratories, North Liberty, IA). Bacterial identification was confirmed by standard algorithms supported by matrix-assisted laser desorption ionization–time of flight mass spectrometry (Bruker Daltonics, Bremen, Germany) as needed.
Among the set of random 412 uropathogens, those displaying ceftriaxone and/or ceftazidime MIC results of ≥2 mg/liter were selected for further characterization of β-lactamase content (non-ESBL, ESBL-, pAmpC- and/or carbapenemase-encoding genes) by genome sequencing and in silico analysis, as previously described (15). In addition, isolates displaying a carbapenem resistance phenotype (MIC results for imipenem [imipenem was not applied to P. mirabilis], meropenem, or doripenem of ≥2 mg/liter) were selected for molecular characterization of β-lactamase-encoding genes. A supplemental challenge set of 117 molecularly characterized isolates was selected, including: E. coli (46 isolates), K. pneumoniae (38 isolates), and P. mirabilis (33 isolates). Isolates of the challenge set were recovered mostly from US (78.6%) hospitals during 2013 to 2015 (84.6%). These isolates were characterized using a combination of Check-MDR CT101 assay and PCR and sequencing, as previously described (15). A summary of species and genotypes/phenotypes observed among selected isolates used in this study for the UTI and challenge sets is described in Table S4, while Table S5 in the supplemental material lists species and β-lactamase-encoding genes detected on both UTI and challenge sets.
Antimicrobial susceptibility testing.
Isolates were tested for susceptibility by broth microdilution following guidelines in the CLSI M07 (2018) document (16). Testing was completed using reference frozen-form 96-well panels manufactured by JMI Laboratories. Fosfomycin MIC values were determined using the agar dilution method as described in the CLSI M07 (2018) document (16), with Mueller-Hinton agar containing 25 mg/liter of glucose-6-phosphate. Quality assurance was performed by concurrently testing CLSI-recommended quality control reference strains (E. coli ATCC 25922 and 35218 and Pseudomonas aeruginosa ATCC 27853). Breakpoint criteria for comparator agents were from the CLSI M100 (2018) and EUCAST (2018) documents (17, 18).
Supplementary Material
ACKNOWLEDGMENTS
This study was performed by JMI Laboratories and supported by Spero Therapeutics. JMI Laboratories received compensation for services related to performing the in vitro study and preparing the manuscript.
The authors express appreciation to the following people for technical support and/or manuscript assistance: L. Flanigan, H. Huynh, M. Janechek, J. Oberholser, C. Smith, and A. Watters. The authors thank Meiji Seika Pharma Co., Ltd. for their critical (or expert) review of the manuscript.
JMI Laboratories contracted to perform services in 2017 for Achaogen, Allecra Therapeutics, Allergan, Amplyx Pharmaceuticals, Antabio, API, Astellas Pharma, AstraZeneca, Athelas, Basilea Pharmaceutica, Bayer AG, BD, Becton, Dickinson and Co., Boston Pharmaceuticals, CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Entasis Therapeutics, Inc., Geom Therapeutics, Inc., GSK, Iterum Pharma, Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., MicuRx Pharmaceuticals, Inc., N8 Medical, Inc., Nabriva Therapeutics, Inc., NAEJA-RGM, Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Ra Pharma, Rempex, Riptide Bioscience Inc., Roche, Scynexis, Shionogi, Sinsa Labs Inc., Skyline Antiinfectives, Sonoran Biosciences, Spero Therapeutics, Symbiotica, Synlogic, Synthes Biomaterials, TenNor Therapeutics, Tetraphase, The Medicines Company, Theravance Biopharma, VenatoRx Pharmaceuticals, Inc., Wockhardt, Yukon Pharma, Zai Laboratory, and Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare. N.C. and A.R. are/were employees of Spero Therapeutics at the time of the study and/or manuscript preparation and may hold stock in this company.
Footnotes
Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02618-18.
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