Imipenem and imipenem-relebactam MICs were determined for 1,445 Pseudomonas aeruginosa clinical isolates and a large panel of isogenic mutants showing the most relevant mutation-driven β-lactam resistance mechanisms. Imipenem-relebactam showed the highest susceptibility rate (97.3%), followed by colistin and ceftolozane-tazobactam (both 94.6%).
KEYWORDS: Pseudomonas aeruginosa, imipenem-relebactam, whole-genome sequencing, multidrug resistance, extensively drug resistant, β-lactam resistance mechanisms, antibiotic resistance
ABSTRACT
Imipenem and imipenem-relebactam MICs were determined for 1,445 Pseudomonas aeruginosa clinical isolates and a large panel of isogenic mutants showing the most relevant mutation-driven β-lactam resistance mechanisms. Imipenem-relebactam showed the highest susceptibility rate (97.3%), followed by colistin and ceftolozane-tazobactam (both 94.6%). Imipenem-relebactam MICs remained ≤2 μg/ml in all 16 isogenic PAO1 mutants and in 8 pairs of extensively drug-resistant clinical strains that had developed resistance to ceftolozane-tazobactam and ceftazidime-avibactam due to mutations in OXA-10 or AmpC.
INTRODUCTION
The growing prevalence of nosocomial infections produced by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa strains is associated with significantly increased morbidity and mortality (1). This increasing threat results from the extraordinary capacity of P. aeruginosa to develop resistance to nearly all available antibiotics by the selection of mutations in chromosomal genes, the growing prevalence of transferable resistance determinants (particularly those encoding carbapenemases or extended-spectrum β-lactamases [ESBLs]), and the dissemination of MDR/XDR global strains, the high-risk clones (2, 3).
On the other hand, the recent introduction of novel β-lactam–β-lactamase inhibitor combinations, such as ceftolozane-tazobactam or ceftazidime-avibactam, which are stable against AmpC hydrolysis, have partially alleviated the urgent clinical need for new agents to combat infections by MDR/XDR P. aeruginosa strains (4, 5). However, emerging resistance to these antibiotics is concerning and calls for continuous development of new therapeutic options (6–8). One of these recently developed novel options for the treatment of MDR/XDR Gram-negative pathogens is the combination of the carbapenem imipenem with relebactam, a novel inhibitor of β-lactamases from classes A and C (9). Thus, the objective of this work was to analyze the added value, if any, of imipenem-relebactam to our antipseudomonal arsenal. For this purpose, we determined the activity of imipenem-relebactam against a recent well-characterized large collection of P. aeruginosa clinical isolates (1,445 isolates from 51 different Spanish hospitals), for which the MICs of ceftolozane-tazobactam, ceftazidime-avibactam, and other antipseudomonals had been determined (10). Moreover, resistance mechanisms and whole-genome sequences (WGSs) from 185 XDR isolates from that collection were available for analysis (10). Additionally, imipenem-relebactam was tested against a large collection of isogenic mutants showing the most relevant mutation-driven β-lactam resistance mechanisms, including those affecting ceftolozane-tazobactam and ceftazidime-avibactam.
Activity of imipenem-relebactam against P. aeruginosa clinical isolates.
The collection of 1,445 isolates studied included up to 30 consecutive health care-associated nonduplicated (1/patient) P. aeruginosa clinical isolates collected during October 2017 from each of the 51 participating hospitals, covering all 17 Spanish regions (10). The distribution of sample types was as follows: respiratory, 32.8%; urine, 23.7%; soft tissue and osteoarticular, 23.1%; blood culture, 5.7%; and others, 14.9%. MICs of ticarcillin, piperacillin-tazobactam, ceftazidime, cefepime, ceftolozane plus tazobactam 4 μg/ml, ceftazidime plus avibactam 4 μg/ml, aztreonam, imipenem, meropenem, ciprofloxacin, tobramycin, amikacin, and colistin had been determined by broth microdilution according to EUCAST guidelines and v 8.1 clinical breakpoints (www.eucast.org). In this work, we used broth microdilution to determine the MICs of imipenem and imipenem plus relebactam 4 μg/ml for the 1,445 isolates. For imipenem-relebactam, the imipenem breakpoints were used. The presence of carbapenemases and ESBLs were assessed in the previous study, and one representative XDR isolate from each clone and hospital (n = 185) were further analyzed through WGS, including multilocus sequence typing (MLST) and resistome analysis (10).
Antimicrobial susceptibility data for the 1,445 isolates tested are shown in Table 1. Imipenem-relebactam showed MIC50/90s of 0.5/1 μg/ml, 4- and 16-fold lower, respectively, than those of imipenem alone. Moreover, imipenem-relebactam showed the highest susceptibility rate (97.3%), followed by colistin (94.6%), ceftolozane-tazobactam (94.6%), and ceftazidime-avibactam (94.2%). The susceptibility rate for imipenem-relebactam of imipenem-resistant strains was 80.5%, whereas that for XDR strains (17.4% of all isolates) was 86.4%. The distributions of imipenem and imipenem-relebactam MICs for the complete collection of clinical isolates and for those showing an XDR phenotype are shown in Fig. 1. Modal MIC values for imipenem and imipenem-relebactam were 2 and 0.25 μg/ml for the overall collection of isolates and 16 and 1 μg/ml for XDR isolates.
TABLE 1.
Antimicrobial susceptibility data for 1,445 P. aeruginosa clinical isolates tested
| Antibiotica | MIC (μg/ml) |
Susceptibility (%)b |
||
|---|---|---|---|---|
| MIC50 | MIC90 | S | R | |
| TIC | 32 | 256 | 18.8 | 81.2 |
| PIP-TZ | 8 | 128 | 73.5 | 26.5 |
| CAZ | 4 | 32 | 79.7 | 20.3 |
| FEP | 4 | 16 | 79.4 | 20.6 |
| TOL-TZ | 1 | 2 | 94.6 | 5.4 |
| CAZ-AVI | 2 | 8 | 94.2 | 5.8 |
| ATM | 4 | 32 | 14.8 | |
| IMI | 2 | 16 | 78.3 | 13.5 |
| IMI-REL | 0.5 | 1 | 97.3 | 2.6 |
| MER | 1 | 16 | 70.1 | 14.1 |
| CIP | 0.25 | >16 | 61.6 | 38.4 |
| TOB | 0.5 | 32 | 83.7 | 16.3 |
| AMI | 4 | 8 | 91.6 | 4.0 |
| COL | 1 | 2 | 94.6 | 5.4 |
TIC, ticarcilin; PIP-TZ, piperacilin-tazobactam; CAZ, ceftazidime; FEP, cefepime; TOL-TZ, ceftolozane-tazobactam; CAZ-AVI, ceftazidime-avibactam; ATM, aztreonam; IMI, imipenem; IMI-REL, imipenem-relebactam; MER, meropenem; CIP, ciprofloxacin; TOB, tobramycin; AMI, amikacin; COL, colistin. Except for IMI and IMI-REL, susceptibility data were obtained from a previous work (10).
S, susceptible; R, resistant; according to EUCAST 2018.
FIG 1.
Distribution of imipenem (IMI) and imipenem-relebactam (IMI/REL) MICs for complete collection of clinical isolates and those showing an XDR phenotype.
Up to 37 of the 1,445 isolates showed imipenem-relebactam resistance (MIC, >8 μg/ml), and all produced an acquired carbapenemase, including 26 VIM (3 VIM-1, 11 VIM-2, and 12 VIM-20), 4 IMP (1 IMP-1, 2 IMP-8, and 1 IMP-33), and 7 GES-5. Two additional isolates showed intermediate susceptibility (MIC, 8 μg/ml), with 1 of them producing a VIM-2; the second intermediate isolate was negative for acquired β-lactamases but showed, in addition to MexXY overexpression (due to mexZ inactivation) and AmpC overexpression (due to PBP4 mutation), unique mutations in the essential penicillin binding proteins PBP 2 (A269V) and PBP 3 (N242S). The potential involvement of these mutations in imipenem-relebactam resistance will be assessed in further studies.
On the other hand, none of the imipenem-relebactam-susceptible isolates showed acquired carbapenemases. However, imipenem-relebactam-susceptible isolates included ESBL-producing strains (4 PER-1, 2 GES-1, and 1 OXA-15) that were resistant to ceftolozane-tazobactam and ceftazidime-avibactam. Likewise, the 4 strains documented to show AmpC mutations (T96I, F147L, G183D, or E247G) involved in ceftolozane-tazobactam and ceftazidime-avibactam resistance were imipenem-relebactam susceptible. Moreover, imipenem-relebactam susceptibility was documented in 39 of 78 (50%) ceftolozane-tazobactam-resistant strains and 51 of 84 (60.7%) ceftazidime-avibactam-resistant strains that were noncarbapenemase producers.
Stability of imipenem-relebactam against P. aeruginosa β-lactam resistance mechanisms.
Imipenem and imipenem-relebactam MICs were determined in duplicate in a well-characterized panel of 16 PAO1 isogenic mutants showing combinations of the most relevant resistance mutations, including AmpC hyperproduction, OprD inactivation, and efflux pump overexpression (11). MICs were also determined in 8 characterized (including WGS) pairs of isogenic XDR clinical isolates that had developed resistance to ceftolozane-tazobactam during treatment (7, 12). Finally, imipenem-relebactam was tested in a panel of derivatives from a PAO1 OprD− AmpC mutant expressing five different AmpC variants, conferring ceftolozane-tazobactam and ceftazidime-avibactam resistance, previously cloned from these clinical isolates.
Imipenem-relebactam MICs remained ≤1 μg/ml (range, 0.125 to 1 μg/ml), and were 4- to 16-fold lower than those of imipenem in the 16 isogenic PAO1 mutants tested, including those showing AmpC hyperproduction (such as AmpD and PBP4 mutants), OprD inactivation, and/or efflux pump (MexAB-OprM, MexXY, and MexCD-OprJ) overexpression (Table 2). Moreover, imipenem-relebactam was highly active (MIC, 0.5 to 2 μg/ml) against the eight pairs of XDR clinical strains that had developed resistance to ceftolozane-tazobactam and ceftazidime-avibactam due to the selection of mutations in OXA-10 (OXA-14; n = 2) or AmpC (T96I, F147L, E247K, E247G, or ΔG299-E247; n = 6) (Table 3). Finally, the imipenem-relebactam MIC (0.5 μg/ml) of the OprD− AmpC PAO1 mutant was not increased by the expression of any of the AmpC variants, confirming the stability against these mutations (Table 4).
TABLE 2.
MICs of imipenem and imipenem-relebactam against PAO1 isogenic mutants, showing combinations of most relevant β-lactam resistance mutations
| Strain | Resistance mechanism | MIC (mg/liter) |
|
|---|---|---|---|
| IMI | IMI-REL | ||
| PAO1 | Wild type | 0.5 | 0.125 |
| PAO1 ΔdacB | AmpC↑ | 1 | 0.125 |
| PAO ΔdacC | AmpC↑ | 0.5 | 0.125 |
| PAO ΔdacB ΔdacC | AmpC↑ | 1 | 0.125 |
| PAO ΔdacB ΔdacC ΔpbpG | AmpC↑ | 0.125 | 0.125 |
| PAO ΔampD | AmpC↑ | 0.5 | 0.125 |
| PAO ΔampD ΔampDh2 ΔampDh3 | AmpC↑ | 0.5 | 0.0625 |
| PAO ΔdacB ΔampD | AmpC↑ | 1 | 0.125 |
| PAOD1 (oprD−) | OprD− | 8 | 0.25 |
| PAO ΔmexR | MexAB-OprM↑ | 0.5 | 0.125 |
| PAO ΔnfxB | MexCD-OprJ↑ | 0.5 | 0.125 |
| PAO ΔmexZ | MexXY↑ | 1 | 0.125 |
| PAO ΔampD ΔmexR | AmpC↑ + MexAB-OprM↑ | 0.5 | 0.125 |
| PAOD1 ΔampD | OprD− + AmpC↑ | 8 | 0.5 |
| PAOD1 ΔdacB | OprD− + AmpC↑ | 8 | 0.5 |
| PAOD ΔmexR | OprD− + MexAB-OprM↑ | 8 | 0.5 |
| PAOD ΔmexZ | OprD− + MeXY↑ | 16 | 1 |
TABLE 3.
Activity of imipenem-relebactam against isogenic XDR clinical isolates that had developed resistance to ceftolozane-tazobactam
| Patient | Isolate ID | Isolation date (day/mo/yr) | Sample type | MLST | MIC (μg/ml) |
β-Lactam resistance genotype | |||
|---|---|---|---|---|---|---|---|---|---|
| TOL-TZ (S ≤ 4) | CAZ-AVI (S ≤ 8) | IMP (S ≤ 4) | IMI-REL (S ≤ 4) | ||||||
| 1 | 96-C4 | 18/7/2016 | Bronchial aspirate | ST179 | 4 | 2 | 1 | 0.5 | OXA-10 |
| 96-H6 | 31/7/2016 | Bronchial aspirate | ST179 | 32 | 32 | 8 | 2 | OXA-14, OprD W417X | |
| 2 | 101-E5 | 7/11/2016 | Bronchial aspirate | ST175 | 2 | 4 | 8 | 1 | OprD Q142X, AmpR G154R |
| 103-H8 | 14/12/2016 | Bronchial aspirate | ST175 | >32 | >32 | 1 | 1 | OprD Q142X, AmpR G154R, AmpC E247K | |
| 3 | 104-B7 | 16/12/2016 | Urine | ST175 | 2 | 4 | 8 | 1 | OprD Q142X, AmpR G154R |
| 104-I9 | 7/1/2016 | Blood | ST175 | >32 | 32 | 1 | 0.5 | OprD Q142X, AmpR G154R, AmpC T96I | |
| 4 | 106-G2 | 3/2/2017 | Bronchial aspirate | ST175 | 2 | 4 | 16 | 0.5 | OprD Q142X, AmpR G154R |
| 107-H1 | 20/2/2017 | Bronchial aspirate | ST175 | >32 | 16 | 1 | 0.5 | OprD Q142X, AmpR G154R, AmpC T96I | |
| 5 | 109-E9 | 27/3/2017 | Sputum | ST175 | 2 | 4 | 16 | 1 | OprD Q142X, AmpR G154R |
| 110-G8 | 7/4/2017 | Bronchial aspirate | ST175 | 32 | 32 | 1 | 0.5 | OprD Q142X, AmpR G154R, AmpC DelG229-E247 | |
| 6 | 109-F7 | 28/3/2017 | Bronchial aspirate | ST235 | 4 | 8 | 16 | 1 | OXA-2, OprD 1bpIns |
| 110-G6 | 19/4/2017 | Bronchial aspirate | ST235 | 32 | 16 | 2 | 0.5 | OXA-2, OprD 1bpIns, AmpC F147L | |
| 7 | 114-G4 | 20/7/2017 | Blood | ST179 | 8 | 8 | 8 | 1 | OXA-10, OprD W6X |
| 117-C6 | 3/9/2017 | Tracheal aspirate | ST179 | 32 | >32 | 8 | 2 | OXA-14, mexR 4bpIns, mexZ 15bpDel, OprD W6X, ftsI (PBP3) F533L | |
| 8 | 116-A9 | 21/8/2017 | Bronchial aspirate | ST175 | 2 | 4 | 8 | 1 | OprD Q142X, AmpR G154R |
| 117-E3 | 4/9/2017 | Tracheal aspirate | ST175 | >32 | 8 | 2 | 0.5 | OprD Q142X, AmpR G154R, AmpC E247G | |
TABLE 4.
Activity of imipenem-relebactam against PAO1 OprD− ΔAmpC mutants expressing AmpC variants conferring ceftolozane-tazobactam and ceftazidime-avibactam resistance
| PAO1 variant | MIC (μg/ml) |
|||
|---|---|---|---|---|
| TOL-TZ (S ≤ 4) | CAZ-AVI (S ≤ 8) | IMP (S ≤ 4) | IMI-REL (S ≤ 4) | |
| PAO1 | ≤0.5 | 1 | 0.5 | 0.125 |
| PAOD1 (OprD−) | ≤0.5 | 1 | 8 | 0.25 |
| PAOD1 ΔAmpC | ≤0.5 | 1 | 0.5 | 0.5 |
| PAOD1 ΔAmpC + pUCP AmpCWT (PDC-1) | 1 | 2 | 4 | 0.5 |
| PAOD1 ΔAmpC + pUCP AmpCT96I (PDC-222) | 32/4 | 8 | 0.5 | 0.5 |
| PAOD1 ΔAmpC + pUCP AmpCE247K (PDC-221) | 32 | 16 | 0.5 | 0.5 |
| PAOD1 ΔAmpC + pUCP AmpCΔG299-E247K (PDC-223) | >32 | 32 | 0.5 | 0.5 |
| PAOD1 ΔAmpC + pUCP AmpCF147L (PDC-316) | 16 | 8 | 0.5 | 0.5 |
| PAOD1 ΔAmpC + pUCP AmpCE247G (PDC-80) | 32 | 4 | 1 | 0.5 |
Concluding remarks.
According to WHO, MDR P. aeruginosa, along with Acinetobacter baumannii and Enterobacterales, is in the list of top pathogens for which the development of novel antibiotic treatments is critical (13). One of the few novel agents on the horizon for the treatment of P. aeruginosa infections is the combination of the carbapenem imipenem with the novel β-lactamase inhibitor relebactam (9, 14). Up to 97% of P. aeruginosa strains isolated in 2017 from Spanish hospitals were found to be susceptible to imipenem-relebactam, slightly higher values than those recently documented in surveillance studies from Europe and the United States (93% to 94%) (15, 16). Note that there was a nearly perfect correlation between imipenem-relebactam resistance and carbapenemase production, which is both bad and good news. The bad news is that carbapenemase production, and particularly metallo-β-lactamase production, is still an unmet challenge for antimicrobial drug development. The good news is that imipenem-relebactam resistance appears to be extremely low among carbapenemase-nonproducing P. aeruginosa isolates. Only one carbapenemase-nonproducing P. aeruginosa isolate had an MIC of 8 μg/ml (intermediate). This isolate showed, in addition to mexXY and ampC overexpression, unique mutations in PBP 2 (A269V) and PBP 3 (N242S); the role of these mutations in reduced imipenem-relebactam susceptibility needs to be experimentally addressed.
Results from the analysis of the isogenic strains were complementary to those of the analysis of the clinical strains and indicated that imipenem-relebactam is highly stable against most relevant P. aeruginosa β-lactam mutation-driven resistance mechanisms, including combinations of OprD inactivation and AmpC and efflux overexpression. Possibly a more interesting finding of the study concerns the activity of imipenem-relebactam against P. aeruginosa isolates that had developed ceftolozane-tazobactam and ceftazidime-avibactam resistance during therapy. Indeed, resistance development mostly included specific mutations in the Ω-loop of AmpC, which conferred resistance to ceftolozane-tazobactam and ceftazidime-avibactam and increased susceptibility to imipenem. Interestingly, imipenem-relebactam remained highly active against both the parent XDR strains (imipenem resistant, ceftolozane-tazobactam susceptible) and the resistant mutants (ceftolozane-tazobactam and ceftazidime-avibactam resistant, imipenem susceptible). Thus, imipenem-relebactam is an attractive option for rescue therapy in cases of ceftolozane-tazobactam and ceftazidime-avibactam resistance development. Likewise, from the perspective of antimicrobial stewardship programs, the usefulness of imipenem-relebactam as a strategy to diversify the selective pressure exerted by ceftolozane-tazobactam and ceftazidime-avibactam should be explored.
ACKNOWLEDGMENTS
The following are members of GEMARA-SEIMC/REIPI Pseudomonas study group: Fátima Galán, Irene Gracia, Manuel Antonio Rodríguez, Lina Martín, Juan Manuel Sánchez, Laura Viñuela, Ma Victoria García, José Antonio Lepe, Javier Aznar, Inma López-Hernández, Cristina Seral, Francisco Javier Castillo-García, Ana Isabel López-Calleja, Carmen Aspiroz, Pedro de la Iglesia, Susana Ramón, Elena Riera, María Cruz Pérez, Carmen Gallegos, Jorge Calvo, María Dolores Quesada, Francesc Marco, Yannick Hoyos, Juan Pablo Horcajada, Nieves Larrosa, Juan José González, Fe Tubau, Silvia Capilla, Mar Olga Pérez-Moreno, Ma José Centelles, Emma Padilla, Alba Rivera, Beatriz Mirelis, Raquel Elisa Rodríguez-Tarazona, Noelia Arenal-Andrés, María del Pilar Ortega, Gregoria Megías, Inmaculada García, Cristina Colmenarejo, José Carlos González, Nora Mariela Martínez, Bárbara Gomila, Salvador Giner, Nuria Tormo, Eugenio Garduño, José Andrés Agulla, Alejandro Seoane, Julia Pita, Isabel Paz Vidal, David Mauricio Guzmán, Marta García, María Luisa Pérez del Molino, Gema Barbeito, Fernando Artiles, José Manuel Azcona-Gutiérrez, Yolanda Sáenz, José Antonio Oteo, Ana González, Jennifer Villa, Fernando Chaves, Emilia Cercenado, Teresa Alarcón, Nelly Daniela Zurita, Irene Merino, María Isabel Morosini, Rafael Cantón, María Isabel Sánchez, Laura Moreno, Genoveva Yagüe, José Leiva, José Luis Barrios, Andrés Canut, and Jesús Oteo.
We thank the students Adela Reus, Sergi Martorell, and Miquel Àngel Sastre for collaboration in the susceptibility testing studies.
The work was supported by MSD and by Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016), and grant PI18/00076 cofinanced by European Regional Development Fund (ERDF) “A way to achieve Europe,” Operative Program Intelligent Growth 2014–2020. The work was partially financed by MSD through Investigator Initiated Studies Program to A.O.
The funders had no role in design, execution, analysis, or reporting of the research.
Contributor Information
Collaborators: Fátima Galán, Irene Gracia, Manuel Antonio Rodríguez, Lina Martín, Juan Manuel Sánchez, Laura Viñuela, Ma Victoria García, José Antonio Lepe, Javier Aznar, Inma López-Hernández, Cristina Seral, Francisco Javier Castillo-García, Ana Isabel López-Calleja, Carmen Aspiroz, Pedro de la Iglesia, Susana Ramón, Elena Riera, María Cruz Pérez, Carmen Gallegos, Jorge Calvo, María Dolores Quesada, Francesc Marco, Yannick Hoyos, Juan Pablo Horcajada, Nieves Larrosa, Juan José González, Fe Tubau, Silvia Capilla, Mar Olga Pérez-Moreno, Ma José Centelles, Emma Padilla, Alba Rivera, Beatriz Mirelis, Raquel Elisa Rodríguez-Tarazona, Noelia Arenal-Andrés, María del Pilar Ortega, Gregoria Megías, Inmaculada García, Cristina Colmenarejo, José Carlos González, Nora Mariela Martínez, Bárbara Gomila, Salvador Giner, Nuria Tormo, Eugenio Garduño, José Andrés Agulla, Alejandro Seoane, Julia Pita, Isabel Paz Vidal, David Mauricio Guzmán, Marta García, María Luisa Pérez del Molino, Gema Barbeito, Fernando Artiles, José Manuel Azcona-Gutiérrez, Yolanda Sáenz, José Antonio Oteo, Ana González, Jennifer Villa, Fernando Chaves, Emilia Cercenado, Teresa Alarcón, Nelly Daniela Zurita, Irene Merino, María Isabel Morosini, Rafael Cantón, María Isabel Sánchez, Laura Moreno, Genoveva Yagüe, José Leiva, José Luis Barrios, Andrés Canut, and Jesús Oteo
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