Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa

Krisztina M. Papp-Wallace, Elise T. Zeiser, Scott A. Becka, Steven Park, Brigid M. Wilson, Marisa L. Winkler, Roshan D'Souza, Indresh Singh, Granger Sutton, Derrick E. Fouts, Liang Chen, Barry N. Kreiswirth, Evelyn J. Ellis-Grosse, George L. Drusano, David S. Perlin, Robert A. Bonomo

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to β-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a "mechanism-based approach" to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-β-lactamases.

Original languageEnglish (US)
Pages (from-to)666-676
Number of pages11
JournalThe Journal of infectious diseases
Volume220
Issue number4
DOIs
StatePublished - Jul 19 2019

Fingerprint

Fosfomycin
Pseudomonas aeruginosa
Stem Cells
Therapeutics
Mutation Rate
Cephalosporinase
Penicillin-Binding Proteins
ceftazidime drug combination avibactam
Lactams
Gene Expression Profiling
Pseudomonas
Infection
Combination Drug Therapy
Genome
Mutation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Infectious Diseases

Keywords

  • Pseudomonas aeruginosa
  • combination therapy
  • fosfomycin
  • β-lactams

Cite this

Papp-Wallace, K. M., Zeiser, E. T., Becka, S. A., Park, S., Wilson, B. M., Winkler, M. L., ... Bonomo, R. A. (2019). Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa. The Journal of infectious diseases, 220(4), 666-676. https://doi.org/10.1093/infdis/jiz149
Papp-Wallace, Krisztina M. ; Zeiser, Elise T. ; Becka, Scott A. ; Park, Steven ; Wilson, Brigid M. ; Winkler, Marisa L. ; D'Souza, Roshan ; Singh, Indresh ; Sutton, Granger ; Fouts, Derrick E. ; Chen, Liang ; Kreiswirth, Barry N. ; Ellis-Grosse, Evelyn J. ; Drusano, George L. ; Perlin, David S. ; Bonomo, Robert A. / Ceftazidime-Avibactam in Combination With Fosfomycin : A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa. In: The Journal of infectious diseases. 2019 ; Vol. 220, No. 4. pp. 666-676.
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abstract = "Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to β-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a {"}mechanism-based approach{"} to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-β-lactamases.",
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Papp-Wallace, KM, Zeiser, ET, Becka, SA, Park, S, Wilson, BM, Winkler, ML, D'Souza, R, Singh, I, Sutton, G, Fouts, DE, Chen, L, Kreiswirth, BN, Ellis-Grosse, EJ, Drusano, GL, Perlin, DS & Bonomo, RA 2019, 'Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa', The Journal of infectious diseases, vol. 220, no. 4, pp. 666-676. https://doi.org/10.1093/infdis/jiz149

Ceftazidime-Avibactam in Combination With Fosfomycin : A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa. / Papp-Wallace, Krisztina M.; Zeiser, Elise T.; Becka, Scott A.; Park, Steven; Wilson, Brigid M.; Winkler, Marisa L.; D'Souza, Roshan; Singh, Indresh; Sutton, Granger; Fouts, Derrick E.; Chen, Liang; Kreiswirth, Barry N.; Ellis-Grosse, Evelyn J.; Drusano, George L.; Perlin, David S.; Bonomo, Robert A.

In: The Journal of infectious diseases, Vol. 220, No. 4, 19.07.2019, p. 666-676.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ceftazidime-Avibactam in Combination With Fosfomycin

T2 - A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa

AU - Papp-Wallace, Krisztina M.

AU - Zeiser, Elise T.

AU - Becka, Scott A.

AU - Park, Steven

AU - Wilson, Brigid M.

AU - Winkler, Marisa L.

AU - D'Souza, Roshan

AU - Singh, Indresh

AU - Sutton, Granger

AU - Fouts, Derrick E.

AU - Chen, Liang

AU - Kreiswirth, Barry N.

AU - Ellis-Grosse, Evelyn J.

AU - Drusano, George L.

AU - Perlin, David S.

AU - Bonomo, Robert A.

PY - 2019/7/19

Y1 - 2019/7/19

N2 - Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to β-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a "mechanism-based approach" to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-β-lactamases.

AB - Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to β-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a "mechanism-based approach" to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-β-lactamases.

KW - Pseudomonas aeruginosa

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