AVIBACTAM – ETIDIoH

Pharmacokinetics and safety of #aztreonam / #avibactam for the #treatment of complicated intra-abdominal #infections in hospitalized adults: results from the REJUVENATE study (Antimicrob Agents Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study

Oliver A Cornely, José M Cisneros, Julian Torre-Cisneros, María Jesús Rodríguez-Hernández, Luis Tallón-Aguilar, Esther Calbo, Juan P Horcajada, Christian Queckenberg, Ulrike Zettelmeyer, Dorothee Arenz, Clara M Rosso-Fernández, Silvia Jiménez-Jorge, Guy Turner, Susan Raber, Seamus O’Brien, Alison Luckey, COMBACTE-CARE consortium/REJUVENATE Study Group

Journal of Antimicrobial Chemotherapy, dkz497, https://doi.org/10.1093/jac/dkz497

Published: 12 December 2019

Abstract

Objectives

To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/β-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI).

Methods

This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5–14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31–50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed.

Results

Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population).

Conclusions

Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

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Keywords: Antibiotics; Drugs Resistance; Aztreonam; Avibactam.

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#Ceftazidime – #avibactam to treat life-threatening #infections from #carbapenem #resistant #pathogens in critically ill mechanically ventilated patients (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Ceftazidime-avibactam to treat life-threatening infections from carbapenem resistant pathogens in critically ill mechanically ventilated patients

Vasiliki Tsolaki, Konstantinos Mantzarlis, Athanasios Mpakalis, Ergina Malli, Fotios Tsimpoukas, Athanasia Tsirogianni, Konstantinos Papagiannitsis, Paris Zygoulis, Maria-Eirini Papadonta, Efthimia Petinaki, Demosthenes Makris, Epaminondas Zakynthinos

DOI: 10.1128/AAC.02320-19

ABSTRACT

Data on the effectiveness of ceftazidime-avibactam (CAZ-AVI) in critically ill, mechanically ventilated patients are limited. The present retrospective observational cohort study, which was conducted in two general Intensive Care Units (ICUs) in central Greece, compared critically-ill, mechanically ventilated patients suffering from carbapenem-resistant enterobacteriaceae (CRE) infections receiving CAZ-AVI to patients who received appropriate available antibiotic therapy. Clinical, microbiological outcomes and safety issues were evaluated. A secondary analysis in patients with blood stream infections (BSI) was conducted. Forty-one patients that received CAZ-AVI (CAZ-AVI group) were compared to thirty-six patients receiving antibiotics other than CAZ-AVI (control group). There was significant improvement in the SOFA score on Day 4 and 10 in the CAZ-AVI compared to the control group (p=0.006, and p=0.003 respectively). Microbiological eradication was accomplished in 33/35 (94.3%) in CAZ-AVI group vs 21/31 (67.7%) patients in control group (p=0.021) and clinical cure was observed in 33/41 (80.5%) vs 19/36 (52.8%) patients (p=0.010), respectively. The results were similar in BSI subgroups for both outcomes (p=0.038 and p=0.014, respectively). 28-day survival was 85.4% in the CAZ-AVI and 61.1% in the control group (log Rank=0.035), while there were 2 and 12 relapses in each group (p=0.042). A CAZ-AVI containing regime was independent predictor of survival and clinical cure (OR 5.575, p=0.012 and OR 5.125, p=0.004, respectively) along with illness severity. In conclusion, no significant side effects were reported. A CAZ-AVI containing regime is more effective than other available antibiotic agents for the treatment of CRE infections in the high-risk, mechanically-ventilated, ICU population.

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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Ceftazidime; Avibactam; Intensive care.

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Successful rescue #treatment of #sepsis due to a #PDR, #NDM-producing #Klebsiella pneumoniae using #aztreonam powder for nebulizer solution as IV therapy in combination with #ceftazidime/avibactam (J Antimicrob Chemother., summary)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Summary, edited.]

Successful rescue treatment of sepsis due to a pandrug-resistant, NDM-producing Klebsiella pneumoniae using aztreonam powder for nebulizer solution as intravenous therapy in combination with ceftazidime/avibactam

Elske Sieswerda, Marre van den Brand, Roland B van den Berg, Joris Sträter, Leo Schouls, Karin van Dijk, Andries E Budding

Journal of Antimicrobial Chemotherapy, dkz495, https://doi.org/10.1093/jac/dkz495

Published: 02 December 2019

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Sir,

Pandrug-resistant Klebsiella pneumoniae that produces New Delhi MBL (NDM) is increasingly reported worldwide.1 These strains contain multiple β-lactamase genes but also may have acquired resistance to last-resort options such as colistin and tigecycline. Combining aztreonam and avibactam is potentially effective in MDR, NDM-producing Enterobacterales.2 Avibactam inhibits class A, C and D ESBLs, cephalosporinases and carbapenemases, while aztreonam is stable to hydrolysis by class B MBLs such as NDM. Until this drug combination becomes available, one could combine aztreonam and ceftazidime/avibactam to treat serious infections with such strains. A small number of studies have reported on 13 patients with serious infections with NDM-producing Enterobacterales who were successfully treated with aztreonam and ceftazidime/avibactam.3–7 Evidence of clinical efficacy and safety is therefore limited at present. Also, aztreonam for IV use is not registered and readily available in many countries, including the Netherlands. We describe successful rescue treatment of a patient with sepsis due to a pandrug-resistant, NDM-producing K. pneumoniae using aztreonam powder for nebulizer solution as IV therapy in combination with ceftazidime/avibactam.

(…)

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Acknowledgements

We presented this study in March 2019 at the Scientific Spring Meeting 2019 from the Dutch Society of Medical Microbiology, Arnhem, the Netherlands.

Funding

This study was carried out as part of our routine work.

Transparency declarations

None to declare.

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Keywords: Antibiotics; Drugs Resistance; NDM; Klebsiella pneumoniae; Sepsis; Aztreonam; Ceftazidime; Avibactam.

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In vitro activity of #ceftazidime / #avibactam against isolates of #carbapenem-non-susceptible #Enterobacteriaceae collected during the INFORM global surveillance programme (2015–17) (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

In vitro activity of ceftazidime/avibactam against isolates of carbapenem-non-susceptible Enterobacteriaceae collected during the INFORM global surveillance programme (2015–17)

Iris Spiliopoulou, Krystyna Kazmierczak, Gregory G Stone

Journal of Antimicrobial Chemotherapy, dkz456, https://doi.org/10.1093/jac/dkz456

Published: 19 November 2019

Abstract

Objectives

To report data for ceftazidime/avibactam and comparators against meropenem-non-susceptible Enterobacteriaceae collected globally (excluding centres in the USA) from 2015 to 2017 as part of the International Network For Optimal Resistance Monitoring (INFORM) surveillance programme.

Methods

MICs and susceptibility were determined using EUCAST broth microdilution methodology and EUCAST breakpoints. Isolates were screened to detect genes encoding β-lactamases using multiplex PCR assays. MBL-positive isolates were those in which one or more of the IMP, VIM and/or NDM genes were detected.

Results

A total of 1460 meropenem-non-susceptible isolates were collected and, of the agents on the panel, susceptibility was highest to ceftazidime/avibactam, colistin and tigecycline [73.0%, 77.0% (1081/1403) and 78.1%, respectively]. Ceftazidime/avibactam was not active against MBL-positive isolates (n = 367); these isolates showed the highest rates of susceptibility to colistin (92.1%, 303/329), tigecycline (71.9%) and amikacin (46.6%). A total of 394 isolates were resistant to ceftazidime/avibactam and, of the 369 isolates that were screened, 98.4% were found to carry a gene encoding an MBL enzyme. Among isolates that were identified as carbapenemase positive and MBL negative (n = 910), susceptibility was highest to ceftazidime/avibactam (99.8%). Susceptibility was also highest to ceftazidime/avibactam among isolates that were carbapenemase negative and MBL negative (94/98, 95.9%).

Conclusions

These data highlight the need for continued surveillance of antimicrobial activity as well as the need for new antimicrobials to treat infections caused by meropenem-non-susceptible Enterobacteriaceae, for which the options are extremely limited.

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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Avibactam; Ceftazidime.

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Searching for the Optimal #Treatment for Metallo- and Serine-β-Lactamase Producing #Enterobacteriaceae: #Aztreonam in Combination with #Ceftazidime-avibactam or #Meropenem-vaborbactam (AAC, abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Searching for the Optimal Treatment for Metallo- and Serine-β-Lactamase Producing Enterobacteriaceae: Aztreonam in Combination with Ceftazidime-avibactam or Meropenem-vaborbactam

M Biagi, T Wu, M Lee, S Patel, D Butler, E Wenzler

DOI: 10.1128/AAC.01426-19

ABSTRACT

Objective:

Metallo-β-lactamase (MBL)-producing Enterobacteriaceae, particularly those that co-harbor serine β-lactamases, are a serious emerging public health threat given their rapid dissemination and the limited number of treatment options. Pre-clinical and anecdotal clinical data support the use of aztreonam in combination with ceftazidime-avibactam against these pathogens, but other aztreonam-based combinations have not been explored. The objective of this study was to evaluate the in vitro activity and compare synergy between aztreonam in combination with ceftazidime-avibactam and meropenem-vaborbactam against serine and MBL-producing Enterobacteriaceae via time-kill analyses.

Methods:

8 clinical Enterobacteriaceae strains (4 Escherichia coli and 4 Klebsiella pneumoniae) co-producing NDM and at least one serine β-lactamase were used for all experiments. Drugs were tested alone, in dual β-lactam combinations, and in triple drug combinations against all strains.

Results:

All strains were resistant to ceftazidime-avibactam and meropenem-vaborbactam and 7/8 (87.5%) strains were resistant to aztreonam. Aztreonam combined with ceftazidime-avibactam was synergistic against all 7 aztreonam-resistant strains. Aztreonam combined with meropenem-vaborbactam was synergistic against all aztreonam-resistant strains with the exception of an OXA-232-producing K. pneumoniae strain. Neither triple combination was synergistic against the aztreonam-susceptible strain. Likewise, neither dual β-lactam combination was synergistic against any strain.

Conclusions:

These data suggest that aztreonam plus meropenem-vaborbactam has similar activity to aztreonam plus ceftazidime-avibactam against Enterobacteriaceae producing NDM and other non-OXA-48-like serine β-lactamases. Confirmation of these findings in future in vitro and in vivo models is warranted.

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Keywords: Antibiotics; Drugs Resistance; Beta-lactams; NDM; Aztreonam; Meropenem; Vaborbactam; Ceftazidime; Avibactam; Enterobacteriaceae.

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#Cost-effectiveness of #ceftazidime – #avibactam for #treatment of #carbapenem – resistant #Enterobacteriaceae #bacteremia and #pneumonia (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Cost-effectiveness of ceftazidime-avibactam for treatment of carbapenem-resistant Enterobacteriaceae bacteremia and pneumonia

Matthew S. Simon [MD, MS], Maroun M. Sfeir [MD, MPH], David P. Calfee [MD, MS], Michael J. Satlin [MD, MS]

DOI: 10.1128/AAC.00897-19

ABSTRACT

Background:

Ceftazidime/avibactam (CAZ-AVI) may improve outcomes among patients with carbapenem-resistant Enterobacteriaceae (CRE) infections compared to conventional therapies. However, CAZ-AVI’s cost-effectiveness is unknown.

Methods:

We used a decision analytic model to estimate the health and economic consequences of CAZ-AVI-based therapy compared to colistin-based therapy (COL) for a hypothetical cohort of patients with CRE pneumonia or bacteremia over a 5-year horizon. Model inputs were from published sources and included CRE mortality with COL (41%), CAZ-AVI’s absolute risk reduction in CRE mortality (23%), daily cost of CAZ-AVI ($926), risk of nephrotoxicity with COL (42%) and probability of discharge to long-term care (LTC) following CRE infection (56%). Outcomes included quality adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICER; $/QALY). 1-way and probabilistic sensitivity analyses were performed and ICERs were compared to willingness to pay standards of $100,000/QALY and $150,000/QALY.

Results:

In the base case, CAZ-AVI had an ICER of $95,000/QALY. At a $100,000/QALY threshold, results were sensitive to a number of variables including: the probability and cost of LTC, quality of life following CRE infection, CAZ-AVI’s absolute risk reduction in mortality, all-cause mortality, daily cost of CAZ-AVI, and healthcare costs after CRE infection. The ICER did not exceed $150,000/QALY after varying all model inputs across a wide range of plausible values. In probabilistic sensitivity analysis, CAZ-AVI was the optimal strategy in 59% and 99% of simulations at $100,000/QALY and $150,000/QALY threshold, respectively.

Conclusion:

CAZ-AVI is a cost-effective treatment for CRE bacteremia and pneumonia based on accepted willingness to pay standards in the US.

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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Ceftazidime; Avibactam; Bacteremia; Pneumonia; USA.

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#Phenotypic, biochemical and #genetic analysis of #KPC-41, a KPC-3 variant conferring #resistance to #ceftazidime-avibactam and exhibiting reduced #carbapenemase activity (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Phenotypic, biochemical and genetic analysis of KPC-41, a KPC-3 variant conferring resistance to ceftazidime-avibactam and exhibiting reduced carbapenemase activity

Linda Mueller, Amandine Masseron, Guy Prod’Hom, Tatiana Galperine, Gilbert Greub, Laurent Poirel, Patrice Nordmann

DOI: 10.1128/AAC.01111-19

ABSTRACT

A novel KPC variant, KPC-41, was identified in a Klebsiella pneumoniae clinical isolate from Switzerland. This ß-lactamase possessed a three amino-acid insertion (Pro-Asn-Lys) located between amino acids 269 and 270 compared to the KPC-3 amino acid sequence. Cloning and expression of the blaKPC-41 gene in Escherichia coli, followed by determination of MIC values and kinetic parameters, showed that KPC-41, compared to KPC-3, has an increased affinity to ceftazidime and a decreased sensitivity to avibactam, leading to resistance to ceftazidime-avibactam once produced in K. pneumoniae. Furthermore, KPC-41 exhibited a drastic decrease of its carbapenemase activity. This report highlights that a diversity of KPC variants conferring resistance to ceftazidime-avibactam already circulate in Europe.

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Keywords: Antibiotics; Drugs Resistance; Klebsiella pneumoniae; Ceftazidime; Avibactam.

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Emergence of #ceftazidime / #avibactam #resistance in #KPC-3-producing #Klebsiella pneumoniae in vivo (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

Stephan Göttig, Denia Frank, Eleonora Mungo, Anika Nolte, Michael Hogardt, Silke Besier,Thomas A Wichelhaus

Journal of Antimicrobial Chemotherapy, dkz330, https://doi.org/10.1093/jac/dkz330

Published: 31 July 2019

Abstract

Objectives

The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro.

Methods

Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination.

Results

The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival.

Conclusions

Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivoinfection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Ceftazidime; Avibactam; Imipenem; Klebsiella pneumoniae.

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Potentiation of #betalactam #antibiotics and β-lactam/β-lactamase inhibitor combinations against #MDR and #XDR #Pseudomonas aeruginosa using non-ribosomal #tobramycin–cyclam conjugates (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Potentiation of β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations against MDR and XDR Pseudomonas aeruginosa using non-ribosomal tobramycin–cyclam conjugates

Temilolu Idowu, Derek Ammeter, Gilbert Arthur, George G Zhanel, Frank Schweizer

Journal of Antimicrobial Chemotherapy, dkz228, https://doi.org/10.1093/jac/dkz228

Published: 28 May 2019

Abstract

Objectives

To develop a multifunctional adjuvant molecule that can rescue β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clinical isolates.

Methods

Preparation of adjuvant was guided by structure–activity relationships, following standard protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold dilution assays. Toxicity was evaluated against porcine erythrocytes, human embryonic kidney (HEK293) cells and liver carcinoma (HepG2) cells via MTS assay. Preliminary in vivo efficacy was evaluated using a Galleria mellonella infection model.

Results

Conjugation of tobramycin and cyclam abrogates the ribosomal effects of tobramycin but confers a potent adjuvant property that restores full antibiotic activity of meropenem and aztreonam against carbapenem-resistant P. aeruginosa. Therapeutic levels of susceptibility, as determined by CLSI susceptibility breakpoints, were attained in several MDR clinical isolates, and time–kill assays revealed a synergistic dose-dependent pharmacodynamic relationship. A triple combination of the adjuvant with ceftazidime/avibactam (approved), aztreonam/avibactam (Phase III) and meropenem/avibactam enhances the efficacies of β-lactam/β-lactamase inhibitors against recalcitrant strains, suggesting rapid access of the combination to their periplasmic targets. The newly developed adjuvants, and their combinations, were non-haemolytic and non-cytotoxic, and preliminary in vivo evaluation in G. mellonella suggests therapeutic potential for the double and triple combinations.

Conclusions

Non-ribosomal tobramycin–cyclam conjugate mitigates the effect of OprD/OprF porin loss in P. aeruginosa and potentiates β-lactam/β-lactamase inhibitors against carbapenem-resistant clinical isolates, highlighting the complexity of resistance to β-lactam antibiotics. Our strategy presents an avenue to further preserve the therapeutic utility of β-lactam antibiotics.

Topic: antibiotics – pseudomonas aeruginosa – immunologic adjuvants – pharmaceutical adjuvants – aztreonam – ceftazidime – lactams – ribosomes – infection – tobramycin – meropenem – toxic effect – potentiation – avibactam – carbapenem resistance

Issue Section: ORIGINAL RESEARCH

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Keywords: Antibiotics; Drugs Resistance; Carbapenem; Beta-lactams; Pseudomonas aeruginosa; Tobramycin; Aztreonam; Avibactam; Ceftazidime.

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#Ceftazidime – #Avibactam in Combination With #Fosfomycin: A Novel #Therapeutic Strategy Against #MDR #Pseudomonas aeruginosa (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

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

The Journal of Infectious Diseases, jiz149, https://doi.org/10.1093/infdis/jiz149

Published: 17 May 2019

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.

Pseudomonas aeruginosa, β-lactams, fosfomycin, combination therapy

Topic: pseudomonas aeruginosa – ceftazidime – fosfomycin – lactams – infection – mice – avibactam – avibactam/ceftazidime

Issue Section: Major Article

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Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Avibactam; Ceftazidime; Fosfomycin.

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