Successful Treatment of Bloodstream Infection Due to Metallo-β-Lactamase-Producing Stenotrophomonas maltophilia in a Renal Transplant Patient

Mojica, María F; Ouellette, Christopher P.; Leber, Amy; Becknell, M. Brian; Ardura, Monica I.; Pérez, Federico; Shimamura, Masako; Bonomo, Robert A.; Aitken, Samuel L; Shelburne, Samuel A.

doi:10.1128/aac.00264-16

Cited by 71 publications

(58 citation statements)

References 21 publications

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“…for optimism. We were interested to read, therefore, a recent clinical case report demonstrating the use of combination therapy with ceftazidime/avibactam plus aztreonam to save the life of a patient with an S. maltophilia infection that had failed all prior therapy (Mojica et al, 2016). Our structural, kinetic and whole bacterial killing data would lead to the conclusion that ceftazidime was probably superfluous in this success, but our work indicates that ceftazidime/avibactam plus aztreonam might be routinely considered in the clinic for use against seemingly untreatable S. maltophilia infections while aztreonam/avibactam works its way through the clinical trials system.…”

Section: Discussionmentioning

confidence: 99%

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Calvopiña

Hinchliffe

Brem

et al. 2017

Molecular Microbiology

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Clavulanic acid and avibactam are clinically deployed serine β-lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo β-lactamases. Here, we show that avibactam and a bicyclic boronate inhibit L2 (serine β-lactamase) but not L1 (metallo β-lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X-ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine. Both inhibitors reverse ceftazidime resistance in S. maltophilia because, unlike clavulanic acid, they do not induce L1 production. Ceftazidime/inhibitor resistant mutants hyperproduce L1, but retain aztreonam/inhibitor susceptibility because aztreonam is not an L1 substrate. Importantly, avibactam, but not the bicyclic boronate is deactivated by L1 at a low rate; the utility of avibactam might be compromised by mutations that increase this deactivation rate. These data rationalize the observed clinical efficacy of ceftazidime/avibactam plus aztreonam as combination therapy for S. maltophilia infections and confirm that aztreonam-like β-lactams plus nonclassical β-lactamase inhibitors, particularly avibactam-like and bicyclic boronate compounds, have potential for treating infections caused by this most intractable of drug resistant pathogens.

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Section: Discussionmentioning

confidence: 99%

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Calvopiña

Hinchliffe

Brem

et al. 2017

Molecular Microbiology

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“…At present, clinical experience using this combination against Stenotrophomonas maltophilia proved to be successful in a single case (15). Finally, the possibility of cumulative toxicity from "double-␤-lactam" combinations must be considered when administering this regimen.…”

Section: Clinical Commentarymentioning

confidence: 99%

Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Marshall

Hujer

Rojas

et al. 2017

Antimicrob Agents Chemother

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250

155

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Based upon knowledge of the hydrolytic profile of major ␤-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-␤-lactamases (MBLs). Disk diffusion and agarbased antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included bla IMP , bla NDM , bla , bla CTX-M , bla AmpC , and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was Ն21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a Ն4-log 10 -CFU decrease for all groups that had CAZ-AVI with ATM (8 g/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log 10 -CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

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“…The growing challenge of treating infections caused by S. maltophilia is reflected in increasing reports of acquired resistance to historically effective drugs, like trimethoprimsulfamethoxazole (SXT), ceftazidime (CAZ), ticarcillin-clavulanate (TIM), and fluoroquinolones, and the documented ability to develop high-level resistance during antibiotic treatment (8,9,12,13). Recently, Mojica et al described a clinical case in which the avibactam and ceftazidime combination coadministered with ATM (CZA) effectively treated a prolonged bacteremia caused by S. maltophilia (13). Notwithstanding the effectiveness of this triple combination, we anticipate that aztreonam-avibactam (ATM-AVI), the planned commercial preparation already in clinical development (ClinicalTrials.gov identifier NCT01689207), would be equally effective against S. maltophilia.…”

mentioning

confidence: 99%

Avibactam Restores the Susceptibility of Clinical Isolates of Stenotrophomonas maltophilia to Aztreonam

Mojica

Papp-Wallace

Taracila

et al. 2017

Antimicrob Agents Chemother

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is an emerging opportunistic pathogen, classified by the World Health Organization as one of the leading multidrug-resistant organisms in hospital settings. The need to discover novel compounds and/or combination therapies for is urgent. We demonstrate the efficacy of aztreonam-avibactam (ATM-AVI) against and kinetically characterize the inhibition of the L2 β-lactamase by avibactam. ATM-AVI overcomes aztreonam resistance in selected clinical strains of, addressing an unmet medical need.

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Successful Treatment of Bloodstream Infection Due to Metallo-β-Lactamase-Producing Stenotrophomonas maltophilia in a Renal Transplant Patient

Cited by 71 publications

References 21 publications

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Avibactam Restores the Susceptibility of Clinical Isolates of Stenotrophomonas maltophilia to Aztreonam

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