Mechanisms of high-level ceftolozane/tazobactam resistance in Pseudomonas aeruginosa from a severely neutropenic patient and treatment success from synergy with tobramycin

So, Wonhee; Shurko, James; Galega, Ralph; Quilitz, Rod; Greene, John N.; Lee, Grace C.

doi:10.1093/jac/dky393

Cited by 19 publications

(22 citation statements)

References 9 publications

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“…One comparative study recently demonstrated an overall improved activity of ceftazidime-avibactam compared to ceftolozanetazobactam (C/T) versus ESBL-producing Escherichia coli and P. aeruginosa (16). Occasional microbiological failure to C/T has also been documented in clinics worldwide (16)(17)(18). Because C/T is frequently used in critical clinical situations for resistant, MDR, and XDR P. aeruginosa, it is natural to question whether its utility can be further optimized by adding a second antibiotic or an adjuvant.…”

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confidence: 99%

“…Indeed, only a few agents have exhibited demonstrable synergy with C/T. For example, amikacin and colistin exhibit different (synergistic or additive/indifferent) interactions with C/T against different P. aerugi- nosa strains in vitro (19), while a separate study reported a clinical treatment success of a C/T-resistant P. aeruginosa strain due to synergy with tobramycin (18). The mechanism of synergism in this clinical success was hypothesized to be due to extensive outer membrane disruption by tobramycin (18).…”

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confidence: 99%

“…For example, amikacin and colistin exhibit different (synergistic or additive/indifferent) interactions with C/T against different P. aerugi- nosa strains in vitro (19), while a separate study reported a clinical treatment success of a C/T-resistant P. aeruginosa strain due to synergy with tobramycin (18). The mechanism of synergism in this clinical success was hypothesized to be due to extensive outer membrane disruption by tobramycin (18). In both cases, the isolates were either susceptible or intermediately resistant to the potentiating antibiotics (i.e., MIC of amikacin ϭ 2 to 8 g/ml; colistin ϭ 1 to 2 g/ml; tobramycin Յ1 to 4 g/ml) (18,19), consistent with known synergism between ␤-lactam antibiotics and ribosomal aminoglycosides (20,21).…”

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confidence: 99%

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A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa and Delays Resistance Development

Idowu

Zhanel

Schweizer

2020

Antimicrob Agents Chemother

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Ceftolozane-tazobactam is a potent β-lactam/β-lactamase inhibitor combination approved for the treatment of complicated intraabdominal and complicated urinary tract infections and, more recently, the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Although the activities of ceftolozane are not enhanced by tazobactam against Pseudomonas aeruginosa, it remains the most potent antipseudomonal agent approved to date. Emerging data worldwide has included reports of microbiological failure in patients with serious bacterial infections caused by multidrug-resistant (MDR) P. aeruginosa as a result of ceftolozane resistance developed within therapy. The objective of this study is to compare the efficacy of a tobramycin homodimer plus ceftolozane versus ceftolozane-tazobactam alone against MDR and extensively drug-resistant (XDR) P. aeruginosa. Tobramycin homodimer, a synthetic dimer of two monomeric units of tobramycin, was developed to abrogate the ribosomal properties of tobramycin with a view to mitigating aminoglycoside-related toxicity and resistance. Herein, we report that tobramycin homodimer, a nonribosomal aminoglycoside derivative, potentiates the activities of ceftolozane versus MDR/XDR P. aeruginosa in vitro and delays the emergence of resistance to ceftolozane-tazobactam in the wild-type PAO1 strain. This combination is also more potent than a standard ceftazidime-avibactam combination against these isolates. Conversely, a tobramycin monomer with intrinsic ribosomal properties does not potentiate ceftolozane under similar conditions. Susceptibility and checkerboard studies were assessed using serial 2-fold dilution assays, following the Clinical and Laboratory Standards Institute (CLSI) guidelines. This strategy provides an avenue to further preserve the clinical utility of ceftolozane and enhances its spectrum of activity against one of the most difficult-to-treat pathogens in hospitals.

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A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa and Delays Resistance Development

Idowu

Zhanel

Schweizer

2020

Antimicrob Agents Chemother

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“…After evidence of early clinical and microbiological cure of BSI obtained by empirical use of combination of ceftolozane/tazobactam and tobramycin, the authors demonstrated in vitro synergistic effects of this combination, which reduced the MIC of ceftolozane/tazobactam from ≥256 to 16 mg/L and the MIC of tobramycin from 4 to 1 mg/L. Therefore, the patient was successfully treated with this antimicrobial combination [45].…”

Section: Ceftolozane/tazobactammentioning

confidence: 98%

Ceftazidime/Avibactam and Ceftolozane/Tazobactam for Multidrug-Resistant Gram Negatives in Patients with Hematological Malignancies: Current Experiences

Criscuolo

Trecarichi

2020

Antibiotics

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Patients suffering from hematological malignancies are at high risk for severe infections, including in particular bloodstream infections, which represent one of the most frequent life-threatening complications for these patients, with reported mortality rates reaching 40%. Furthermore, a worrisome increase in antimicrobial resistance of Gram-negative bacteria (e.g., cephalosporin- and/or carbapenem-resistant Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa) involved in severe infectious complications among patients with hematological malignancies has been reported during the last years. The two novel combination of cephalosporins and β-lactamase inhibitors, ceftolozane/tazobactam and ceftazidime/avibactam, were recently approved for treatment of complicated intra-abdominal and urinary tract infections and nosocomial pneumonia and display activity against several MDR Gram-negative strains. Although not specifically approved for neutropenic and/or cancer patients, these drugs are used in this setting due to increasing rates of infections caused by MDR Gram-negative bacteria. The aim of this review is to describe the actual evidence from scientific literature about the “real-life” use of these two novel drugs in patients with hematological malignancies and infections caused by MDR Gram-negative bacteria.

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“…P seudomonas aeruginosa causes roughly 20% of hospital-acquired and ventilatorassociated bacterial pneumonia cases in the United States, and 4 in every 10 such cases are fatal (1). Resistance to recently marketed ␤-lactam/␤-lactamase inhibitor antibiotics such as ceftazidime-avibactam and ceftolozane-tazobactam (C/T) has been documented (2,3), contributing to the growing concern surrounding these opportunistic pathogens. WCK 5222 (cefepime-zidebactam), a ␤-lactam/␤-lactam enhancer antibiotic under development as a single intravenous formulation, has demonstrated in vitro (4) and in vivo (5) activity against multidrug-resistant (MDR) P. aeruginosa strains.…”

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Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa

Mullane

Avery

Nicolau

2020

Antimicrob Agents Chemother

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The in vitro activity of WCK 5222 (cefepime-zidebactam) was compared to that of several available combination therapies among 30 clinical carbapenem-resistant Pseudomonas aeruginosa (CRP) strains using gradient diffusion strips. The combinations included nonsusceptible β-lactams (cefepime, ceftolozane-tazobactam, and meropenem) with amikacin and fosfomycin. WCK 5222 MICs ranged from 2 to 32 mg/liter, and 97% were ≤16 mg/liter, while 105/146 (72%) combinations demonstrated inhibition below established susceptibility breakpoints. WCK 5222 monotherapy may be preferred over the combinations assessed for CRP infections.

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Mechanisms of high-level ceftolozane/tazobactam resistance in Pseudomonas aeruginosa from a severely neutropenic patient and treatment success from synergy with tobramycin

Cited by 19 publications

References 9 publications

A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa and Delays Resistance Development

A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa and Delays Resistance Development

Ceftazidime/Avibactam and Ceftolozane/Tazobactam for Multidrug-Resistant Gram Negatives in Patients with Hematological Malignancies: Current Experiences

Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa

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