In vivo impact of the MexAB-OprM efflux system on β-lactam efficacy in an experimental model of Pseudomonas aeruginosa infection

Boutoille, David; Jacqueline, Cédric; Mabecque, Virginie Le; Potel, G.; Caillon, Jocelyne

doi:10.1016/j.ijantimicag.2008.10.029

Cited by 9 publications

(5 citation statements)

References 21 publications

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“…q8h and ceftazidime (CAZ) at 2 g i.v. q8h, which served as control treatments, were administered in humanized dosages (18,(31)(32)(33)(34)(35). Adjustments in dosing intervals were required because of the more rapid elimination of ceftolozane (0.75 h versus 2.5 h), CAZ (4 h versus 8 h), and TZP (4 h versus 8 h) in rabbits than in humans.…”

Section: Methodsmentioning

confidence: 99%

Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance

Petraitis

Petraitienė

Naing

et al. 2019

Antimicrob Agents Chemother

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Ceftolozane-tazobactam (C/T) is a novel cephalosporin with in vitro activity against Pseudomonas aeruginosa that is resistant to extended-spectrum penicillins and antipseudomonal cephalosporins. In order to assess the antimicrobial effect of C/T in treatment of Pseudomonas pneumonia, we investigated the pharmacokinetics and efficacy of C/T in persistently neutropenic rabbits. Pseudomonas pneumonia was established by direct endotracheal inoculation. Treatment groups consisted of C/T, ceftazidime (CAZ), piperacillin-tazobactam (TZP), and untreated controls (UC). Rabbits received a dosage of C/T of 80 mg/kg every 4 h (q4h) intravenously (i.v.) (53 mg/kg ceftolozane/26 mg/kg tazobactam) to match the free drug time above the MIC as well as a comparable plasma area under the concentration-time curve (AUC) (humanized doses of ceftolozane-tazobactam of 3 g [2 g/1 g]) q8h, due to the more rapid elimination of ceftolozane in rabbits (0.75 h) than in humans (2.5 h). Four molecularly characterized clinical P. aeruginosa isolates from patients with pneumonia were studied, including one isolate from each classification group: pan-susceptible (PS), outer membrane porin D (OPRD) porin loss (OPRDPL), efflux pump expression (EPE), and AmpC hyperexpression (ACHE). Treatment was continued for 12 days. Treatment with ceftolozane-tazobactam resulted in a ≥105 reduction in residual pulmonary and bronchoalveolar lavage (BAL) fluid bacterial burdens caused by all 4 strains (P ≤ 0.01). This antibacterial activity coincided with reduction of lung weight (an organism-mediated pulmonary injury marker) (P < 0.05). CAZ was less active in ACHE-infected rabbits, and TZP had less activity against EPE, ACHE, and OPRDPL strains. Survival was prolonged in the C/T and CAZ treatment groups in comparison to the TZP and UC groups (P < 0.001). Ceftolozane-tazobactam is highly active in treatment of experimental P. aeruginosa pneumonia in persistently neutropenic rabbits, including infections caused by strains with the most common resistance mechanisms.

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Section: Methodsmentioning

confidence: 99%

Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance

Petraitis

Petraitienė

Naing

et al. 2019

Antimicrob Agents Chemother

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“…Nevertheless, it can reasonably be assumed that even low-level-resistant mutants will survive chemotherapy better than wild-type bacteria if inappropriate agents are used to treat the infection or if only suboptimal drug concentrations reach the infection site because of limited diffusion in vivo or an insufficient antibiotic dosage. As demonstrated in an animal model of infective endocarditis, management of difficult-to-treat infections requires higher doses of a ␤-lactam if MexAB-OprM-upregulated mutants develop (428).…”

Section: Pseudomonas Aeruginosamentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…[229–234] Thus, efflux mechanisms are considered as a key factor in optimizing the treatment of P. aeruginosa infections. [235–237] Meanwhile, approaches for detection of overexpressed Mex efflux systems are in development. [238]…”

Section: Drug Efflux In Gram-negative Bacteriamentioning

confidence: 99%

Efflux-Mediated Drug Resistance in Bacteria

Nikaido²

2009

Drugs

921

875

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Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome although they can also be plasmid-encoded. A previous article (Li X-Z and Nikaido H, Drugs, 2004; 64[2]: 159–204) had provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past five years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.

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In vivo impact of the MexAB-OprM efflux system on β-lactam efficacy in an experimental model of Pseudomonas aeruginosa infection

Cited by 9 publications

References 21 publications

Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance

Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Efflux-Mediated Drug Resistance in Bacteria

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