Polymyxins for CNS infections: Pharmacology and neurotoxicity

Velkov, Tony; Dai, Chongshan; Ciccotosto, Giuseppe D.; Cappai, Roberto; Hoyer, Daniel; Li, Jian

doi:10.1016/j.pharmthera.2017.07.012

Cited by 74 publications

(63 citation statements)

References 46 publications

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“…Our report suggests a potentially interesting and highly demanded additional indication for ceftolozane-tazobactam, for which at present very little information is available: CNS infections caused by XDR-PA [ 5 , 8 ]. Meningitis is the most common intracranial complication of otomastoiditis.…”

Section: Discussionmentioning

confidence: 99%

“…In patients with Blood Stream Infections and/or pneumonia caused by Extensively Drug Resistant Pseudomonas aeruginosa (XDR-PA), use of colistin and/or aminoglycosides consequently increased [ 2 ]. Central Nervous System (CNS) infections may be challenging for such alternative regimens, associated with reduced clinical and microbiological success [ [3] , [4] , [5] ]. Ceftolozane-tazobactam (C-T), a new combination of antipseudomonal cephalosporin and beta-lactamase inhibitor, exhibiting potent in vitro activity against XDR-PA strains and other Gram-negative microorganisms, may represent an effective alternative for XDR-PA infections with CNS involvement [ 3 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Central Nervous System (CNS) infections may be challenging for such alternative regimens, associated with reduced clinical and microbiological success [ [3] , [4] , [5] ]. Ceftolozane-tazobactam (C-T), a new combination of antipseudomonal cephalosporin and beta-lactamase inhibitor, exhibiting potent in vitro activity against XDR-PA strains and other Gram-negative microorganisms, may represent an effective alternative for XDR-PA infections with CNS involvement [ 3 , 5 ]. The drug is so far approved for complicated urinary tract infections, including acute pyelonephritis, as well as of complicated intra-abdominal infections, the latter in association with metronidazole [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Ceftolozane-tazobactam and Fosfomycin for rescue treatment of otogenous meningitis caused by XDR Pseudomonas aeruginosa: Case report and review of the literature

Frattari

Savini

Polilli

et al. 2018

IDCases

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HighlightsInfections due to XDR Pseudomonas are at increased risk of complications and death.CNS involvement may be due to poor CNS penetration of drugs with residual activity.XDR-PA meningitis ensued during treatment with colistin for pneumonia and bacteremia.CNS involvement by XDR-PA was timely suspected and quickly documented on CSF.High dose C-T and Fosfomycin provided rapid control of meningitis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ceftolozane-tazobactam and Fosfomycin for rescue treatment of otogenous meningitis caused by XDR Pseudomonas aeruginosa: Case report and review of the literature

Frattari

Savini

Polilli

et al. 2018

IDCases

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“…However, one safety concern is the nephrotoxicity and neurotoxicity occurring during the systemic polymyxin therapy, which strongly limits the clinical applications of polymyxins . For instance, injection of high‐dose polymyxin may cause kidney damage and nervous system dysfunction in many cases . Hence, there is an emergency to find a strategy to minimize the toxicity of polymyxin with effective dose.…”

Section: Methodsmentioning

confidence: 99%

Polymyxin B‐Polysaccharide Polyion Nanocomplex with Improved Biocompatibility and Unaffected Antibacterial Activity for Acute Lung Infection Management

Chai

Gao

et al. 2020

Adv Healthcare Materials

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The decade‐old antibiotic, polymyxin B (PMB), is regarded as the last line defense against gram‐negative “superbug.” However, the serious nephrotoxicity and neurotoxicity strongly obstruct further application of this highly effective antibiotic. Herein, a charge switchable polyion nanocomplex exhibiting pH‐sensitive property is proposed to deliver PMB which is expected to improve the biosafety of PMB on the premise of retaining excellent antibacterial activity. The polyion nanocomplex is prepared through electrostatic interaction of positively charged PMB and negatively charged 2,3‐dimethyl maleic anhydride (DA) grafted chitoligosaccharide (CS). The negative charge of CS‐DA will convert to positive due to the hydrolysis of amide bonds in acidic infectious environment, leading to the disassembly of CS‐DA/PMB nanocomplex and release of PMB. CS‐DA/PMB nanocomplex does not show significant toxicity to mammalian cells while retaining excellent bactericidal capability equivalent to free PMB. The nephrotoxicity and neurotoxicity of CS‐DA/PMB dramatically decrease compared to free PMB. Moreover, CS‐DA/PMB nanocomplex exhibits superior bactericidal activity against Pseudomonas aeruginosa in an acute lung infection mouse model. The pH‐sensitive polyion nanocomplexes may provide a new way to reduce the side effects of highly toxic antibiotics without reducing their intrinsic antibacterial activity, which is the key factor to achieve extensive in vivo clinical applications.

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“…These peptides re-emerged in clinics to treat multidrug-resistant Gram-negative infections. Polymyxin E, otherwise known as colistin, is now the last-resort treatment for infections caused by carbapenem-resistant pathogens [96,97]. The dose regime for polymyxins needs to be very carefully controlled due to their inherent nephrotoxicity.…”

Section: Om Permeabilisersmentioning

confidence: 99%

Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

Venter

2019

Bioscience Reports

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The speed at which bacteria develop antimicrobial resistance far outpace drug discovery and development efforts resulting in untreatable infections. The World Health Organisation recently released a list of pathogens in urgent need for the development of new antimicrobials. The organisms that are listed as the most critical priority are all Gram-negative bacteria resistant to the carbapenem class of antibiotics. Carbapenem resistance in these organisms is typified by intrinsic resistance due to the expression of antibiotic efflux pumps and the permeability barrier presented by the outer membrane, as well as by acquired resistance due to the acquisition of enzymes able to degrade β-lactam antibiotics. In this perspective article we argue the case for reversing resistance by targeting these resistance mechanisms – to increase our arsenal of available antibiotics and drastically reduce antibiotic discovery times – as the most effective way to combat antimicrobial resistance in these high priority pathogens.

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Polymyxins for CNS infections: Pharmacology and neurotoxicity

Cited by 74 publications

References 46 publications

Ceftolozane-tazobactam and Fosfomycin for rescue treatment of otogenous meningitis caused by XDR Pseudomonas aeruginosa: Case report and review of the literature

Ceftolozane-tazobactam and Fosfomycin for rescue treatment of otogenous meningitis caused by XDR Pseudomonas aeruginosa: Case report and review of the literature

Polymyxin B‐Polysaccharide Polyion Nanocomplex with Improved Biocompatibility and Unaffected Antibacterial Activity for Acute Lung Infection Management

Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

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