Adverse Reactions Associated with Systemic Polymyxin Therapy

Justo, Julie Ann; Bosso, John A.

doi:10.1002/phar.1493

Cited by 111 publications

(104 citation statements)

References 41 publications

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“…However, antibiotic administration is not recommended in human STEC infections and should even be strongly discouraged during the prodromal intestinal phase because the antimicrobial treatment may cause 1) phage induction and consequent enhanced Stx expression in bacteria, and 2) bacterial lysis with subsequent toxin release (4). Moreover, caution must be used in proposing polymyxin B administration in STEC-infected children, because severe adverse reactions are associated with systemic polymyxin therapy in humans (53). The most serious adverse effects are paradoxically nephrotoxicity and, to a lower extent, neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

Carnicelli

Arfilli

Ricci

et al. 2016

The Journal of Immunology

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Hemolytic uremic syndrome (HUS) is the life-threatenig sequela of intestinal infections by Shiga toxin (Stx)–producing Escherichia coli (STEC) in children. Human neutrophils specifically bind Stx through TLR4, the receptor of LPS. The binding could be considered protective (Stx sequestration) or harmful (toxin delivery to target organs). The amount of Stx on neutrophils is in equilibrium with the amount of Stx present in the gut, and it is also related to renal and neurologic symptoms. The TLR4-mediated interaction of LPS with innate immune cells is hampered by the well-known antibiotic polymyxin B. In this study, we show that the same antibiotic impairs the binding of Stx to neutrophils, also blocking their functional effects (release of CXCL8, formation of neutrophil/platelet aggregates) involved in HUS pathogenesis. Controls for contaminating LPS in Stx-induced neutrophil responses inhibited by polymyxin B were performed. Stx interact with human neutrophils through their A chain, since these leukocytes do not express globotriaosylceramide, the specific receptor for Stx B chains. Consistently, polymyxin B blocked the enzymatic activity of Stx1, Stx2, Stx1 A chain, and the analogous plant protein gelonin, whereas the antibiotic did not show any protective effect on Stx-induced cytotoxicity in globotriaosylceramide-expressing Raji cells. Antibiotic administration is not recommended in human STEC infections during the prodromal intestinal phase, and the toxicity of polymyxin B could further discourage its therapeutic use. However, nontoxic, nonbactericidal polymyxin derivatives have been developed and might be used in animal models of STEC infection to study their efficacy in preventing the onset of HUS during the systemic blood phase of Stx.

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Section: Discussionmentioning

confidence: 99%

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

Carnicelli

Arfilli

Ricci

et al. 2016

The Journal of Immunology

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“…36,37 The nephrotoxicity is dose-limiting necessitating a careful balance between the dose required for efficacy and that which causes an unacceptable level of toxicity. 10 Colistin has been developed in a prodrug form (colistin methane sulfonate) to reduce toxicity, but PMB is dosed in the active form.…”

Section: Toxicitymentioning

confidence: 99%

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

Brown¹,

Dawson²

2017

J Antibiot

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Over the last decade, there has been a resurgence of interest in polymyxins owing to the rapid rise in multi-drug resistant Gram-negative bacteria against which polymyxins offer a last-resort treatment. Although having excellent antibacterial activity, the clinical utility of polymyxins is limited by toxicity, especially renal toxicity. There is much interest therefore in developing polymyxin analogues with an improved therapeutic index. This review describes recent work aimed at improving the activity and/or reducing the toxicity of polymyxins. Consideration to providing activity against emerging strains with reduced susceptibility to polymyxins is also made.

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“…27,28 Pharmacokinetic-pharmacodynamic (PK-PD) modeling demonstrates the potential for improved likelihood of adequate drug exposure against organisms with elevated MICs when dose optimization strategies such as high-dose, prolonged infusion regimens are employed. 29 The emergence of multidrug-resistant Gram- 32 Tigecycline is another parenterally administered, broadspectrum antibiotic with potent in vitro activity against CRE. 30 Tigecycline has a large volume of distribution that leads to extensive distribution into tissue, resulting in minimal serum drug concentrations.…”

Section: Antimicrobial Agentsmentioning

confidence: 99%

Beyond Susceptible and Resistant, Part III: Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases

Narayanan

Johnson

MacDougall

2016

The Journal of Pediatric Pharmacology and Therapeutics

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Carbapenemases are enzymes that are capable of inactivating all or almost all beta-lactam antimicrobial agents. These enzymes are frequently coexpressed with other resistance mechanisms to non-beta-lactams, leading to extremely drug-resistant pathogens. Once a curiosity, these enzymes have spread into organisms that are among the most common causes of infection, such as Klebsiella pneumoniae and Escherichia coli. Identification of these organisms has proved challenging for clinical microbiology laboratories, leading to revisions in susceptibility standards for carbapenems. Although currently a rare cause of infection in children, these carbapenem-resistant Enterobacteriaceae (CRE) are becoming endemic in a variety of healthcare settings. Management of infections due to CRE is complicated by a lack of effective treatment options and clinical data on their effectiveness. Treatment of CRE infections in children is particularly challenging because therapeutic options for CRE lack adequate data on dosing and safety in children. Use of unconventional combination treatment regimens, including agents to which the organism is resistant in vitro, may provide some benefit in the treatment of severe CRE infection. Fortunately, several agents with the potential for treatment of CRE infections have been recently approved or are in late clinical development, although few data will be available in the short term to inform use in children.

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Adverse Reactions Associated with Systemic Polymyxin Therapy

Cited by 111 publications

References 41 publications

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

Beyond Susceptible and Resistant, Part III: Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases

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