Polymyxins: Wisdom Does Not Always Come With Age

Kassamali, Zahra; Rotschafer, John C.; Jones, Ronald N.; Prince, Randall A.; Danziger, Larry H.

doi:10.1093/cid/cit367

Cited by 38 publications

(26 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Future studies should focus on correlating microbiologic, PK, and clinical outcome data. For this to happen, quality assurance standards utilized in determining the potencies of clinically administered drugs also need to be reassessed and updated, given that these still rely on derivatives of diffusion-based methods (37). Nevertheless, the adoption of a standard reference methodology and continued harmonization of breakpoints by the CLSI and EUCAST, along with work such as that by…”

mentioning

confidence: 99%

Susceptibility Testing for the Polymyxins: Two Steps Back, Three Steps Forward?

Vasoo

2017

J Clin Microbiol

View full text Add to dashboard Cite

Optimizing and standardizing susceptibility testing for the polymyxins have become pressing issues, given the rise in multidrug-resistant Gram-negative bacilli. Recently, both the CLSI and EUCAST have recommended broth microdilution (BMD) (without polysorbate) as the reference method for polymyxin susceptibility testing. In this issue, K. L. Chew et al. (J Clin Microbiol 55:2609 -2616, https://doi .org/10.1128/JCM.00268-17) compare the performances of three commercial BMD panels and the Etest to the reference, BMD, for polymyxin B and colistin, using 76 Enterobacteriaceae isolates (21 of which were mcr-1 positive). Although none of the commercial BMD panels strictly met FDA performance standards in this evaluation, possibly because of the small number isolates tested, the Sensititre panel achieved Ͼ90% categorical agreement for both polymyxin compounds. These results also reaffirm CLSI and EUCAST guidance that gradient diffusion testing, which had unacceptable error rates, should be abandoned. In a simulated analysis with lowered breakpoints (susceptible, Յ1 mg/liter; intermediate, 2 mg/liter; resistant, Ն4 mg/liter), error rates and agreement were improved across the various methods and the rate of detection of mcr-1-positive isolates improved. These observations, taken together with recent pharmacokinetic data on optimizing target attainment for the polymyxins, suggest that more-stringent (lower) breakpoints may be reasonable, although such an approach may be limited by the inherent reliability of current testing methodologies and a lack of robust clinical correlative data, which are sorely needed. S usceptibility testing for the polymyxins has been beleaguered over the years. The polymyxins were first isolated from Paenibacillus polymyxa in 1947 by two independent American groups (1, 2), and there has been a therapeutic renaissance in the use of both polymyxin B and colistin (polymyxin E) over the last decade, given the rise of multidrug-resistant (MDR) Gram-negative bacilli, such as MDR Acinetobacter and Pseudomonas and carbapenemase-producing Enterobacteriaceae.Despite susceptibility testing being available for a long time, clarity has been lacking for appropriate methods of testing and optimal dosing for the polymyxins. Polymyxins are cationic polypeptides comprised of a heptapeptide ring, an exocyclic chain, and a fatty acid tail with positively charged residues which interact with and disrupt the Gram-negative lipopolysaccharide membrane; polymyxin B and colistin differ by only one amino acid in the heptapeptide ring (3, 4). Several reasons have accounted for difficulties with susceptibility testing for the polymyxins, including their cationic nature, their poor diffusion in agar due to their large molecular size, concerns over drug powder composition, and their heteroresistance. Further, the complex pharmacokinetics (PK) and pharmacodynamics (PD) of these compounds and the paucity of data correlating MIC data, drug concentration, and clinical outcomes have made setting clinical breakpoints chal...

show abstract

mentioning

confidence: 99%

Susceptibility Testing for the Polymyxins: Two Steps Back, Three Steps Forward?

Vasoo

2017

J Clin Microbiol

View full text Add to dashboard Cite

show abstract

“…While nebulization of an intravenous formulation of colistimethate is generally employed for inhalation therapy, dry powder formulations of colistimethate have also been administered (13,14). After administration, the prodrug is activated by slow nonspecific hydrolysis, releasing formaldehyde-bisulfite adducts while progressing through a variety of partially methanesulfonylated intermediates to eventually generate the active form of the drug, colistin sulfate (1,2,8,15). The active drug is a collection of closely related cyclic cationic peptides, also known as polymyxin E, with the 2 major components, known as polymyxin E1 and E2, differing only in the fatty acid moiety ( Fig.…”

mentioning

confidence: 99%

“…Closely related polymyxin B (Fig. 1, structure 3) is used directly as the active compound (polymyxin B sulfate) for intravenous, intramuscular, intrathecal, or topical dosing; it is also a mixture of peptides, with the major peptides known as polymyxin B1 and B2 (1,2). In contrast to polymyxin B sulfate, colistin sulfate is normally not administered to humans without being masked as the polymethanesulfonylated prodrug.…”

mentioning

confidence: 99%

Mucin Binding Reduces Colistin Antimicrobial Activity

Huang

Blaskovich

Pelingon

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Colistin has found increasing use in treating drug-resistant bacterial lung infections, but potential interactions with pulmonary biomolecules have not been investigated. We postulated that colistin, like aminoglycoside antibiotics, may bind to secretory mucin in sputum or epithelial mucin that lines airways, reducing free drug levels. To test this hypothesis, we measured binding of colistin and other antibiotics to porcine mucin, a family of densely glycosylated proteins used as a surrogate for human sputum and airway mucin. Antibiotics were incubated in dialysis tubing with or without mucin, and concentrations of unbound antibiotics able to penetrate the dialysis tubing were measured over time using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The percentage of antibiotic measured in the dialysate after 4 h in the presence of mucin, relative to the amount without mucin, was 15% for colistin, 16% for polymyxin B, 19% for tobramycin, 52% for ciprofloxacin, and 78% for daptomycin. Antibiotics with the strongest mucin binding had an overall polybasic positive charge, whereas those with comparatively little binding were less basic. When comparing MICs measured with or without added mucin, colistin and polymyxin B showed >100-fold increases in MICs for multiple Gram-negative bacteria. Preclinical evaluation of mucin binding should become a standard procedure when considering the potential pulmonary use of new or existing antibiotics, particularly those with a polybasic overall charge. In the airways, mucin binding may reduce the antibacterial efficacy of inhaled or intravenously administered colistin, and the presence of sub-MIC effective antibiotic concentrations could result in the development of antibiotic resistance.

show abstract

“…The confusion surrounding the decision to dose these agents in units of milligrams or international units was detailed previously elsewhere (166)(167)(168). The currently recommended conversion factors between units and milligrams are 12,500 U colistin methanosulfate (CMS)/mg or 30,000 U colistin/mg for colistin and 10,000 U/mg for polymyxin B.…”

Section: Animalsmentioning

confidence: 99%

Inhaled Antibiotics for Gram-Negative Respiratory Infections

et al. 2016

View full text Add to dashboard Cite

SUMMARYGram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects,in vitroand microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.

show abstract

Polymyxins: Wisdom Does Not Always Come With Age

Cited by 38 publications

References 26 publications

Susceptibility Testing for the Polymyxins: Two Steps Back, Three Steps Forward?

Susceptibility Testing for the Polymyxins: Two Steps Back, Three Steps Forward?

Mucin Binding Reduces Colistin Antimicrobial Activity

Inhaled Antibiotics for Gram-Negative Respiratory Infections

Contact Info

Product

Resources

About