From The Archives: The Polymyxins: Why am I using them all the time, and what are they?

November 21, 2013

Please enjoy this post from the archives dated December 8, 2010

By Jon-Emile S Kenny

Faculty Peer Reviewed

A 65-year-old female with locally advanced rectal cancer is admitted to the ICU, hypotensive and febrile. Her PICC line is removed and blood cultures drawn. Fourty-eight hours later all cultures return ESBL Klebsiella with susceptibility only to polymyxin.

I sat on the venerable call-room couch staring mindlessly at the cluttered, nauseating walls repeating the word ‘polymyxin’ like an endless antimicrobial mantra. What strange dosing it has, and an even more peculiar name.

The polymyxins (B and E – the latter also known as Colistin), were developed in the 1950s as anti-pseudomonal agents [1]. In the long evolutionary struggle between gram positives and gram negatives, Bacillus Polymyxa (a gram positive) began secreting cyclic peptides with long hydrophobic chains that selectively bind to gram-negative lipopolysaccharide (LPS). These polymyxins cause rapid destabilization of gram-negative outermembranes, permeability changes, and cell death [2]. Chemical modification of the polymyxins (e.g. treatment with formaldehyde and sodium bisulfate) have rendered these chemicals safe for intravenous use [5].

Resistance, however, can occur. Gram-negatives sensitive to polymyxin have their LPS molecules bridged, and stabilized by divalent cations (e.g. Magnesium). The hydrophobic tail of polymyxin promotes its intercalation into the outermembrane, while the cyclic peptide portion binds to the divalent cation and disrupts membrane architecture [3]. However, in resistant gram-negatives, the divalent cation is replaced by a positively charged H1 protein that is hardy to polymyxin’s mechanism of action [4].

There is a general paucity of data for the pharmacokinetics and pharmacodynamics of the polymyxins, and dosing is confusing [5]. The dose of polymyxin depends on the type (i.e. Polymyxin B vs. Colistin) and with regards to the latter, the formulation. This information would be best gleaned from a friendly infectious disease fellow, hospital pharmacist or Micromedex. Of note, dosage alterations must be made based on a patient’s renal function and it is usually a twice-daily infusion over one hour [5]. Interestingly, recent pharmacodynamic studies with Pseudomonas suggest that the bacteriocidal activity of Polymyxin B is related to the ratio of the area under the concentration-time curve to MIC [6]. This suggests that it may be the total daily dose, and not the frequency of administration that is important (1).

As the mechanism of action detailed above alluded, synergism between the polymyxins and other antibiotics including: rifampin, azithromycin, imipenem have been reported against pan-resistant Klebsiella, Acinetobacter, and Pseudomonas [5].

The overuse of broad-spectrum antibiotics has led to increasing antibiotic resistance, rendering many typical antimicrobials ineffective. The use of polymyxin is reserved for patients with severe sepsis caused by multi-drug resistant gram negative bacteria. Consequently, intravenous polymyxin B is used frequently for the treatment of a myriad of nosocomial infections including: bacteremia, postoperative wound infections, urinary tract infections and intra-abdominal infections [1]. However, Polymyxin – due to its large molecular size, and ionic charge – has poor pleural penetration and does not have adequate efficacy for severe pulmonary infections by itself, but may be used synergistically with other antimicrobials [7]. Interestingly, lipid emulsification of Polymyxin has been shown to increase its penetration into pulmonary tissue in animal models [8].

Polymyxins were originally abandoned due to nephro- and neurotoxicities, the latter including neuromuscular blockade and need for mechanical ventilation [5]. However, contemporary studies have found the rates and degrees of these side-effects to be less concerning even after four weeks of therapy [9]. While nephrotoxicity is still common, it is roughly two times more likely in patients with baseline renal insufficiency [3].

My trance was broken quite suddenly when a nurse opened the door to the call room. She informed me that a patient’s potassium level was 3.2 on an ABG. I looked at the intern and he motioned to order some repletion.

Commentary by Melanie J. Maslow, M.D., F.A.C.P., Associate Professor of Clinical Medicine

Years back, as an Infectious Diseases Fellow, I participated in a study of Ro-139904, now known to providers as ceftriaxone. Ceftriaxone was one of the earlier third generation cephalosporins, which now include cefotaxime and ceftazidime. At last, there was an alternative to the standard therapy of the time for resistant gram-negatives, polymyxin B. Thirty years later, a new generation of physicians is paying the price for decades of overusing extended-spectrum antibiotics and selection of multidrug resistant gram-negative bacilli, including species of Pseudomonas, Acinetobacter, and Klebsiella. As the author discusses, the new dosing regimens appear to be better tolerated with less renal toxicity than we observed but there is intrinsic resistance to this drug. Providers should be aware that polymyxin B is inactive against some organisms, including Proteus spp., Providencia spp., and most Serratia spp. The take home message here is that overuse of broad-spectrum antibiotics has brought us back to the era of using a “detergent” to treat multidrug resistant bacterial infections.

Dr. Kenny is a chief resident at NYU Langone Medical Center

Peer reviewed by Melanie Maslow, section editor, pharmacology, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

(1) Yuan and Tam Polymyxin B: a new strategy for multidrug-resistant Gram-negative organisms. Expert Opin Investig Drugs. 2008 May;17(5):661-8. http://www.ncbi.nlm.nih.gov/pubmed/18447592

(2) LaPorte et al. Inhibition of Escherichia coli growth and respiration by polymyxin B covalently attached to agarose beads. Biochemistry 1977 ; 16 : 1642 -8

(3) Zavascki et al. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. Journal of Antimicrobial Chemotherapy (2007) 60, 1206–1215. http://jac.oxfordjournals.org/content/60/6/1206.abstract

(4) Brown MR, Watkins WM. Low magnesium and phospholipid content of cell walls of Pseudomonas aeruginosa resistant to polymyxin. Nature 1970 ; 227 : 1360 -1

(5) Landman et al. Polymyxins Revisited. Clinical Microbiology Reviews , July 2008, p. 449–465. http://cmr.asm.org/cgi/content/short/21/3/449

(6) Tam et al. Pharmacodynamics of polymyxin B against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005 ; 49 : 3624 -30

(7) Sobieszczyk et al. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. J Antimicrob Chemother 2004 ; 54 : 566 -9

(8) Omri A, et al. Enhanced activity of liposomal polymyxin B against Pseudomonas aeruginosa in a rat model of lung infection. Biochem Pharmacol 2002 ; 64 : 1407 -13

(9) Falagas et al Toxicity after prolonged (more than four weeks) administration of intravenous colistin. 2005 BMC Infect. Dis. 5:1–8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC547910/

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