Clinical Therapeutics: The polymyxins, existing challenges and new opportunities

D. Suryaprabha1,*, K Sathyapriya2

1Senior Executive-Clinical Research, Kauvery Hospitals, India

2Clinical Pharmacist, Kauvery Hospital, Bengaluru, India

*Correspondence: Tel.: +91 98414 86267; email: [email protected]

Abstract

The global rise in nosocomial pneumonia caused by multidrug-resistant (MDR) pathogens and the increasingly limited antibiotic treatment options are growing threats to modern medicine. As a result, older antibiotics such as polymyxins (colistin and polymyxin B) are being used as last-resort drugs for MDR-nosocomial pneumonia. The review provides pharmacokinetic/pharmacodynamic data in order to redefine appropriate dosing strategies and also ensure safety from toxicity.

Keywords:Polymyxins, Acinetobacter, Nosocomial pneumonia, Pharmacodynamics, Pharmacokinetics

Background

The global rise in nosocomial pneumonia caused by multidrug-resistant (MDR) gram-negative pathogens and the increasingly limited antibiotic treatment options are growing threats to modern medicine. Polymyxins are bactericidal against most of aerobic gram-negative bacilli.

The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures [1,2]. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections, most notably multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae [3].

Since their reintroduction into the clinic, significant confusion remains regarding polymyxin use due to differences in the formulations. Colistin is administered as an inactive prodrug, colistimethate (also known as colistin methanesulfonate (CMS)), whereas polymyxin B is administered in its active form. Also, different conventions are used to describe dosing of the polymyxins, particularly colistin; product information is outdated; and uncertainties remain regarding susceptibility testing [4]. Thus, a lack of clarity remains about how optimally to utilize and dose colistin and polymyxin B.

Unfortunately, polymyxins are highly nephrotoxic agents, and acute kidney injury (AKI) occurs frequently with conventional doses. Given the narrow therapeutic windows (low therapeutic indices) of polymyxins, this guideline provides clinicians with a practical framework for use in treating infections caused by MDR and XDR gram-negative pathogens. This article provides the consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use [4,5].

Clinical Pharmacology

Chemical structure

Colistin is a cationic, multicomponent lipopeptide consisting of a cyclic heptapeptide with a tripeptide side chain acylated at the N-terminus by a fatty acid.

History

Polymyxins are the naturally occurring lipopeptides isolated from the bacterium Paenibacillus polymyxa is also known as Bacillus polymyxa. The antibacterial activity of polymixin was first isolated in the year 1947, from the crude mixture of P. polymyxa by Benedict and Langlykke. At the same time, the purified form of antibiotic is also isolated from P. polymyxa by American Cyanamid company. Later in the year of 1948, the Brownlee and his coworkers found the antibiotic from Bacillus aerosporus and it was named as aerosporin. Both the polymyxin and aerosporin were basic peptides and have similar antibacterial property, they were designated as polymyxin antibiotics.

Mechanism of action

Colistin and polymyxin B have their antimicrobial activity mainly directed against the bacterial cell membrane. The cationic polypeptides of colistin and polymyxin B interact with anionic lipopolysaccharide (LPS) molecules in the outer membrane of gram-negative bacteria, leading to displacement of calcium (Ca2+) and magnesium (Mg2+), which stabilize the LPS membrane, thus causing derangement of the cell membrane. This results in an increase in the permeability of the cell membrane, leakage of cell contents, and ultimately cell death. Colistin also has potent anti-endotoxin activity. The endotoxin of gram-negative organism is the lipid A portion of LPS molecule and colistin binds and neutralizes this LPS molecule (Fig. 1).

Clinical-Therapeutics

Fig. 1. Mechanisms of antibacterial activity of polymyxins in Gram negative bacteria via disruption of the outer membrane [6].

Pharmacokinetics

The serum half-life has been estimated to be 3 to 4.5 h with normal renal function and increases with declining renal function

Dosage

The recommended dosage of intravenous Colistin is containing half million or 1 million units per vial and the dose followed is 50,000 to 75,000 IU/kg/day.

The recommended dosage of intravenous polymyxin B is 1.5 to 2.5 mg/kg/day (1 mg = 10,000 IU) divided in two equal doses.

In patients with renal impairment, the dosage of colistin and polymyxin B needs modification.

For a serum creatinine level of 1.3 to 1.5 mg/dL, 1.6 to 2.5 mg/dL, or above 2.6 mg/dL, the recommended dosage of IV colistin is 160 mg (2 million IU) every 12, 24, or 36 h, respectively. For patients undergoing hemodialysis, the dosage of colistin is 80 mg (1 million IU) after each hemodialysis treatment.

In polymyxin B dose adjustment is based on creatinine clearance (CrCL). If CrCL is 20 to 50 mL/min, administer 75 to 100% of the normal daily dose in divided doses every 12 h. If CrCL is between 5 to 20 mL/min, administer 50% of the normal daily dose in divided doses every 12 h.

Administration

Intravenous Dissolve 2 million units in 300 to 500 ml of 5% dextrose for a continuous intravenous drip. In patients with renal failure not on any renal replacement therapy, dissolve the 24 h dose in 50 ml of normal saline and administer it as a 24 h infusion via an infusion pump. The antibiotic can also be given at regular intervals by dividing the daily dosage into three or four equal doses and dissolving it in 100 ml of 5% dextrose.

International Consensus Guidelines for the Optimal Use of the polymyxins are 34 recommendations for using polymyxin B and colistin, also known as polymyxin E. A press release from the University of Buffalo described the following as highlights:

  1. The maximum tolerable dosage of polymyxin B and colistin is set at 2 mg/L.
  2. Polymyxin B is preferred for routine systemic use against invasive infections, while colistin is preferred for the treatment of lower urinary tract infections and for delivery to the heart, brain, and spinal canal.
  3. Patients receiving polymyxins should avoid agents that are toxic to the kidneys, such as nonsteroidal anti-inflammatory drugs and ACE inhibitors.
  4. To reduce confusion over labeling conventions used in different parts of the world, hospitals and prescription orders should specify doses of colistin in either international units or milligrams of colistin base activity.
  5. In the treatment of the superbugs carbapenem-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae, polymyxins should be used in combination with one or more antibiotics, ideally a drug the bacteria are susceptible to.
  6. In the treatment of the superbug carbapenem-resistant A. baumannii, polymyxins should be used only in combination with an antibiotic that the bacteria are susceptible to. If no such drug is available, the polymyxin should be delivered alone.
  7. We recommend that if a patient develops AKI while on colistin, the daily dose should be decreased to the appropriate renally.
  8. Multiple analyses with both colistin [7,8] and polymyxin B [9] showed concomitant vancomycin to be an independent predictor of polymyxin-associated AKI.
  9. We recommend that for invasive infections due to CRAB, CRE, polymyxin B or colistin should be used in combination with one or more additional agents to which the pathogen displays a susceptible MIC (best practice recommendation).

Conclusion

The global rise in nosocomial pneumonia caused by multidrug-resistant (MDR) gram-negative pathogens and the increasingly limited antibiotic treatment options are growing threats to modern medicine. In conclusion, the usefulness of polymyxin B and polymyxin E has been clearly demonstrated by optimizing their clinical use and developing their derivatives with less nephrotoxicity than earlier believed and they have been used as bactericidal agents for around five decades. Different mechanisms of polymyxin-resistance have been found in bacteria. Resistance to the current polymyxins could become a big global health challenge, because this means that virtually no antibiotics will be available for treatment of serious infections caused by polymyxin-resistant “superbugs” [10]. Further research focusing on the appropriate dosage, clinical indications and safety profile of polymyxins is urgently needed. Meanwhile, strict use of polymyxins by clinicians worldwide is required to prevent the rapid development and dissemination of pandrug-resistant gram-negative bacteria [11].

References

  1. Tsuji BT, Pogue JM, Zavascki AP et al. International consensus guidelines for the optimal use of the polymyxins. Pharmacotherapy 2019;39(1):10-39.
  2. Li J, Nation RL, Turnidge JD et al. Colistin: the re-emerging antibiotic for multidrug-resistant gram-negative bacterial infections. Lancet Infect Dis. 2006;9:589-601.
  3. Lim LM, Ly N, Anderson D et al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy 2010;12:1279-91.
  4. Onufrak NJ, Rao GG, Forrest A et al. Critical need for clarity in polymyxin B dosing. Antimicrob Agents Chemother. 2017;61(5).
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  6. Velkov T, Yun B, Schneider EK et al. A novel chemical biology approach for mapping. ACS Infect Dis. 2016;2(5):341-51.
  7. Garnacho-Montero J, Amaya-Villar R, Gutierrez-Pizarraya A et al. Clinical efficacy and safety of the combination of colistin plus vancomycin for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii. Chemotherapy 2013;3:225-31.
  8. Rattanaumpawan P, Ungprasert P, Thamlikitkul V. Risk factors for colistin-associated nephrotoxicity. J Infect. 2011;2:187-90.
  9. Dubrovskaya Y, Prasad N, Lee Y et al. Risk factors for nephrotoxicity onset associated with polymyxin B therapy. J Antimicrob Chemother. 2015;6:1903-7.
  10. Yu Z, Qin W, Lin J et al. Antibacterial mechanisms of polymyxin and bacterial resistance. Biomed Res Int. 2015;2015:679109.
  11. Falagas ME, Bliziotis IA, Kasiakou SK et al. Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria. BMC Infect Dis. 2005;5:24.
D.-Suryaprabha

D. Suryaprabha
Senior Executive-Clinical Research

 

K.-Sathyapriya

K. Sathyapriya
Clinical Pharmacist

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