Polymyxin B versus other antimicrobials for the treatment of Pseudomonas aeruginosa bacteraemia

Kvitko, Carlos Henrique Cezimbra; Rigatto, Maria Helena; Moro, Ana Laura Didonet; Zavascki, Alexandre Prehn

doi:10.1093/jac/dkq390

Cited by 59 publications

(36 citation statements)

References 13 publications

(14 reference statements)

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“…Polymyxins B and E (colistin) have reemerged as agents of last resort to treat infections caused by XDR-GNB (1), but despite treatment with these drugs, mortality is usually high (2)(3)(4).…”

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confidence: 99%

Multicenter Prospective Cohort Study of Renal Failure in Patients Treated with Colistin versus Polymyxin B

Rigatto

Oliveira

Neto

et al. 2016

Antimicrob Agents Chemother

112

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Nephrotoxicity is the main adverse effect of colistin and polymyxin B (PMB). It is not clear whether these two antibiotics are associated with different nephrotoxicity rates. We compared the incidences of renal failure (RF) in patients treated with colistimethate sodium (CMS) or PMB for >48 h. A multicenter prospective cohort study was performed that included patients aged >18 years. The primary outcome was renal failure (RF) according to Risk, Injury, Failure, Loss, and End-stage renal disease (RI-FLE) criteria. Multivariate analysis with a Cox regression model was performed. A total of 491 patients were included: 81 in the CMS group and 410 in the PMB group. The mean daily doses in milligrams per kilogram of body weight were 4.2 ؎ 1.3 and 2.4 ؎ 0.73 of colistin base activity and PMB, respectively. The overall incidence of RF was 16.9% (83 patients): 38.3% and 12.7% in the CMS and PMB groups, respectively (P < 0.001). In multivariate analysis, CMS therapy was an independent risk factor for RF (hazard ratio, 3.35; 95% confidence interval, 2.05 to 5.48; P < 0.001) along with intensive care unit admission, higher weight, older age, and bloodstream and intraabdominal infections. CMS was also independently associated with a higher risk of RF in various subgroup analyses. The incidence of RF was higher in the CMS group regardless of the patient baseline creatinine clearance. The development of RF during therapy was not associated with 30-day mortality in multivariate analysis. CMS was associated with significantly higher rates of RF than those of PMB. Further studies are required to confirm our findings in other patient populations.

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confidence: 99%

Multicenter Prospective Cohort Study of Renal Failure in Patients Treated with Colistin versus Polymyxin B

Rigatto

Oliveira

Neto

et al. 2016

Antimicrob Agents Chemother

112

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“…Moreover, there are few new antibacterial agents available in the clinical drug development pipeline for these life-threatening infections. Consequently, this has led to the revival of old antibiotics, such as the polymyxins, as the treatment of last resort for infections caused by multidrugresistant Gram-negative pathogens (9)(10)(11)(12)(13).…”

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confidence: 99%

Characterization of Polymyxin B Biodistribution and Disposition in an Animal Model

Manchandani

Zhou

Ledesma

et al. 2016

Antimicrob Agents Chemother

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Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing.T he emergence of multidrug-resistant bacterial infections has become a medical crisis worldwide (1, 2). Infections caused by Gram-negative bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp., are extremely challenging to treat (3-6). These infections also are associated with high rates of mortality and morbidity (7,8). Moreover, there are few new antibacterial agents available in the clinical drug development pipeline for these life-threatening infections. Consequently, this has led to the revival of old antibiotics, such as the polymyxins, as the treatment of last resort for infections caused by multidrugresistant Gram-negative pathogens (9-13).Polymyxins (primarily polymyxin B and polymyxin E [colistin]) are cyclic polypeptide antibiotics isolated from Bacillus polymyxa (14). Commercially available polymyxin B is a mixture of several related analogs, primarily polymyxin B1, B2, and B3 and isoleucine B1 (15, 16). Polymyxin B first became available for clinical use in the 1950s, but its clinical use has been limited largely due to its nephrotoxic potential.Despite being available for clinical use for more than 50 years, there is still a paucity of published reports correlating the pharmacokinetics of polymyxin B with its toxicity profile. Furthermore, we lack a thorough understanding of the biodistribution pattern, cel...

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“…Two polymyxins, namely, polymyxin B and polymyxin E (synonym, colistin), have been available clinically since the late 1950s but were abandoned in the 1970s due to their potential for nephrotoxicity (5,6). There is little doubt that there is an association between polymyxin therapy and nephrotoxicity (7)(8)(9), and recent clinical studies have shown that the incidence rate is up to 60%, depending on the definition of nephrotoxicity (7,(10)(11)(12). Unfortunately, the mechanism(s) of polymyxin-induced nephrotoxicity is not clear (13).…”

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Polymyxin B Induces Apoptosis in Kidney Proximal Tubular Cells

Azad

Finnin

Poudyal

et al. 2013

Antimicrob Agents Chemother

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Polymyxin B versus other antimicrobials for the treatment of Pseudomonas aeruginosa bacteraemia

Abstract: intravenous polymyxin B therapy was inferior to other drugs in the treatment of P. aeruginosa bacteraemia, as indicated by the higher rate of in-hospital mortality.

Cited by 59 publications

References 13 publications

Multicenter Prospective Cohort Study of Renal Failure in Patients Treated with Colistin versus Polymyxin B

Multicenter Prospective Cohort Study of Renal Failure in Patients Treated with Colistin versus Polymyxin B

Characterization of Polymyxin B Biodistribution and Disposition in an Animal Model

Polymyxin B Induces Apoptosis in Kidney Proximal Tubular Cells

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