Uptake of Polymyxin B into Renal Cells

There is significant variation in the use of polymyxin B (PMB), and optimal dosing has not been defined. The purpose of this retrospective study was to evaluate the relationship between PMB dose and clinical outcomes. We included patients with bloodstream infections (BSIs) due to carbapenem-resistant Gram-negative rods who received >48 h of intravenous PMB. The objective was to evaluate the association between PMB dose and 30-day mortality, clinical cure at day 7, and development of acute kidney injury (AKI). A total of 151 BSIs were included. The overall 30-day mortality was 37.8% (54 of 151), and the median PMB dosage was 1.3 mg/kg (of total body weight)/day. Receipt of PMB dosages of <1.3 mg/kg/day was significantly associated with 30-day mortality (46.5% versus 26.3%; P ‫؍‬ 0.02), and this association persisted in multivariable analysis (odds ratio [OR] ‫؍‬ 1.58; 95% confidence interval [CI] ‫؍‬ 1.05 to 1.81; P ‫؍‬ 0.04). Eighty-two percent of patients who received PMB dosages of <1.3 mg/kg/day had baseline renal impairment. Clinical cure at day 7 was not significantly different between dosing groups. AKI was more common in patients receiving PMB dosages of >250 mg/day (66.7% versus 32.0%; P ‫؍‬ 0.03), and this association persisted in multivariable analysis (OR ‫؍‬ 4.32; 95% CI ‫؍‬ 1.15 to 16.25; P ‫؍‬ 0.03). PMB dosages of <1.3 mg/kg/day were administered primarily to patients with renal impairment, and this dosing was independently associated with 30-day mortality. However, dosages of >250 mg/day were independently associated with AKI. These data support the use of PMB without dose reduction in the setting of renal impairment. O ver the last decade, carbapenem-resistant Gram-negative rods (CRGNRs) have emerged as important health care-associated pathogens that are associated with significant morbidity and mortality (1, 2). Due to broad antimicrobial resistance among CRGNRs, clinicians have been increasingly forced to rely upon polymyxins for the treatment of infections caused by these organisms (3-5). The polymyxins, colistin and polymyxin B, came into use in the 1960s, but due to high rates of nephrotoxicity and neurotoxicity, they were replaced with less toxic alternatives (6, 7). Unfortunately due to the early development of polymyxins and a subsequent lack of use in a clinical setting, there is a paucity of information describing optimal dosing (6).Several recent studies have provided a better description of polymyxin B pharmacokinetics (PK) and pharmacodynamics (PD). As with colistin, the bactericidal activity of polymyxin B is concentration dependent and appears to be best correlated with the area under the concentration-time curve over 24 h in steady state divided by the MIC (AUC/MIC) (8). However, unlike with colistin, polymyxin B elimination is minimally affected by creatinine clearance, and dose reduction in the setting of renal impairment may result in subtherapeutic serum drug concentrations and decreased efficacy (9-11). In clinical practice, polymyxin B doses have traditionally been reduced ...

Section: Discussionmentioning

confidence: 30%

Clinical Outcomes Associated with Polymyxin B Dose in Patients with Bloodstream Infections Due to Carbapenem-Resistant Gram-Negative Rods

Nelson

Eiras

Gomez‐Simmonds

et al. 2015

“…It is possible that differences in the shape of the plasma concentration-versus-time profiles for formed colistin (relatively "flat" profile) following administration of CMS (41) and PMB (larger "peak-to-trough" fluctuation) (19) may influence the extent of accumulation in tubular cells and consequently the relative risk of AKI in patients. In apparent support of this suggestion is that the rate of uptake of polymyxin B1 by porcine kidney proximal tubular (LLC-PK1) cells grown in vitro as a monolayer was saturable (23). However, the extent of nonlinearity in the rate of uptake was relatively small across the range of PMB concentrations likely to be present in the proximal tubular urine over a dosage interval in patients, i.e., associated with the plasma "peak-to-trough" fluctuations arising from clinical dosage regimens (19).…”

Section: Why Might Cms Be More Nephrotoxic Than Pmb In Patients?mentioning

confidence: 69%

“…In regard to the tubular reabsorption of colistin and PMB, it appears that megalin, an endocytic receptor expressed in the apical membrane domain of proximal tubular cells and involved in the reabsorption of proteins, peptides, and cationic compounds, is a key player in the reabsorption of the polymyxins (21)(22)(23). The affinity of polymyxin B for megalin appeared to be substantially greater than that of gentamicin (21), which is also a substrate of megalin (24).…”

Section: Why Do Polymyxins Have the Propensity To Cause Nephrotoxicity?mentioning

confidence: 99%

Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B?

Zavascki

Nation

2017

174

120

Nephrotoxicity is a common adverse effect of the clinically used polymyxins, colistin and polymyxin B. This adverse effect is dose limiting for both polymyxins, as the plasma polymyxin concentrations associated with renal damage overlap those required for antibacterial effect. Since development of acute kidney injury (AKI) during therapy is highly undesirable, it is extremely important to know whether there is any difference between the nephrotoxic potential of colistin (administered as its inefficient prodrug, colistimethate) and polymyxin B (administered as the active form). Both polymyxins are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells, processes that are reviewed in this article. Also reviewed are the emerging data that strongly suggest significantly higher rates of AKI in patients treated with colistimethate compared to patients treated with polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of colistimethate and formed colistin versus polymyxin B, and consequently the relative amount of polymyxin material delivered to tubular cells. A lower risk of AKI with polymyxin B is one of several potential advantages over colistimethate. The relative safety and efficacy of the two agents require closer examination in well-designed clinical studies.

“…The propensity for polymyxins to cause nephrotoxicity is almost certainly related to the very extensive renal tubular reabsorption that has been demonstrated in both animals (18) and patients (19), thereby exposing these cells to a large load of polymyxins (20)(21)(22). The avid reabsorption may be attributed to numerous transporters located in the proximal tubules (20,23). Megalin, encoded by a member of the low-density lipoprotein receptor gene family, is an endocytosis receptor expressed in the apical membranes of proximal tubular epithelial cells (24).…”

mentioning

confidence: 99%

“…Megalin, encoded by a member of the low-density lipoprotein receptor gene family, is an endocytosis receptor expressed in the apical membranes of proximal tubular epithelial cells (24). It is evident that megalin plays a role in the uptake and accumulation of polymyxin B and colistin into renal cells (23,25,26). Recent studies have suggested that colistininduced nephrotoxicity might be associated with oxidative stress (22,27).…”

mentioning

confidence: 99%

Preliminary Clinical Study of the Effect of Ascorbic Acid on Colistin-Associated Nephrotoxicity

Sirijatuphat

Limmahakhun

Sirivatanauksorn

et al. 2015

c Nephrotoxicity is a dose-limiting factor of colistin, a last-line therapy for multidrug-resistant Gram-negative bacterial infections. An earlier animal study revealed a protective effect of ascorbic acid against colistin-induced nephrotoxicity. The present randomized controlled study was conducted in 28 patients and aimed to investigate the potential nephroprotective effect of intravenous ascorbic acid (2 g every 12 h) against colistin-associated nephrotoxicity in patients requiring intravenous colistin. Thirteen patients received colistin plus ascorbic acid, whereas 15 received colistin alone. Nephrotoxicity was defined by the RIFLE classification system. Additionally, urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-D-glucosaminidase (NAG) were measured as markers of renal damage, and plasma colistin concentrations were quantified. The baseline characteristics, clinical features, and concomitant treatments of the patients in the two groups were comparable. The incidences of nephrotoxicity were 53.8% (7/13) and 60.0% (9/15) in the colistin-ascorbic acid group and the colistin group, respectively (P ‫؍‬ 0.956; relative risk [RR], 0.9; 95% confidence interval, 0.47 to 1.72). In both groups, the urinary excretion rates of NGAL and NAG on day 3 or 5 of colistin treatment and at the end of colistin treatment were significantly higher than those at the respective baselines (P < 0.05). However, the urinary excretion rates of these biomarkers at the various times during colistin treatment did not differ significantly between the groups (P > 0.05). The plasma colistin concentrations in the two groups were not significantly different (P > 0.28). The clinical and microbiological outcomes and mortality of the patients in the two groups were not significantly different. This preliminary study suggests that ascorbic acid does not offer a nephroprotective effect for patients receiving intravenous colistin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01501968.) I nfections caused by carbapenem-resistant Gram-negative bacteria, such as Acinetobacter baumannii, have become a serious problem globally, including in Thailand (1-3). Colistin (i.e., polymyxin E) and polymyxin B have been reintroduced over the past decade for therapy of multidrug-resistant (MDR) Gram-negative bacterial infections, especially those caused by carbapenem-resistant Gram-negative pathogens (4). Colistin is administered parenterally as colistimethate sodium (CMS), an inactive prodrug that is converted to colistin, the entity that possesses both antibacterial activity and the potential to cause toxicity (5, 6). The efficacy of colistin for treatment of infections by MDR Gram-negative bacteria is modest, and nephrotoxicity is the major dose-limiting factor in the clinical use of colistin (7, 8). The incidence of colistinassociated nephrotoxicity ranges from approximately 10% to 55%, and it appears to be related to the total dose of CMS, the duration of therapy, and the plasma colistin concentrat...