Pharmacokinetics of polymyxin B1 in patients with multidrug-resistant Gram-negative bacterial infections

Kwa, Andrea Lay Hoon; Lim, Tze-Peng; Low, Jenny; Hou, Jingguo; Kurup, Asok; Prince, Randall A.; Tam, Vincent H.

doi:10.1016/j.diagmicrobio.2007.08.008

Cited by 71 publications

(66 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with previous reports (2,3,(7)(8)(9), the paper by Thamlikitkul et al (1). provides further evidence of the dissonance between contemporary PK studies of polymyxin B and the product label.…”

supporting

confidence: 79%

Critical Need for Clarity in Polymyxin B Dosing

Onufrak

Rao

Forrest

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

W e read with interest the report by Thamlikitkul et al. describing polymyxin B exposures in 19 adult patients with and without renal insufficiency (1). No significant difference was observed in the dose-normalized 24-h area under the concentration-time curve (AUC 24 ) at steady state between those with normal renal function, defined as an estimated creatinine clearance (CL CR ) of Ն80 ml/min (n ϭ 5; mean CL CR , 90.0 Ϯ 12.5 ml/min; mean AUC 24 , 28.6 Ϯ 7.0 mg · h/liter) and those with renal insufficiency (n ϭ 14; mean CL CR , 40.8 Ϯ 21.8 ml/min; mean AUC 24 , 29.7 Ϯ 11.2 mg · h/liter; P ϭ 0.80). A sensitivity analysis using lower CL CR threshold values of Ͻ60 and Ͻ40 ml/min yielded similar results.This study adds to mounting evidence that polymyxin B undergoes negligible renal excretion; thus, dose adjustment based solely on a patient's renal function may not be prudent (2, 3). Unfortunately, such observations conflict with current polymyxin B labeling, which instructs physicians to decrease doses in the setting of "renal impairment" (4). Administering less than the suggested 1.5 to 2.5 mg/kg of actual body weight daily may, in fact, be detrimental, increasing the risk of death as a consequence of insufficient drug exposure (5). However, the potential for nephrotoxicity and interpatient variability must also be considered when selecting polymyxin B dosing regimens (6). This raises two important questions: (i) what steps are necessary to provide clarity in polymyxin B dosing that will simultaneously achieve adequate pharmacodynamic (PD) response and minimize toxicodynamic (TD) events?; and (ii) how can we best apply information gained from the present (1) and previous (2, 3) studies to optimize polymyxin B dosing regimens?The first question may be answered by considering the overall paucity of polymyxin B clinical pharmacokinetic (PK) studies; with the inclusion of Thamlikitkul et al. 's cohort, the literature is composed of 65 patients' data (1-3, 7-10). While such reports conclude that polymyxin B doses should not be modified because of differences in renal function (1-3, 7-9), larger, prospective studies are necessary to confirm their findings. Such efforts are under way; a multicenter clinical study will enroll 250 critically ill patients treated with intravenous polymyxin B, assessing the drug's PK, PD, and TD characteristics, expanding the evidence base nearly 4-fold (NCT02682355). The solution to the second question lies in the ability to harness the predictive power of combining population PK models with adaptive feedback control to derive patient-specific PK information (11, 12). Leveraging population PK parameter estimates, their degree of interpatient variability, and measured drug concentrations, a Bayesian estimator indiCitation Onufrak NJ, Rao GG, Forrest A, Pogue JM, Scheetz MH, Nation RL, Li J, Kaye KS. 2017. Critical need for clarity in polymyxin B dosing. Antimicrob Agents Chemother 61:e00208-17.

show abstract

supporting

confidence: 79%

Critical Need for Clarity in Polymyxin B Dosing

Onufrak

Rao

Forrest

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…A major barrier is the use of the USP mixture, which is composed of multiple components (14). Our group has previously examined the pharmacokinetics of polymyxin B1 following intravenous administration to a group of patients with multidrugresistant Gram-negative bacterial infections (11). However, since purified standards of other components were not available at that time, we were able to characterize the pharmacokinetics only of polymyxin B1.…”

Section: Discussionmentioning

confidence: 94%

“…Recently, several attempts have been made to characterize the pharmacokinetics and pharmacodynamics of polymyxin B (11,17,19). Knowledge of the pharmacokinetics/pharmacodynamics as well as the toxicodynamics of the drug could lead to the design of dosing regimens that yield maximum effectiveness and minimal toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Serum was stored at Ϫ70°C until analysis. The serum samples were assayed for major components of polymyxin B using the ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method (11) and purified standards (17) described previously. The ADAPT II program was used to fit various models (e.g., one-and twocompartment open models) to the observed serum polymyxin B concentrations over time (2).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics and Renal Disposition of Polymyxin B in an Animal Model

Abdelraouf

Ledesma

et al. 2012

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The increasing prevalence of multidrug-resistant Gram-negative infections has led to the resurgence of systemic polymyxin B, but little is known about its pharmacokinetics. The objective of this study was to characterize the pharmacokinetics and renal disposition of polymyxin B. Eight female Sprague-Dawley rats (weight, 225 to 250 g) were administered a single intravenous polymyxin B dose (4 mg/kg of body weight). Serial serum samples were collected and assayed for major polymyxin B components using a validated ultraperformance liquid chromatography-tandem mass spectrometry method. The best-fit pharmacokinetic parameters of each component were derived and compared using one-way analysis of variance. Cumulative urine was also collected daily for 48 h and assayed for polymyxin B. Kidney drug concentrations were measured at 6 h (n ‫؍‬ 3) and 48 h (n ‫؍‬ 3) after the same dose. Additionally, three rats were administered 2 doses of intravenous polymyxin B (4 mg/kg) 7 days apart. Serial serum samples were collected pre-and post-renal insufficiency (induced by uranyl nitrate) and assayed for polymyxin B. The pharmacokinetic parameters of the major components did not appear to be significantly different (P > 0.05). Less than 1% of the dose was recovered unchanged in urine collected over 48 h following administration. Therapeutic drug concentrations persisted in kidney tissue at 48 h. The post-renal insufficiency to pre-renal insufficiency ratio of the area under the serum concentration-time curve from time zero to infinity was 1.33 ؎ 0.04. Polymyxin B components appear to have similar pharmacokinetics. Polymyxin B preferentially persists in kidneys, which suggests a selective uptake process in renal cells. A mechanism(s) other than renal excretion could be involved in polymyxin B elimination, and dosing adjustment in renal insufficiency may not be necessary.

show abstract

“…Desse modo, a concentração de droga livre fica próxima ou inferior à concentração inibitória mínima (CIM) de -1 susceptibilidade (<2 μg.ml ) (RIGATTO, 2011). Outro estudo relatou que menos de 1% de polimixina B infundida foi recuperada inalterada na urina (KWA et al, 2008). As polimixinas são pouco retiradas no processo de diálise (KVITKO, 2010).…”

Section: Farmacocinéticaunclassified

Resistência Às Polimixinas Em Bactérias Gram-Negativas: Uma Revisão Microbiológica

Carvalho

Cogo²

2014

View full text Add to dashboard Cite

RESUMO:Antibióticos são substâncias químicas antimicrobianas que tem a finalidade de inibir o crescimento de microrganismos ou destruí-los. As polimixinas são antimicrobianos empregados no tratamento de infecções causadas por bacilos Gram-negativos, atuando na desestabilização da membrana externa bacteriana e causando a sua morte. O uso desse fármaco reemergiu nos últimos anos devido ao número crescente de microrganismos multirresistentes às classes de antimicrobianos comumente empregados, sendo a última escolha no tratamento de cepas resistentes. Entretanto, estudos realizados em todo mundo já relataram resistência às polimixinas, principalmente na América Latina e Ásia, evidenciando um problema de saúde pública mundial. Palavras-chave: Polimixinas, Resistência Bacteriana, Bactérias Gram-negativas. ABSTRACT:Antibiotics are antimicrobial chemical substances that have the purpose of inhibiting the growth of microrganisms or destroy them. The polymyxins are antimicrobial agents used in the treatment of infections caused by Gram-negative bacilli, acting in the destabilization of the bacterial outer membrane and causing its death. The use of this drug has reemerged in recent years due to the increasing number of multiresistant microrganisms to classes of antimicrobials commonly used, being the last choice in the treatment of resistant strains. However, worldwide researches have already reported resistance to the polymyxins, mainly in Latin America and Asia, indicating a global public health problem.

show abstract

Pharmacokinetics of polymyxin B1 in patients with multidrug-resistant Gram-negative bacterial infections

Cited by 71 publications

References 12 publications

Critical Need for Clarity in Polymyxin B Dosing

Critical Need for Clarity in Polymyxin B Dosing

Pharmacokinetics and Renal Disposition of Polymyxin B in an Animal Model

Resistência Às Polimixinas Em Bactérias Gram-Negativas: Uma Revisão Microbiológica

Contact Info

Product

Resources

About