Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies

Oliota, Ana Flavia Redolfi; Penteado, Suelem Tavares da Silva; Tonin, Fernanda S.; Fernández-Llimós, Fernando; Sanches, Andréia Cristina Conegero

doi:10.1016/j.diagmicrobio.2018.11.008

Cited by 72 publications

(59 citation statements)

References 107 publications

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“…It is important to recognize that our pharmacovigilance analysis confirmed safety profiles and known toxicities both of older and newer agents used in KPC infections, in line with findings reported in the literature and relevant Summary of Product Characteristics [31–37]. The lack of unexpected safety signals is reassuring, since clinicians must deal with known adverse events and can use with less concerns newer agents, including Ceftazidime-Avibactam.…”

Section: Discussionsupporting

confidence: 78%

Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study

Gatti

Raschi

Ponti

2019

BMC Pharmacol Toxicol

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BackgroundThe management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections.MethodsThree spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999–2008 vs. 2009–2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009–2017) was investigated for both Italy and UK.ResultsA total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01). No significant increase in tigecycline ADRs was reported in FAERS and UK database. Unexpected safety signals involving selected antibiotics were not detected. Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p < 0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found.ConclusionKPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues.

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Section: Discussionsupporting

confidence: 78%

Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study

Gatti

Raschi

Ponti

2019

BMC Pharmacol Toxicol

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“…As discussed above, there may be a greater margin of safety for polymyxin B compared to colistin. Studies reported over the last decade and meta-analyses on the derived data suggest that the risk of nephrotoxicity may be lower with polymyxin B [5,17,18,29,39,48,61,62], although a recent meta-analysis that included a large number of older studies suggested that there was no difference in nephrotoxicity prevalence between the two polymyxins [4]. It should be noted that several of the studies, especially from earlier literature, are difficult to interpret due to confounding influences, diversity in definitions of nephrotoxicity and lack of detail [63].…”

Section: Dosing Strategies To Reduce Nephrotoxicitymentioning

confidence: 99%

“…However, it became clear that multiple definitions for nephrotoxicity impaired a more accurate estimate of the real incidence of acute kidney injury (AKI) in patients treated with polymyxins [3]. More recent studies using standardized criteria for AKI, such as Kidney Disease: Improving Global Outcomes (KDIGO), Acute Kidney Injury Network (AKIN) and Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE), have been published, among which, a recent meta-analysis showed that the occurrence of AKI remained undesirably high with mean rates of 31.3%, 32.6% and 39.4%, respectively [4]. Patients treated with colistimethate may have higher AKI rates than those treated with polymyxin B [5], although a more recent meta-analysis showed that there was no significant difference of nephrotoxicity between polymyxins [4].…”

Section: Introductionmentioning

confidence: 99%

Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

et al. 2019

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Polymyxins are valuable antimicrobials for the management of multidrug-resistant Gram-negative bacteria; however, nephrotoxicity associated with these drugs is a very common side effect that occurs during treatment. This article briefly reviews nephrotoxic mechanisms and risk factors for polymyxin-associated acute kidney injury (AKI) and discusses dosing strategies that may mitigate kidney damage without compromising antimicrobial activity. Polymyxins have a very narrow therapeutic window and patients requiring treatment with these drugs are frequently severely ill and have multiple comorbidities, which increases the risk of AKI. Notably, there is a significant overlap between therapeutic and toxic plasma polymyxin concentrations that substantially complicates dose selection. Recent dosing protocols for both colistin and polymyxin B have been developed and may help fine tune dose adjustment of these antibiotics. Minimizing exposure to modifiable risk factors, such as other nephrotoxic agents, is strongly recommended. The dose should be carefully selected, particularly in high-risk patients. The administration of oxidative stress-reducing drugs is a promising strategy to ameliorate polymyxin-associated AKI, but still requires support from clinical studies.

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“…polymyxin agents. 42 As with many drugs, dose and duration of therapy have been associated with increased toxicity for both colistin and polymyxin b. 43 In addition, studies have found that the polymyxins carry higher nephrotoxicity risk than other agents used for similar indications, 44,45 most notably βlactams, which largely limits their use to treatment of infections caused by bacteria resistant to other available agents.…”

Section: Polymyxins and Nephrotoxicitymentioning

confidence: 99%

Too Much of a Good Thing: Defining Antimicrobial Therapeutic Targets to Minimize Toxicity

Downes

Goldman

2021

Clin Pharma and Therapeutics

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Antimicrobials are a common cause of drug toxicity. Understanding the relationship between systemic antimicrobial exposure and toxicity is necessary to enable providers to take a proactive approach to prevent undesired drug effects. When an exposure threshold has been defined that predicts drug toxicity, therapeutic drug monitoring (TDM) can be performed to assure drug exposure does not exceed the defined threshold. Although some antimicrobials have well-defined dose-dependent toxicities, many other exposure-toxicity relationships have either not been well-defined or, in some cases, not been evaluated at all. In this review, we examine the relationship between exposures and toxicities for antibiotic, antifungal, and antiviral agents. Furthermore, we classify these relationships into four categories: known association between drug exposure and toxicity such that clinical implementation of a specific exposure threshold associated with toxicity for TDM is supported (category 1), known association between drug exposure and toxicity but the specific exposure threshold associated with toxicity is undefined (category 2), association between drug exposure and toxicity has been suggested but relationship is poorly defined (category 3), and no known association between drug exposure and toxicity (category 4). Further work to define exposure-toxicity thresholds and integrate effective TDM strategies has the potential to minimize many of the observed antimicrobial toxicities.

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Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies

Cited by 72 publications

References 107 publications

Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study

Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study

Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

Too Much of a Good Thing: Defining Antimicrobial Therapeutic Targets to Minimize Toxicity

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