Talactoferrin in Severe Sepsis

Vincent, Jean‐Louis; Marshall, John C.; Dellinger, R Phillip; Simonson, Steven G.; Guntupalli, Kalpalatha K.; Levy, Mitchell M.; Singer, Mervyn; Malik, Rajesh

doi:10.1097/ccm.0000000000001090

Cited by 42 publications

(13 citation statements)

References 20 publications

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“…A single multicenter trial was conducted using talactoferrin in 750–1500 g neonates, which examined 120 infants and showed a trend towards decreased infectious morbidity but did not achieve statistical significance [ 125 ] ( Table 1 ). Further trials with this protein, however, currently appear to be on hold following recent data showing no benefit in a trial in adult ICU patients [ 126 ].…”

Section: Examination For Clinical Efficacy Of Lf In Neonatesmentioning

confidence: 99%

Lactoferrin: A Critical Player in Neonatal Host Defense

Telang

2018

Nutrients

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Newborn infants are at a high risk for infection due to an under-developed immune system, and human milk has been shown to exhibit substantial anti-infective properties that serve to bolster neonatal defenses against multiple infections. Lactoferrin is the dominant whey protein in human milk and has been demonstrated to perform a wide array of antimicrobial and immunomodulatory functions and play a critical role in protecting the newborn infant from infection. This review summarizes data describing the structure and important functions performed by lactoferrin in protecting the neonate from infection and contributing to the maturation of the newborn innate and adaptive immune systems. We also briefly discuss clinical trials examining the utility of lactoferrin supplementation in the prevention of sepsis and necrotizing enterocolitis in newborn infants. The data reviewed provide rationale for the continuation of studies to examine the effects of lactoferrin administration on the prevention of sepsis in the neonate.

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Section: Examination For Clinical Efficacy Of Lf In Neonatesmentioning

confidence: 99%

Lactoferrin: A Critical Player in Neonatal Host Defense

Telang

2018

Nutrients

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“…A second trial utilized similar enrollment criteria and treatment in randomizing 205 patients. The 28-day all-cause mortality in the hLF arm was 25 % compared to 18 % in the placebo group ( p = 0.11), although ICU and long-term mortality were increased in the hLF group [ 45 ]. However, on combining the results of the two trials in a meta-analysis, the relative risk of hospital mortality was 0.88 (95 % CI 0.35 to 2.26) (unpublished data).The cause for the discrepant results between these studies is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Due to conflicting results on the effects of LF when used as a treatment for sepsis [ 44 , 45 ] a priori, we will conduct a subgroup analysis of patients presenting with sepsis [ 46 ]. No formal interim analyses are planned.…”

Section: Methodsmentioning

confidence: 99%

Prevention of nosocomial infections in critically ill patients with lactoferrin (PREVAIL study): study protocol for a randomized controlled trial

Muscedere

Maslove

Boyd

et al. 2016

Trials

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BackgroundNosocomial infections remain an important source of morbidity, mortality, and increased health care costs in hospitalized patients. This is particularly problematic in intensive care units (ICUs) because of increased patient vulnerability due to the underlying severity of illness and increased susceptibility from utilization of invasive therapeutic and monitoring devices. Lactoferrin (LF) and the products of its breakdown have multiple biological effects, which make its utilization of interest for the prevention of nosocomial infections in the critically ill.Methods/designThis is a phase II randomized, multicenter, double-blinded trial to determine the effect of LF on antibiotic-free days in mechanically ventilated, critically ill, adult patients in the ICU. Eligible, consenting patients will be randomized to receive either LF or placebo. The treating clinician will remain blinded to allocation during the study; blinding will be maintained by using opaque syringes and containers. The primary outcome will be antibiotic-free days, defined as the number of days alive and free of antibiotics 28 days after randomization. Secondary outcomes will include: antibiotic utilization, adjudicated diagnosis of nosocomial infection (longer than 72 h of admission to ICU), hospital and ICU length of stay, change in organ function after randomization, hospital and 90-day mortality, incidence of tracheal colonization, changes in gastrointestinal permeability, and immune function. Outcomes to inform the conduct of a larger definitive trial will also be evaluated, including feasibility as determined by recruitment rates and protocol adherence.DiscussionThe results from this study are expected to provide insight into a potential novel therapeutic use for LF in critically ill adult patients. Further, analysis of study outcomes will inform a future, large-scale phase III randomized controlled trial powered on clinically important outcomes related to the use of LF.Trial registrationThe trial was registered at www.ClinicalTrials.gov on 18 November 2013. Trial registration number: NCT01996579.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1590-z) contains supplementary material, which is available to authorized users.

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“…APPs have potential as stand alone therapeutics or as adjunctive agents, to reduce either length of antibiotic treatment and/or inflammation induced by killed microbes/microbial products ( 52 ). Important APPs that have undergone clinical trials include rBPI 21 ; Pexiganan, an analog of Magainin (MSI-78) ( 53 ); Iseganan (IB-367), a protegrin mimetic; Omiganan pentahydrochloride (CLS001), an Indolicidin analog; Brilacidin, a defensin mimetic; LTX-109, a short lactoferricin-based peptide ( 54 ), and Talactoferrin, an analog of LF ( 55 , 56 ). The terms analog and mimetic are used, respectively, to describe synthetic compounds with closely similar molecular structure versus those with a closely similar functional capacity to that of an endogenous APP (see Table 4 ).…”

Section: What Are Antimicrobial Peptides and Proteins?mentioning

confidence: 99%

“…Several pharmaceutical companies are developing APPs for systemic administration, such as Agennix AG who are pursuing the development of oral Talactoferrin in severe sepsis (NCT00630656). Results from their phase II randomized controlled trial (RCT) showed a significant reduction in all-cause mortality at 28 days and 6 months in the treatment group ( 82 ) yet, the recent follow on phase II/III RCT (OASIS trial) was terminated prematurely over concerns of safety and efficacy ( 55 ). Interestingly the APP that has undergone most advanced clinical testing using the intravenous (IV) route is rBPI 21 , which was assessed for its efficacy in meningococcemia in children ( 42 ).…”

Section: Clinical Application Of Apps: Promising Evidence From Clinicmentioning

confidence: 99%

Antimicrobial Proteins and Peptides in Early Life: Ontogeny and Translational Opportunities

et al. 2016

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While developing adaptive immune responses, young infants are especially vulnerable to serious infections, including sepsis, meningitis, and pneumonia. Antimicrobial proteins and peptides (APPs) are key effectors that function as broad-spectrum anti-infectives. This review seeks to summarize the clinically relevant functional qualities of APPs and the increasing clinical trial evidence for their use to combat serious infections in infancy. Levels of APPs are relatively low in early life, especially in infants born preterm or with low birth weight (LBW). There are several rationales for the potential clinical utility of APPs in the prevention and treatment of infections in infants: (a) APPs may be most helpful in those with reduced levels; (b) during sepsis microbial products signal via pattern recognition receptors causing potentially harmful inflammation that APPs may counteract; and (c) in the era of antibiotic resistance, development of new anti-infective strategies is essential. Evidence supports the potential clinical utility of exogenous APPs to reduce infection-related morbidity in infancy. Further studies should characterize the ontogeny of antimicrobial activity in mucosal and systemic compartments, and examine the efficacy of exogenous-APP formulations to inform translational development of APPs for infant groups.

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Talactoferrin in Severe Sepsis

Abstract: Administration of oral talactoferrin was not associated with reduced 28-day mortality in patients with severe sepsis and may even be harmful.

Cited by 42 publications

References 20 publications

Lactoferrin: A Critical Player in Neonatal Host Defense

Lactoferrin: A Critical Player in Neonatal Host Defense

Prevention of nosocomial infections in critically ill patients with lactoferrin (PREVAIL study): study protocol for a randomized controlled trial

Antimicrobial Proteins and Peptides in Early Life: Ontogeny and Translational Opportunities

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