Pentoxifylline Therapy for Late-Onset Sepsis in Preterm Infants

Abstract

Background:The role of pentoxifylline (PTX) in reducing mortality associated with neonatal sepsis is not well established. We aimed to assess the efficacy and safety of PTX as an adjunct to antibiotics on mortality and morbidity in preterm infants with late-onset sepsis (LOS). Methods: Double blind, randomized controlled trial was conducted on 120 preterm infants with LOS. They were randomly assigned to receive either intravenous PTX 5 mg/kg/hr for 6 hours on 6 successive days or placebo. Death before hospital discharge was our primary outcome and secondary outcomes were length of hospital stay, duration of respiratory support, duration of antibiotics use, short-term morbidity of preterm infants, tumor necrosis factor-alpha concentrations, C-reactive protein concentrations, and adverse effects of PTX. Results: A total of 120 infants were enrolled, 60 in each group, 78 (65%) infants had confirmed and 42 (35%) had suspected LOS. There were no significant differences between groups regarding mortality [6 (10%) in PTX vs. 10 (16.5%) in placebo, P = 0.44], short-term morbidity and combined mortality and/or short-term morbidity [18 (30%) vs. 24 (40%), P = 0.23]. PTX therapy was associated with significant reduction of serum tumor necrosis factor-alpha and C-reactive protein concentrations. The length of hospital stay, durations of respiratory support and antibiotic therapy were significantly shorter in the PTX group. Patients in PTX group had less need for vasopressors, lower incidence of metabolic acidosis, disseminated intravascular coagulopathy and thrombocytopenia. No adverse effects to PTX were reported. Conclusions: PTX has a beneficial adjuvant effect to antibiotic therapy in preterm infants with LOS without significant impact on neonatal mortality and morbidity.

Bakterielle Infektionen bei Neugeborenen. Leitlinie der GNPI, DGPI, DGKJ und DGGG. (S2k-Level, AWMF-Leitlinien-Register-Nr. 024/008, April 2018)

“…Allerdings muss die Evidenz aufgrund der heterogenen Studienqualität als niedrig bezeichnet werden [131]. In einer anderen Studie [132] war die Mortalität und Kurzzeitmorbiditätunbeeinflusst,jedochsankenunterPentoxifyllin die Inzidenzen von DIC und Thrombozytopenie sowie die Gesamtdosis verabreichter Katecholamine im Vergleich zur Placebogruppe. Die in den Studien verwendete Dosierung betrug 5 mg/kg/h als Infusion über 6 h an 5-6 konsekutiven Tagen.…”

Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late‐onset sepsis or necrotizing enterocolitis: a pilot study incorporating clinical outcomes

“…In previous neonatal pilot studies, PTX improved endothelial cell function, reduced coagulopathy in sepsis and NEC and diminished intestinal permeability by reducing myeloperoxidase activity and oxygen free radical generation [4]. PTX also significantly reduces inflammatory host responses to various stimuli in neonatal blood in vitro and in vivo [5][6][7]. A recent Cochrane review concluded that PTX increases survival and shortens length of hospital stay in neonates with sepsis, and recommended appropriately powered clinical trials be undertaken to confirm these findings [8].…”

Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns

“…PTX competitively inhibits phosphodiesterases in a range of cells and tissues, thereby increasing intracellular cAMP, a second messenger which acts via protein kinase A to suppress gene transcription of proinflammatory mediators including tumor necrosis factor (TNF) (5,6). Due to its anti-TNF activity, PTX has been studied in animals and human adults and newborns to ameliorate inflammatory conditions such as sepsis, BPD, meconium aspiration, and hypoxic ischemic encephalopathy (7)(8)(9)(10)(11). Adverse reactions of PTX in adults include gastrointestinal and CNS symptoms, whereas significant adverse reactions at therapeutic doses are rare in adults (www.pdr.net/drug-summary/Pentoxifylline, www.fda.…”