Herpesviridae comprises a large family of double-stranded DNA viruses that infect both animals and humans. Eight herpesviruses are known to infect humans: herpes simplex virus type-1 and -2, varicella zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 type-A and -B, human herpesvirus type-7 and -8 or Kaposi's sarcoma virus. Despite the fact that the past two decades have been evolutionary in the development of antiviral agents, therapeutic choices are restricted by limited efficacy and toxicity. Viral infections remain the cause of significant mortality worldwide, thus indicating the high medical need for the introduction of novel promising compounds in the antiviral chemotherapy era. This review focuses on recent data regarding several novel groups of agents that have proved to be effective as antiherpetic drugs. The agents mentioned are those considered to be the most likely candidates for entering clinical trials and those in the process of being granted approval by the US Food and Drug Administration. The diversity in their molecular mechanism of action highlights the different perspectives currently encountered in the era of antiviral therapy.

Background Data are limited regarding the clinical effectiveness and safety of intravenous colistin for treatment of infections due to MDR Gram-negative bacilli (GNB) in paediatric ICUs (PICUs). Methods Systematic review of intravenous colistin use in critically ill paediatric patients with MDR-GNB infection in PubMed, Scopus and EMBASE (up to 31 January 2018). Results Out of 1181 citations, 7 studies were included on the use of intravenous colistin for 405 patients in PICUs. The majority of patients were diagnosed with lower respiratory tract infections, Acinetobacter baumannii being the predominant pathogen. Colistin dosages ranged between 2.6 and 18 mg/kg/day, with only one case reporting a loading dose. Emergence of colistin resistance during treatment was reported in two cases. Nephrotoxicity and neurotoxicity were reported in 6.1% and 0.5%, respectively, but concomitant medications and severe underlying illness limited our ability to definitively associate use of colistin with nephrotoxicity. Crude mortality was 29.5% (95% CI = 21.7%–38.1%), whereas infection-related mortality was 16.6% (95% CI = 12.2%–21.5%). Conclusions While the reported incidence of adverse events related to colistin was low, reported mortality rates for infections due to MDR-GNB in PICUs were notable. In addition to severity of disease and comorbidities, inadequate daily dosage and the absence of a loading dose may have contributed to mortality. As the use of colistin for treatment of MDR-GNB infections increases, it is imperative to understand whether optimal dosing of colistin in paediatric patients differs across different age groups. Thus, future studies to establish the pharmacokinetic properties of colistin in different paediatric settings are warranted.

Synopsis 26Background: Data are limited regarding the clinical effectiveness and safety of 27 intravenous colistin for treatment of infections by multidrug-resistant gram-negative 28 bacilli (MDR-GNB) in the paediatric intensive care unit (PICU). 29Methods: Systematic review of intravenous colistin use in critically ill paediatric 30 patients with MDR-GNB infection in PubMed, Scopus and Embase (through January 31 31 st , 2018). 32Results: Out of 1,181 citations, 7 studies were included on the use of intravenous 33 colistin for 405 patients in PICU. Majority of patients were diagnosed with lower 34 respiratory tract infections, with Acinetobacter baumannii being the predominant 35 pathogen. Colistin dosages ranged between 2.6-18 mg/kg/day, with none but one case 36 reporting a loading dose. Emergence of colistin-resistance during treatment was 37 reported in two cases. Nephrotoxicity and neurotoxicity were reported in 6.1% and 38 0.5% respectively, but concomitant medications and severe underlying illness limited 39 our ability to definitively associate use of colistin with nephrotoxicity. Crude 40 mortality was 29.5% (95%CI 21.7-38.1%), whereas infection-related mortality was 41 16.6% (95%CI 12.2-21.5%). 42 Conclusions: While the reported incidence of adverse events related to colistin were 43 low, reported mortality rates for infections by MDR-GNB in PICU were notable. In 44 addition to severity of disease and comorbidities, inadequate daily dosage and the 45 absence of a loading dose may have contributed to mortality. As the use of colistin for 46 treatment of MDR-GNB infections increases, it is imperative to understand whether 47 optimal dosing of colistin in paediatric patients differs across different age groups. As 48 such, future studies to establish the pharmacokinetic properties of colistin in different 49 paediatric settings are warranted. 50 51

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