Pamela Palasanthiran

Antifungal Therapy in Children With Invasive Fungal Infections: A Systematic Review

Invasive fungal infections are associated with significant morbidity and mortality. Differences between children and adults are reported, yet few trials of antifungal agents have been performed in pediatric populations. We performed a systematic review of the literature to guide appropriate pediatric treatment recommendations. From available trials that compared antifungal agents in either prolonged febrile neutropenia or invasive candidal or Aspergillus infection, no clear difference in treatment efficacy was demonstrated, although few trials were adequately powered. Differing antifungal pharmacokinetics between children and adults were demonstrated, requiring dose modification. Significant differences in toxicity, particularly nephrotoxicity, were identified between classes of antifungal agents. Therapy needs to be guided by the pathogen or suspected pathogens, the degree of immunosuppression, comorbidities (particularly renal dysfunction), concurrent nephrotoxins, and the expected length of therapy.

Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy

Congenital cytomegalovirus is the most frequent, yet under-recognised, infectious cause of newborn malformation in developed countries. Despite its clinical and public health importance, questions remain regarding the best diagnostic methods for identifying maternal and neonatal infection, and regarding optimal prevention and therapeutic strategies for infected mothers and neonates. The absence of guidelines impairs global efforts to decrease the effect of congenital cytomegalovirus. Data in the literature suggest that congenital cytomegalovirus infection remains a research priority, but data are yet to be translated into clinical practice. An informal International Congenital Cytomegalovirus Recommendations Group was convened in 2015 to address these questions and to provide recommendations for prevention, diagnosis, and treatment. On the basis of consensus discussions and a review of the literature, we do not support universal screening of mothers and the routine use of cytomegalovirus immunoglobulin for prophylaxis or treatment of infected mothers. However, treatment guidelines for infected neonates were recommended. Consideration must be given to universal neonatal screening for cytomegalovirus to facilitate early detection and intervention for sensorineural hearing loss and developmental delay, where appropriate. The group agreed that education and prevention strategies for mothers were beneficial, and that recommendations will need continual updating as further data become available.

Nontuberculous Mycobacterial Infection in Children A Prospective National Study

Background: The epidemiology and management of nontuberculous mycobacterial (NTM) infection in Australian children is unknown. Methods: From July 2004 to June 2007, clinicians identified children with NTM infection as part of a nationwide active surveillance network. Following notification, detailed data were collected. Results: From 192 reports, data were received on 153 cases (response rate: 79.7%). Of these, 102 met inclusion criteria. The median age was 2.9 years. Predisposing conditions were infrequent and included chronic respiratory disease (n = 12) and immunosuppression (n = 6). Lymphadenitis was the most frequent presentation (n = 68) with pulmonary and disseminated disease infrequent (n = 14 and 3, respectively). NTM was isolated in 68 cases with Mycobacterium avium-intracellulare complex most frequently isolated (33/68; 48.5%). Surgery was performed in 78 cases and 42 children were treated with antimycobacterial therapy. Twenty-five subjects received surgery and antimycobacterial therapy. Follow-up data were available for 77 children with recurrence observed in 18 cases. Complete excision was associated with a higher rate of treatment success when compared with all other therapies (OR: 9.48 [95% CI: 2.00–44.97], P = 0.001). Mycobacterium lentiflavum infection accounted for 4.4% of culture confirmed cases and had a lower rate of treatment success than other species (0% vs. 78.2%; P = 0.016). Conclusions: The incidence of NTM infection in Australian children is 0.84 of 100,000 (95% CI: 0.68–1.02). Infection occurs most often in young children without predisposing conditions. Despite therapy, there was recurrence in 23.4% of cases.

Antibiotic duration and timing of the switch from intravenous to oral route for bacterial infections in children: systematic review and guidelines

Few studies are available to inform duration of intravenous antibiotics for children and when it is safe and appropriate to switch to oral antibiotics. We have systematically reviewed antibiotic duration and timing of intravenous to oral switch for 36 paediatric infectious diseases and developed evidence-graded recommendations on the basis of the review, guidelines, and expert consensus. We searched databases and obtained information from references identified and relevant guidelines. All eligible studies were assessed for quality. 4090 articles were identified and 170 studies were included. Evidence relating antibiotic duration to outcomes in children for some infections was supported by meta-analyses or randomised controlled trials; in other infections data were from retrospective series only. Criteria for intravenous to oral switch commonly included defervescence and clinical improvement with or without improvement in laboratory markers. Evidence suggests that intravenous to oral switch can occur earlier than previously recommended for some infections. We have synthesised recommendations for antibiotic duration and intravenous to oral switch to support clinical decision making and prospective research.

Improved Neurodevelopmental Outcomes following Long-Term High-Dose Oral Acyclovir Therapy in Infants with Central Nervous System and Disseminated Herpes Simplex Disease

OBJECTIVE:Infants with neonatal herpes, classified as central nervous system or disseminated disease, have a high incidence of moderate and severe neurologic deficits despite standard acute therapy.STUDY DESIGN:Following completion of parenteral therapy, infants with central nervous system and/or disseminated disease received 2 years of continuous oral acyclovir therapy. Target minimum peak serum acyclovir concentrations were >2 μg/ml for the first three patients, and >3 μg/ml for the subsequent 13 patients. Safety assessments were made every 3 months. We evaluated neurodevelopmental outcomes with Bayley Scales of Infant Development.RESULTS:A total of 16 consecutive herpes simplex virus-infected infants born during 1990 to 2003 received the treatment plan; 13/16 infants had central nervous system disease; 3 had disseminated disease without central nervous system involvement. A total of 69% (11/16) had Bayley scores in the normal range for mental development and 79% (11/14) had motor scores in the normal range. At the final assessment, five children had developmental delays. One child had severe mental delay with normal motor development. Four children had mild mental delays, with severe motor delays in three. All children were independently mobile, without seizure disorder, had normal vision, and had speech development. During the 2-year course of treatment, five children had brief recurrences of dermal lesions, and none had evidence of neurologic deterioration. There were no serious or sustained adverse drug reactions.CONCLUSION:This pilot study reports improved outcomes in a small cohort of infants with a prolonged course of oral acyclovir. A minority of these children exhibited mild or significant developmental delays. Further investigation of this approach to treatment is warranted.

Tolerabilities of Antiretrovirals in Paediatric HIV Infection

Data on the efficacy and tolerability of antiretrovirals in children are limited as, in contrast to adult studies, large paediatric cohort studies are lacking. Thus, data pertaining to adults are often extrapolated to children despite the acknowledgement that children are not little adults. This review summarises information gathered from existing reports and focuses on the tolerabilities of antiretrovirals in children infected with HIV-1. The efficacy of antiretrovirals is not included in the scope of the discussion.Taste of antiretrovirals should be an important factor when considering the tolerability of antiretrovirals in children. However, antiretroviral options are often limited in young children as only some of the antiretrovirals are available as paediatric formulations. All antiretrovirals have been associated with toxicities in children, but in general, they are relatively well tolerated. The gastrointestinal system including hepatic system is most prone to being affected by these drugs. Skin rashes and hypersensitivity reactions are also associated with antiretroviral use, particularly with the non-nucleoside reverse transcriptase inhibitors. Mitochondrial toxicities that lead to impairment of liver function, pancreatic function and lactic acidosis are associated with most of the nucleoside analogues. Haematological toxicity is often a dose limiting adverse effect especially of the nucleoside analogues, in particular zidovudine. The protease inhibitors are associated with gastrointestinal intolerance (diarrhoea) and metabolic derangements that can lead to hypercholesterolaemia and hypertriglyceridaemia, which in turn and can lead to changes in body habitus. The renal system is also affected by several drugs, the most important of which is indinavir, which has been associated with renal stones and damage to the renal tubules.Fortunately, with lower incidence of major toxicity and with the range of drugs now available for paediatric use, toxicities are usually not a barrier to effect antiretroviral therapy in children.

Influenza vaccine safety in children less than 5 years old: the 2010 and 2011 experience in Australia.

In August 2010, the United States Advisory Committee on Immunization Practices recommended that the 2010–2011 CSL seasonal vaccine (Afluria) not be administered to children 6 months to 8 years of age because of the risk of febrile convulsion after immunization. This study reports a low rate (6%–7%) of fever after immunization with 2 non-CSL brands of 2011 seasonal influenza vaccine in Australian children <5 years of age. These data are reassuring for parents and healthcare workers regarding 2011 influenza vaccination in the northern hemisphere.

Once-daily Gentamicin in Infants and Children A Prospective Cohort Study Evaluating Safety and the Role of Therapeutic Drug Monitoring in Minimizing Toxicity

Background: The clinical evidence base for ototoxicity and nephrotoxicity outcomes with once-daily dosing (ODD) of gentamicin in children is suboptimal. Therapeutic drug monitoring (TDM) in once-daily gentamicin regimens is variable and its role in predicting or preventing clinical toxicity is unclear. We aimed to assess the safety of ODD of gentamicin and the usefulness of TDM in a pediatric cohort. Methods: Children with suspected sepsis were prospectively enrolled to receive ODD of gentamicin at 7 mg/kg/day. Hearing and renal function were objectively assessed at baseline, during therapy, and after therapy. TDM was performed using an interval-adjusted graphical method (Hartford nomogram). Results: A total of 79 children (median age: 5.6 years; range: 1 month–16 years) received 106 episodes of therapy. In all, 61% of these episodes were for febrile neutropenia. Evaluation was complete in 88% for ototoxicity and 92% for nephrotoxicity. Two patients (1.88%, 95% confidence interval: 0.10%–7.13%) experienced permanent hearing loss. One patient (0.94%, 95% confidence interval: <0.10%–5.73%) experienced transient nephrotoxicity. No abnormal serum gentamicin values were detected, even in those experiencing toxicity. Children experiencing toxicity were undergoing treatment for malignancies and had received nephrotoxic or ototoxic medicines before gentamicin. Conclusions: In this pediatric cohort receiving ODD of gentamicin, nephrotoxicity was uncommon and reversible, but irreversible ototoxicity occurred more frequently. TDM using a nomogram neither predicted nor prevented toxicity, which was only observed in those with risk factors.

Consequences of an unrecognized measles exposure in an emergency department

A recent measles case in a paediatric hospital ED resulted in 111 individuals (patients, family members and health‐care workers) potentially being exposed to measles. This report documents the efforts taken to contact trace and provide best practice care for all those exposed to the index case. It also provides a snapshot of community prevalence information on immunity to measles. One hundred per cent of contacted children (n= 24) eligible for vaccination were immunized, whereas 96% of adults surveyed or tested (n= 44) had assumed or proven immunity. However, six infants aged between 6 and 9 months were exposed and might have been a sufficiently large reservoir to facilitate the ongoing spread of measles in the community, if contact tracing and preventative measures had not occurred. This scenario also highlights the need to consider measles in the ED, particularly among travellers, with urgent isolation of suspected cases in the ED according to guidelines discussed.

Global challenges in the development and delivery of paediatric antiretrovirals.

By the end of 2006, compared with 28% coverage for adults, only 15% of children with HIV that needed antiretroviral treatment were receiving it. Major challenges in delivering treatment include the lack of paediatric antiretrovirals that can be dosed in small children and limited studies examining safety and efficacy for existing antiretroviral formulations. The high costs of treatment have been reduced through the use of generic, fixed-dose combination drugs. Evidence-based strategies for managing resistance and the scale-up of pharmacological trials for children in low- and middle-income countries are crucial to the success and future development of paediatric antiretrovirals.