Amanda Gwee

Ureaplasma--Are you sitting comfortably?

The role of Ureaplasma spp. in human disease has been controversial, as these bacteria are commonly isolated as part of the normal genital tract flora. Ureaplasma has been shown to have a causal role in urogenital infections and is associated with significant foetal and neonatal morbidity and mortality when infection occurs during the perinatal period. Although rare, invasive Ureaplasma infection (meningitis, renal abscess, mediastinitis and arthritis) has also been reported in both adults and children. This review outlines the unique microbiological features and various clinical presentations of Ureaplasma infection. It also discusses the treatment options, which in the neonatal period can be particularly challenging.

Question 1: what are the options for treating latent TB infection in children?

You are looking after a previously well, HIV-negative 4-year-old boy who has recently migrated to Australia from Sudan. He is BCG-immunised and reports no history of TB contact. His tuberculin skin test (TST) is positive (16 mm induration) and his chest x-ray (CXR) is normal. You diagnose latent tuberculosis infection (LTBI) and wonder what would be the best treatment regimen. In a child with LTBI [patient], what is the best treatment regimen [intervention] taking into account four criteria: treatment compliance, drug adverse effects, treatment efficacy and cost [outcomes]? Medline and EMBASE were searched using the Ovid interface (1974 to current date) in December 2012. The following keywords were used: (latent tuberculosis/[drug therapy, therapy]) OR (latent AND *tuberculosis/[diet therapy, drug therapy, surgery, therapy]). Limit set: English-language. Studies of LTBI treatment that included children aged less than 15 years were selected. Case reports, brief reports, studies of LTBI treatment for drug-resistant TB, studies including less than five children and studies of HIV-infected children were excluded. Of the 78 articles identified by the original search, 10 were relevant. The references of these publications were then reviewed and two additional articles were identified giving a total of 12 relevant studies (table 1). We contacted the corresponding authors of 10 of the articles and obtained further paediatric data from two (Li and Cook). View this table: Table 1 What are the options for treating latent TB infection in children? ### Background Children with LTBI have a significant risk of developing active TB without treatment, including those that have been BCG-immunised.1 Progression to active TB has been reported in up to 40% of infected infants.2 Recommendations for the treatment of LTBI in children vary: the Centers for Disease Control and Prevention recommend 9 months of isoniazid monotherapy3; the UK NICE …

To x-ray or not to x-ray? Screening asymptomatic children for pulmonary TB: a retrospective audit

Objective Recent studies found that a chest x-ray (CXR) has limited value in the assessment of asymptomatic adults with tuberculosis (TB) infection. We aimed to determine in asymptomatic children with a positive tuberculin skin test and/or interferon-γ release assay (TST/IGRA) whether a CXR identifies findings suggestive of pulmonary TB. Design, setting and patients All children with TB infection (defined as TST ≥10 mm and/or positive IGRA) presenting to The Royal Childrens Hospital Melbourne during a 54-month period were included. All CXRs were reviewed by a senior radiologist blinded to the clinical details. The medical records of those with radiological abnormalities suggestive of TB were examined to identify those who were asymptomatic when the CXR was done. Demographical data were also collected. Results CXRs were available for 268 of 330 TB-infected children, of whom 60 had CXR findings suggestive of TB. Of the 57 for whom clinical details were available, 26 were asymptomatic. Of these asymptomatic children with radiological abnormalities suggestive of TB, 6 had CXR findings suggestive of active TB, 14 had CXR findings suggestive of prior TB and 6 had isolated non-calcified hilar lymphadenopathy. The six with findings suggestive of active TB represented 2.6% (95% CI 0.9 to 5.5%) of asymptomatic TST/IGRA-positive children with evaluable CXRs. One child with isolated hilar lymphadenopathy had microbiologically-confirmed TB. Conclusions In contrast to the results from studies in adults, a CXR identified a small but noteworthy number of children with findings suggestive of pulmonary TB in the absence of clinical symptoms.

Pristinamycin: old drug, new tricks?

Osteoarticular infections with Gram positive bacteria present an increasing challenge in an era of multidrug-resistant organisms. Prolonged intravenous antibiotic treatment is often required, with associated risks, costs and difficulties with administration; a safe, effective oral option would be ideal for this indication. Pristinamycin, an oral streptogramin antibiotic with bactericidal activity against Gram positive organisms including methicillin-resistant Staphylococcus aureus, has been used for over 50 years in Europe for the treatment of osteoarticular infections. We review the published evidence for the treatment of native bone and prosthesis-related osteoarticular infections with pristinamycin.

Screening asymptomatic children for pulmonary TB: to X-ray or not to X-ray?

Objective Recent studies found that a chest x-ray (CXR) has limited value in the assessment of asymptomatic adults with tuberculosis (TB) infection. We aimed to determine in asymptomatic children with a positive tuberculin skin test and/or interferon-γ release assay (TST/IGRA) whether a CXR identifies findings suggestive of pulmonary TB. Design, setting and patients All children with TB infection (defined as TST ≥10 mm and/or positive IGRA) presenting to The Royal Childrens Hospital Melbourne during a 54-month period were included. All CXRs were reviewed by a senior radiologist blinded to the clinical details. The medical records of those with radiological abnormalities suggestive of TB were examined to identify those who were asymptomatic when the CXR was done. Demographical data were also collected. Results CXRs were available for 268 of 330 TB-infected children, of whom 60 had CXR findings suggestive of TB. Of the 57 for whom clinical details were available, 26 were asymptomatic. Of these asymptomatic children with radiological abnormalities suggestive of TB, 6 had CXR findings suggestive of active TB, 14 had CXR findings suggestive of prior TB and 6 had isolated non-calcified hilar lymphadenopathy. The six with findings suggestive of active TB represented 2.6% (95% CI 0.9 to 5.5%) of asymptomatic TST/IGRA-positive children with evaluable CXRs. One child with isolated hilar lymphadenopathy had microbiologically-confirmed TB. Conclusions In contrast to the results from studies in adults, a CXR identified a small but noteworthy number of children with findings suggestive of pulmonary TB in the absence of clinical symptoms.

Australia-wide Point Prevalence Survey of Antimicrobial Prescribing in Neonatal Units: How Much and How Good?

Background: There is increasing recognition of the threat to neonatal patients from antibiotic resistance. There are limited data on antimicrobial prescribing practices for hospitalized neonates. We aimed to describe antimicrobial use in hospitalized Australian neonatal patients, and to determine its appropriateness. Methods: Multicentre single-day hospital-wide point prevalence survey in 2012, in conjunction with the Antimicrobial Resistance and Prescribing in European Children study. The appropriateness of antimicrobial prescriptions was also assessed. All patients admitted at 8 am on the survey day, in 6 neonatal units in tertiary children’s hospitals across 5 states, were included in an analysis of the quantity and quality of all antimicrobial prescriptions. Results: The point prevalence survey included 6 neonatal units and 236 patients. Of 109 patients (46%) receiving at least 1 antimicrobial, 66 (61%) were being treated for infection, with sepsis the most common indication. There were 216 antimicrobial prescriptions, 134 (62%) for treatment of infection and 82 (38%) for prophylaxis, mostly oral nystatin. Only 15 prescriptions were for targeted as opposed to empirical treatment. Penicillin and gentamicin were the most commonly prescribed antibiotics, with vancomycin third most common. Half of all treated patients were receiving combination antimicrobial therapy. There was marked variation in vancomycin and gentamicin dosing. Overall, few prescriptions (4%) were deemed inappropriate. Conclusion: This is the first Australia-wide point prevalence survey of neonatal antimicrobial prescribing in tertiary children’s hospitals. The findings highlight positive practices and potential targets for quality improvement.

Voriconazole dosing and therapeutic drug monitoring in children: experience from a paediatric tertiary care centre.

OBJECTIVES Therapeutic drug monitoring (TDM) of voriconazole is recommended to achieve trough concentrations of 1-5 mg/L. In children, this is challenging due to age-related variability in voriconazole pharmacokinetics. This study describes our experience with voriconazole, focusing on dosing regimens, dose adjustment and TDM. METHODS We reviewed the medical records of immunocompromised children who received voriconazole from July 2009 to January 2015 and had TDM. Demographic, clinical and voriconazole dosing and monitoring data were collected. RESULTS Fifty-five children received 62 courses of voriconazole and had TDM, with a total of 256 samples taken. Only 71.0% of courses (44/62) had TDM at the correct time, and at least one therapeutic level was achieved in only 52.3% (23/44) of these. Twenty-six courses had at least one sub-therapeutic level and in only 61.5% was the dose adjusted. Patients aged <6, 6-12 and >12 years required median intravenous doses of 8.8, 7.5 and 4.0 mg/kg twice daily, respectively (P < 0.001). With oral administration, patients aged 6-12 and >12 years required median doses of 4.7 and 4.3 mg/kg twice daily, respectively (P = 0.307). Levels within the target range were observed to fall below 1 mg/L in 36.4% of unchanged dosing regimens. Photosensitive skin reactions (20.0%) and hepatotoxicity (12.7%) were the most frequent adverse events and occurred in children with voriconazole levels <5 mg/L. CONCLUSIONS There is significant intra- and inter-individual variability in voriconazole concentrations in children, particularly in children <6 years of age. This warrants repeated TDM throughout treatment. Standardized guidelines for TDM and dose adjustment are required in children.

The controversial role of breast milk in GBS late-onset disease

Group B streptococcus (GBS) is one of the most common causes of neonatal sepsis and meningitis. Intra-partum antibiotic prophylaxis does not play a significant role in reducing the risk of GBS late-onset disease. One of the proposed mechanisms for GBS late-onset disease is infection through contaminated breast milk. Infants in whom breast milk is thought to be the source for GBS late-onset disease are more heavily colonised and reports suggest they have a higher recurrence rate compared to infants with other potential sources. There is no consensus whether the breast milk of mothers of infants with GBS late-onset disease, especially those with recurrent episodes, should be tested for GBS. In addition, recommendations differ on whether breast-feeding should be interrupted or breast milk pasteurised, or whether the mother and infant should be treated for colonisation. In this review we discuss these different approaches.

Australia-wide point prevalence survey of the use and appropriateness of antimicrobial prescribing for children in hospital.

Objectives: To describe antimicrobial use in hospitalised Australian children and to analyse the appropriateness of this antimicrobial use.

Neonatal vancomycin continuous infusion: still a confusion?

Background: Continuous infusions of vancomycin over 24 hours have been shown in adults to reduce drug toxicity, lower treatment costs and require fewer blood samples for therapeutic drug monitoring. They may also improve clinical outcome through earlier attainment of target drug concentrations. In neonates, there is no consensus on vancomycin dosing. We reviewed the literature to assess the evidence for vancomycin dosing regimens for continuous infusion in neonates. Methods: Medline and Embase were searched for studies about continuous vancomycin dosing regimens in neonates that reported serum drug concentrations. The search identified 469 articles, of which 5 were relevant. Results: Five prospective studies were included; 2 studies used non-linear mixed effects modeling. Vancomycin was administered with parenteral nutrition or 5% dextrose. Target serum concentrations varied (range: 10–30 mg/L). Four studies used loading doses before continuous infusion; only 1 documented achievement of therapeutic concentrations after the load. The time to a therapeutic concentration was not reported for the other studies. Attainment of target concentrations ranged from 56% to 89% of measurements. Only 1 study compared intermittent to continuous infusions, reporting higher attainment of target concentrations with continuous dosing (82% vs. 46%). No adverse effects were reported, although 3 neonates developed a reversible raised serum creatinine in the setting of septicemia. Conclusion: Continuous infusions of vancomycin in neonates are well tolerated, require less blood sampling and may result in improved attainment of target concentrations. Further prospective studies are needed in this population.