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Azithromycin, Ureaplasma and chronic lung disease of prematurity: a case study for neonatal drug development
Mark A Turner,1 Evelyne Jacqz-Aigrain,2 Sailesh Kotecha3
of Womens and Childrens Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK 2Pharmacologie Pdiatrique et Pharmacogntique, Hpital Robert Debr, Paris, France 3Department of Child Health, School of Medicine, Cardiff University, Cardiff, UK Correspondence to Sailesh Kotecha, Department of Child Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; KotechaS@cardiff.ac.uk Accepted 23 May 2011 Published Online First 22 June 2011
1Department
ABSTRACT Chronic lung disease of prematurity (CLD) remains a major cause of morbidity and mortality in preterm infants. Ureaplasma has received intermittent attention over the last two decades as a possible contributory factor. In addition, pulmonary inammation is associated with the development of CLD. The macrolide azithromycin provides an attractive option to determine if it can decrease the development of CLD as it has both anti-inammatory and anti-infective properties. In this article, the authors review the evidence for the role of Ureaplasma in the development of CLD and the obstacles faced in the development of a drug before it reaches clinical practice. INTRODUCTION
Advances in neonatal care have improved the survival of extremely preterm infants, but morbidity1 including neurodevelopmental sequelae and chronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia, remains signicant. CLD is associated with prolonged hospital stay and often a need for domiciliary oxygen, 2 and places a signicant burden on the family. Indeed, CLD was identied as having the largest therapeutic gap in a recent survey of UK neonatologists. 3 The Paediatric Regulation from the European Commission has stimulated work on systematic drug development for neonates. It is now feasible to obtain a marketing authorisation for off-patent medicines for use in children.4 5 The aims of this review are: 1. to outline the state-of-the-art for one potential intervention for CLD and 2. to use this intervention as a case study for the current approach to drug development for neonates in the context of developing a paediatric investigation plan with a view to applying for a marketing authorisation. Multiple factors appear to contribute to the development of CLD. In infants who are at risk of developing CLD, one frequent nding is colonisation of the preterm lung with the microbe Ureaplasma.6 7 Ureaplasma belongs to the class of Mollicutes which are thought to be the smallest free-living, self-replicating organisms. A s they do not have a cell wall, they are limited to a parasitic existence in eukaryotic cells. Ureaplasma urealyticum, the only species known to infect humans, was recently subdivided into two separate species, U urealyticum and U parvum, on the basis of their 16S ribosomal RNA gene sequences.8
Two meta-analyses have suggested an association between the presence of pulmonary Ureaplasma and the development of CLD.9 10 The more recent report by Schelonka et al which included 23 studies and 2216 babies,10 showed a relative risk of 2.83 (95% CI 2.29 to 3.51) for CLD diagnosed as oxygen dependency at 28 days of life. For the 751 infants who were oxygen-dependent at 36 weeks postconceptional age, the relative risk was 1.62 (1.13 to 2.33). The studies, however, are disparate with most calling for a de nitive randomised trial to assess if eradication of pulmonary Ureaplasma reduces the rates of CLD. In addition, lung in ammation during the rst week of life is the hallmark of preterm babies who subsequently develop CLD.11 12 Tafari and colleagues described the isolation of Ureaplasma from the lungs of stillborn infants with pneumonitis.13 Further support for the contributory role of Ureaplasma in human disease comes from demonstration of a specic IgM response in the neonate resulting in radiographic changes indicative of pneumonia in culture positive infants and demonstration of the organism in lung tissue by immunouorescence and electron microscopy.14 15 Animal models have contributed substantially to understanding of the in ammatory processes that are triggered by Ureaplasma in the mammalian respiratory tract, primarily in mouse, sheep and primate models.16 17 For example, Novy et al used a rhesus monkey model of antenatal Ureaplasma infection in the amniotic uid.17 They demonstrated histopathological ndings of chorioamnionitis, a systemic fetal in ammatory response and pneumonitis, which worsened as the duration of in utero infection increased. Initial clinical trials in preterm neonates used erythromycin, a macrolide antibiotic commonly used to treat Ureaplasma. Two randomised controlled trials were included in the Cochrane review by Mabanta et al which examined studies that treated Ureaplasma to decrease the rate of CLD.18 In the rst study, 75 ventilated infants of less than 30 weeks gestation whose Ureaplasma status was unknown when treatment commenced, were randomly assigned to receive erythromycin intravenously for 7 days or to no treatment.19 Nine infants (13%) were positive for Ureaplasma. Both groups had similar rates of CLD and erythromycin did not decrease CLD severity.19 In the second study, erythromycin was commenced once Ureaplasma status was known. Endotracheal aspirates and nasopharynx swabs from ventilated preterm infants (n=155; median gestational age
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(GA) 26 (range 2329) weeks) were cultured for Ureaplasma. 20 Colonised infants (29/155, 19%) were randomly assigned to treatment with intravenous or oral erythromycin 40 mg/kg/ day. Erythromycin treatment was effective in eradicating colonisation in 12/14 (86%) of the treated infants. Treatment with erythromycin reduced colonisation but did not signicantly alter the length of time with supplemental oxygen. Neither trial showed a statistically signicant effect of erythromycin on CLD, death or the combined outcome CLD or death. Since the two studies differed markedly in their design, the results were not combined in the meta-analyses. Neither study noted adverse effects for 710-day courses of erythromycin. While neither study supports a role for erythromycin in CLD, they provide evidence of tolerability. These studies are at best seen as early phase clinical trials rather than as underpowered tests of efcacy. Other approaches to this problem have been suggested. and reported an improvement in CLD rates in Ureaplasma colonised infants with wide condence intervals. Ballards work indicates that azithromycin may affect surrogate outcomes, provides proof-of-concept for the anti-in ammatory effects of azithromycin in preterm neonates and demonstrates the tolerability of azithromycin in the target population. 31 This extends the proof-of-concept to a group comprising Ureaplasma colonised and non-colonised neonates. Clearly, at least one sufciently powered randomised controlled trial is needed to address the role of azithromycin in preterm neonates and would have support from the neonatal community. 33 However, before a large randomised controlled trial can be conducted, a number of decisions need to be taken so that a large trial has the best chance of giving a clear answer.
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up a Paediatric Committee to balance the scientic and patient welfare issues in paediatric drug development. On the other hand, death may be related to CLD, in which case a composite outcome would be a conservative approach. Secondary end points should include length of oxygen dependency, hospital stay and respiratory support with intubated or non-invasive mechanical ventilation (including continuous positive airway pressure), drug usage including postnatal corticosteroids and antibiotics, infection rates, intraventricular haemorrhage, necrotising enterocolitis and retinopathy of prematurity. For the diagnosis of CLD, it is important to use a standardised physiological end point, as recommended by the National Institutes of Health consensus47 or a physiological test.48 49 It is important to follow-up after discharge. CLD at 36 weeks is an important outcome that reects hospital costs and predicts subsequent events, so it is a reasonable outcome to use to assess efcacy. Outcomes to 2 years, for example, are important to assess safety and provide preliminary evidence of effectiveness.
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Figure 1 Sample drug development plan. DSMB, data and safety monitoring board; PD, pharmacodynamics; PK, pharmacokinetics; SUSAR suspected unexpected serious adverse reaction.
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manufacturers to invest in a medicine and provides protection for that investment. If the market is large enough, a marketing authorisation will be the optimal way for neonatal drug development in the future.
curiosity driven but must be based on a careful line of thinking about formulation, optimised dosage regimen, clinical trials that explore the therapeutic possibility of the medicine and clinical trials that con rm the efcacy of the medicine.
Funding The authors are part of the EU funded FP7 programme TINN2. Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
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CONCLUSIONS
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Azithromycin, Ureaplasma and chronic lung disease of prematurity: a case study for neonatal drug development
Mark A Turner, Evelyne Jacqz-Aigrain and Sailesh Kotecha Arch Dis Child 2012 97: 573-577 originally published online June 22, 2011
doi: 10.1136/adc.2010.195180
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