Clarithromycin in Preventing Bronchopulmonary Dysplasia in Ureaplasma urealyticum –Positive Preterm Infants

Dysplasia in

Ureaplasma urealyticum

–Positive

Preterm Infants

WHAT’S KNOWN ON THIS SUBJECT: Despite numerous studies, controversy still exists about whetherUreaplasma urealyticum colonization or infection of the respiratory tract contributes to the development of bronchopulmonary dysplasia. Additional controversy exists on the use of macrolides for the treatment of U urealyticum.

WHAT THIS STUDY ADDS: Clarithromycin treatment prevents development of bronchopulmonary dysplasia in preterm infants who are born at 750 to 1250 g and colonized withU urealyticum.

abstract

OBJECTIVE:To evaluate the efficacy and safety of clarithromycin treat-ment in preventing bronchopulmonary dysplasia (BPD) inUreaplasma urealyticum–positive preterm infants.

PATIENTS AND METHODS:Nasopharyngeal swabs forU urealyticum culture were taken from infants with a birth weight between 750 and 1250 g in the first 3 postnatal days. Infants with a positive culture forU urealyticumwere randomly assigned to 1 of 2 groups to receive either intravenous clarithromycin or placebo. All the patients were followed at least up to the 36th postmenstrual week.

RESULTS:A total of 224 infants met the eligibility criteria of the study. Seventy-four (33%) infants had a positive culture forU urealyticumin the first 3 day cultures. The rate of BPD development was significantly higher in patients withU urealyticumpositivity (15.9% vs 36.4%;P⬍ .01). However, multivariate logistic regression analysis failed to reveal a significant association between the presence ofU urealyticumand BPD development (odds ratio: 2.4 [95% confidence interval: 0.9 – 6.3]; P⫽.06). Clarithromycin treatment resulted in eradication ofU urea-lyticumin 68.5% of the patients. The incidence of BPD was significantly lower in the clarithromycin group than in the placebo group (2.9% vs 36.4%;P⬍.001). Multivariate logistic regression analysis confirmed the independent preventive effect of clarithromycin for the develop-ment of BPD (odds ratio: 27.2 [95% confidence interval: 2.5–296.1];P⫽ .007).

CONCLUSIONS:Clarithromycin treatment prevents development of BPD in preterm infants who are born at 750 to 1250 g and colonized withU urealyticum.Pediatrics2011;128:e1496–e1501

AUTHORS:Ramazan Ozdemir, MD,a_{Omer Erdeve, MD,}a

Evrim Alyamac Dizdar, MD,a_{Serife Suna Oguz, MD,}a

Nurdan Uras, MD,a_{Sibel Saygan, MD,}b_{Erdem Karabulut,}

PhD,c_{and Ugur Dilmen, MD}a

a_{Neonatal Intensive Care Unit and}b_{Department of Microbiology,}

Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey; andc_{Department of Biostatistics, Hacettepe University, Ankara,}

Turkey

KEY WORDS

bronchopulmonary dysplasia, clarithromycin, premature infants,Ureaplasma urealyticum

ABBREVIATIONS

BPD—bronchopulmonary dysplasia OR—odds ratio

CI—confidence interval

RDS—respiratory distress syndrome PDA—patent ductus arteriosus

This trial has been registered at www.clinicaltrials.gov (identi-fier NCT01326611).

www.pediatrics.org/cgi/doi/10.1542/peds.2011-1350

doi:10.1542/peds.2011-1350

Accepted for publication Aug 15, 2011

Address correspondence to Ramazan Ozdemir, MD, Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity Teaching Hospital, 06110 Hamamonu, Ankara, Turkey. E-mail: ramazanoz@ yahoo.com.tr

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

Bronchopulmonary dysplasia (BPD) is a significant cause of morbidity and mortality in premature infants and oc-curs in 30% of infants born at ⱕ28 weeks’ gestation. The etiology of the BPD is likely to be multifactorial. Be-cause of the serious long-term health consequences of BPD, prevention of the disease is the focus of major research.1

Ureaplasma urealyticum has long been implicated in the pathogenesis of chronic lung disease of prematurity, but despite numerous studies, reviews and meta-analyses, controversy still exists about whether U urealyticum colonization or infection of the respira-tory tract contributes to the develop-ment of BPD. Inconsistence between the studies may be because of small sample sizes, vastly different inclusion criteria, methods of sampling and test-ing, and different diagnostic criteria for various outcomes including BPD. A meta-analysis by Schelonka et al,2

which included 23 studies and 2216 in-fants, revealed an odds ratio (OR) of 2.83 (95% confidence interval [CI]: 2.29 –3.51) for the relationship be-tween the presence of Ureaplasma and BPD diagnosed at 28 days of life. However, a causative role ofU urealyti-cumcould not be proven.

Additional controversy exists on the use of macrolides, particularly erythromy-cin, for the treatment ofU urealyticum colonization. A recent Cochrane analy-sis3 _{identified 2 randomized studies. In}

neither trial was a significant effect of erythromycin shown on development of BPD or death. But both studies had a small sample size and underpowered to detect a true benefit. The lack of efficacy of erythromycin on the incidence of BPD may also be secondary to low rate of eradication of U urealyticumfrom the airway.4

In this study, we aimed to determine the relation ofU urealyticum coloniza-tion to BPD in preterm infants with a

birth weight ofⱕ1250 g and to evalu-ate, for the first time, the efficacy and safety of clarithromycin treatment in eradicatingU urealyticumin the respi-ratory tract and preventing BPD in culture-positive preterm infants.

PATIENTS AND METHODS

This placebo-controlled, prospective, randomized study was conducted in Zekai Tahir Burak Maternity Teaching Hospital, which is one of the largest maternity hospitals in Turkey and per-forms 20 000 deliveries annually. The NICU includes 150 incubators and ad-mits ⬃4000 infants annually. Infants who were eligible for the study were determined as preterms with a birth weight between 750 and 1250 g. Exclu-sion criteria consisted of the presence of major congenital abnormalities, lack of parental informed consent, and intrauterine growth retardation with a birth weight at the⬍10th percentile for gestational age.

The primary outcomes for this study were eradication of U urealyticumin the airways and the composite chronic lung disease and/or death. BPD was defined as a persistent oxygen require-ment at 36 weeks’ postmenstrual age. A physiologic test was used to confirm the need for oxygen at the time when BPD was being diagnosed. Infants with moderate dependency on oxygen at 36 weeks’ postmenstrual age (⬍30% oxy-gen) were challenged with room air breathing to determine if the supple-mental oxygen was in fact needed.

Perinatal characteristics of the pa-tients including birth weight, gesta-tional age, route of delivery, prenatal steroid use, the presence of prema-ture rupprema-ture of membrane, chorioam-nionitis, sepsis, respiratory distress syndrome (RDS), surfactant use, pneu-monia, patent ductus arteriosus (PDA), as well as postnatal clinical parame-ters including duration of mechanical ventilation, nasal continuous positive

airway pressure, O₂therapy, caffeine, and diuretic treatment were recorded.

Infants were diagnosed with RDS if they had tachypnea, grunting, and cya-nosis within several hours of birth, required mechanical ventilation in-cluding continuous positive airway pressure and oxygen in the first hours of life, and typical radiographic find-ings on the chest radiograph.5_{BPD was}

diagnosed by using the US National In-stitutes of Health diagnostic criteria for BPD.1 _{PDA diagnosis required an}

echocardiogram with Doppler verifica-tion and cardiology recommendaverifica-tion of ibuprofen therapy on the basis of significance of flow.6

Nasopharyngeal swabs forU urealyti-cum were taken in first 3 postnatal days and on the 12th day after the com-mencing of the treatment only in culture-positive infants, transported to the laboratory, and cultured forU urea-lyticumimmediately in special medium. U urealyticumis detected according to method defined by Biernat-Sudolska et al7_{and culture results were obtained in}

a maximum of 48 hours.

Infants with a positive culture for U urealyticum in the first 3 days were randomly assigned to 1 of 2 groups to receive either intravenous clarithro-mycin (10 mg/kg twice per day for 10 days) or placebo. Randomization was performed by the use of sealed enve-lopes with the allocation of the pa-tients to either clarithromycin treat-ment or placebo. Colonization by other potential pathogens was treated as warranted, according to the attending physician. Repeat cultures were ob-tained in the clarithromycin group to determineU urealyticum eradication. All the patients were followed up to at least the 36th postmenstrual week of gestation, when the presence of BPD was assessed, or death.

in BPD incidence resulting from clari-thromycin treatment.8 _Independent

samplesttest or Mann-WhitneyUtest was used to compare continuous vari-ables and␹2_{test or Fisher’s exact test}

for categorical variables. Multivariate (backward) logistic regression analy-sis was performed to simultaneously measure the influence of the indent variables with BPD as the depen-dent variable. Variables that had a P value of⬍.25 in the univariate analysis were used in multivariate analysis as possible risk factors. APvalue of⬍.05 was considered statistically significant.

The study was approved by the institu-tional local ethics committee, and in-formed parental consent was obtained from all participants.

RESULTS

During the study period, 272 infants with a birth weight between 750 and 1250 g were enrolled in the study. Forty-eight infants were excluded be-cause of major congenital abnormali-ties, lack of parental informed con-sent, intrauterine growth retardation, or death. There were a total of 224 in-fants who met the eligibility criteria, and 150 infants were culture-negative forU urealyticumin the first 3 days, whereas 12 infants in the culture-negative group died by follow-up. Seventy-four (33%) infants had a posi-tive culture for U urealyticum in the first 3 day cultures (Fig 1).

To search for an association between U urealyticumpositivity and the devel-opment of BPD, we have assessed the characteristics and outcomes of theU urealyticum–negative patients and U urealyticum–positive patients who did not receive clarithromycin (Table 1). BPD development was significantly higher in patients withU urealyticum positivity (15.9% vs 36.4%; P ⬍ .01). However, multivariate logistic

regres-sion analysis including birth weight, gestational age, gender, presence of RDS, pneumonia and PDA, culture positivity for U urealyticum, caffeine treatment, and mechanical ventilation in model failed to demonstrate a signif-icant association between the

pres-ence of U urealyticum and BPD de-velopment, althoughPbordered signif-icance (OR: 2.4 [95% CI: 0.9 – 6.3];P⫽ .06). The only significant variable asso-ciated with BPD development was du-ration of mechanical ventilation (OR: 1.1 [95% CI: 1–1.2];P⫽.01).

Culture-negative (n = 150) -Death (n = 12) Randomly assigned

Culture-positive (n = 74)

Analyzed: 35 Clarithromycin treatment

(n = 37)

Discontinued intervention Death; sepsis (3), necrotizing

enterocolitis (1) Discontinued intervention

Death; sepsis (1), necrotizing enterocolitis (1)

(N = 272)

No treatment (n = 37)

Analyzed: 33

Randomization

Allocation

Fo

ll

o

w

-u

p

Analysis

Enrollment —

— — —

Major congenital abnormality (n = 7) Refused to participate (n = 21) Death (n = 12)

Intrauterine growth retardation (n = 8)

FIGURE 1

Flowchart.

TABLE 1 Characteristics and Outcomes ofU urealyticum–Negative and UntreatedU urealyticum– Positive Patients

U urealyticum–Negative (N⫽138)

U urealyticum–Positive, Clarithromycin-Negative

(N⫽33)

P

Birth weight, mean⫾SD, g 1028⫾160 978⫾195 .13 Gestational age, mean⫾SD, wk 28.2⫾1.6 27.3⫾1.8 ⬍.01

Male,n/N(%) 57/138 (41.3) 17/33 (51.5) .28

Cesarean delivery,n/N(%) 116/138 (84) 19/33 (57.6) ⬍.01 Prenatal steroids,n/N(%) 101/138 (73) 20/33 (60.6) .15 PROM⬎18 h,n/N(%) 22/138 (15.9) 3/33 (9.1) .41 Histologic chorioamnionitis,n/N(%) 5/138 (3.6) 0/33 (0) .33

Sepsis,n/N(%) 55/138 (38.4) 14/33 (42.4) .67

Pneumonia,n/N(%) 13/138 (9.4) 3/33 (9.1) .95

PDA,n/N(%) 46/138 (33.3) 15/33 (45.5) .19

RDS,n/N(%) 87/138 (63) 21/33 (63.6) .94

Poractant alfa treatment,n/N(%) 59/87 (67.8) 13/21 (61.9) .60 Caffeine treatment,n/N(%) 114/138 (82.6) 28/33 (84.8) .75 Diuretic treatment,n/N(%) 13/138 (9.4) 1/33 (3) .31 Duration of mechanical ventilation,

mean⫾SD, d

1.9⫾4.3 3.1⫾4.6 .16

U urealyticum–positive patients were prospectively randomly assigned to re-ceive either clarithromycin (n⫽37) or placebo (n⫽ 37). Characteristics of the U urealyticum–positive patients who received clarithromycin or pla-cebo are shown in Table 2. According to the repeat cultures 2 days after the discontinuation of the treatment, clari-thromycin treatment resulted in erad-ication ofU urealyticumin 68.5% of the patients. Groups did not have signifi-cant difference in incidences of PDA, sepsis, and pneumonia, whereas the incidence of BPD was significantly lower in the clarithromycin group (2.9% vs 36.4%;P⬍.001). Deaths in the groups had occurred before the evalu-ation of BPD at the 36th postmenstrual week, and they were not related to pul-monary problems; therefore, we did not choose to use the composite out-come of death or BPD. However, when statistical analysis was performed for the composite outcome defined as death or BPD, there was still a highly significant difference between the treatment and control groups (P⫽.001).

Variables that had aPvalue of⬍.25 in the univariate analysis were used in

multivariate analysis as possible risk factors in subgroup analysis. Multivar-iate logistic regression analysis in-cluding birth weight, presence of pneumonia and PDA, caffeine and cla-rithromycin treatment, mechanical ventilation, and nasal continuous pos-itive airway pressure in model con-firmed the independent preventive ef-fect of the clarithromycin (OR: 27.2 [95% CI: 2.5–296.1];P⫽.007) for the development of BPD. No serious ad-verse event related to clarithromycin use was documented.

DISCUSSION

We demonstrated that 33% of the pre-term infants with birth weight between 750 and 1250 g hadU urealyticum pos-itivity in nasopharyngeal swabs. U urealyticumpositivity was associated with higher rate of BPD development, but we failed to demonstrate this asso-ciation in multivariate analysis, proba-bly because of low number of patients; thePvalue and 95% CI bordered signif-icance. Treatment of these infants with clarithromycin resulted in lower rates of BPD than those treated with placebo.

Ureaplasma comprises 2 species (U parvumandU urealyticum) and 14 se-rovars.Ureaplasmais a commensal in the adult female genital tract with low virulance. However, previous studies have shown association ofU urealyti-cum with infertility, adverse preg-nancy outcomes, and perinatal death.9–12_{Vertical transmission rate is}

inversely related to gestational age (18%–55% in term infants versus 29%– 60% in preterm infants)10–13_and

increases with duration of rupture of membranes.14–16_{Respiratory tract}

col-onization was detected in 20% of in-fants born at⬍1500 g by cultures and 25% to 48% by polymerase chain reac-tion. Culture positivity was 30% in our study, consistent with the literature. Differences in colonization rates may be a result of differences in communi-ties or in specimen collection and processing.

Since the 1980s, many studies have searched for the link betweenU urea-lyticumcolonization and BPD develop-ment.17–19_{Although not all the studies}

have confirmed the association, the meta-analysis by Wang et al20_{in 1995}

showed that the relative risk for the development of BPD inU urealyticum colonized infants was 1.72 (95% CI: 1.5–1.96). These findings were con-firmed by Schelonka et al2 _{in their}

meta-analysis in 2005, which revealed a significant association between Ureaplasma infection and develop-ment of BPD, at both 28 days (P⬍.001) and 36 weeks (P⬍.001) by definition.

In a number of subsequent trials, the therapeutic efficacy of erythromycin therapy was searched for in the first few weeks of life, given the in vitro sen-sitivity ofU urealyticumto erythromy-cin. In 1 study, Lyon et al21 _randomly

assigned 75 infants born at ⬍30 weeks’ gestation and ventilated from birth for lung disease to receive eryth-romycin (n⫽34) intravenously for 7 days or to no treatment (n⫽41). Nine TABLE 2 Characteristics and Outcomes ofU urealyticum–Positive Patients Treated With

Clarithromycin or Placebo

U urealyticum–Positive Clarithromycin-Treated

(N⫽35)

U urealyticum–Positive, Clarithromycin-Negative

(N⫽33)

P

Birth weight, mean⫾SD, g 988⫾104 978⫾195 .79 Gestational age, mean⫾SD, wk 27.4⫾1.3 27.3⫾1.8 .65

Male,n/N(%) 13/35 (37.1) 17/33 (51.5) .23

Cesarean delivery,n/N(%) 22/35 (62.9) 19/33 (57.6) .65 Prenatal steroids,n/N(%) 24/35 (68.6) 20/33 (60.6) .49

PROM⬎18 h,n/N(%) 7/35 (20) 3/33 (9.1) .20

Histologic chorioamnionitis,n/N(%) 1/35 (2.9) 0/33 (0) .33

Sepsis,n/N(%) 16/35 (45.7) 14/33 (42.4) .78

Pneumonia,n/N(%) 3/35 (8.6) 3/33 (9.1) .94

PDA,n/N(%) 10/35 (28.6) 15/33 (45.5) .14

RDS,n/N(%) 20/35 (57.1) 21/33 (63.6) .58

Poractant alfa treatment,n/N(%) 11/20 (55) 13/21 (61.9) .65 Caffeine treatment,n/N(%) 26/35 (74.3) 28/33 (84.8) .28 Diuretic treatment,n/N(%) 3/35 (8.6) 1/33 (3) .33 Duration of mechanical ventilation,

mean⫾SD, d

1.8⫾4.7 3.1⫾4.6 .25

Duration n-CPAP, mean⫾SD, d 3.7⫾3.6 5.8⫾6.2 .10 BPD at 36 wk,n/N(%) 1/35 (2.9) 12/33 (36.4) ⬍.001 PROM indicates premature rupture of membrane; n-CPAP, nasal continuous positive airway pressure.

reaction. Those treated with erythro-mycin had a similar incidence of BPD as untreated infants. A small number of infected patients made it impossible to analyze infected infants alone. In the second study, Jonsson et al22

investi-gated colonization withU urealyticum in 155 infants born at⬍30 weeks’ ges-tation and assessed the effect of treat-ment with erythromycin. The rate of colonization was 29 of 155 (19%). More colonized infants needed supplemen-tal oxygen at 36 weeks’ postconcep-tional age compared with noncolo-nized infants. Colononcolo-nized infants were randomly assigned to treatment with erythromycin 40 mg/kg per day, intra-venously or orally (n⫽14), or no treat-ment (n ⫽ 14). Erythromycin treat-ment eradicated colonization in 12 of 14 (86%) treated infants. However, there was no significant difference be-tween treated and untreated infants in the rate of BPD at 36 weeks’ postcon-ceptional age (64% in treated infants versus 71% in untreated group). These 2 randomized trials of erythromycin had low number of infected infants and no specific analysis in this sub-group could be made in the first trial, whereas only 14 patients could be eval-uated in both arms in the second trial, which increases the possibility to miss a true benefit of erythromycin because of type II error. Another reason why erythromycin was ineffective in pre-venting BPD development might be relatively lower anti-inflammatory ac-tivity of erythromycin in preterm infants.4,21,23

We preferred to use clarithromycin in our study instead of erythromycin. In vitro activity of clarithromycin against U urealyticum is much higher than erythromycin.24,25_{Second, penetration}

of clarithromycin into bronchial mu-cosa, bronchial secretions, and epithe-lial lining as reflected by the tissue/

a better toxicity profile are other advantages of clarithromycin over erythromycin.26

In a recent study by Ballard et al,27₂₂₀

infants who had a birth weight of

⬍1250 g were randomly assigned to azithromycin 10 mg/kg per day for 7 days followed by 5 mg/kg per day for a maximum of 6 weeks (n⫽111) or pla-cebo (n⫽109) within 12 h of beginning mechanical ventilation and within 72 h of birth. The incidence of BPD in theU urealyticum–positive subgroup was 73% in those treated with azithromycin versus 94% in the placebo group (P⫽ .03). The authors concluded that early treatment ofU urealyticumcolonized/ infected patients might be beneficial.27

Our study also yielded benefit from treatment in culture-positive infants, similar to this study. BPD incidence was overall lower in our study than in the study of Ballard et al.27_{This might}

be secondary to the differences in pa-tient characteristics of studies. Mean birth weight was 803 g in their study versus 1013 g in our study, and mean gestational age was 25.7 vs 27.9 weeks, respectively.

Several studies in the literature show that macrolides affect many inflamma-tory processes including migration of neutrophils, the oxidative burst in phagocytes, and production of pro-inflammatory cytokines.28

Clarithromy-cin inhibits superoxide production by activated neutrophils and also has a membrane-stabilizing activity.29

Clari-thromycin was also found to suppress interleukin 1␤gene expression in hu-man nasal epithelial cells.30_{We believe}

that anti-inflammatory effects of clari-thromycin also contribute to overall lower incidence of BPD in the treat-ment group, but we could not evaluate pure anti-inflammatory effect of clari-thromycin in our study because no culture-negative infants received

clari-culture-positive infants but not in the whole group in the study of Ballard et al.27_{Thus, anti-microbial activity seems}

to be more considerable compared with anti-inflammatory activity in pre-vention of BPD. Prospective trials are needed to confirm these hypotheses. Because of an overall low rate of BPD in patients treated with clarithromy-cin, we could not assess whether fail-ure to eradicateU urealyticumwas as-sociated with higher incidence of BPD.

There are a number of limitations to our study. First, ours was a single-center study, and our findings should be con-firmed by additional well-designed clini-cal trials in different settings. Second, although there were not significant dif-ferences in incidences of PDA, sepsis and pneumonia between groups, there was a tendency to lower rates of these param-eters in treatment group, which might affect BPD development. Third, this study was a pioneering one, and it seems that there is a requirement for additional studies with larger sample size esti-mates for the cohort of infants randomly assigned to the treatment and placebo groups.

CONCLUSIONS

REFERENCES

1. Jobe AH, Bancalari E. Bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2001; 163(7):1723–1729

2. Schelonka RL, Katz B, Waites KB, Benjamin DK. Critical appraisal of the role of Urea-plasmain the development of bronchopul-monary dysplasia with metaanalytic tech-niques.Pediatr Infect Dis J. 2005;24(12): 1033–1039

3. Mabanta CG, Pryhuber GS, Weinberg GA, Phelps DL. Erythromycin for the prevention of chronic lung disease in intubated pre-term infants at risk for, or colonized or in-fected withUreaplasma urealyticum. Co-chrane Database Syst Rev. 2003;4(4): CD003744

4. Baier RJ, Loggins J, Kruger TE. Failure of erythromycin to eliminate airway coloniza-tion withUreaplasma urealyticumin very low birth weight infants.BMC Pediatr. 2003; 3:10

5. Sinha SK, Gupta S, Donn SM. Immediate re-spiratory management of the preterm in-fant.Semin Fetal Neonatal Med. 2008;13(1): 24 –29

6. Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen D. Efficacy and safety of oral ver-sus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus.J Pediatr. 2011;158(4):549 –554 7. Biernat-Sudolska M, Rojek-Zakrzewska D, Drzewiecki A, Lauterbach R. Antimicrobial susceptibility ofUreaplasma urealyticum

andUreaplasma parvumisolated from pre-mature infants with respiratory disorders.

Przegl Epidemiol. 2007;61(2):371–376 8. Statistical power calculators. DSS

Re-search. Available at: www.dssreRe-search. com/toolkit/spcalc/power_a2.asp. Ac-cessed May 4, 2009

9. Schelonka RL, Waites KB.Ureaplasma infec-tion and neonatal lung disease.Semin Peri-natol. 2007;31(1):2–9

10. Waites KB, Katz B, Schelonka RL. Mycoplas-mas and ureaplasMycoplas-mas as neonatal patho-gens. Clin Microbiol Rev. 2005;18(4): 757–789

11. Volgmann T, Ohlinger R, Panzig B. Urea-plasma urealyticum: harmless commensal or underestimated enemy of human

repro-duction? A review.Arch Gynecol Obstet. 2005;273(3):133–139

12. Kirchner L, Helmer H, Heinze G, et al. Amnio-nitis withUreaplasma urealyticumor other microbes leads to increased morbidity and prolonged hospitalization in very low birth weight infants.Eur J Obstet Gynecol Reprod Biol. 2007;134(1):44 –50

13. Viscardi RM, Hasday JD. Role ofUreaplasma

species in neonatal chronic lung disease: epidemiologic and experimental evidence.

Pediatr Res. 2009;65(5 pt 2):84 –90 14. Grattard F, Soleihac B, De Barbeyrac B,

Be-bear C, Seffert P, Pozzetto B. Epidemiologic and molecular investigations of genital my-coplasmas from women and neonates at delivery.Pediatr Infect Dis J. 1995;14(10): 853– 858

15. Abele-Horn M, Peters J, Genzel-Boroviczeny O, Wolff C, Zimmermann A, Gottschling W. V a g i n a l U r e a p l a s m a u r e a l y t i c u m

colonization: influence on pregnancy out-come and neonatal morbidity. Infection. 1997;25(5):286 –291

16. Kafetzis DA, Skevaki CL, Skouteri V, et al. Ma-ternal genital colonization withUreaplasma urealyticumpromotes preterm delivery: as-sociation of the respiratory colonization of premature infants with chronic lung dis-ease and incrdis-eased mortality.Clin Infect Dis. 2004;39(8):1113–1122

17. Cassell GH, Waites KB, Crouse DT, et al. As-sociation ofUreaplasma urealyticum infec-tion of the lower respiratory tract with chronic lung disease and death in very low birth weight infants.Lancet. 1988;2(8605): 240 –245

18. Wang EE, Frayha H, Watts J, et al. Role of

Ureaplasma urealyticumand other patho-gens in the development of chronic lung dis-ease of prematurity.Pediatr Infect Dis J. 1988;7(8):547–551

19. Sánchez PJ, Regan JA.Ureaplasma urealyti-cumcolonization and chronic lung disease in low birth weight infants.Pediatr Infect Dis J. 1988;7(8):542–546

20. Wang EE, Ohlsson A, Kellner JD. Association ofUreaplasma urealyticumcolonization with chronic lung disease of prematurity: results of a metaanalysis.J Pediatr. 1995; 127(4):640 – 644

21. Lyon AJ, McColm J, Middlemist L, Fergusson S, McIntosh N, Ross PW. Randomised trial of erythromycin on the development of chronic lung disease in preterm infants.

Arch Dis Child Fetal Neonatal Ed. 1998;78(1): 10 –14

22. Jónsson B, Rylander M, Faxelius G. Urea-plasma urealyticum, erythromycin and re-spiratory morbidity in high-risk preterm ne-o n a t e s . A c t a P a e d i a t r. 1 9 9 8 ; 8 7 ( 1 0 ) : 1079 –1084

23. Waites KB, Sims PJ, Crouse DT, et al. Serum concentrations of erythromycin after intra-venous infusion in preterm neonates treated forUreaplasma urealyticum infec-tion. Pediatr Infect Dis J. 1994;13(4): 287–293

24. Renaudin H, Bebear C. Comparative in vitro activity of azithromycin, clarithromycin, erythromycin, and lomefloxacin against My-coplasma pneumoniae,Mycoplasma homi-nisandUreaplasma urealyticum.Eur J Clin Microbiol Infect Dis. 1990;9(11):838 – 841 25. Krausse R, Schubert S. In-vitro activities of

tetracyclines, macrolides, fluoroquinolones and clindamycin againstMycoplasma homi-nisandUreaplasmassp. isolated in Ger-many over 20 years.Clin Microbiol Infect. 2010;16(11):1649 –1655

26. Zhanel GG, Dueck M, Hoban DJ, et al. Review of macrolides and ketolides: focus on respi-ratory tract infections. Drugs. 2001;61(4): 443– 498

27. Ballard HO, Shook LA, Bernard P, et al. Use of azithromycin for the prevention of broncho-pulmonary dysplasia in preterm infants: a randomized, double-blind, placebo con-trolled trial.Pediatr Pulmonol. 2011;46(2): 111–118

28. Zalewska-Kaszubska J, Gorska D. Anti-inflammatory capabilities of macrolides.

Pharmacol Res. 2001;44(6):451– 454 29. Theron AJ, Feldman C, Anderson R.

Investi-gation of the anti-inflammatory and membrane-stabilizing potential of spiramy-cin in vitro.J Antimicrob Chemother. 2000; 46(2):269 –271

30. Miyanohara T, Ushikai M, Matsune S, Ueno K, Katahira S, Kurono Y. Effects of clarithromy-cin on cultured human nasal epithelial cells and fibroblasts.Laryngoscope. 2000;110(1): 126 –131

DOI: 10.1542/peds.2011-1350 originally published online November 28, 2011;

2011;128;e1496

Pediatrics

Uras, Sibel Saygan, Erdem Karabulut and Ugur Dilmen

Ramazan Ozdemir, Omer Erdeve, Evrim Alyamac Dizdar, Serife Suna Oguz, Nurdan

Services

Updated Information &

http://pediatrics.aappublications.org/content/128/6/e1496

including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/128/6/e1496#BIBL

This article cites 29 articles, 1 of which you can access for free at:

Subspecialty Collections

http://www.aappublications.org/cgi/collection/bronchiolitis_sub

Bronchiolitis

http://www.aappublications.org/cgi/collection/pulmonology_sub

Pulmonology

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

DOI: 10.1542/peds.2011-1350 originally published online November 28, 2011;

2011;128;e1496

Pediatrics

Uras, Sibel Saygan, Erdem Karabulut and Ugur Dilmen

Ramazan Ozdemir, Omer Erdeve, Evrim Alyamac Dizdar, Serife Suna Oguz, Nurdan

Positive Preterm Infants

−

urealyticum

Ureaplasma

Clarithromycin in Preventing Bronchopulmonary Dysplasia in

http://pediatrics.aappublications.org/content/128/6/e1496

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.