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中华妇幼临床医学杂志(电子版)

中华妇幼临床医学杂志(电子版) ›› 2014, Vol. 10 ›› Issue (01) : 29 -40. doi: 10.3877/cma.j.issn.1673-5250.2014.01.008

所属专题： 文献；

论著

儿童肺炎支原体的耐药性与临床用药相关性研究
张涛1, 王波1, 王穗琼1, 唐远平1, 刘妙玲1, 彭淑梅1, 林英1, 李容汉1, 邓文喻1, 何天文1, 杨琳琳1,*,*()   
  1. 1. 510010，广州医科大学附属广东省妇女儿童医院儿科
  • 收稿日期:2013-11-30 修回日期:2014-01-15 出版日期:2014-02-01
  • 通信作者: 杨琳琳

Correlation Between Drug-Resistance and Clinical Treatment of Mycoplasma Pneumoniae

Tao Zhang1, Bo Wang1, Suiqiong Wang1, Yuanping Tang1, Miaoling Liu1, Shumei Peng1, Ying Lin1, Ronghan Li1, Wenyu Deng1, Tianwen He1, Linlin Yang1()   

  1. 1. Guangdong Women and Children Hospital Affiliated Guangzhou Medical University, Guangzhou 510010, Guangdong Province, China
  • Received:2013-11-30 Revised:2014-01-15 Published:2014-02-01
  • Corresponding author: Linlin Yang
  • About author:
    (Corresponding author: Yang Linlin, Email: )
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引用本文：

张涛, 王波, 王穗琼, 唐远平, 刘妙玲, 彭淑梅, 林英, 李容汉, 邓文喻, 何天文, 杨琳琳. 儿童肺炎支原体的耐药性与临床用药相关性研究[J]. 中华妇幼临床医学杂志(电子版), 2014, 10(01): 29-40.

Tao Zhang, Bo Wang, Suiqiong Wang, Yuanping Tang, Miaoling Liu, Shumei Peng, Ying Lin, Ronghan Li, Wenyu Deng, Tianwen He, Linlin Yang. Correlation Between Drug-Resistance and Clinical Treatment of Mycoplasma Pneumoniae[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2014, 10(01): 29-40.

目的

探讨阿奇霉素序贯疗法治疗儿童肺炎支原体（MP）感染的有效性和安全性，并检验不规律使用阿奇霉素与MP耐药性是否相关。

方法

以MP抗体滴度1∶320为诊断MP感染标准，收集2011年3月至2013年2月于广州医科大学附属广东省妇女儿童医院住院治疗的792例5~ 13岁合并发热或（和）咳嗽的MP感染患儿中，MP-IgM呈阳性的431例患儿为研究对象。按照其1年内大环内酯类抗菌药物应用和MP感染次数分别纳入实验组（n＝217，半年内无MP感染和大环内酯类抗菌药物应用史）；对照组（n＝214, 1年内反复MP感染且不规律应用大环内酯类抗菌药物≥2次）。患儿入院当天于不同时间进行2次MP培养，对培养结果MP呈阳性者提取DNA进行23S rRNA V PCR产物合成与23S rRNA V区基因突变位点检测，并进行MP呈阳性者的9种抗菌药物的药敏性试验。对两组MP株的耐药性等进行比较。对大环内酯类抗菌药物敏感和23S rRNA V区无突变患儿进行阿奇霉素序贯疗法。于治疗2周及4周末再行MP培养，对阳性者分析23S rRNA V区基因位点突变情况。对实验组阿奇霉素敏感且23S rRNA V区测序无基因位点无突变的患儿进行阿奇霉序贯治疗，分别于治疗2周及4周时判断阿奇霉素序贯疗法治疗疗效。对于对照组214例反复MP感染患儿不规律应用大环内酯类抗菌药物频次与耐药性关系进行统计学比较。对两组患儿的肺外并发病及住院时间分别进行统计学比较（本研究遵循的程序符合广州医科大学附属广东省妇女儿童医院人体试验委员会制定的伦理学标准，得到该委员会批准，分组征得受试对象监护人的知情同意，并与其签署临床研究知情同意书）。两组患儿年龄及性别等一般临床资料比较，差异无统计学意义（P>0.05）。

结果

本组患儿的MP感染率为54.4%（431/ 792）。对本组药敏实验结果MP-IgM呈阳性患儿咽拭子进行快速MP培养的阳性率为26.6%（115/ 431）．实验组与对照组MP株耐药率比较，差异有统计学意义（χ2＝4.651，P＝0.041）。对照组214例患儿1年内不规律大环内酯类药物应用频次与耐药率比较，不规律用药次数越多，耐药率越高，差异有统计学意义（χ2／χ2趋势值＝22.056，21.932；P<0.05）。实验组14例患儿的药敏实验结果显示阿奇霉素敏感且23S rRNA V区测序无基因位点无突变，对其进行阿奇霉序贯治疗2周后，咽拭子培养结果显示MP呈阳性为4例，根治率为71.42% （10/ 14）。对此4例进行药敏试验结果提示对阿奇霉素仍敏感，并对其进行23S rRNA V区测序发现无基因位点突变，继续阿奇霉素序贯治疗，至4周末时，实验组14例患儿的根治率为92.85%（13/ 14）。实验组14例MP药物敏感株与对照组37例MP耐药株患儿的肺外并发症发生率比较，实验组显著低于对照组，且差异有统计学意义（χ2 ＝4.443，P<0.05）．实验组患儿的住院时间显著短于对照组，且差异有统计学意义（χ2 ＝7.305，P<0.05）。

结论

阿奇霉素序贯疗法治疗儿童MP感染安全有效，并不会诱导出耐药株，而不规律应用阿奇霉素可诱导耐药株，且耐药率与不规律应用的次数呈正相关。

关键词: 肺炎支原体, 耐药性, 阿奇霉素, 序贯疗法, 儿童
Objective

To explore the effectiveness and safety of azithromycin sequential therapy for children with Mycoplasma pneumoniae (MP) infection, and analysis correlation of drug-resistance with indisciplined used of macrolide antibiotics application.

Methods

According to MP antibody titers 1: 320 for MP infection as standard to clinical diagnosis MP-IgM positive. From March 2011 to February 2013, a total of 792 children(screened 5-13 years old) with upper respiratory infection complicating cough or(and) fever who suspected MP infected were recruited. Among them 431 cases MP-IgM positive were as subjects. According to differences frequency of macrolide antibiotics application and frequency of MP infection in one year, 431 children with MP positive were divided into experimental group (n=217) and control group (n=214) . Patients in experimental group were preliminary screening subjects who without MP infection and macrolide antibiotics applied history in half of a year. Patients in control group were repeated MP infected and indisciplined used of macrolide antibiotics≥2 times in one year. MP cultures of children in both groups were detected twice times when they admitted. If their culture MP positive, 23S rRNA V PCR product were synthesis, and drug sensitivity test to 9 kinds of antibiotics were detected. Children in experimental group whose positive culture MP antibiotics sensitivity and 23S rRNA V had no mutation were gave macrolides sequential therapy. In the end of 2 weeks after macrolides sequential therapy, detection MP cuture again. If their culture MP positive, analysed drug sensitivity and screened the 23S rRNA V mutation or not. At those two time points, the curative effects of azithromycin sequential therapy were judged . Analysed whether it had correlation between frequency of macrolide antibiotics irregular application and drug resistant in control group. Drug resistance, extrapulmonary complications and hospitalization time between two groups were analysis by statistics methods. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Guangdong Women and Children Hospital Affiliated Guangzhou Medical University. Informed consent was obtained from the parents of each participating participant.

Results

In this study the MP infection rate was 54.4%(431/ 792) . MP culture positive rate was 26.6% (115/ 431) in MP-IgM positive children. There had significance difference between experimental group and control group in MP resistant strain rates, and MP-resistant strain rate in experimental group were much lower than that in control group (χ2 =4.651 , P=0.041) . There had significance difference of frequency of indisciplined used of macrolide antibiotics in control group among 214 cases, and the higher frequency of indisciplined used of macrolide antibiotics, the higher rate of MP-resistant strain (χ2/χ2 trend value=22.056, 21.932; P<0.05) . A total of 14 children in experimental group whose positive culture MP antibiotics sensitivity and 23S rRNA V had no mutation were gave macrolides sequential therapy. There were 4 cases after treatment of 2 and 4 weeks, their MP acute detection results also positive. In the end of 2 and 4 weeks after macrolides sequential therapy, the curative effect was 71.42 %(10/ 14) . among of 4 cases, only one case sequencing result and shew 23S rRNA V had no mutation. Those 4 cases were gaven macrolides sequential therapy again. There were only one case after treatment of another 2 weeks MP acute detection results also positive. In the end of 4 weeks after macrolides sequential therapy, the curative effects of azithromycin sequential therapy was 92.85%(13/ 14) . There had significance difference between 14 cases positive culture MP of antibiotics sensitivity in experimental group and 37 cases MP-resistant strain in control group in incidence of extrapulmonary complications, and those incidence in experimental group was much lower than those in contral group (χ2 =4.443, P<0.05) . There had significance difference between two groups in hospitalization time, and hospitalization time in experimental group was much shorter than that in control group (χ2 =7.305, P<0.05) .

Conclusions

Azithromycin sequential therapy for children infected with MP is safe, effective, and does not induce drug resistant strains. Resistant strains can be induced by irregular application of macrolide antibiotics application, and resistance rate is positively correlated with the frequency of irregular applications them.

Key words: Pneumoniae, Mycoplasma, Drug-resistance, Azithromycin, Sequential therapy, Child
表1 两组115例肺炎支原体培养结果呈阳性患儿的药敏试验结果比较[n（％）]
Table 1 Comparison of drug resistance rates among 115 cases children with mycoplasma cuture positive samples between two groups[n（%）]
组别 n 耐药率
实验组 56 31(55.4)
对照组 49 37(75.5)
χ2 　 4.651
P 　 0.041
表2 对照组214例患儿1年内不规律用药次数与耐药率关系比较[n（%）]
Table 2 Comparison of drug resistance rates among 214 cases with irregular treatment by azithromycin in one year in control group[n（%）]
1年内不规则用药次数(次) n 耐药率
4 68 22(32.3)
3 71 13(18.3)
2 75 2 (6.6)
χ2/χ2趋势值 　 22.056/21.932
P 　 <0.05
表3 115例肺炎支原体培养结果呈阳性患儿的药敏试验结果比较[n（％）]
Table 3 Comparison of drug sensitivity among 115 cases children with mycoplasma culture positive samples [n（%）]
药物名称 敏感率 中度敏感率 耐药率
红霉素 23(22.61) 19(17.39) 63(60.10)
阿奇霉素 62(54.10) 21(17.84) 32(28.06)
罗红霉素 23(20.00) 13(11.47) 79(68.53)
克拉霉素 45(38.90) 31(27.21) 39(33.89)
乙酰螺旋霉素 23(20.41) 30(25.78) 62(55.07)
克林霉素 27(23.54) 25(21.39) 63(55.07)
左氧氟沙星 112(97.39) 1 (0.87) 2 (1.74)
加替沙星 111(96.52) 3 (2.61) 1 (0.87)
司帕沙星 113(98.26) 2 (1.74) 0 (0.00)
图1 入院时实验组肺炎支原体培养呈阳性患儿23S rRNA V区PCR产物电泳结果（电泳样本编号。1: 2＃样本；2: 4＃样本；3: 11＃样本；4: 21＃样本；5: 35 ＃样本；6: 49＃样本；7: 55＃样本；8: 79＃样本；9: takara marker；10：140＃样本；11: 144＃样本；12: 180＃样本；13: 184＃样本；14: 199＃样本；15: 203＃样本）
Figure 1 Electrophoresis results of Mycoplasma pheumoniae culture positive patients in experimental group of 23S rRNA V PCR products （Number of sample．1：sample 2 ＃；2：sample 4 ＃; 3：sample 11＃；4 ：sample 21 ＃；5 ：sample 35＃；6：sample 49＃；7：sample 55 ＃；8：sample 79 ＃；9：takara marker; 10：sample 140 ＃；11：sample 144 ＃；12：sample 180 ＃；13：sample 184 ＃；14 ：sample 199 ＃；15：sample 203 ＃）
图2 入院时实验组患儿23S rRNA V区测序结果（图2A: 55＃样本；图2B: 184＃样本）
Figure 2 The 23S rRNA V sequencing results of experimental group （Figure 2A: sample 55 ＃；Figure 2B: sample 184 ＃）
图3 治疗2周后实验组肺炎支原体培养阳性的23S rRNA V PCR产物扩增后电泳结果（电泳样本编号。1: 2＃样本；2: takara marker; 3: 79＃样本；4: 140＃样本；5: 199＃样本）
Figure 3 The 23S rRNA V PCR electrophoresis results of Mycoplasma pneamoniae culture positive in experimental group after treatment 2 weeks （Number of sample．1 ：sample 2 ＃；2 ：takara marker；3：sample 79 ＃；4：sample 140 ＃；5 ：sample 199 ＃）
图4 治疗2周后实验组肺炎支原体培养阳性患儿的23S rRNA V区测序结果（图4A: 79＃样本；图4B: 199＃样本）
Figure 4 The 23S rRNA V sequencing results of experimental groups Mycoplasma pneumoniae culture postive after treatment 2 weeks （Figure 4A：samples 79 ＃；Figure 4B：samples 199 ＃）
图5 治疗4周后实验组肺炎支原体培养阳性患儿23S rRNA V PCR产物电泳结果（电泳样本编号。1：2＃样本；2: takara marker）
Figure 5 The23S rRNA V PCR electrophoresis results of Mycoplasma pneumoniae culture positive in experimental group after treatment 4 weeks （Number of sample．1：sample 2＃；2：takara marker）
图6 治疗4周后实验组肺炎支原体培养阳性患儿的23S rRNA V区测序结果（2＃样本）
Figure 6 The 23S rRNA V sequencing result of experimental groups Mycoplasma pneumoniae culture postive after treatment 4 weeks （sample 2＃）
图7 对照组肺炎支原体培养阳性患儿23S rRNA V区PCR产物电泳结果（13, 34：takara marmer; 1~ 12, 14～27：共计26个样本23S出现A2063G突变；28～30: 3个样本23S出现A2064G突变；31～32：2个样本23S出现A2063C突变；33, 35：2个样本23S出现A2063T突变；36~ 38：3个样本23S出现G2062A突变；39: 1个样本23S出现C2617G突变）
Figure 7 The 23S rRNA V PCR electrophoresis results of Mycoplasma pneumoniae culture positive in control group （13, 34：takara marmer；1-12，14-27：a total of 26 samples A2063G mutation in 23S rRNA V zone；28-30: 3 samples A2064G mutation in 23S rRNA V zone；31-32：2 samples A2063C mutation in 23S rRNA V zone；33，35：2 samples A2063Tmutation in 23S rRNA V zone；36-38: 3samples G2062A mutation in 23S rRNA V zone; 39: 1 sample C2617G mutation in 23S rRNA V zone）
图8 对照组37个样本23S rRNA V区突变测序结果（图8A:1#样本；图8B:33#样本；图8C:56#样本；箭头所指为突变位点）
Figure 8 The sequencing result of A2063G mutation in 23S rRNA V zone of 37 samples in control group(Figure 8A：samples 1 # ；Figure 8B：samples 33 # ；Figure 8C： samples 56 # ； mutations showed by arrows)
图9 对照组3个样本23S rRNA V区突变测序结果（图9A: 7＃样本；图9B：174＃样本；箭头所指为突变位点）
Figure 9 The sequencing result of A2064G mutiation in 23S rRNA V zone of 3 samples in control group(Figure 9A：sample 7＃；Figure 9B：sample 174 ＃；mutations showed by arrows）
图10 对照组2个样本23S rRNA V区突变测序结果（197＃样本；箭头所指为突变位点）
Figure 10 The sequencing result A2064C mutiation in 23S rRNA V zone of 2 samples in control group(sample 197 ＃；mutations showed by arrows）
图11 对照组2个样本23S rRNA V区突变测序结果（243 ＃样本；箭头所指为突变位点）
Figure 11 The sequencing result A2063T mutiation in 23S rRNA V zone of 2 samples in control group(sample 243＃；mutations showed by arrows）
图12 对照组3个样本23S rRNA V区突变测序结果（图12a: 10＃样本；图12b: 175＃样本；箭头所指为突变位点）
Figure 12 The sequencing result G2062A mutiation in 23S rRNA V zone of 37 samples in control group(Figure 12a：sample 10＃；Figure 12b: sample 175 ＃；mutations showed by arrows）
图13 实验组2个样本23S rRNA V区突变测序结果（256＃样本；箭头所指为突变位点）
Figure 13 The sequencing result C2617G mutiation in 23S rRNA V zone of 1 sample in experimental group(sample 256＃；mutations showed by arrows）
表4 实验组25例MP药物敏感株与对照组37例MP耐药株患儿的肺外并发症发生率比较[n（%）]
Table 4 Comparison of the complication between 14 cases drug sensitivity samples in experimental group and 37 cases drug resistant samples in control group[n（%）]
组别 n 肺外并发症发生率
实验组 25 1 (4.0)
对照组 37 16(43.2)
χ2 　 4.443
P 　 <0.05
表5 实验组与对照组患儿的住院时间比较（±s）
Table 5 Comparison of the hospitalization time between two groups （±s）
组别 n 住院平均时间(d)
实验组 217 7.71±1.35
对照组 214 11.91±1.97
χ2 　 7.305
P 　 <0.05
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