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Open Access

Peer-reviewed

Research Article

The timing of azithromycin treatment is not associated with the clinical prognosis of childhood Mycoplasma pneumoniae pneumonia in high macrolide-resistant prevalence settings

  • Dehua Yang,

    Roles Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Writing – original draft, Writing – review & editing

    Affiliation Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China

    ⨯
  • Linghong Chen,

    Roles Data curation, Funding acquisition, Investigation, Methodology, Software, Writing – original draft

    Affiliations Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China, The First People’s Hospital of Wenling, Wenling, Zhejiang, P.R. China

    ⨯
  • Zhimin Chen

    Roles Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing – review & editing

    drchenzm@163.com

    Affiliation Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China

    ⨯

Abstract

Background

Mycoplasma pneumoniae infection is a major cause of community-acquired pneumonia in children. We performed a retrospective study to evaluate the clinical impact of the timing of azithromycin treatment in children with Mycoplasma pneumoniae pneumonia in high macrolide-resistant prevalence settings.

Methods and findings

A total of 623 patients were enrolled in this study and were divided into 2 groups according to the timing of azithromycin therapy. Children who received azithromycin within 3 days (72 hours) after the onset of Mycoplasma pneumoniae pneumonia were classified into the early azithromycin treatment group (n = 174), whereas the late azithromycin treatment group (n = 449) comprised children treated with azithromycin more than 72 hours after symptom onset. We evaluated clinical prognosis according to demographic, clinical and laboratory characteristics. Although the early azithromycin treatment group exhibited a longer fever duration after azithromycin administration (7.17±4.12 versus 4.82±3.99 days, P<0.01), the total fever duration exhibited no significant difference (9.02±4.58 versus 9.57±4.91 days, P = 0.212). After azithromycin therapy, the two groups exhibited no significant differences with respect to improvements in the laboratory and radiological findings (all P>0.05).

Conclusion

The timing of azithromycin treatment is not associated with the clinical prognosis of Mycoplasma pneumoniae pneumonia in children in high macrolide-resistant Mycoplasma pneumoniae prevalence settings.

Citation: Yang D, Chen L, Chen Z (2018) The timing of azithromycin treatment is not associated with the clinical prognosis of childhood Mycoplasma pneumoniae pneumonia in high macrolide-resistant prevalence settings. PLoS ONE 13(1): e0191951. https://doi.org/10.1371/journal.pone.0191951

Editor: Senthilnathan Palaniyandi, University of Kentucky, UNITED STATES

Received: March 23, 2017; Accepted: January 15, 2018; Published: January 29, 2018

Copyright: © 2018 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: This work was supported by grant 2012WLCA0057 from the Wenling Science and Technology Project Fund (http://new.wl.gov.cn/col/col1402190/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Linghong Chen received the funding.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Mycoplasma pneumoniae (M. pneumoniae) pneumonia is a common disease in children, representing 10–30% of all pediatric cases of community-acquired pneumonia[1–2]. Macrolides are suitable for children with M. pneumoniae pneumonia, and azithromycin remains the first-choice treatment due to its well tolerance and compliance. Azithromycin has been believed to exhibit satisfactory effects in the treatment of M. pneumoniae pneumonia in the past[3–6]. However, there have been an increasing number of cases of M. pneumoniae pneumonia as well as increasing severity in recent years[7–10]. Emergence of macrolide-resistant Mycoplasma pneumoniae (MRMP), which is much more severe in eastern Asia[8–10], may be one of the most important reasons. However, there is no enough evidence proving that macrolides are invalid in treating MRMP in vivo. We can not design a research of treating children infected MRMP without macrolides as ethics violation. Therefore, we made a retrospective research and compared outcomes of different timing of azithromycin administration to reflect its effect in high macrolide-resistant prevalence settings.

Methods

Ethics statement

The Ethics Committee of the Children’s Hospital, Zhejiang University School of Medicine, approved the study. Data were accessed anonymously and used as statistical analysis only, exempting us from informed consent.

Subjects

The medical records of children admitted to the Children’s Hospital, Zhejiang University School of Medicine in China from January 2011 to December 2014 were collected. Children with the criteria below were enrolled:

  1. Pneumonia: fever (>37.5°C), cough, abnormal breath sounds on auscultation and abnormal chest X-rays[11].
  2. Positive M. pneumoniae polymerase-chain-reaction (PCR) testing of nasopharyngeal secretions or bronchoalveolar lavage fluid.
  3. Severe M. pneumoniae pneumonia: The disease severity was defined by scores from 0 to 5 based on the following clinical findings according to a previous studies with modification: rapid breathing or use of accessory muscles of respiration, fever (>38.5°C), more than two affected pulmonary lobes on chest X-rays, and hospital stay greater than seven days. Severity scores of 3 or greater were considered severe pneumonia[12–13].

Exclusion criteria

Patients were excluded if they had chronic cardiac or pulmonary diseases, immunodeficiency or infections with other pathogens detected during treatment.

Study design

This was a retrospective study. All of the enrolled subjects received sequential azithromycin therapy (10 mg/kg/day for 3–5 days, withdraw for 3–4 days, and then 10 mg/kg/day for 3 days). These patients were classified into two groups according to the timing of azithromycin therapy. Patients who received azithromycin within 3 days (72 hours) after the onset of M. pneumoniae pneumonia were classified into the early administration group, whereas the late administration group comprised children treated with azithromycin more than 3 days (72 hours) after symptom onset.

Data collection

The following data were recorded: age, sex, duration of fever, chest radiographic findings, severity scores, extrapulmonary complications, and blood tests, including white blood cell (WBC) count, neutrophil count, and C-reactive protein (CRP).

Statistical analysis

SPSS (Version 18; SPSS, Chicago, IL, USA) was used to analyze the data. Normally distributed data are expressed as the mean±SD. An independent sample t test was utilized to compare the data. Data with a skewed distribution were expressed as median values (25th-75th interquartile ranges). The comparisons were made by Mann-Whitney U test. Chi-square tests were used to compare the categorical data. The statistical significance was defined as P≤0.05.

Results

Basic clinical data

Six hundred twenty-three patients ranged from 0.30 to 15.92 years were enrolled. One hundred seventy-four patients were classified in the early group (98 males, 76 females), with a median age of 4.54 (2.65~7.19) years. In this group, the median WBC count before azithromycin therapy was 7.52 (6.20~10.09)×109/L with (59.28±16.07)% neutrophils, and the CRP was 10.15 (5.00~21.00) mg/L. Four hundred forty-nine patients were enrolled in the late group (243 males, 206 females), with a median age of 3.75 (2.08~6.67) years. In this group, the median WBC count before azithromycin therapy was 8.04 (6.50~10.10)×109/L with (57.83±16.48)% neutrophils, and the CRP was 10.00 (4.00~24.00) mg/L. The group characteristics, including sex, age, WBC, neutrophils, and CRP did not differ significantly (Table 1).

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Table 1. Clinical characteristic of the early and late administration groups.

https://doi.org/10.1371/journal.pone.0191951.t001

There was no significant difference in the total fever duration between these two groups (P = 0.212). Fever duration before azithromycin administration in the early group was significantly shorter than that of the late group (1.84±1.08 versus 4.75±2.47 days, t = 19.546, P<0.01). Fever duration after azithromycin administration was 7.17±4.12 days for the early administration group and 4.82±3.99 days for the late administration group, which represented a statistically significant difference (P<0.001; Table 1).

Severity of M. pneumoniae pneumonia

We also evaluated the severity of M. pneumoniae pneumonia, including the presence of severe pneumonia, pulmonary atelectasis, and pleural effusion, and detected no significant differences between these two groups (P = 0.442, 0.499, 0.301, respectively). However, extra-pulmonary complications were less common in the early administration group compared with the late administration group (χ2 = 5.127, P = 0.024), as shown in Table 2.

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Table 2. Pneumonia severity in the early and late administration groups.

https://doi.org/10.1371/journal.pone.0191951.t002

Therapeutic effects

The WBC and CRP of most patients recovered within 10 days after azithromycin therapy. Atelectasis and pleural effusion did not resolve until one month post-treatment. The improvements in the laboratory and radiological findings did not differ significantly between the early and late administration groups (all P>0.05; Table 3).

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Table 3. Clinical efficacy of azithromycin therapy.

https://doi.org/10.1371/journal.pone.0191951.t003

Discussion

In our study, there was no significant difference between the early group and the late group with respect to total fever duration, nor were there any differences with respect to severity or therapeutic effects. According to these results, the early use of azithromycin did not shorten the fever duration or contribute to recovery, which means azithromycin therapy may be ineffective. A third group without azithromycin treatment as a reference would be more convincing, but due to the ethical issues surrounding this protocol, there remains no further proof.

Biondi et al[14] reported there was insufficient evidence to support the efficacy of macrolides in community-acquired lower respiratory tract infection of M. pneumoniae in children. Macrolide-unresponsive M. pneumoniae pneumonia is believed to represent infection with macrolide-resistant strains[15–17] and/or to represent an overactivation of the immune response[18–19]. Transition mutations at A2063G in domain V of the 23S rRNA gene are present in MRMP strains, and these mutations induce high-level resistance to macrolides with minimum inhibitory concentration (MIC) of 8 to >256 μg/ml[15–17]. In our study, the total fever duration of 9.41±4.82 days was much longer than that of macrolide-sensitive M. pneumoniae (MSMP) infections[15–16] and early reports[6] but was similar to that of MRMP infections[15–16]. Cases of MRMP are increasing annually, especially in Asia. For example, in Japan, Morozumi et al. have reported that the prevalence of MRMP increased rapidly from 5.0% in 2003[20] to 39% in 2008[9], and Okada et al. reported rates of 87.1% in 2011[10]. In our country, MRMP represented 83%[21], 87.7%[22], and 92%[23] of M. pneumoniae pneumonia in Shanghai, Hangzhou, and Beijing, respectively, which is significantly higher than the rates in Europe and the United States[7, 24–26]. These findings suggest that the cases of M. pneumoniae in our study may be MRMP.

An over-reactive immune response is always presents in M. pneumoniae infection, especially in cases with extra-pulmonary complications. Azithromycin is reported to possess immune regulation effects, which are believed to be beneficial in cases of M. pneumoniae pneumonia[27–30]. In our study, 28.41% of cases exhibited extra-pulmonary complications, including myocardial damage, liver function abnormalities, and dermatologic damage. The early administration group exhibited significant fewer extra-pulmonary complications than did the late administration group, which suggests that the early use of azithromycin may help reduce extra-pulmonary complications.

We were unable to isolate MRMP strains from our patients as it was a retrospective study. It would be more convincing if we confirmed patients infected with MRMP though the incidence of MRMP was more than 80% in our city[22].

Our retrospective study provided evidence to support the conclusion that the timing of azithromycin treatment is not associated with the clinical prognosis of M. pneumoniae pneumonia in children in high macrolide-resistant prevalence settings, with the exception of extra-pulmonary complications. Azithromycin may be ineffective in treating MRMP pneumonia in vivo, but we are unable to withhold antibiotic treatment to confirm test this hypothesis due to ethical issues. However, the early use of azithromycin aids in reducing extra-pulmonary complications in M. pneumoniae pneumonia.

References

  1. 1. Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen[J]. ClinMicrobiol Rev 2004; 17(4):697–728. pmid:15489344
  2. 2. Michelow IC, Olsen K, Lozano J, Rollins NK, Duffy LB, Ziegler T, et al. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children[J]. Pediatrics 2004; 113(4):701–7. pmid:15060215
  3. 3. Shah SS, Test M, Sheffler-Collins S, Weiss AK, Hall M. Macrolide therapy and outcomes in a multicenter cohort of children hospitalized with Mycoplasma pneumoniae pneumonia[J]. J Hosp Med 2012; 7(4):311–17. pmid:22271440
  4. 4. Lu YJ, Chen TH, Lin LH, Shen CM, Huang CH. Macrolide use shortens fever duration in Mycoplasma pneumoniae infection in children: a 2-year experience[J]. J Microbiol Immunol Infect 2008; 41:307–10. pmid:18787737
  5. 5. Esposito S, Bosis S, Faelli N, Begliatti E, Droghetti R, Tremolati E, et al. Role of atypical bacteria and azithromycin therapy for children with recurrent respiratory tract infections[J]. Pediatric Infectious Disease Journal 2005; 24(5):438–444. pmid:15876944
  6. 6. Kogan R, Martinez MA, Rubilar L, Paya E, Quevedo I, Puppo H, et al. Comparative randomized trial of azithromycin versus erythromycin and amoxycillin for treatment of community-acquired pneumonia in children[J]. Pediatric Pulmonology 2003; 35(2):91–98. pmid:12526069
  7. 7. Uldum SA, Bangsborg JM, Gahrn-Hansen B, Ljung R, Mølvadgaard M, Føns Petersen R, et al. Epidemic of Mycoplasma pneumoniae infection in Denmark, 2010 and 2011[J]. Euro Surveill 2012; 17(5). pmid:22321137
  8. 8. Morozumi M, Hasegawa K, Kobayashi R, Inoue N, Iwata S, Kuroki H, et al. Emargence of macrolide-resistant Mycoplasma pneumoniae with a 23S rRNA gene mutation[J]. Antimicrob Agents Chemother 2005; 49:2302–6. pmid:15917525
  9. 9. Morozumi M, Takahashi T, Ubukata K. Macrolide-resistant Mycoplasma pneumoniae: characteristics of isolates and clinical aspects of community-acquired pneumonia[J]. Infect Chemother 2010; 16:78–86. pmid:20094751
  10. 10. Okada T, Morozumi M, Tajima T, Hasegawa M, Sakata H, Ohnari S, et al. Rapid effectiveness of minocycline or doxycycline against macrolide-resistant Mycoplasma pneumoniae infection in a 2011 outbreak among Japanese children[J]. Clin Infect Dis 2012; 56:1642–9. pmid:22972867
  11. 11. Scott JA, Wonodi C, Moïsi JC, Deloria-Knoll M, DeLuca AN, Karron RA, et al. The definition of pneumonia, the assessment of severity, and clinical standardization in the Pneumonia Etiology Research for Child Health study[J]. Clin Infect Dis 2012; 54 (Suppl 2):109–16. pmid:22403224
  12. 12. Kin Key N, Araujo-Neto CA, Nascimento-Carvalho CM. Severity of childhood community-acquired pneumonia and chest radiographic findings[J]. Pediatr Pulmonol 2009; 44(3):249–252. pmid:19205052
  13. 13. Mathisen M, Strand TA, Sharma BN, Chandyo RK, Valentiner-Branth P, Basnet S, et al. Clinical presentation and severity of viral community-acquired pneumonia in young Nepalese children[J]. Pediatr Infect Dis J 2010; 29(1):e1–6. pmid:19935451
  14. 14. Biondi E, McCulloh R, Alverson B, Klein A, Dixon A, Ralston S. Treatment of mycoplasma pneumonia: a systematic review[J]. Pediatrics 2014; 133(6):1081–90. pmid:24864174
  15. 15. Suzuki S, Yamazaki T, Narita M, Okazaki N, Suzuki I, Andoh T, et al. Clinical evaluation of macrolide-resistant Mycoplasma pneumoniae[J]. Antimicrob Agents Chemother 2006; 50:709–12. pmid:16436730
  16. 16. Matsubara K, Morozumi M, Okada T, Matsushima T, Komiyama O, Shoji M, et al. A comparative clinical study of macrolide-sensitive and macrolide-resistant Mycoplasma pneumoniae infections in pediatric patients[J]. Infect Chemother 2009; 15(6):380–3. pmid:20012728
  17. 17. Okada T, Morozumi M, Tajima T, Hasegawa M, Sakata H, Ohnari S, et al. Rapid effectiveness of minocycline or doxycycline against macrolide-resistant Mycoplasma pneumoniae infection in a 2011 outbreak among Japanese children[J]. Clin Infect Dis 2012; 56:1642–9. pmid:22972867
  18. 18. Tamura A, Matsubara K, Tanaka T, Nigami H, Yura K, Fukaya T. Methylprednisolone pulse therapy for refractory Mycopplasma pneumoniae pneumonia in children[J]. J Infect 2008; 57(2):223–8. pmid:18656264
  19. 19. Radisic M, Torn A, Gutierrez P, Defranchi HA, Pardo P. Severe acute lung injury caused by Mycoplasma pneumoniae: potential role for steroid pulses in treatment[J]. Clin Infect Dis. 2000 Dec;31(6):1507–11. pmid:11096025
  20. 20. Morozumi M, Hasegawa K, Kobayashi R, Inoue N, Iwata S, Kuroki H, et al. Emargence of macrolide-resistant Mycoplasma pneumoniae with a 23S rRNA gene mutation[J]. Antimicrob Agents Chemother 2005; 49:2302–6. pmid:15917525
  21. 21. Liu Y, Ye X, Zhang H, Xu X, Li W, Zhu D, et al. Antimicrobial suscepetibility of Mycoplasma pneumoniae isolates and molecular analysis of macrolide-resistant from Shanghai, China[J]. Antimicrob Agents Chenother 2009; 53(5):2160–2. pmid:19273684
  22. 22. Zhou Y, Zhang Y, Sheng Y, Zhang L, Shen Z, Chen Z. More complications occur in macrolide-resistant than in macrolide-sensitive Mycoplasma pneumoniae pneumonia[J]. Antimicrob Agents Chemother 2014; 58(2):1034–8. pmid:24277047
  23. 23. Xin D, Mi Z, Han X, Qin L, Li J, Wei T, et al. Molecular mechanisms of macrolide resistance in clinical isolates of Mycoplasma pneumoniae from China[J]. Antimicrob Agents Chenother 2009; 53(5):2158–9. pmid:19273685
  24. 24. Spuesens EB, Meijer A, Bierschenk D, Hoogenboezem T, Donker GA, Hartwig NG, et al. Macrolide resistance determination and molecular typing of Mycoplasma pneumoniae in respiratory specimens collected between 1997 and 2008 in The Netherlands[J]. Clin. Microbiol 2012; 50(6):1999–2004. pmid:22495561
  25. 25. Pereyre S, Touati A, Petitjean-Lecherbonnier J, Charron A, Vabret A, Bébéar C. The increased incidence of Mycoplasma pneumoniae in France in 2011 was polyclonal, mainly involving M. pneumoniae type 1 strains[J]. Clin Microbiol Infect. 19:212–7. pmid:23279613
  26. 26. Yamada M, Buller R, Bledsoe S, Storch GA. Rising rates of macrolide-resistant Mycoplasma pneumoniae in the central United States[J]. Pediatr Infect Dis J 2012; 31(4):409–10 pmid:22209916
  27. 27. Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome[J]. Am J Respir Crit Care Med 2006; 174(5):566–70. Epub 2006 Jun 1. pmid:16741151
  28. 28. Aghai ZH, Kode A, Saslow JG, Nakhla T, Farhath S, Stahl GE, et al. Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants[J]. Pediatr Res 2007; 62(4):483–8. pmid:17667842
  29. 29. Sugiyama K, Shirai R, Mukae H, Ishimoto H, Nagata T, Sakamoto N, et al. Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells[J]. Clin Exp Immunol 2007; 147(3):540–6. pmid:17302905
  30. 30. Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics[J]. Eur J Pharmacol 2001; 429:209–29. pmid:11698042