Hsieh et al The Pediatric Infectious Disease Journal • Volume 31, Number 2, Februry 2012
Oberste and the staff at the Picornavirus Laboratory, Division of
Viral Diseases, CDC for their assistance in the characterization of
the isolate.
REFERENCES
1. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and
treatment of Guillain Barre syndrome. Lancet Neurol. 2008;7:939 –950.
2. McMinn P, Stratov I, Nagarajan L, et al. Neurological manifestations of
enterovirus 71 infection in children during an outbreak of hand, foot, and
mouth disease in Western Australia. Clin Infect Dis. 2001;32:236 –242.
3. Alexander JP Jr, Baden L, Pallansch MA, et al. Enterovirus 71 infections and
neurologic disease—United States, 1977–1991. J Infect Dis. 1994;169:905–
908.
4. Hart DE, Rojas LA, Rosario JA, et al. Childhood Guillain-Barre syndrome in
Paraguay, 1990 to 1991. Ann Neurol. 1994;36:859 – 863.
5. Takeuchi Y, Kikuchi T, Kimura M. Guillain-Barre syndrome associated with
ECHO virus type 7 infections. Pediatrics. 1970;45:294 –295.
6. Gomes ML, Kopecka H, Linhares AC. Detection of enteroviruses in cases of
neurological disorders in the State of Para, Brazil. Rev Inst Med Trop Sao
Paulo. 2001;43:321–324.
7. Foley JF, Chin TD, Gravelle CR. Paralytic disease due to infection with
ECHO virus type 9 report of a case with residual paralysis. N Engl J Med.
1959;260:924 –926.
8. Centers for Disease Control and Prevention. Preliminary results: surveillance
for Guillain-Barre syndrome after receipt of influenza A (H1N1) 2009
monovalent vaccine—United States, 2009 –2010. Morb Mortal Wkly Rep.
2010;59:657– 661.
9. Liang XF, Li L, Liu DW, et al. Safety of influenza A (H1N1) vaccine in
postmarketing surveillance in China. N Engl J Med. 2011;364:638 – 647.
LIFE-THREATENING PNEUMONIA CAUSED BY
MACROLIDE-RESISTANT MYCOPLASMA
PNEUMONIAE
Yu-Chia Hsieh, MD, PhD,* Kuo-Chien Tsao, BS,†
Chung-Guei Huang, BS,† Suxiang Tong, PhD,‡
Jonas M. Winchell, PhD,§ Yhu-Chering Huang, MD, PhD,*
Shao-Hsuan Shia, MD, PhD,* Shen-Hao Lai, MD,*
and Tzou-Yien Lin, MD*
Abstract: Two siblings had pneumonia caused by macrolide-resistant
Mycoplasma pneumoniae as determined by polymerase chain reaction and
serology. One of them developed adult respiratory distress syndrome and
required extracorporeal membrane oxygenation therapy. This report high-
lights the need for studies to evaluate the optimal treatment in severe cases
of macrolide-resistant M. pneumoniae pneumonia.
Key Words: pneumonia, macrolide resistant, Mycoplasma pneumoniae,
adult respiratory distress syndrome
Accepted for publication August 22, 2011.
From the *Department of Pediatrics, Chang Gung Children’s Hospital, Chang
Gung Memorial Hospital, Chang Gung University College of Medicine,
Taoyuan, Taiwan; †Department of Laboratory Medicine, Chang Gung
Memorial Hospital, Chang Gung University College of Medicine, Taoyuan,
Taiwan; and Divisions of ‡Viral Diseases and §Bacterial Diseases, Centers
for Disease Control and Prevention, Atlanta, GA.
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: Yhu-Chering Huang, MD, PhD, Division of
Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung
children’s Hospital, 5 Fu-Hsin St, Kwei-Shan Hsiang, Taoyuan County
333, Taiwan. E-mail: ychuang@adm.cgmh.org.tw.
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text and are provided in the HTML and
PDF versions of this article on the journal’s Web site (www.pidj.com).
DOI: 10.1097/INF.0b013e318234597c
208 | www.pidj.com
M ycoplasma pneumoniae is a common pathogen responsible
for pediatric community-acquired pneumonia, accounting for
10% to 40% of cases.1 The illness is usually self-limiting, with
symptoms lasting several weeks, but sometimes it causes severe
pneumonia. Although there is still insufficient evidence to show
that antibiotics are effective in children with pneumonia caused by
M. pneumoniae, macrolides are the drug of choice for treating
children with M. pneumoniae infection.2 Since 2000, macrolide
resistance in M. pneumoniae strains has been increasing since the
report of a pediatric patient infected by macrolide-resistant M.
pneumoniae in Japan.3,4 Disease caused by macrolide-resistant M.
pneumoniae has a longer duration of fever than those caused by
macrolide-susceptible M. pneumoniae.5
This report describes 2 siblings with severe pneumonia
caused by macrolide-resistant M. pneumoniae.
MATERIALS AND METHODS
Case Report 1. In May 2008, a previously healthy 7-year-old boy
was admitted to our hospital with a 5-day history of fever, cough,
and rhinorrhea. A chest radiograph revealed consolidation over the
left lower lobe. Laboratory investigations showed a white blood
cell count of 7300/mm3 with 60% segmented neutrophils and 2%
band neutrophils. The C-reactive protein concentration was 96.64
mg/L. Therapy with intravenous amoxicillin/clavulanic acid plus
azithromycin was started. Acute fever (40°C– 41°C) was still
present even after we replaced amoxicillin/clavulanic acid by
ceftriaxone and added oseltamivir. The serum samples investigated
on the first day of hospitalization were negative for IgM and IgG
(Savyon Diagnostics, Ashdod, Israel) against M. pneumoniae, but
results for IgM against M. pneumoniae were positive (55 BU/mL)
6 days later. Doxycycline was then added to cover Coxiella
burnetii, as the family had been to a ranch before the illness and
there was no improvement on chest radiography. After treatment
with doxycycline, the fever decreased to 38°C to 39°C. On the
ninth day of hospitalization, the patient underwent lung biopsy for
definite diagnosis and to save his sister’s life (case 2). Oral
prednisolone (1 mg/kg/d) was used to reduce the low-grade fever
on the 12th day of hospitalization, and the patient became afebrile
on the 13th day. He was discharged on day 17 after admission.
Case Report 2. The 6-year-old sister of case 1 was also admitted
to our hospital with a 7-day history of fever, cough, and rhinorrhea
at the same day. Chest radiography revealed patchy opacity over
the left upper lobe and right lower lobe. Laboratory investigations
showed a white blood cell count of 15,400/mm3 with 88% segmented
neutrophils and 3% band neutrophils. The C-reactive protein level
was 149 mg/L. Empiric treatment with vancomycin, ceftriaxone,
azithromycin, and oseltamivir were initiated. On the second day of
hospitalization, she was intubated because of hypoxemia. On the
fourth day of hospitalization, she developed acute respiratory
distress syndrome (ARDS) (PaO2/FiO2, ⬍200 mm Hg). Extra-
corporeal membrane oxygenation therapy was undertaken. Re-
sults for serologic tests performed on the first day of hospital-
ization were positive for IgM (24 BU/mL) and negative for IgG
against M. pneumoniae; IgM increased to 72 BU/mL and IgG
results remained negative 4 days later. Doxycycline was added
on the seventh day of hospitalization. After use of doxycycline,
oxygenation improved gradually, and the patient was success-
fully decannulated from extracorporeal membrane oxygenation
after 12 days and received conventional ventilator support for
an additional 3 days. High-resolution computed tomography
revealed multiple cystic lesions with ground glass appearance in
both lung fields. Systemic steroid (methylprednisolone, 3.5
mg/kg/d) therapy was initiated for persistent tachypnea and
fever. The patient was discharged on day 40 after admission.
© 2012 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 31, Number 2, Februry 2012
Specimen Collection, and Analysis of M. pneumoniae by
Polymerase Chain Reaction. Results of M. pneumoniae real-time
polymerase chain reaction (PCR) assay from nasopharygeal aspi-
rate, lung tissue, and pleural fluid of the brother and nasopharygeal
aspirate of the sister were positive (Fig. A, Supplemental Digital
Content 1, http://links.lww.com/INF/A964).6 In the meantime,
PCR assay results for M. pneumoniae from lung tissue of the
brother was positive, performed by Centers for Disease Control
and Prevention in the United States. Sequencing of the 23S rRNA
in both cases identified an A2064G transition in domain V (Fig. B,
Supplemental Digital Content 1, http://links.lww.com/INF/A964),
which is indicative of a macrolide-resistant phenotype.4 For find-
ing other possible concomitant infections in 2 cases, extensive
viral studies including PCR test for adenovirus; influenza A and B;
human coronavirus 229E, OC43, and NL-63; and SARS corona-
virus were performed, and the results were negative in both our
laboratory and Centers for Disease Control and Prevention of the
United States. Throat swabs were negative for virus isolation,
blood culture, and urine pneumococcal antigen (NOW Streptococcus
pneumoniae Antigen Test; Binax, Portland, ME).
DISCUSSION
For the first time, we documented a case of ARDS caused by
macrolide-resistant M. pneumoniae. In Japan, Morozumi et al4
showed that macrolide-resistant M. pneumoniae increased to 30.6% in
2006. In China, the prevalence of macrolide-resistant M. pneumoniae
is extremely high, reaching 100% in 2007 and 2008.7 Peuchant et al8
found that the rate of macrolide-resistant M. pneumoniae isolates
increased to 9.8% between 2005 and 2007 in France. The mechanism
of resistance to macrolides in M. pneumoniae frequently involves
mutations in the 23S rRNA including transitions of A2063G and
A2064G. The mutation at A2063G is more common than A2064G,
but the mutation at A2064G confers resistance to a broader spectrum
of other antimicrobial agents.4,7 Despite the emergence of macrolide-
resistant M. pneumoniae, no cases of severe disease related to mac-
rolide-resistant strains have been reported in Japan.5 Recently, Li et al
found 2 children with pneumonia and hypoxemia caused by mac-
rolide-resistant M. pneumoniae in the United States.9
A proportion of M. pneumoniae pneumonia was noted to be
refractory to macrolide therapy and presented with persistent fever,
hypoxemia, and radiographic deterioration.10,11 Pleural effusion,
necrotizing pneumonitis, lung abscess, bronchiolitis obliterans
organizing pneumonia, and ARDS have been reported in association
with M. pneumoniae pneumonia in children.12–15 Severe lung injury
in M. pneumoniae pneumonia was presumed to be a consequence of
overproduction of cytokines and an exuberant cell-mediated immune
response.16 In a mouse model, macrolides plus systemic steroids had
the greatest effect in decreasing cytokine production and pulmonary
inflammation, whereas monotherapy with systemic steroids did not
reduce the bacterial load or pulmonary inflammation.17 Clinical ex-
periences and animal models suggest that the use of both antimicro-
bial therapy and immunomodulatory agents is important to improve
the outcome of severe M. pneumoniae pneumonia.16,17 Given the
increase of macrolide-resistant M. pneumoniae in recent years,4,7–9
effective antimicrobial treatment should be a critical component of
managing severe cases of macrolide-resistant strain infection. In the
siblings, high fever persisted and clinical deterioration developed even
after macrolide therapy. We observed that clinical conditions in the 2
cases improved after doxycycline treatment. Strains with the A2064G
transition were usually susceptible to minocycline.4 Although we did
not isolate the strain and perform susceptibility tests, doxycycline, a
© 2012 Lippincott Williams & Wilkins
Mycoplasma Pneumoniae
member of tetracycline antibiotic, should have good activity against
macrolide-resistant M. pneumoniae. The limitations of our report
included the following: (1) we could not completely exclude
concommitant infection in the siblings; (2) no extensive immuno-
logic work-up was done for the siblings to study whether there was
host-related factors that could explain the severity of the cases.
However, our cases warrant more studies on the prevalence of
macrolide-resistant M. pneumoniae and to evaluate the optimal
treatment in severe cases of macrolide-resistant M. pneumoniae
pneumonia.
REFERENCES
1. Principi N, Esposito S, Blasi F, et al. Role of Mycoplasma pneumoniae and
Chlamydia pneumoniae in children with community-acquired lower respi-
ratory tract infections. Clin Infect Dis. 2001;32:1281–1289.
2. Mulholland S, Gavranich JB, Chang AB. Antibiotics for community-
acquired lower respiratory tract infections secondary to Mycoplasma pneu-
moniae in children. Cochrane Database Syst Rev. 2010:CD004875.
3. Okazaki N, Narita M, Yamada S, et al. Characteristics of macrolide-
resistant Mycoplasma pneumoniae strains isolated from patients and in-
duced with erythromycin in vitro. Microbiol Immunol. 2001;45:617– 620.
4. Morozumi M, Iwata S, Hasegawa K, et al. Increased macrolide resistance
of Mycoplasma pneumoniae in pediatric patients with community-acquired
pneumonia. Antimicrob Agents Chemother. 2008;52:348 –350.
5. Suzuki S, Yamazaki T, Narita M, et al. Clinical evaluation of macrolide-
resistant Mycoplasma pneumoniae. Antimicrob Agents Chemother. 2006;
50:709 –712.
6. Welti M, Jaton K, Altwegg M, et al. Development of a multiplex real-time
quantitative PCR assay to detect Chlamydia pneumoniae, Legionella pneu-
mophila and Mycoplasma pneumoniae in respiratory tract secretions. Diagn
Microbiol Infect Dis. 2003;45:85–95.
7. Liu Y, Ye X, Zhang H, et al. Antimicrobial susceptibility of Mycoplasma
pneumoniae isolates and molecular analysis of macrolide-resistant strains
from Shanghai, China. Antimicrob Agents Chemother. 2009;53:2160 –2162.
8. Peuchant O, Menard A, Renaudin H, et al. Increased macrolide resistance
of Mycoplasma pneumoniae in France directly detected in clinical speci-
mens by real-time PCR and melting curve analysis. J Antimicrob Che-
mother. 2009;64:52–58.
9. Li X, Atkinson TP, Hagood J, et al. Emerging macrolide resistance in
Mycoplasma pneumoniae in children: detection and characterization of
resistant isolates. Pediatr Infect Dis J. 2009;28:693– 696.
10. Lee KY, Lee HS, Hong JH, et al. Role of prednisolone treatment in severe
Mycoplasma pneumoniae pneumonia in children. Pediatr Pulmonol. 2006;
41:263–268.
11. Tamura A, Matsubara K, Tanaka T, et al. Methylprednisolone pulse therapy
for refractory Mycoplasma pneumoniae pneumonia in children. J Infect.
2008;57:223–228.
12. Chiou CC, Liu YC, Lin HH, et al. Mycoplasma pneumoniae infection
complicated by lung abscess, pleural effusion, thrombocytopenia and dis-
seminated intravascular coagulation. Pediatric Infect Dis J. 1997;16:327–
329.
13. Wachowski O, Demirakca S, Muller KM, et al. Mycoplasma pneumoniae
associated organising pneumonia in a 10 year old boy. Arch Dis Child.
2003;88:270 –272.
14. Wang RS, Wang SY, Hsieh KS, et al. Necrotizing pneumonitis caused by
Mycoplasma pneumoniae in pediatric patients: report of five cases and
review of literature. Pediatr Infect Dis J. 2004;23:564 –567.
15. Yoshida T, Asato Y, Kukita I, et al. A 7-year-old boy with mycoplasmal
infection requiring extracorporeal membrane oxygenation. Eur J Pediatr.
2003;162:44 – 46.
16. Radisic M, Torn A, Gutierrez P, et al. Severe acute lung injury caused by
Mycoplasma pneumoniae: potential role for steroid pulses in treatment. Clin
Infect Dis. 2000;31:1507–1511.
17. Tagliabue C, Salvatore CM, Techasaensiri C, et al. The impact of steroids
given with macrolide therapy on experimental Mycoplasma pneumoniae
respiratory infection. J Infect Dis. 2008;198:1180 –1188.
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