Pediatric Pulmonology 48:519–522 (2013)

Combination Therapy With Immune-Modulators and

Moxifloxacin on Fulminant Macrolide-Resistant
Mycoplasma pneumoniae Infection: A Case Report
Yuelin Shen, MD, Jin Zhang, MD, Yinghui Hu, MD,* and Kunling Shen, PhD*
Summary. This report entails a case of refractory pneumonia with a wild variety of extra-
pulmonary manifestations due to macrolide-resistant Mycoplasma pneumoniae infection in a
7-year-old boy. The diagnosis was based on isolating M. pneumoniae through cultivation from
the patient’s bronchial aspirations at admission and the following susceptibility testing. Initial
treatments consisting of a combination of azithromycin and standard-dosed methylprednisone
(2 mg/kg) were completely nonresponsive and the patient’s condition deteriorated rapidly.
However, methylprednisone pulse therapy (20 mg/kg for 3 days, tapering within 1 month) and
intravenous immunoglobulin (1 g/kg/day, two doses), in addition to moxifloxacin (10 mg/kg for
7 days) were remarkably effective and led to a favorable outcome without any observed side
effects during inpatient hospitalization and outpatient follow-up. Pediatr Pulmonol. 2013;
48:519–522. ß 2012 Wiley Periodicals, Inc.

Key words: Mycoplasma pneumoniae; macrolide resistance; methylprednisolone pulse

therapy; moxifloxacin; children.

Funding source: none reported.

INTRODUCTION CASE REPORT

Mycoplasma pneumoniae is one of the commonest
causes of childhood community-acquired pneumonia,
accounting for 18.9% of cases and an even higher inci-
dence during epidemics in China.1 M. pneumoniae
pneumonia (MP) is usually benign and self-limited.
However, it may in rare situations develop into a severe
life-threatening disease with a wide range of pulmonary
and extra-pulmonary manifestations such as myocardi-
tis, encephalitis, hepatitis, and hemolytic anemia.2–4
Although macrolides are generally considered the first-
choice agents for children with MP, occasional clinical
deterioration occurs despite appropriate therapy. The
pathogenesis of macrolide-nonresponsive and progres-
sive MP remains unclear, which may include hyper-
active responses in cellular-immunity5 and the wide
spread of macrolide-resistant (MLr) M. pneumoniae
strains.6 Recently, corticosteroids have shown promising
efficacy for treating severe or refractory MP.7–10 How-
ever, appropriate methods of steroid use have not been
fully clarified and the necessity of substitution to sensi-
tive antibiotics remains controversial.6,7,11 In this report,
we describe a 7-year-old patient with severe progressive
MP, who dramatically responded to the combined
treatments with immune-modulatory therapy (methyl-
prednisone and intravenous immunoglobulin) and fluo-
roquinolones (moxifloxacin).
A previously healthy, fully vaccinated 7-year-old
Chinese male presented with a 10-day history of high-
grade and intermittent daily fever (up to 40.78C), non-
productive cough and fatigue. Six days prior to admis-
sion, the patient was seen in a pediatric emergency
department and received a course of intravenous (IV)
azithromycin (10 mg/kg/day  6 days). However, the
fever persisted and the respiratory condition deteriorat-
ed day by day. Physical examination revealed tachycar-
dia, tachypnea (respiratory rate of 55/min), nasal
Respiratory Department, Beijing Children’s Hospital, Capital Medical
University, Beijing, People’s Republic of China.
Conflict of interest: None.
*Correspondence to: Yinghui Hu, MD and Kunling Shen, PhD, Beijing
Children’s Hospital Affiliated to Capital Medical University, 56 Nanlishi
Road, Xicheng District, Beijing 100045, People’s Republic of China.
E-mail: huyinghui2001@yahoo.com.cn; kunlingshen@hotmail.com
Received 21 April 2012; Accepted 28 June 2012.
DOI 10.1002/ppul.22650
Published online 4 September 2012 in Wiley Online Library
(wileyonlinelibrary.com).

ß 2012 Wiley Periodicals, Inc.

520 Shen et al.

Fig. 1. Chest radiographs of 7-year-old patient with severe MP on admission (A), before com-
bination treatment (hospital Day 3, B), 3 days after combination treatment (hospital Day 6, C),
12 days after combination therapy (hospital Day 15, D), and 20 days after discharge (E).

flaring, bilateral fine diffuse crackles, and diminished moxifloxacin was weaned and oral erythromycin (5 mg/
breath sounds in right upper lobe on lung auscultation. kg/day) was administered for its mild immune-modulat-
Abnormal laboratory findings included leukocytosis ing and antibacterial effects. On Day 13, the boy be-
(11.14  103/ml) with predominant neutrophils (89.3%), came afebrile. On Day 15, all of the inflammatory
an elevated C-reactive protein (CRP 99.3 mg/L, normal biomarkers were markedly decreased, meanwhile, the
range 0–8.0 mg/L), erythrocyte sedimentation rate transaminase and myocardial enzyme both improved
(ESR 56 mm/hr, normal range 0–15 mm/hr), serum fer- (Table 1). The patient mostly recovered and was dis-
ritin (SF 807.9 ng/ml, normal range 6.0–159.0 ng/ml), charged 20 days after admission. The total course of
lactate dehydrogenase (LDH 995 IU/L, normal range methylprednisolone therapy (for infusion in hospital
50–240 IU/L), and D-Dimmer (8.08 mg/ml, normal and oral administration at home) was 1 month. One
range 0.01–0.50 mg/ml). M. pneumoniae IgM serology month after admission, culture of M. pneumonia from
was positive (Mycoplasma IgM titer 1:640). Com- bronchial aspirations at admission turned out positive
prehensive viral studies and cultures from the throat, and MLr. Consequently, the boy remained in good
bronchoalveolar lavage specimen and blood were all physical condition during the third month follow-up.
negative. Chest X-ray (Fig. 1A) showed patchy consoli-
dation at the right upper zone. Although a three-drug DISCUSSION
regimen that included azithromycin (10 mg/kg/day),
ceftriaxone (100 mg/kg/day), and a standard-dosed IV In this report we describe a severe case of
methylprednisolone (2 mg/kg/day) were started, the M. pneumoniae infection with a fulminant course and
fever spike persisted and the patient became more ill multi-organ involvement (acute respiratory failure,
appearing with chest distress, progressive hypoxemia, pleural and pericardial effusion, myocarditis, suspected
headache, acute behavioral changes, splenomegaly, and encephalitis, hemorrhagic conjunctivitis, haptic dys-
a bilateral positive Babinski sign. A new chest roent- function, splenomegaly, and lymphopenia). Most of the
genogram (Fig. 1B) and high resolution computed to- severe or refractory M. pneumoniae infection share
mography (HR-CT) scan images showed notable common laboratory findings such as increased serum
aggravation of consolidation of the right upper lobe levels of CRP, ESR, SF, D-Dimmer, transaminase, and
complicated with pleural effusion. The echocardiogram
demonstrated left ventricular enlargement with a mini-
mal amount of pericardial effusion. Blood chemistry
revealed myocardial damage and hepatic dysfunction.
On the third hospital day, continuous positive airway
pressure (CPAP) was established. High-dosed methyl-
prednisolone therapy (20 mg/kg/day  3 days) and
intravenous immunoglobulin (IVIG, 1 g/kg/day  2 days)
were started and antibiotics were substituted to moxi-
floxacin (10 mg/kg/day  7 days; Fig. 2).
The patient improved dramatically 3 days after
receiving the combination therapy (hospital Day 6).
He had only low-grade febrile (less than 388C) and
mild dyspnea. The chest radiograph showed notable
improvement of infiltration and consolidation without
pleural effusion (Fig. 1C). Thus the dosage of methyl-
prednisolone was gradually reduced (half the dose every Fig. 2. Fever curve and the treatment modalities of this
3 days) and CPAP was removed. On day 10, IV patient.

Pediatric Pulmonology
 Combination Therapy for M. Pneumonia Infection 521
TABLE 1— Laboratory Findings in Inpatient Hospital Course

Day 1 Day 3 Day 6 Day 15

WBC count, 10 cells/ml

3
11.14 10.82 7.44 12.30
Neutrophils, % 89.3 78.0 62.9 79.2
CRP, mg/L 99.3 68.0 14.0 <8.0
ESR, mm/hr 56 — — 26
SF, ng/ml 807.90 — 616.7 154.2
D-Dimmer, mg/ml 8.08 — 5.66 3.68
ALT, IU/L 20 67 93 50
AST, IU/L 60 150 159 20
CK, IU/L 257 1299 66 22
CK-MB, IU/L 23 25 10 8
LDH, IU/L 995 893 338 192
Methylprednisolone dosage, 2 20 10 1.5
mg/kg/day
Antibiotic regimen Azithromycin/ceftriax Moxifloxacin Moxifloxacin Oral erythromycin
Other treatment IVIG/CPAP/low-molecular-weight Off CPAP
heparin/mannite

WBC, white blood cells; CK, creatine kinase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

LDH similar to those we observed in severe acute respi-
ratory syndrome12 and H5N1 avian influenza.13
It has been proposed that cell-mediated immunity
plays an important role in the progress of severe infec-
tion with multi-organ injury which includes immune
cell hyper-activation (antigen-presenting cells and
T cells) and cytokine overproduction (interleukin (IL)-
2, IL-5, IL-6, IL-8, and IL-18).5 Therefore, improved
understanding of the underlying immune-pathogenesis
may shed light on a more effective therapy for treating
refractory cases with immune-modulators. However, the
courses of corticosteroid use, including the different
subtype choice, dosage, and duration, varied widely in
different pediatric centers. Lee et al.9 administered oral
prednisolone therapy (1 mg/kg/day, for 3–7 days, then
weaned over 1 week). Lu et al.7 applied IV methylpred-
nisone at a dose of 2 mg/kg/day and then changed to
prednisone 1 mg/kg/day orally when the fever dropped.
In addition, Tamura et al.8 employed methylpredniso-
lone pulse therapy (30 mg/kg over 3 consecutive days).
All three of the regimens showed dramatically clinical
and radiological improvements. For safety reason,
we initially gave methylprednisolone intravenously at
a standard dose of 2 mg/kg/day. However, low-dosed
corticosteroids were completely nonresponsive and the
patient’s condition deteriorated rapidly into multi-organ
injury including the respiratory failure and central
nervous system involvement. Then we switched to
methylprednisone pulse therapy (20 mg/kg for 3 days,
tapering within 1 month) and IVIG (1 g/kg/day, two
doses), which were remarkably effective and led to a
favorable outcome without any observed side effects
during inpatient hospitalization and outpatient follow-
up. When compared with previous pediatric publi-
cations,7–9 the most significant clinical characteristic
in this case report is the presence of a wild variety of
extra-pulmonary multi-organ injury, which is the reason
why we chose IV methylprednisone at a relatively high
dosage and longer treatment duration. In addition, IVIG
has been applied as an effective immune-modulator for
various immune-mediated diseases including Kawasaki
disease. Although IVIG use for severe MP is rarely
reported, we expected the combined immune-modulating
therapy of high-dosed methylprednisolone and IVIG to
be more effective.
In parallel with the prevalence of M. pneumoniae in-
fection, the prevalence of MLr isolates have increased
rapidly, attaining 90% in 2010 in China.14 Questions
might be posed as to whether the virulence of MLr
M. pneumonia impacts the clinical manifestation, the
disease severity or even the therapeutic effect. Although
fluoroquinolones have an excellent tissue penetration
and broad spectrum of activity against Gram-positive/
negative and other organisms such as Mycoplasma and
Chlamydia, they are not ordinarily recommended for
children because of the potential joint toxicity reported
from animal experiments. However, fluoroquinolones
have been reported to be successfully prescribed in
some severe infectious disease in children when there
was no alternative.15 In the case report, the patient had
a 12-day history of high-grade daily fever (exceeding
408C) and a rapid exacerbation to multi-organ diseases
despite the 8-day consecutive administration of IV
azithromycin until the third hospital day. Therefore, we
had little choice but to prescribe fluoroquinolones
(moxifloxacin) to this highly suspected MLr M. pneu-
monia infection case (informed consent was obtained
from the legal caretaker). Fortunately, the patient recov-
ered from the disease without any observed adverse
joint events by monitoring limb radiography and we
Pediatric Pulmonology
522 Shen et al.
could confirm our suspected etiologic agent by culture
of MLr M. pneumonia. Interestingly, although there was
an apparent treatment failure of macrolides and serious
disease progression present in this case, some previous
reports on MLr M. pneumoniae infection showed good
responses to macrolide therapy.11,16 The conflicting
manifestations might be because of the different strains
of MLr M. pneumonia. Therefore, more longitudinal
studies are needed to clarify the association between
clinical features and mutation sites in 23S rRNA from
MLr M. pneumonia. Currently, accurate and timely
diagnosis of MLr M. pneumonia infection early in the
clinical course is difficult because isolation by culture
is time-consuming. Therefore, there was no information
present for the pediatricians regarding the susceptibility
of isolates at the time of clinical decision-making.
Although no data confirmed the relationship of clinical
outcomes including the incidence of extra-pulmonary
compliance with early intervention using fluoroquino-
lones, we recommend increased worldwide surveillance
for MLr M. pneumonia and establish more appropriate
chemotherapy in suspected pediatric cases.
It was difficult to assess whether it was the immune-
modulatory therapy or the sensitive antibiotics or both
accounting for the outcomes of the severe M. pneumo-
niae infection case. Only one pediatric study previously
reported the efficacy of combined therapy of corticoste-
roids and fluoroquinolones.7 The current case further
emphasized the advantage and value of combination
therapy. Nevertheless, more prospective studies with a
larger sample size are needed to compare the therapeu-
tic benefits of independent and combined application of
these two treatments in the future.
REFERENCES
1. Xu YC, Zhu LJ, Xu D, Tao XF, Li SX, Tang LF, Chen ZM.
Epidemiological characteristics and meteorological factors of
childhood Mycoplasma pneumoniae pneumonia in Hangzhou.
World J Pediatr 2011;7:240–244.
2. Meyer Sauteur PM, Streuli JC, Iffl T, Goetsche P. Mycoplasma
pneumoniae-associated encephalitis in childhood–nervous sys-
tem disorder during or after a respiratory tract infection. Klin
Padiatr 2011;223:209–213.
Pediatric Pulmonology
3. Narita M. Pathogenesis of extrapulmonary manifestations of
Mycoplasma pneumoniae infection with special reference to
pneumonia. J Infect Chemother 2010;16:162–169.
4. Kountouras D, Deutsch M, Emmanuel T, Georgiadis G,
Koskinas J. Fulminant Mycoplasma pneumoniae infection with
multi-organ involvement: a case report. Eur J Intern Med 2003;
14:329–331.
5. Youn YS, Lee KY. Mycoplasma pneumoniae pneumonia in
children. Korean J Pediatr 2012;55:42–47.
6. Morozumi M, Iwata S, Hasegawa K, Chiba N, Takayanagi R,
Matsubara K, Nakayama E, Sunakawa K, Ubukata K, Acute
Respiratory Diseases Study Group. Increased macrolide resis-
tance of Mycoplasma pneumoniae in pediatric patients with
community-acquired pneumonia. Antimicrob Agents Chemother
2008;52:348–350.
7. Lu A, Wang L, Zhang X, Zhang M. Combined treatment for
child refractory Mycoplasma pneumoniae pneumonia with
ciprofloxacin and glucocorticoid. Pediatr Pulmonol 2011;46:
1093–1097.
8. Tamura A, Matsubara K, Tanaka T, Nigami H, Yura K, Fukaya
T. Methylprednisolone pulse therapy for refractory Mycoplasma
pneumoniae pneumonia in children. J Infect 2008;57:223–228.
9. Lee KY, Lee HS, Hong JH, Lee MH, Lee JS, Burgner D, Lee
BC. Role of prednisolone treatment in severe Mycoplasma
pneumoniae pneumonia in children. Pediatr Pulmonol 2006;41:
263–268.
10. Cimolai N. Corticosteroids complicated Mycoplasma pneumo-
niae infection. Pediatr Pulmonol 2006;41:1008–1009.
11. Suzuki S, Yamazaki T, Narita M, Okazaki N, Suzuki I, Andoh
T, Matsuoka M, Kenri T, Arakawa Y, Sasaki T. Clinical evalua-
tion of macrolide-resistant Mycoplasma pneumoniae. Antimi-
crob Agents Chemother 2006;50:709–712.
12. Wang JY, Lee CH, Cheng SL, Chang HT, Hsu YL, Wang HC,
Chu SH. Comparison of the clinical manifestations of severe
acute respiratory syndrome and Mycoplasma pneumoniae
pneumonia. J Formos Med Assoc 2004;103:894–899.
13. Carter MJ. A rationale for using steroids in the treatment of
severe cases of H5N1 avian influenza. J Med Microbiol 2007;
56:875–883.
14. Liu Y, Ye X, Zhang H, Xu X, Li W, Zhu D, Wang M. Charac-
terization of macrolide resistance in Mycoplasma pneumoniae
isolated from children in Shanghai, China. Diagn Microbiol
Infect Dis 2010;67:355–358.
15. Gendrel D, Chalumeau M, Moulin F, Raymond J. Fluoroquino-
lones in paediatrics: a risk for the patient or for the community?
Lancet Infect Dis 2003;3:537–546.
16. Matsuoka M, Narita M, Okazaki N, Ohya H, Yamazaki
T, Ouchi K, Suzuki I, Andoh T, Kenri T, Sasaki Y, et al.
Characterization and molecular analysis of macrolide-resistant
Mycoplasma pneumoniae clinical isolates obtained in Japan.
Antimicrob Agents Chemother 2004;48:4624–4630.