Pediatric Pulmonology 46:1093–1097 (2011)

Combined Treatment for Child Refractory

Mycoplasma pneumoniae Pneumonia
With Ciprofloxacin and Glucocorticoid
Aizhen Lu, PhD, Libo Wang, MD,* Xiaobo Zhang, PhD, and Mingzhi Zhang, MD

Summary. Objects: To evaluate the efficacy of combined treatment of ciprofloxacin and gluco-
corticoid for child refractory Mycoplasma pneumoniae (M. pneumoniae) pneumonia. Methods:
Clinical and laboratory characteristics of six pediatric refractory M. pneumoniae pneumonia
cases treated with ciprofloxacin and glucocorticoids were reported. Results: Five cases compli-
cated with pleural effusion. The average febrile period prior to admission was 8.5
2.0 days,
the average total febrile period was 14.6
7.6 days, and the average febrile period after treat-
ment was 3.3
3.0 days. The average time in hospital for patients was 23.6
4.8 days. The
initial mean WBC count was 10,100
2,400/mm3. The erythrocyte sedimentation rate (ESR),
lactate dehydrogenase (LDH), and C-reactive protein (CRP) in all cases were elevated during
the course of illness. After combined therapy, all children clinically improved, with resolution of
radiographic findings and normal laboratory items. We analyzed the 23S rRNA gene in four
nasopharyngeal secretions, and found mutations in A2063G of domain V in three cases, and
mutation in A2064G in the other case. Conclusion: Combined treatment of ciprofloxacin and
glucocorticoids can significantly ameliorate child refractory M. pneumoniae pneumonia further
comparative study is needed to well evaluate the treatment efficacy. Pediatr Pulmonol.
2011;46:1093–1097. ß 2011 Wiley Periodicals, Inc.

Key words: ciprofloxacin; glucocorticoid; refractory M. pneumoniae pneumonia;

children.

Funding source: none reported.

INTRODUCTION fluoroquinolones in children is limited because of the

potential risk of joint toxicity. Despite this concern, flu-
Mycoplasma pneumoniae (M. pneumoniae) is one
oroquinolones are successfully prescribed in some
of the major pathogens causing community-acquired
severe pediatric infections.6 In addition, many clinical
respiratory tract infections in children. Although
studies show that corticosteroids dramatically benefit
M. pneumoniae pneumonia (MP) is usually a benign
patients with severe MP,1,7,8 which is related to cell-
self-limited disease, it may develop into a severe life-
mediated immunity in M. pneumoniae infections.
threatening pneumonia in rare cases. These cases are
Therefore, we suppose that the combined treatment
defined as refractory MP showing clinical and radio-
of ciprofloxacin and corticosteroid may have good
logical deterioration after macrolide antibiotic therapy
efficacy in severe M. pneumoniae infections. Here,
for 7 days or more.1
Refractory MP may be related to emergency of
macrolide (ML) resistant M. pneumoniae. In children,
macrolide antibiotics are the first-choice agents for Respiratory Department, Children’s Hospital of Fudan University,
M. pneumoniae infections, and these antibiotics have Shanghai, China.
been thought to have excellent effectiveness against
*Correspondence to: Libo Wang, MD, Respiratory Department, Child-
M. pneumoniae for many years. However, in recent ren’s Hospital of Fudan University, No. 399, Wangyuan Road, Shanghai,
years, many isolates of M. pneumoniae from clinical China. E-mail: wanglbc@163.com
samples showed resistance to macrolides. Mutations in
domain V of 23S rRNA of M. pneumoniae are proved Received 10 September 2010; Revised 15 March 2011; Accepted 26
as main mechanism of resistance.2–5 March 2011.
Fluoroquinolones have a broad spectrum of activity DOI 10.1002/ppul.21481
against Gram-positive, Gram-negative, and other organ- Published online 22 June 2011 in Wiley Online Library
isms such as Mycoplasma and Chlamydia. The use of (wileyonlinelibrary.com).

ß 2011 Wiley Periodicals, Inc.

1094 Lu et al.

we reported six pediatric patients with refractory
M. pneumoniae infections, who dramatically responded
to this combined therapy. Clinical and radiological
evaluations showed significant improvement in these
patients. Our study suggests that this combined therapy
is effective in refractory M. pneumoniae infections.
MATERIALS AND METHODS
Subjects
We retrospectively reviewed the records of six pre-
viously healthy children who had refractory
M. pneumoniae infections at Children’s Hospital of
Fudan University between 2007 and 2009. During the
period, 614 children with M. pneumoniae infections
were admitted to the hospital. The M. pneumoniae
infection was confirmed by serologic test (detecting
M. pneumoniae IgM by ELISA) and M. pneumoniae
PCR tests of nasopharyngeal secretions. All children
had negative results of TB-IgM test and PPD test. And
they had negative results of respiratory syncytial
viruses, influenza viruses, adenovirus, and parainfluenza
virus tests. They also had negative results of bacterial
cultures of nasopharyngeal secretions and two blood
cultivations.
Sequence Analysis of 23S rRNA Genes
DNA was isolated from nasopharyngeal specimens.
Primers: MP23SF (5-CAA TAA GTT ACT AAG GGC
TTA TGG TGG ATG C-3) and MP23SR (5-TCC AAT
AAG TCC TCG AGC AAT TAG TAT TAC TCA G-3)
were used to amplify and sequence the full length of
the 23S rRNA fragment.
Treatment Schedule
All patients had macrolide treatment for more than
7 days before admission. On admission, all patients
received azithromycin and one kind of third generation
of cephalosporins. Once the clinical characteristics got
worse, the combined therapy was prescribed. Ciproflox-
acin therapy was treated as 10 mg/kg/day by intrave-
nous drip for 7–12 days. Once clinical manifestation
was improved, cephalosporins were used instead of
ciprofloxacin for safety. Corticosteroids were applied as
below: methylprednisolone was given 2 mg/kg/day by
intravenous drip till patients’ temperature became nor-
mal, then replaced by prednisone oral treatment as
1 mg/kg/day and decreased gradually until the patient
showed normal radiological graph. Patients who
received this combined therapy were informed consent
document.
RESULTS
Clinical Characteristics and Chest Radiographic
Findings
On admission, all patients had symptoms and signs
of pneumonia, including fever (>388C per axilla),
cough, and abnormal breath sounds. Five patients had
pleural effusions, and one of them required admission
to the intensive care unit because of dyspnea. Five cases
were male. The mean age of the six children was
7.1
2.7 years old. The average febrile period prior to
admission was 8.5
2.0 days, the average total febrile
period was 14.6
7.6 days, and the average febrile
period after combination therapy was 3.3
3.0 days.
The mean hospital stay was 23.6
4.8 days. Initial
chest radiographic findings of these patients showed
segmental or lobar infiltrates. In combined therapy,
all children showed a persistent fever with aggravated
respiratory symptoms and signs, and their radiographic
findings had progressed to severe pneumonia. After
combined treatment, the symptoms of all children were
clinically improved, with defervescence and resolution
of radiographic findings (Table 1, Fig. 1). All patients

TABLE 1— Clinical and Radiographic Characteristics of Patients With Refractory MP Pneumonia

Fever (day)
Hosp. ML X-ray Extra-pulmonary
Patients Age Gender A B C (day) before findings manifestation

1 6 M 8 16 0 21 Azithromycin, clarithromycin RUL consolidation None

2 4 M 7 21 7 30 Azithromycin RL infiltration, RUL atelectasis, Increased myocardial
pleural effusion enzyme
3 7 M 12 20 2 24 Azithromycin RUL consolidation, pleural effusion, Increased liver enzymes
LLL infiltration
4 6 M 7 16 6 24 Erythromycin, azithromycin, RLL consolidation, pleural effusion None
clarithromycin
5 12 F 10 10 0 16 Azithromycin RL infiltration, pleural effusion None
6 8 M 7 15 5 27 Azithromycin, clarithromycin RUL consolidation, pleural effusion Increased liver enzymes

A, Fever prior to admission; B, total fever duration; C, fever duration after combination treatment; RL, right lobe; RUL, right upper lobe;
LLL, left low lobe; RLL, right low lobe.

Pediatric Pulmonology
 Ciprofloxacin and Steroid in M. pneumoniae Pneumonia 1095

Fig 1. Chest radiographs of case 2 (male, 4 years old). (A) Before admission, (B) on
admission, (C) 3 days after combination therapy, (D) 7 days after combination therapy, and
(E) 12 days after combination therapy.

were followed up a month after their discharge, and
there were no articular complications.
Laboratory Findings
In this study, one case had negative M. pneumoniae-
IgM at admission, but became positive after 3 days.
One case had the procedure of closed thoracic drainage.
Five patients had positive M. pneumoniae IgM in the
pleural fluid test. The initial mean WBC count was
10,100
2,400/mm3 (neutrophil, 71.8
5.9% and
lymphocyte 24.1
4.6%). The mean max erythrocyte
sedimentation rate (ESR, Wintrobe method) was
92.2
24.3 mm/hr. All C-reactive protein (CRP) elev-
ated dramatically. The mean max lactate dehydrogenase
(LDH) was 534
289 IU/L (Table 2). All these data
became normal after the combined therapy.
We succeeded in amplifying the domain V of 23S
rRNA gene in four nasopharyngeal specimens, the other
two specimens failed. Three specimens harbored an
A2063G mutation in domain V of 23S rRNA genes, and
one had A2064G mutation.
DISCUSSION
The refractory MP may be associated with emer-
gence and increase of ML-resistance strains. In China,
prevalence of ML-resistant M. pneumoniae isolates in
pediatrics has increased rapidly. In 2009, Xin et al.9
reported that 46/50 (92%) M. pneumoniae isolates from

TABLE 2— Laboratory Findings

Serum IgM
Total WBC (109/L) differentials CRPM ESRM LDHM Pleural Mutation
Patient (neutrophil/lymphocyte %), On (mg/L) (mm/hr) (IU/L) On Max fluid IgM position

1 14.5 (78.9/20.1) >160 97 244 >1:1,280 >1:1,280 ND A2063G

2 8.2 (68.6/28.4) 58 80 779 1:320 >1:1,280 >1:1,280 ND
3 8.9 (69.2/23.2) 115 104 633 1:640 1:1,280 >1:1,280 A2063G
4 9.0 (77.3/19.8) >160 132 ND Negative >1:5,120 1:320 A2063G
5 8.9 (73.5/22) 76 64 207 1:320 1:320 1:320 ND
6 11.4 (63.2/31) >160 76 808 1:320 1:640 1:160 A2064G

LDH normal range: 114–240 IU/L.

On, on admission; M, maximum during the course; ND, not determined.

Pediatric Pulmonology
1096 Lu et al.
pediatric patients are resistant to macrolides. In 2010,
Liu et al.2 reported that 90/100 (90%) M. pneumoniae
isolates are resistant to macrolides. All these ML-
resistant isolates have the mutation at position 2063 or
2064 in 23S rRNA genes. In our study, four samples of
nasopharyngeal secretions harbored the amplication of
23S rRNA genes, three with the mutation of A2063G,
one with A2064G. This suggested the four patients had
ML-resistant M. pneumoniae infections.
It has been proposed that cell-mediated immunity
play an important role in the progress of M. pneumoniae
infection.11 Animal study showed that when animals
are infected with mycoplasma, a large number of
lymphocytes, mainly CD4þ T-cells, initially infiltrate
the peribronchiolar and perivascular regions.12 Open-
lung biopsy findings in patients with MP also revealed
infiltration of peribronchiolar lymphoplasmocytic cells
and exudates, with prominent neutrophils in the bron-
chiolar lumens (cellular bronchiolitis).10 Many cyto-
kines are involved in M. pneumoniae infection, such
as IL2, IL1, IL5, IL6, and IL8.13,14 These cytokines
promote the inflammatory response. It was suggested
that hyperimmune reaction of T-cells which produce a
variety of inflammatory mediators is involved in the
lung tissue destruction.13,14 Thus, stronger immunologi-
cal reactions may induce more severe pneumonic infil-
trations. In our study, the marked elevated CRP and
ESR suggested the severe systemic inflammatory
response to M. pneumoniae infections.
Given that the M. pneumoniae infection was an
immune-mediated disease, immune suppressive therapy
would be valid. Corticosteroids have roles of immune
regulation and anti-inflammation. It was reported that
corticosteroids could improve symptoms and pulmonary
lesion rapidly in children and adults with M. pneumo-
niae infection.1,8 Animal experiments also showed that
combined treatment of clarithromycin and dexametha-
sone can reduce lung histopathologic score and cyto-
kines than clarithromycin or dexamethasone only.15
However, there was no evidence-based report about
appropriate methods of steroid use, in particular, those
of dosage, administration route, or duration of treat-
ment. Lee et al.8 reported that oral prednisolone of
1 mg/kg/day tapering within a week for severe MP in
children may be helpful. Tamura et al.1 reported that
intravenously administered methylprednisolone at a
dose of 30 mg/kg once daily for three consecutive days
is effective for refractory MP in children. For safety, we
initially gave methylprednisolone intravenously at a
dose of 2 mg/kg /day, till the patient’s fever dropped,
then we changed to predisone 1 mg/kg/day orally. This
regiment also improved clinical manifestation without
any side-effect. Since all these three reports were cases-
based and the severity of pneumonia and clinical mani-
festations of the patients might be different, further
Pediatric Pulmonology
controlled studies for corticosteroid use in MP may be
necessary.
Although the high prevalence of ML-resistant
M. pneumoniae isolates exists in China, severe M.
pneumoniae infections are rare. Macrolides are pre-
scribed widely, they also seem effective on ML-resistant
M. pneumoniae. There may be two reasons, one is that
most M. pneumoniae infections are mild and self-limit-
ing, the other is that macrolides may have immunomo-
dulatory effects. According to our experience, only
6 patients among 614 patients with M. pneumoniae
infections treated with macrolides showed progressive
pneumonia. A study in Japan reported that children
infected with ML-resistant M. pneumoniae have longer
fever duration than those with macrolide sensitive
M. pneumoniae when treated with macrolides.16 It
suggests that virulence of M. pneumoniae itself also
impact the clinical manifestation. In our case series,
four patients were confirmed infected by ML-resistant
M. pneumoniae and initial macrolides did not effect
on the progression of the disease. Therefore, it is a
possible explanation that ML-resistant M. pneumoniae
itself could be responsible for the severity of disease.
M. pneumoniae is very sensitive to fluoroquinolones.
Ciprofloxacin is the third generation of fluoroquino-
lones, and its cartilage toxic effect is considered the
least.6,16 A system review about ciprofloxacin use in
severe neonatal infections finds that no serious adverse
events, particularly joint toxicity are not observed.17 In
addition, there is a case report that fluoroquinolones are
effective for ML-resistant M. pneumoniae infection in
adults.18 However, the experience of using fluoroquino-
lones to treat MP in children is rare. In this study, we
combined ciprofloxacin with steroid to treat refractory
MP and got good effect without adverse events.
Although we did not perform a case–control study
owing to small numbers of cases, the rapid clinical and
radiological improvement of refractory M. pneumoniae
infections in children showed the beneficial effects of
the combined therapy. Since the appropriate courses of
corticosteroids or ciprofloxacin therapy in children are
not well established, further comparative study is
needed to define the optimal methods of this combi-
nation therapy.
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Pediatric Pulmonology