Acta Pdiatrica ISSN 0803-5253

REVIEW ARTICLE

Treating paediatric community-acquired pneumonia in the era

of antimicrobial resistance
L Galli, C Montagnani, E Chiappini (elena.chiappini@unifi.it), M de Martino
Department of Health Sciences, University of Florence, Anna Meyer Childrens University-Hospital, Florence, Italy

Keywords
Antimicrobial resistance, Children, Communityacquired pneumonia, Drug-resistant bacteria,
Paediatricians
Correspondence
Elena Chiappini, MD, PhD, Department of Health
Sciences, University of Florence, Anna Meyer
Childrens University Hospital, Viale Pieraccini 24,
I-50139 Florence, Italy.
Tel: +39 055 5662518 |
Fax: +39 055 4221012 |
Email: elena.chiappini@unifi.it

ABSTRACT
Increasing levels of paediatric community-acquired pneumonia (CAP), caused by drugresistant bacteria and antimicrobial resistance, vary with age and countries and, in some
cases, serotypes. When empirical first-line treatment administration fails, paediatricians
should consider second-line treatments based on the prevalence of local resistance. A
more judicious use of antimicrobial agents is also required.
Conclusion: Knowledge of local epidemiology and an appropriate use of antimicrobial
drugs are necessary to treat CAP in this era of antimicrobial resistance.

DOI:10.1111/apa.12503

According to data from the World Health Organization,

pneumonia is a major health problem and is still the main
cause of global child mortality (1).
Despite improvements in diagnostic methods, identifying
the aetiology of community-acquired pneumonia (CAP) in
children is still challenging. Causative pathogens can be
identified in 5481% of cases of CAP (2). Moreover, the
epidemiology of CAP has been changed in the last few
decades as a result of the introduction of the pneumococcal
conjugate and Haemophilus influenzae type B vaccines.
In industrialised countries, viruses account for up to
83% of CAP in children, and the human metapneumovirus
and bocavirus have been described in an increasing
number of cases in recent years (3,4). After the introduction of the pneumococcal conjugate vaccine, Elemraid
et al. (2) detected bacteria in 17.5% of children with CAP,
whereas viruses, either alone or as co-pathogens, were
found in 43%.

Key notes


This review provides an overview on drug resistance

mechanisms and debates therapy options for community-acquired pneumonia (CAP) due to drug-resistant
Streptococcus pneumoniae, Staphylococcus aureus
and Mycoplasma pneumoniae.
It shows that CAP, caused by drug-resistant bacteria and
antimicrobial resistance, varies with age and countries
and, in some cases, serotypes.
Knowledge of local epidemiology and an appropriate
use of antimicrobial drugs are necessary to treat CAP in
this era of antimicrobial resistance.

However, bacterial aetiology plays a significant role in

children with severe pneumonia and even more in fatal
cases (5).
Antimicrobial resistance is an increasing problem worldwide. The impact of antibiotic resistance is more consistent
in hospital settings, where multidrug-resistant and extensive
drug-resistant bacteria are spreading. However, there is
growing evidence of an increasing proportion of CAP cases
being caused by drug-resistant bacteria in the last 10 years,
both in adults and in children (68). The proportion of
isolates resistant to antimicrobials is increasing among
Streptococcus pneumoniae, Staphylococcus aureus and
Mycoplasma pneumoniae, and treatment of infections due
to these pathogens can be a challenge for paediatricians. A
possible role for nontypeable Haemophilus influenzae in
paediatric CAP has been suggested (9), but further studies
are necessary to determine whether it can play a significant
clinical role in CAP in children.
Hence, the aims of this review were to analyse the drug
resistance mechanisms of Streptococcus pneumoniae,
Staphylococcus aureus and Mycoplasma pneumoniae and
discuss therapy options for CAP due to drug-resistant
pathogens.

STREPTOCOCCUS PNEUMONIAE
Antibiotic resistance among Streptococcus pneumoniae
isolates, the major cause of CAP in children, has been
widely documented worldwide. To date, 93 different
Streptococcus pneumoniae serotypes have been identified.
Serotype distribution varies widely by geographical region,
pneumococcal vaccination coverage and age. In the 2000s,
many resource-rich countries introduced the seven-valent

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25

Treating community-acquired pneumonia

Galli et al.

conjugated vaccine (PC7), containing 4, 6B, 9V, 14, 18C,

19F and 23F serotypes, and this was associated with a
reduction in invasive pneumococcal diseases, particularly
in younger children (1012). PCV7 showed good effectiveness (30%; 95% CI: 10.745.7) in preventing pneumonia in
children under 5 years of age (13), but other studies
reported that PCV7 had no significant efficacy when it
came to preventing complicated pneumonia (14). Of note,
several reports documented an increase in hospitalisations
for complicated pneumonia, particularly for empyema, after
the PCV7 was introduced (15). The reasons for this increase
are not completely understood. A role for ibuprofen has
also been suggested (16), as well as replacing the PCV7
serotypes with other more virulent serotypes, such as 19A,
7, 1, 3 (1517). A further reason for this increase may be the
increasing proportion of antimicrobial-resistant pneumococcal isolates in the 2000s (18,19). A large number of
studies documented growing resistance to b-lactams, macrolides and tetracyclines and found an association between
specific serogroups/serotypes and resistance patterns
(Fig. 1). For example, in a study on multidrug resistance,
Lismond et al. (20) stated that the 19A serotype showed a
73.5% resistance to clarithromycin, about 20% resistance to
amoxicillin, cefuroxime and ceftriaxone, but only 3%
resistance to penicillin G. Meanwhile, other authors have
described an additional 30% resistance to meropenem (21).
The PCV7 vaccine was recently replaced by the PCV13, and
this should be able to reduce the spread of these multidrug18

Dual non-sucepblility

16

Single macrolides nonsuscepble

14

Single penicillin nonsuscepble

Proporon (%)

12

Fully suscepble

10
8
6
4
2

rs
he

15

ot

Serogroups

23

14

22

12

19

Figure 1 Proportion of susceptible pneumococcal isolates in Europe by

serogroups. Data from the Annual Report of the European Antimicrobial
Resistance Surveillance Network (16).

26

resistant serotypes among children. However, a further

cause of the increase in pneumococcal isolates resistant to
b-lactams and macrolides is antibiotic consumption at a
national level. Data from the European Antimicrobial
Resistance Surveillance System clearly show that antibiotic
resistance in pneumococcal isolates has increased in those
European countries where consumption of b-lactams and
macrolides is higher (22).
Minimum inhibitory concentration (MIC) breakpoints
for defining clinical susceptibility of Streptococcus pneumoniae to b-lactams have been suggested by the European
Committee on Antibiotic Susceptibility Testing (EUCAST):
susceptible is quantified as 0.5 mg/L and resistant is
quantified as >2 mg/L. Antimicrobial susceptibility has
been differently defined by the United States Clinical and
Laboratory Standards Institute (CLSI). Lack of susceptibility to penicillin and other b-lactams is, in fact, associated
with the modification of pneumococcal cell wall penicillinbinding proteins. This results in decreased, but not absent,
affinity with these antibiotics. Therefore, higher b-lactam
concentrations resulting from higher dosages and good
tissue distribution, as in the lung but not in the central
nervous system, may overcome resistance. In 2008, the
CLSI changed its MIC breakpoints for parenterally administered penicillin (2 mg/L: susceptible; 8 mg/L resistant),
after studies reported the clinical effectiveness of penicillin
and aminopenicillins when treating pneumococcal diseases
other than meningitis, even if classified as resistant in vitro
(23). Breakpoints to define nonsusceptibility to b-lactams in
pneumococcal meningitis remain unchanged (0.5 mg/L).
As a consequence, a high proportion of pneumococcal
isolates from CAP, categorised as intermediate to b-lactams
using the EUCAST breakpoint, may be considered susceptible according to CLSI criteria. In clinical practice,
high-dose penicillin or high-dose amoxicillin can be still
considered in the empirical treatment of pneumococcal
CAP, even in those countries where penicillin nonsusceptible isolates are above 25% (22).
Pneumococcal resistance to macrolide antibiotics
(clarithromicin, erythromicin and azithromicin) is the result
of a mutation on the mef (A) gene, whereas a mutation on
the erm (B) gene results in resistance to both macrolides
and lincosamides (24). As the mutations modify the 23S
subunit of the ribosomal RNA, blocking macrolide binding
to the ribosome, differently to resistance to b-lactams,
macrolide resistance cannot be overcome using higher
macrolide dosages. Furthermore, there have been several
reports of clinical failure of macrolide treatment for CAP
when macrolide-resistant (MIC 1 mg/L) Streptococcus
pneumoniae is isolated (25). Therefore, empirical macrolide
monotherapy treatment for CAP in children should be
avoided, and macrolide treatment should be used when
there is a reasonable clinical suspicion of Mycoplasma
pneumoniae aetiology.
In conclusion, studies from United States isolates suggest
that, at present, Streptococcus pneumoniae has the highest
susceptibility to ampicillin, piperacillin, respiratory fluoroquinolones (levofloxacin and moxifloxacin), ertapenem,

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Galli et al.

linezolid and vancomycin (>99% susceptibility), followed

by penicillin G, ceftriaxone, cefotaxime and cefepime (85
92% susceptibility) and meropenem, imipenem and clindamycin (7081% susceptibility) (6). Only 6065% of isolates
are susceptible to macrolides.

STAPHYLOCOCCUS AUREUS
Methicillin-resistant Staphylococcus aureus (MRSA) is an
increasing cause of CAP in children, mainly associated with
severe infections. MRSA was first reported in 1961, soon
after the clinical introduction of methicillin, and in the
1980s, these strains began to spread worldwide as nosocomial pathogens.
Methicillin resistance is due to the acquisition of the
staphylococcal cassette chromosome mec (SCCmec), which
carries the mec gene for methicillin and resistance to all
other b-lactam drugs (7).
Over the last decade, the epidemiology of MRSA has
been evolving rapidly, with the diffusion of communityacquired MRSA (CA-MRSA) strains, which have different
genetic backgrounds to the healthcare-associated (HA)
strains and are more related to CA methicillin-sensitive
SA (CA-MSSA). CA-MRSA carries smaller SCCmec elements than HA-MRSA, generally type IV, V and VII (26).
Several sequence types of CA-MRSA have been described
worldwide, and their prevalence varies widely from area to
area. USA300/ST8 has become the dominant clone in USA,
whereas ST80 clone is prevalent in Europe, ST59 in Taiwan
and ST93 in Australia (27,28).
In addition, SA strains producing Panton-Valentine
leukocidin (PVL) cause severe necrotising pneumonia in
young healthy people. PVL is a bicomponent toxin that
causes the lysis of leucocytes, forming a pore in their
membrane and representing a main virulence factor of SA,
independent of methicillin resistance (29).
Community-acquired MRSA is typically susceptible to
most non-b-lactam drugs, such as trimethoprim-sulfamethoxazole, clindamycin and tetracycline, even if the ST80
clone is variably resistant to fluoroquinolones. Strains
resistant to erythromycin, and susceptible to clindamycin,
have to be tested for inducible clindamycin resistance (30).
Community-acquired MRSA pneumonia is becoming a
major concern in United States, Taiwan, Canada and
Australia, but there are also increasing reports of CAMRSA and PVL-SA pneumonia in Europe (31). A study
conducted at Texas Childrens Hospital over a 7-year period
showed an increasing rate of SA pneumonia, from 4.81
hospitalisations per 10 000 admissions in 2001 to 9.75 per
10 000 admissions in 2009. MRSA was responsible for 74%
of infections. More than 90% of the MRSA and MSSA
isolates carried PVL genes (32). In Taiwan, more than 50%
of staphylococcal infections in children are caused by
MRSA and these are mainly PVL carried (33). CA-MRSA
and PVL-SA are frequently associated with necrotising
pneumonia and typically affect previously healthy young
people who dont carry any risk factors because of their
exposure to the healthcare system (29). Schultz et al. (34)

Treating community-acquired pneumonia

reported that CA-MRSA has replaced Streptococcus pneumoniae as a more frequent pathogen isolated from children
with complicated pneumonia. Moreover, in a recent series
of 41 French paediatric patients with necrotising pneumonia, PVL-SA was the most commonly isolated pathogen
(35).
Community-acquired MRSA CAP has a rapidly progressive course and a 5663% mortality rate (30). Therefore, as
we recently reported (36), MRSA and PVL-SA infections
should be suspected in all children with severe acquired
pneumonia, characterised by leukopenia, necrotising or
cavitary infiltrates, haemoptysis or empyema, previous
history or family history of recurrent furuncles or skin
abscesses (37), independent of culture results and finally by
intensive care unit admission (31,38).

MYCOPLASMA PNEUMONIAE
Mycoplasma pneumoniae is a common cause of CAP in
children aged five to 14 years, accounting for up to 40% of
bacterial forms (39). In most of cases, infections are mild to
moderate, and signs and symptoms tend to resolve spontaneously without specific therapy.
Due to the absence of a cell wall, Mycoplasma pneumoniae is not sensitive to b-lactams. Macrolides, tetracyclines
and fluoroquinolones are indicated, but only macrolides are
recommended in children (39).
Since 2000, the prevalence of macrolide resistance
Mycoplasma pneumonia (MRMP) has been described with
increasing incidence worldwide. MRMP has become widespread in far East Asia, with up to 90% of Mycoplasma
pneumonia strains being resistant in China (40). Recent
reports have also documented the emergence of MRMP in
the West, but still with lower prevalence: 8.2% in United
States, 0.92.9% in Denmark, 3% in Germany, 10% in
France and 32% in Israel (40,41). Chironna et al. (42)
found that 26% of strains were resistant during a paediatric
outbreak in southern Italy in 2010. Moreover, macrolide
resistance has been always shown to be more frequent in
children than in adults (39).
Macrolide resistance is strongly associated with a specific
point mutation in the V domain of the 23S rRNA gene (39).
A-to-G transition at position 2063 and A-to-C transition at
position 2064 induce a high level of macrolide resistance,
whereas C-to-A or G transition at position 2617 and A-to-T
transition at position 2063 induces a low-level resistance
(43). Some studies have found that macrolide resistance can
be directly induced during the course of infection by the use
of macrolides, even when proper dosages are administered
(42,44). As the Mycoplasma cultures are often difficult to
obtain, several studies on MRMP are based on molecular
diagnosis of resistance. Therefore, the real antimicrobial
pattern of susceptibility is unknown. However, all the
genetically determined MRMP seem to have high resistance
to macrolides, with MICs 16 lg/mL (42,45).
The presence of macrolide resistance does not seem to
influence the presentation of CAP in terms of symptoms,
laboratory results and radiographic findings, but it is

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Galli et al.

associated with longer duration of signs and symptoms,

hospitalisation and antibiotic treatment (46). Kawai et al.
(47) reported that microbiological and clinical efficacy of
macrolides were low in patients with MRMP infections.
On the other hand, some authors have reported good
outcomes when children with MRMP pneumonia are
treated with macrolides (48), and they suggest that this is
as a result of the anti-inflammatory activity of macrolides.
As a matter of fact, severe lung disease due to Mycoplasma pneumoniae was presumed to be determined by
overproduction of cytokines and excessive cell-mediated
immune response. Therefore, many investigators suggested
that these cases could benefit from combined therapy with
antimicrobial agents and immune modulators (49). Prednisolone (1 mg/kg/day for 37 days, tapering within
1 week), methylprednisone (2 mg/kg/day or 2030 mg/kg
for 3 days, tapering within 1 month) and intravenous
immunoglobulins (1 g/kg/day, one or two doses) have
therefore been successfully used (49,50).
As a result, even if evidence of a relationship between
lack of clinical efficacy of macrolides and the presence of
MRMP is controversial, molecular characterisation of
Mycoplasma pneumoniae can be useful in all patients with
severe CAP who fail to respond to macrolides.
However, given that Mycoplasma pneumoniae infection
is typically mild and self-limited, the opportunity to provide
alternative therapy in MRMP infections requires careful
evaluation and has to be limited to severe CAP.

ANTIMICROBIAL TREATMENT IN DRUG-RESISTANT CAP

Recommendations from international guidelines on the
treatment of CAP are reported in the systematic review by
Berti et al. in this supplement. Guideline recommendations
are controversial when a penicillin-resistant Streptococcus
pneumoniae is suspected or confirmed. If Streptococcus
pneumoniae isolates have MICs to penicillin 4.0 lg/mL,
the 2011 United States guidelines recommend ceftriaxone
or alternatively ampicillin or levofloxacin or linezolid (51).
Clindamycin or vancomycin may be also prescribed. Oral
levofloxacin or oral linezolid is suggested as a step-down
therapy or for mild infection. Because of limited evidence
on the relationship between penicillin nonsusceptibility and
worse clinical outcome, the 2011 UK guidelines still suggest
oral amoxicillin as the first choice of antibiotic therapy for
all children, alternatively suggesting amoxicillin/clavulanate, cefaclor, erythromycin, azithromycin and clarithromycin (52).
Despite conflicting recommendations by the guidelines
on second-line treatments, all guidelines, including a review
by the European Society of Paediatric Infectious Diseases
(53), suggest oral high-dose amoxicillin (90 mg/kg/day) as
the first-line antimicrobial drug in the empirical treatment
of noncomplicated pneumococcal CAP, even in those
countries where penicillin nonsusceptibility among pneumococcal isolates is increasing.
In our opinion, when parenteral treatment is required
and/or drug-resistant Streptococcus pneumoniae (MICs to

28

penicillin 4.0 lg/mL) is documented, high-dose ampicillin

(300400 mg/kg/die), ceftriaxone (100 mg/kg/day), vancomycin (60 mg/kg/day) or clindamycin are alternatives. In
selected cases, linezolid or levofloxacin is possible alternatives and can also be used for oral step-down treatment.
This approach is quite similar to that suggested in the
United States guidelines (51).
Vancomycin, linezolid and clindamycin are the first-line
antibiotics to treat suspected or confirmed MRSA pneumonia (31,38,51) and should be administered for at least
14 days (51).
Vancomycin is a glycopeptide agent that inhibits cell
wall peptidoglycan synthesis. It has slow bactericidal
activity against gram-positive pathogens. Vancomycin is
associated with nephrotoxicity and ototoxicity, other than
the well known red man syndrome. The pharmacokinetic
and pharmacodynamic literature on vancomycin use in
children is limited. The suggested dose is 4060 mg/kg/
day, divided into 68 h doses (38,51) (Table 1). Therapeutic range monitoring is recommended, with a target
trough serum concentration of 1520 lg/mL or an AUC/
MIC 400 lg/mL (30). Maintaining a trough serum
concentration of 1520 lg/mL does not seem to be
associated with an increased rate of nephrotoxicity (54).
A recent study suggested that vancomycin doses of
70 mg/kg/day are necessary in children <12 years old
with normal renal function and 60 mg/kg/day in children
12 years old. Resistance of SA to vancomycin remains
rare, but when isolates have an MIC of >2 lg/mL, or
doses above 80 mg/kg/day are required to obtain an
AUC/MIC >400, alternative antibiotics to treat MRSA
should be used (55).
Teicoplanin, another member of glycopeptides family, is
widely used in Europe and Japan, but is not approved for
use in the United States (56). It provides bactericidal
activity against gram-positive infections, with similar clinical efficacy to vancomycin (57). However, teicoplanin
seems to be associated with a lower adverse event rate,
except for thrombocytopenia (58,59). Teicoplanin presents
a long elimination half-life, which means that once daily
administration is possible. However, because it takes a long
time to achieve an optimal plasma concentration, an initial
loading-dose regimen has been recommended (56). A
teicoplanin MIC value >1.52 mg/L is associated with an
increased risk of treatment failure among patients with
MRSA pneumonia and bacteraemia (60,61). Teicoplanin
trough concentration >10 lg/mL has been considered
appropriate, but more recent data have encouraged experts
to recommend 1530 lg/mL as the new target trough
concentration (62). Ito et al. (56) found that adequate
serum trough concentrations are rarely reached in children
treated with standard doses. Matsumoto et al. suggested
that an initial loading dose of 1115 mg/kg every 12 h for
three doses is necessary to reach the suggested trough
concentration in critically ill patients. Moreover, toddlers
have a high risk of presenting low trough concentration,
even with three loading dose of 1015 mg/kg (59)
(Table 1).

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Galli et al.

Treating community-acquired pneumonia

Table 1 Antibiotics used in drug-resistant community-acquired pneumonia

Antibiotics

Dose

Route

Adverse effects

Comments

Species

Vancomycin

15 mg/kg every 68 h

IV

Nephrotoxicity, ototoxicity, red

man syndrome

Slowly bactericidal. Therapeutic

levels to be monitored

Teicoplanin

10 mg/kg every 12 h for three

doses then 10 mg/kg/day
10 mg/kg (max 600 mg) every 8
<12 years; every 12 h
>12 years
610 mg/kg (max 1.2 g) every
6h
10 mg/kg (max 600 mg) every
12 h

IV/IM

Nephrotoxicity, ototoxicity,
thrombocytopenia
Lactic acidosis, myelosuppression,
peripheral and optic neuropathy

Bactericidal. Therapeutic levels to

be monitored
Bacteriostatic. Inhibit toxin
synthesis
Treatment duration <28 days
Bacteriostatic. Inhibit toxin
synthesis
Bactericidal. Colours biological
fluids red. Rapid development of
resistance in monotherapy
Bactericidal. Not approved for
children
Bactericidal. Not approved for
children
Bacteriostatic. Not approved for
children

Streptococcus
pneumoniae
Staphylococcus
aureus
S. pneumoniae
S. aureus
S. pneumoniae
S. aureus

Linezolid

Clindamycin
Rifampicin

IV/PO

IV/PO

Diarrhoea, C. difficile colitis

IV/PO

Hepatotoxicity, anaphylaxis
agranulocytosis
Nausea, vomiting, taste sense
disorders, nephrotoxicity
Rash

Telavancin

10 mg/kg/day

IV

Ceftaroline

600 mg every 12 h

IV

Tigecycline

2 mg/kg stat, then 1 mg/kg

IV

Doxycycline

12 mg/kg (max 200 mg) every

12 h
4 mg/kg stat (max 200 mg) then
2 mg/kg (max 100 mg)

PO/IV

Minocycline

Ciprofloxacin
Levofloxacin
Moxifloxacin

1015 mg/kg every 12 h PO,

every 812 h IV
8 mg/kg (max 500 mg) every
12 h
10 mg/kg/day (max 400 mg)

PO

IV/PO
IV/PO
IV/PO

Diarrhoea, nausea, vomiting,

headache, raised ALT/AST,
pancreatitis
Diarrhoea, Hepatotoxicity, tooth
discolouration in children
Dizziness, headache,
hepatotoxicity, diarrhoea, tooth
discolouration in children
Rupture of tendon. Cartilage
damage reported in animals
Rupture of tendon. Cartilage
damage reported in animals
Rupture of tendon. Cartilage
damage reported in animals

Telavancin is a new glycopeptide approved in Europe for

hospital-acquired pneumonia (30). It presents rapid bactericidal activity against gram-positive pathogens, and once
daily administration is possible, due to its long half-life (63)
(Table 1). It has been shown to have potent activity against
MRSA, but its safety and effectiveness have not been
established in children (64).
Linezolid is the first member of the oxazolidinone family.
It provides bacteriostatic activity against gram-positive
pathogens, including MRSA, and inhibits toxin synthesis.
It inhibits protein synthesis by preventing binding of the
30S and 50S ribosomal subunits (58). Because of this
ability, linezolid is also recommended for PVL-SA CAP.
The recommended paediatric dose is 10 mg/kg every 8 h in
children <12 years old and 10 mg/kg every 12 h in children
12 years old (Table 1). Due to its optimal oral bioavailability, an early switch from intravenous to oral administration is possible (65).
Linezolid is generally safe and well tolerated in children.
Adverse events have been associated with treatment duration
>28 days. The most common adverse events are headache,
diarrhoea and nausea. Lactic acidosis, myelosuppression,

S. pneumoniae
S. aureus
S. aureus

S. pneumoniae
S. aureus
S. pneumoniae
S. aureus
S. pneumoniae
S. aureus

Bacteriostatic. Not recommended

<8 years
Bacteriostatic. Not recommended
<8 years

Mycoplasma
pneumoniae
M. pneumoniae

Bactericidal. Not recommended for

children
Bactericidal. Not recommended for
children
Bactericidal. Not recommended
for children

S. pneumoniae
M. pnuemoniae
S. pneumoniae
M. pnuemoniae
S. pneumoniae
M. pnuemoniae

peripheral and optic neuropathy have also been reported and

need careful monitoring (65).
Wunderink et al. (66) reported that the clinical outcomes
of adult patients with hospital-acquired pneumonia were
significantly better with linezolid than with adjusted-dose
vancomycin, even if 60-day mortality was similar. However,
several meta-analyses have found that linezolid is superior
to glycopeptides for treating hospital-acquired pneumonia.
Similar clinical cure, microbiological eradication and
adverse events rates were found in both therapeutic groups
(6770). Moreover, vancomycin is considered to have a
poor lung penetration, whereas linezolid achieves high
concentration in lung tissue. However, clinical significance
of different levels of pulmonary penetration requires further
clinical studies (71).
Linezolid is an expensive drug, but the early switch from
endovenous to oral therapy could be a cost saving (72).
Cost analysis studies have produced conflicting results (73).
Clindamycin is an effective agent for susceptible MRSA
and Streptococcus pneumoniae in the absence of bacteremia
or intravascular infection (38,51) (Table 1). It inhibits
protein synthesis by blocking the peptidyltransferase

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Galli et al.

reaction on the 50S ribosomal subunits (74). It should be

used alone, or in combination with another anti-MRSA
antibiotic, in case of PVL-SA pneumonia, because of its
ability to inhibit toxin synthesis (30). However, it is not
recommended that it is used alone in the case of bacteraemia.
Inducible resistance to clindamycin may be present in the
case of SA pneumonia, and therefore, a D-test should be
performed (51). The most frequent adverse event is diarrhoea, which can be associated with Clostridium difficile
colitis (30).
Rifampicin is often used as an adjunct to vancomycin
therapy in the case of MRSA pneumonia, even if limited
evidence exists to support this practice (75). However, it has
a role in PVL-SA pneumonia, as it inhibits protein synthesis. Rifampicin should not be used alone, because of the risk
of developing resistance (29).
Ceftaroline fosamil is a fifth-generation cephalosporin
with bactericidal activity against gram-positive and gramnegative pathogens. Ceftaroline fosamil is shown to be
active against the resistant gram-positive pathogens
involved in CAP, such as MRSA and MDR Streptococcus
pneumoniae (76). It is generally well tolerated, with an
adverse events profile similar to other cephalosporins (77).
It has been approved for the treatment for CAP in adults,
but it is not recommended in children (77) (Table 1).
Tigecycline is the first member of glycylcyclines, derived by
minocycline (78). It provides bacteriostatic activity against
gram-positive and gram-negative pathogens, including MRSA
and penicillin-resistant Streptococcus pneumoniae. Tigecycline also seems to be active against Mycoplasma pneumoniae, and due to its ability to reduce protein synthesis, it is
effective against PVL-SA (79). It was recently approved in
United States for the treatment for CAP, but there are still no
data to support its use for MRSA pneumonia (30) and it is not
recommended for use in children. Even so, Purdy et al. (80)
reported a dosage of 1.2 mg/kg every 12 h as the most
appropriate dose for children aged eight to 11 years.
However, recent meta-analyses of clinical trials involving
tigecycline monotherapy in adults reported an increasing
mortality rate with this drug (81).
Most studies have shown that fluoroquinolones and
tetracyclines have excellent in vitro antimycoplasma activity in children with MRMP pneumonia (43,45). Several
studies have also reported that children with severe MRMP
CAP have been successfully treated with ciprofloxacin,
levofloxacin, moxifloxacin, minocycline and doxycycline
(40,46,49,82) (Table 1).
However, tetracyclines are not approved for use in
children under 8 years old due to the potential for tooth
discoloration, and fluoroquinolones are not recommended
in children under the age of 18 because of the risk of
cartilaginous abnormalities reported in animal models.
However, they have been successfully prescribed for severe
infection in children, and they do not appear to be
associated with arthropathy (49).
Minocycline and tosufloxacin have been approved in
Japan to treat suspected MRMP pneumonia in children, but
not in Europe or the United States (82).

30

Recent reports suggested that tetracyclines are significantly more effective than fluoroquinolones in treating
children with MRMP pneumonia. Minocycline and doxycycline achieve better clinical improvements and decrease
the Mycoplasma pneumoniae DNA copy number more
effectively than tosufloxacin (41,82,83). Therefore, minocycline and doxycycline are the drugs of choice for MRMP
in children over 8 years old, and levofloxacin, moxifloxacin
or tosufloxacin could be an alternative in adolescents with
skeletal maturity. In children aged <8 years old, tetracyclines and fluoroquinolones should only be used in severe
CAP that does not respond to macrolide treatment, after an
accurate assessment of risk-benefit and for the shortest
possible period. This is because of the possible spontaneous
healing of Mycoplasma pneumonia and the risk of adverse
events related to these drugs.

CONCLUSIONS
Antimicrobial resistance is an increasing problem in the
treatment of CAP, particularly in a paediatric age when
there are limited therapeutic options. Preventing further
increases in resistance is the better strategy, and paediatricians should follow treatment guidelines and recommendations on the judicious use of antimicrobial agents. In
particular, they should avoid using antibiotics in common
respiratory infections, mostly those of viral aetiology.
Surveillance on the prevalence of antimicrobial resistance
at a country level should be implemented. The results
should be disseminated, and educational programmes and
guidelines should be updated in the light of local resistance
patterns. An appropriate therapy should be chosen, based
on knowledge of local epidemiology, an accurate evaluation
of CAP severity and of the risk-benefit ratio, as off-label and
expensive drugs are often required. Efforts should also be
made to obtain a microbiological diagnosis, to limit the use
of antibiotics to bacterial CAP and prevent prescribing
broad-spectrum antibiotics.

CONFLICT OF INTERESTS
The authors have no conflict of interest to declare.

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